key: cord- -vbzy hc authors: damjanovic, v.; taylor, n.; williets, t.; van saene, h. k. f. title: outbreaks of infection in the icu: what’s up at the beginning of the twenty-first century? date: - - journal: infection control in the intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: vbzy hc surveillance cultures are the only cultures that allow the distinction between secondary endogenous and exogenous infections. these types of infection are the two known to cause outbreaks. secondary endogenous infections can be controlled by enterally administered antimicrobials and should be integrated into the routine infection control measures. exogenous infections can be controlled by topically applied antimicrobials and hygiene. two recent sets of publications were taken into consideration when preparing our analysis of infectious outbreaks in the intensive care unit (icu). the first concerns the emergence of severe acute respiratory syndrome (sars) and avian flu in , and a spread across the world of a novel influenza caused by swh n in . these viral infections had a major impact on intensive care and are described in chap. . this chapter is dedicated to describing outbreaks caused by bacteria and fungi, with references to secondary infections associated with flu and sars [ , ] . the second publication concerns the ''international study of the prevalence and outcomes of infection in intensive care units'' published in december [ ] . although this is a point-prevalence study, it provides information about the global epidemiology of infection in icus. unfortunately, it could not give insight into outbreaks of infection in icus, so we searched for specific publications describing such outbreaks. in the second ( ) edition of this book, we analysed the usefulness of molecular techniques in selected outbreaks [ ] . the majority of outbreaks occurred in the last decade of the twentieth century. however, reports were usually published several years later. a similar pattern was observed when we analysed outbreaks published in the first decade of the twenty-first century: the actual outbreaks occurred a few years earlier. indeed, the above-mentioned point-prevalence study was conducted on may but published in december [ ] . therefore, for accuracy, this analysis indicates when outbreaks actually happened and when they were subsequently published. acinetobacter outbreaks were selected to illustrate this point ( fig. . ). in addition to the reported outbreaks, a number of publications considered many relevant aspects of infection and outbreaks in icu. some of these are included in this chapter. we analysed publications, the majority of which met the definition of an outbreak in neonatal (nicu), paediatric (picu) and adult (aicu) icus and reported since . the main objective of this analysis was to find out whether there were any new features in the outbreaks of infection in icu at the beginning of the new century, including those influenced by new viruses. we searched medline for outbreaks published between january and september . the search terms used were intensive care unit, adult icu, paediatric icu, neonatal icu and outbreaks. we used the same framework as in the second edition of this book; however, outbreaks were not presented separately per icu type but according to causative organisms, in the following order: methicillin-resistant staphylococcus aureus (mrsa), vancomycin-resistant enterococci (vre), aerobic gramnegative bacilli (agnb), pseudomonas spp., acinetobacter spp. and fungi, together with the selected features searched (table . ). the number of analysed outbreaks is stated, but only selected outbreaks are shown and listed in the references. we retrieved reports on six outbreaks [ ] [ ] [ ] [ ] [ ] [ ] published since ; five occurred in aicus and one in an animal icu. reports of two outbreaks were published in and three in , all occurring between and . one report published in did not report the actual time of the outbreak. these outbreaks are summarised briefly according to their countries of origin. a paper from italy published in reported a unique experience of controlling a mrsa outbreak of months' duration in a medical/surgical aicu in using enterally administered vancomycin in mechanically ventilated patients [ ] . another report from italy, published in , described the identification of a variant of the ''rome clone'' of mrsa responsible for an outbreak in a cardiac surgery icu, which occurred in in a hospital in rome. this strain had decreased sensitivity to vancomycin and was resistant to many antibiotics [ ] . a study from germany published in described the occurrence of mrsa in icu in terms of endemic and epidemic infections followed from january to june .this study involved icus, of which ( %) had mrsa infections. outbreaks (three or more mrsa infections within months) were registered in icus, clusters (two mrsa infections within months) in further units and single events in [ ] . a publication from spain showed that enterally administered vancomycin can control endemic mrsa in icus without promoting vre. this study was carried out over a -month period from july to and published in [ ] . in , a report from canada presented a recent outbreak of mrsa carriage in an animal icu. this finding appears important, as the strain responsible for the animal outbreak was indistinguishable from a strain in humans commonly isolated in canada and the usa. infection control measures, including active surveillance of all animals in the icu, were used to control the outbreak. as transmission of mrsa within the unit occurred without infections and did not persist for a prolonged period of time, staff screening was surprisingly not initiated [ ] . a paper from china published in described an mrsa outbreak due to an increased there have been ten outbreaks in aicus published since : eight were caused by vre, one was sensitive to vancomycin and one was sensitive to vancomycin but resistant to linezolid. we selected seven reports and summarised them according to the countries of origin and time of events and publishing. a paper from pakistan published in was the country's first experience with a vancomycin resistant enterococcus faecium outbreak in the icu and nicu. the outbreak occurred in , lasted month and all but one isolate was of a single clone [ ] . all isolates were resistant to gentamicin, ampicillin and tetracycline but sensitive to chloramphenicol. six patients were colonised and four infected, with positive blood cultures; two of each died before specific therapy could be started ( % mortality rate). in , a report from italy described an outbreak of vre colonisation and infection in an icu that lasted months ( - ) [ ] . fifty-six patients were colonised by e. faecium, and e. faecalis was detected in only two cases. because of the low pathogenicity of vre, the authors questioned whether it was worthwhile to have a specific vre surveillance programme. for the lowbury lecture, pearman reported the australian experience with vre, which he described as ''from disaster to ongoing control''. this was the first outbreak of vre, which was caused by e. faecium in an icu and hospital wards and lasted months in . a vigilant vre control programme prevented the epidemic strain from becoming endemic in the hospital [ ] . an outbreak due to glycopeptide-resistant enterococci (gre) in an icu with simultaneous circulation of two different clones was reported from france in . the outbreak lasted several months in without infections, but the significant colonisation caused organisational problems in the icu [ ] . an outbreak of vre in an icu was reported from china in . the outbreak was caused by e. faecium and lasted months ( - ) . a detailed molecular analysis showed that genetically unrelated isolates had transferred vancomycin resistance by conjugation [ ] . a paper from korea reported an outbreak of vre in a neurological icu. vre was mainly isolated from urine specimens associated with the presence of a foley catheter. of patients colonised with vre, only two had active infection [ ] . in , a report from spain presented an outbreak of linezolid-resistant e. faecalis in an icu and reanimation unit [ ] . this was the first report of a clonal outbreak of linezolid-resistant e. faecalis in spain. the strain was sensitive to imipenem, vancomycin, teicoplanin and rifampicin. most patients were exposed to linezolid within a year ( ) ( ) . the use of linezolid began in . the increase in its use continued until when a mutant was identified by molecular analysis. fourteen reports on outbreaks were retrieved since . eight were caused by klebsiella pneumoniae, four by serratia marcescens, one by enterobacter cloacae and one by simultaneous infection of e. cloacae and s. marcescens. three klebsiella, three serratia and the remaining two were selected for analysis. we discuss pseudomonas and acinetobacter outbreaks separately. an outbreak of klebsiella infection in nicu and picu was published from spain in ; this outbreak occurred in - and lasted year [ ] . the outbreak was polyclonal. two predominant clones of klebsiella harboured a special gene (shv ) for the beta-lactamase enzyme responsible for multi-drugresistant klebsiella. according to the authors, this type of klebsiella was not reported previously in spain. another clone harbouring two different genes responsible for multidrug resistance but dissimilar from the above was reported. a report from the netherlands published in described an outbreak of infections with a multi-drug-resistant klebsiella strain [ ] associated with contaminated roll boards in operating rooms. this outbreak in showed how an unusual source of the outbreak can be revealed by systematic surveillance. in , a polyclonal outbreak of extended spectrum beta-lactamase (esbl)-producing k. pneumoniae in an icu of a university hospital in belgium was reported [ ] . this was a -month outbreak that occurred in with isolates. there was one predominant clone, two clones with several isolates and four with unique isolates. the cause of the outbreak was not clear but was associated with a dramatic increase in the number of imported carriers during the previous weeks. an outbreak caused by esbl-producing e. cloacae in a cardiothoracic icu was reported from spain in [ ] . the outbreak occurred in , lasted months, and involved seven patients. molecular analysis revealed two clones responsible for the outbreak: one carried a single esbl; the other carried two esbls. both clones showed resistance to quinolones and aminoglycosides. the outbreak was brought under control by the implementation of barrier measures and cephalosporin restrictions. an outbreak was reported from germany in [ ] in both the nicu and picu, lasted from september to november and involved patients. two epidemic strains were associated with cross-infection in groups of five and ten patients, respectively. two epidemic clones were detected from the surfaces of an icu room, but an original source was not identified. the outbreak was stopped by routine infection-control measures. a report from malaysia in described an outbreak of serratia infections that lasted days in an aicu [ ] . the single outbreak strain was found in insulin and sedative solutions administered to patients. an outbreak of s. marcescens colonisation and infection in a neurological icu that occurred from may to march was reported from a dutch university medical centre in [ ] . the outbreak strain was traced to a healthcare worker (hcw) with longterm carriage on the hands. the skin of the hcw's hands was psoriatic. the epidemic ended after the colonised hcw went on leave, with subsequent eradication treatment. a heterogeneous outbreak of e. cloacae and s. marcescens infections in a surgical icu was published by a group of authors from san francisco, usa [ ] . the outbreak lasted from december through january . molecular techniques ruled out a point source or significant cross-contamination as modes of transmission. the authors concluded that patient-related factors, such as respiratory tract colonisation and duration of central line placement might have played a role in this outbreak. several reports have been published on infections caused by multi-drug-resistant pseudomonas spp. in icus since . we retrieved reports; not all were outbreaks, as some were described as endemic infections. in addition, one outbreak was caused by burkholderia cepacia. we selected a few outbreaks that we believed would represent the main problems occurring in icus, such as multidrug resistance, clonality, transmission source and mode and infection severity. in , a publication from norway reported an outbreak of multi-drug-resistant p. aeruginosa associated with increased risk of death [ ] . the outbreak occurred from december to september , was monoclonal and the strain was introduced into the icu early in and was maintained thereafter. all patients were ventilated. the strain was resistant to carbapenems, quinolones and azlocillin. in infected patients, ten of whom died, pseudomonas was found in one or all specimens, such as respiratory secretions, ventilator tubes, connection tubes and the water catcher of the ventilator system. the bacterium was also isolated from water taps. in addition to enhanced control of infection measures, complete elimination of the outbreak was achieved after water taps were pasteurised and sterile water was used when a solvent was needed. in , french authors published a report on the epidemiology of p. aeruginosa in an icu [ ] . although between and the prevalence of p. aeruginosa infections reached % of all hospital-acquired infections, the authors did not call this an outbreak, despite the fact that this was twice the national prevalence of % observed in icus. however, this high prevalence prompted the authors to conduct a prospective epidemiological study from july to february . we selected this study as a good example of activities necessary to prevent a major outbreak. the authors described how systematic surveillance was carried out (oropharyngeal and rectal swabs on admission and twice weekly afterwards). this practice revealed that during the study period, the overall incidence of p. aeruginosa carriage was %: % on admission and % acquired in the icu. in addition / ( %) patients developed the infection. the authors also pointed out that intestinal carriage was a prerequisite for colonisation or infection. genotyping analysis of isolates indicated that % belonged to genotype , % to genotype and that remaining isolates were not genetically related. it has also been shown that mechanical ventilation was associated with p. aeruginosa carriage and ineffective antibiotics significantly increased the risk of colonisation and infection in icu. the authors concluded that not only do endogenous sources account for the majority of colonisation or infection due to p. aeruginosa but that exogenous sources may be involved in some instances. in an epidemic setting, the authors' stance was to reinforce standard barrier precautions. however, the main message of this study is the necessity to adopt and pursue preventive measures. in , an outbreak of severe b. cepacia infections in an icu was reported from spain [ ] . the outbreak occurred over a period of days in august when b. cepacia were recovered from different clinical samples associated with bacteraemia in three cases, lower respiratory tract infection in one and urinary tract infection in one. samples of antiseptics, eau de cologne and moisturising milk available on treatment carts were collected and cultured. b. cepacia was isolated not only from three samples of the moisturising body milk that had been applied to the patients but also from two new hermetically closed units. all strains recovered from environmental and clinical samples belonged to the same clone. the cream was withdrawn from all hospital units, and no new cases of b. cepacia developed. the authors concluded that the presence of bacteria in cosmetic products, even within accepted limits, may lead to severe life-threatening infections in severely ill patients. we retrieved publications on acinetobacter outbreaks, of which were not strictly outbreaks, and actually not reported as such, but rather described general epidemiology, antibiotic resistance, infection control or treatment options. most of these problems are dealt with in relevant chapters of this edition. following our approach, we summarise only a few outbreaks, which appeared to offer some new findings or insights. a report from italy described an outbreak of infusion-related a. baumannii bacteraemia in an eight-bed icu [ ] . from june to july , six cases were identified. all patients received parenterally administered solutions prepared by icu nurses, which was subsequently proven to be the source of infection. three patients died from sepsis despite treatment with a combination of meropenem and amikacin, which were shown by laboratory tests to be synergistic. this high mortality rate ( %) was explained by the authors as being due to persistent bacteraemia related to the repeated infusions of contaminated solutions. once aseptic preparation was carried out in the hospital pharmacy, this outbreak was controlled, and further infusion-related nosocomial bacteraemia was prevented. from the usa, a publication in reported an outbreak of multiresistant acinetobacter colonisation and infection in an icu [ ] . the strain was sensitive only to polymyxin. the outbreak lasted an entire year between and and involved patients, of whom were infected and colonised. the arrival of a colonised burn patient ([ % total body surface area) from an outside hospital was responsible for the outbreak. although on typing two strains were found, the only identified primary source was the original burn patient. ten deaths resulted from infections ( % of infected patients). the authors claimed that this outbreak served as a model of eradication of multi-drug-resistant organisms, as the acinetobacter was eliminated from all icu patients by multidisciplinary measures that included the following: cohort and contact isolation of all colonised and infected patients; introduction of strict aseptic measures such as hand washing, barrier isolation, equipment and room cleaning; sterilisation of ventilator equipment; and individual dedication of medical equipment to each patient. a paper was published from australia in regarding carbapenem-resistant a. baumannii [ ] . we selected this publication as an illustration of an extensive molecular analysis rather than for a critical review of the outbreak, which occurred in an icu between and . based on their findings, the authors claim that antibiotic-resistant genes are readily exchanged between co-circulating strains in epidemics of phenotypically indistinguishable organisms. in conclusion, they recommend that epidemiological investigation of major outbreaks should include whole-genome typing as well as analysis of potentially transmissible genes and their vehicles. finally, we found a paper in a journal from kuwait not found by our internet research [ ] . the authors reported three different outbreaks of multi-drug-resistant a. baumannii infections involving patients aged - years that occurred in an icu in the course of year between and . the outbreak was polyclonal and successfully controlled with tigecycline, to which two causative clones were sensitive. three additional distinct clones were isolated from the environment. due to lack of appropriate surveillance cultures, no explanation was offered for the origin of epidemic clones. subsequently, in a letter to the editor, our interpretation that ''…microbial gut overgrowth increased spontaneous mutation, which led to polyclonality and antibiotic resistance in the critically ill'' was accepted by the authors [ , ] . thirteen publications were retrieved from medline, five of which described outbreaks of remarkable findings. the remaining papers reported some important aspects of fungal species, colonisation, infection and treatments, predominantly as surveys, and as such were not included in our analysis. outbreaks presented here were caused by uncommon opportunistic fungi. two reports described icu outbreaks caused by hansenula anomala, an opportunistic yeast first reported from a liverpool, uk, nicu in [ ] . in , a report from croatia described an outbreak in a surgical icu [ ] . h. anomala was isolated from blood taken from eight patients between august and december . all patients were treated with antifungal therapy; three died from complications of underlying disease. the introduction of strict hygienic measures stopped the spread of infection, but the outbreak ceased with the introduction of a new batch of cotton from another manufacturer, which was used for venipuncture-site disinfection. however, the authors could not find evidence for infection source and transmission route. the second report, from brazil ( ), describes an outbreak in a picu [ ] . the authors reported their finding as an outbreak of pichia anomala, a newly introduced name for h. anomala. from october to january , children developed p. anomala fungemia. the median age was . year, and the main underlying conditions were congenital malformations and neoplastic disease. the overall mortality rate was . % despite treatment with amphotericin b. during a -week period in april , when new cases occurred, surveillance cultures revealed that . % of patients were colonised with yeasts, but no single patient was found to be colonised with p. anomala. thus, no source was found at that time. the outbreak was not controlled until orally administered prophylaxis with nystatin and topical application of an iodoform to venipuncture sites were started. an extraordinary outbreak of invasive gastritis caused by rhizopus microsporus in an adult icu was reported from spain in [ ] . over a -week period (between november and march ), gastric mucormycosis was diagnosed in five patients, four of whom were admitted to icu with severe communityacquired pneumonia and one with multiple trauma. the main symptom was upper gastrointestinal haemorrhage. isolated filamentous fungi were identified as r. microsporus var. rhizopodiformis and were detected in gastric aspiration samples and traced to wooden tongue depressors used to prepare medication for oral administration (and given to patients through a nasogastric catheter) and in some tongue depressors stored in unopened boxes unexposed to the icu environment. the outbreak was terminated when contaminated tongue depressors were withdrawn from use. this outbreak was attributable to the % mortality rate; wooden material should not be used in the hospital setting. in , an outbreak of three cases of dipodascus capitatus infection in an icu was reported from japan [ ] . the index case was pulmonary infection with a fulminant course of fungal infection, which resulted in death, in a patient with acute myelocytic leukaemia who shared a room for at least week with the two other patients, suggesting the possibility of transmission. one of the other two patients died from multiple organ dysfunction. the presence of d. capitatus might have been due to contamination in the respiratory icu. in all cases, d. capitatus was identified in sputum, deep tracheal aspiration samples, blood and urine samples. the authors concluded that d. capitatus should be added to the lengthening list of opportunistic fungal pathogens that can cause infection in immune-compromised patients, with the danger of transmission and potential outbreak. an outbreak of saccharomyces cerevisiae fungemia in an icu was reported from spain in [ ] . during the period from to april, three patients with s. cerevisiae fungemia were identified. the only identified risk factor was treatment with a probiotic containing this yeast. the three patients received the product via nasogastric tube for a mean of . days before the culture was positive. surveillance cultures for the control patients admitted at the same time did not reveal any carriers. all three patients died from causes unrelated to s. cerevisiae. discontinuation of use of the product for treatment or prevention of clostridium difficile-associated diarrhoea in the unit stopped the outbreak of infection. in conclusion, the authors warned that the use of s. cerevisiae should be carefully reassessed in immune-compromised or critically ill patients. an outbreak is defined as an event where two or more patients in a defined location are infected by identical, often multi-drug-resistant, microorganisms transmitted via the hands of hcw, usually within an arbitrary time period of weeks. there are two different types of infection involved in outbreaks: secondary endogenous and exogenous. outbreaks of secondary endogenous infections are invariably preceded by outbreaks of carriage of abnormal flora, whereas outbreaks of exogenous infections are not preceded by outbreaks of abnormal carriage. these two types of outbreaks each require a different type of management: enterally and topically administered antimicrobials for secondary endogenous and exogenous outbreaks, respectively. ongoing surveillance efforts, i.e. throat and rectal swabs on admission and twice weekly thereafter, to monitor the efficacy of systematic decontamination of the digestive tract (sdd) and to identify the emergence of antimicrobial resistant threats, is an intrinsic component of any decontamination programme. in this sense, a well-designed programme contains an intrinsic degree of protection against antibiotic-resistant organism emergence. surveillance cultures of throat and rectum are more sensitive in detecting resistance than are diagnostic samples [ ] . additionally, there is a close relationship between surveillance and diagnostic samples. once a resistant microorganism reaches overgrowth concentrations, i.e. c /ml saliva and/or gram of faeces, diagnostic samples become positive [ ] . in our review, outbreaks were selected to illustrate the situation at the beginning of this century. as a matter of fact, the majority of the outbreaks was related to the previous decade. however, biased or not, our analysis described outbreaks that occurred after and nine from last century, although the outbreaks were published in this century (fig. . ). this suggests that some new problems indeed emerged in this century. it is important to record the number of papers retrieved according the causative organisms: mrsa six, vre ten, agnb , pseudomonas spp. , acinetobacter spp. and fungi . perhaps, against our expectation, agnb organisms-in particular, opportunists such as pseudomonas and acinetobacter-prevailed significantly, for which there must be a reason. if we take mrsa as an example, all around the world, this drug-resistant pathogen has been a primary focus for nosocomial infection control and treatment for years. thus, there are fewer outbreaks. an extensive study from germany that involved icus showed that cluster and single mrsa infections were significantly more common than actual outbreaks ( icus compared with , respectively) [ ] . to our knowledge, there were no similar studies for vre and agnb, but one would anticipate similar findings and interpretation. on the other hand, opportunistic pathogens such as pseudomonas spp., acinetobacter spp. and fungi often caused unexpected outbreaks, particularly in immunocompromised patients. they originated from external sources and were difficult to treat because of their resistance to multiple antibiotics. our search for specific features relevant to published outbreaks revealed some new, and confirmed some older, trends (table . ). probably the best example of how new viral infections-such as sars-can change the rate of bacterial and fungal infections in icus came from the experience in china [ ] . there was a significant increase in the rate of mrsa and candida spp. acquisition in an icu during the sars period. it may be anticipated, therefore, that in the future, sars and influenza viral infections would lead to complex icu outbreaks. we pointed out earlier how using molecular techniques revealed that many outbreaks were due to more than one clone [ ] . our analysis confirms this, although the origin of different clones remained obscure in all reports in which polyclonality was detected. however, we recently put forward a hypothesis that microbial gut overgrowth is responsible for increased spontaneous mutation leading to polyclonality and antibiotic resistance [ ] . furthermore, extensive use of molecular techniques not only revealed a number of new genes responsible for antibiotic resistance [ ] but showed that genetically unrelated organisms readily exchange antibiotic resistance genes [ , ] . yet further, a new trend is related to the sdd concept. two studies, one from italy and one from spain, reported the use of enterally administered vancomycin to control and prevent, respectively, mrsa outbreaks [ , ] . this is further evidence that the principle of sdd can be used with antimicrobials directed specifically to the causative organism. as early as we reported how selective decontamination with nystatin successfully controlled a candida outbreak in an nicu [ ] . among older trends, surveillance cultures, or lack of them, are still prominent. even in there were authors responsible for infection control in hospitals and icus who claimed that ''…surveillance cultures of all patients with potential to develop infection are difficult and very costly…'' [ ] . some time ago ( ), we expressed an alternative view in response to an identical attitude [ ] . needless to say, lack of surveillance cultures not only delays the recognition of an outbreak and its control but also precludes the understanding of the pathogenesis of the majority of outbreaks. surveillance cultures are also crucial for detecting outbreaks of exogenous pathogenesis, i.e. without carriage. on the other hand, the source of an exogenous outbreak is readily identified with molecular techniques. some of these outbreaks are striking, such as one from this analysis in which acinetobacter-contaminated parentally administered solutions were repeatedly infused to patients, leading to a very high mortality rate of % [ ] . in conclusion, new trends as well as old confirm what we indicated in the previous edition of this book, which is that to control and prevent icu outbreaks, surveillance cultures and sdd should be integrated in routine infection-control measures. severe acute respiratory syndrome: another challenge for critical care nurses h n influenza is here international study of the prevalence and outcome of infection in intensive care units outbreaks of infection in intensive care units-usefulness of molecular techniques for outbreak analysis enteral vancomycin to control methicillinresistant staphylococcus aureus outbreak in mechanically ventilated patients identification of a variant 'rome clone' of methicillin-resistant staphylococcus aureus with decreased susceptibility to vancomycin, responsible for an outbreak in an intensive care unit occurrence of methicillin-resistant staphylococcus aureus infections in german intensive care units effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant staphylococcus aureus in a medical/surgical intensive care unit cluster of methicillin-resistant staphylococcus aureus colonisation in a small animal intensive care unit increase in methicillin-resistant staphylococcus aureus acquisition rate and change in pathogen pattern associated with an outbreak of severe acute respiratory syndrome emergence of vancomycin-resistant enterococcus faecium at a tertiary care hospital in karachi outbreak of vancomycin-resistant enterococcus spp. on an italian general intensive care unit lowbury lecture: the western australian experience with vancomycin-resistant enterococci-from disaster to ongoing control glycopeptide-resistant enterococcus outbreak in an icu with simultaneous circulation of two different clones molecular characterization of outbreak-related strains of vancomycin-resistant enterococcus faecium from an intensive care unit in beijing incidence and risk factors of infections caused by vancomycin-resistant enterococcus colonization in neurosurgical intensive care unit patients nosocomial outbreak of linezolid-resistant enterococcus faecalis infection in a tertiary care hospital outbreak of shv- beta-lactamase-producing klebsiella pneumoniae in a neonatal-pediatric intensive care unit in spain outbreak of infection with a multiresistant klebsiella pneumoniae strain associated with contaminated roll boards in operating rooms intensive care unit outbreak of extended-spectrum beta-lactamase-producing klebsiella pneumoniae controlled by cohorting patients and reinforcing infection control measures nosocomial outbreak due to extended-spectrumbeta-lactamase-producing enterobacter cloacae in a cardiothoracic intensive care unit nosocomial neonatal outbreak of serratia marcescens-analysis of pathogens by pulsed field gel electrophoresis and polymerase chain reaction using pulsed-field gel electrophoresis in the molecular investigation of an outbreak of serratia marcescens infection in an intensive care unit outbreak of serratia marcescens colonization and infection traced to a healthcare worker with long-term carriage on the hands a heterogeneous outbreak of enterobacter cloacae and serratia marcescens infections in a surgical intensive care unit an outbreak of multidrug-resistant pseudomonas aeruginosa associated with increased risk of patient death in an intensive care unit epidemiology of pseudomonas aeruginosa and risk factors for carriage acquisition in an intensive care unit mosturizing body milk as a reservoir of burkholderia cepacia: outbreak of nosocomial infection in a multidisciplinary intensive care unit clinical and molecular epidemiology of an outbreak of infusion-related acinetobacter baumannii bacteremia in an intensive care unit eradication of multi-drug resistant acinetobacter from an intensive care unit hospital gene transfer in a polyclonal outbreak of carbapenem-resistant acinetobacter baumannii role of tigecycline in the control of carbapenemresistant acinetobacter baumannii outbreak in an intensive care unit origin of epidemic clones of acinetobacter in the critically ill control of acinetobacter outbreaks in the intensive care unit infection and colonisation of neonates by hansenula anomala hansenula anomala outbreak at a surgical intensive care unit: a search for risk factors an outbreak of pichia anomala fungaemia in a brazilian pediatric intensive care unit outbreak of gastric mucormycosis associated with the use of wooden tongue depressors in critically ill patients an outbreak of dipodascus capitatus infection in the icu: three case reports and review of the literature saccharomyces cerevisiae fungemia: an emerging infectious disease colonization with broadspectrum cephalosporin-resistant gram-negative bacilli in intensive care units during a nonoutbreak period: prevalence, risk factors, and rate of infection microbial gut overgrowth guarantees increased spontaneous mutation leading to polyclonality and antibiotic resistance in the critically ill selective decontamination with nystatin for control of a candida outbreak in a neonatal intensive care unit candida colonisation as a source of candaemia the multiple value of surveillance cultures: an alternative view key: cord- - dcnext authors: corpus, carla; williams, victoria; salt, natasha; agnihotri, tanya; morgan, wendy; robinson, lawrence; maze dit mieusement, lorraine; cobbam, sonja; leis, jerome a title: prevention of respiratory outbreaks in the rehabilitation setting date: - - journal: bmj open qual doi: . /bmjoq- - sha: doc_id: cord_uid: dcnext background: respiratory viral (rv) outbreaks in rehabilitation facilities can jeopardise patient safety, interfere with patient rehabilitation goals and cause unit closures that impede patient flow in referring facilities. problem: despite education about infection prevention practices, frequent rv outbreaks were declared each year at our rehabilitation facility. methods: before and after study design. the primary outcome was the number of bed closure days due to outbreak per overall bed days. process measures included delays in initiation of transmission-based precautions, rv testing and reporting of staff to occupational health and safety (ohs). balancing measures included the number of isolation days and staff missed work hours. interventions: based on comprehensive analysis of prior outbreaks, the following changes were implemented: ( ) clear criteria for initiation of transmission-based precautions, ( ) communication to visitors to avoid visitation if infectious symptoms were present, ( ) exemption of staff absences if documented due to infectious illness, ( ) development of an electronic programme providing guidance to staff about whether they should be excluded from work due to infectious illness. results: the number of bed closure days due to outbreak per overall bed days dropped from . % to . % during the intervention season and sustained at . % during the postintervention season (p< . ). there were fewer delays in initiation of droplet and contact precautions ( . % to . %, p= . ) and collection of rv testing ( . % to . %, p< . ), better reporting to ohs ( vs . reports per employees; p< . ) and fewer isolation days ( . % vs . %; p= . ) without a significant increase in missed work hours per hours worked ( . vs . ; p= . ). conclusion: this quality improvement study highlights the process changes that can prevent respiratory outbreaks in the rehabilitation setting. nosocomial transmission of respiratory viruses (rvs) can lead to unanticipated complications for patients during their contact with the healthcare system. in rehabilitation facilities, these outbreaks jeopardise patient safety, interfere with patient rehabilitation goals and cause unit closures that impede patient flow in referring facilities. multicomponent infection prevention and control (ipac) strategies including hand hygiene, early symptom identification, transmission-based precautions, use of personal protective equipment by healthcare personnel and environmental cleaning, can be successful in preventing nosocomial transmission of rvs. [ ] [ ] [ ] [ ] [ ] [ ] despite this, adherence to these best practices is frequently suboptimal and rv outbreaks in healthcare remain a common yet preventable occurrence. at our rehabilitation institution in toronto, canada, we experienced frequent rv outbreaks every season despite continued efforts to educate healthcare providers about best ipac practices. we hypothesised that rv outbreaks could be prevented using quality improvement (qi) methodology, beginning by a systematic understanding of the problem, engagement of key stakeholders and design of new processes that support improved ipac practices. our aim was to reduce bed closure days due to outbreak by over % during subsequent rv seasons. st. john's rehabilitation centre (sjr) is a -bed rehabilitation facility located in toronto, ontario, canada and is a tertiary care teaching hospital affiliated with university of toronto. the patient population includes cardiac, amputee, stroke, trauma, medical debility, burn and musculoskeletal patients. the average length of stay is approximately days and there are about admissions per year. at baseline, six rv outbreaks were declared in the / season resulting in bed closure days ( . % of all rehabilitation bed days). ipac strategies in place prior to the qi study included: mandatory core competency training for all clinical staff on hire and renewal every years; a healthy workplace policy that required healthcare workers to open access stay home if they were ill; droplet and contact precautions for patients with respiratory symptoms including patient placement (single room and cohorting); routine daily and terminal environmental cleaning of horizontal and high touch surfaces; monthly hand hygiene directly observed audits (compliance rate ~ %- %); multiplex rv testing via polymerase chain reaction (turnaround time ~ hours); antiviral treatment and prophylaxis for confirmed cases of influenza and exposed roommates and annual influenza vaccination campaign with uptake of % for staff and ~ % for patients. the rv season was defined as october to april during baseline ( / ), intervention ( / ) and postintervention ( / ) seasons. patients with respiratory symptoms were prospectively identified through active surveillance based on unit reporting and tracking of laboratory specimens. mid-turbinate (mt) swabs were collected from all patients with new or worsening onset of one or more respiratory symptom (rhinorrhoea, cough, sore throat, wheeze or dyspnoea). a case was considered nosocomial if symptoms developed > hours after admission. a rv outbreak was defined as two nosocomial cases (non-roommates) in a designated unit with symptom onset within hours and a lab-confirmed respiratory virus detected in a least one case. in the absence of laboratory confirmation of a respiratory virus, three nosocomial cases (non-roommates) within hours in one unit was considered a rv outbreak. rv outbreaks were declared over on day following the onset of the last nosocomial rv case, in accordance with local public health guidelines. any unit where a rv outbreak was declared was immediately closed to new admissions. accordingly, the census on the unit decreased throughout each outbreak as patients were discharged without new patient admissions. reducing the number of bed-closure days due to outbreak was thus chosen as the primary aim of this study because it reflected the impact of these outbreaks on our facility's ability to fulfil its mission of providing inpatient rehabilitation. the improvement team was convened by senior leaders of the institution in may and began by trying to identify the most important drivers of rv outbreaks during the two preceding seasons. first, a comprehensive retrospective review of the line listed cases and epidemiological curves were conducted to adjudicate primary precipitant of the prior rv outbreaks. this review identified that outbreaks resulted from a delay in initiation of droplet and contact precautions ( / , %), staff working while ill ( / , %), shared accommodations ( / , %) and no definite cause identified but sick visitor suspected ( / , %). second, a half-day interdisciplinary stakeholder meeting was held ( healthcare providers present) where they completed an ishikawa diagram aimed at identifying the contributing factors to rv outbreaks. this activity revealed additional contributors including: the facility's infrastructure (only % of all inpatient accommodations are private rooms) leading to higher threshold for initiation of transmission-based precautions, confusion about how many symptoms should trigger initiation of droplet and contact precautions, visitors coming into the facility with infectious symptoms due to lack of awareness about the consequences, healthcare worker perceptions about the implications of taking days off when sick on human resources attendance management and limited access to occupational health and safety (ohs) after regular work hours. between september and december , new processes were fully implemented to address the most important contributors of rv outbreaks. table summarises the four new processes developed and their relationship to the problems identified. first, clarity was achieved regarding the criteria for initiation of droplet and contact precautions to include any patient with any of the following symptoms: new or worsening cough, runny nose, congestion or sore throat (september ). second, communication to visitors to please not visit if they have any of those symptoms was included in two forms: an automated telephone message heard on calling the rehabilitation centre and signs placed in the lobby entrance (november ). third, communication to staff regarding exemption for illness due to infectious causes was communicated to all healthcare providers in an attempt to address the perceived barrier of not coming to work ill (october ). to mitigate the risk of abuse of this exemption policy, improved reporting to ohs was required, which in turn necessitated a more efficient process for reporting to ohs. the fourth intervention was the development of an electronic programme allowing staff to report illness to ohs and simultaneously receive guidance about whether they are excluded from work due to infectious illness (december ). this programme incorporated questions about specific symptoms and symptom-onset and provided a personalised recommendation about whether the healthcare provider should work or remain home, based on whether or not they were considered infectious (see online supplementary material). in the event that the system identified a staff person as being infectious, the recommendation could be forwarded to the manager of the unit in order to exempt the employee from the attendance management system. the primary outcome measure was the number of bed closure days due to outbreaks during a rv season adjusted for the facility's overall bed availability. this was defined as any bed-closure occurring during a rv outbreak. process measures included percentage of staff that received training about criteria for initiation of table description of factors contributing to viral respiratory outbreaks and the corresponding interventions implemented staff lack clarity regarding criteria that warrant initiation of transmission-based precautions ► min face to face education sessions using real patient story ► visual reminders (posters) on units listing the criteria for initiation of transmission-based precautions visitors coming into the facility with infectious symptoms ► bold and bright posters incorporating photos to alleviate language barriers were strategically posted at facility and unit entrances asking visitors not to enter if they have any of the depicted symptoms ► automated telephone message on calling the facility reminding visitors not to visit when ill with infectious symptoms ► unit managers empowered frontline staff to send visitors home if noted to be ill staff working while ill due to perceived implications on human resource attendance management ► clear communication to staff regarding exemption of any absences from human resources attendance management on condition that illness is documented to be infectious (through online or in-person reporting to occupational health & safety) lack of after-hours access to occupational health and safety to report infectious illness ► creation of electronic reporting system (occupational health & safety e-nurse (parklane-canada)) which allows healthcare workers to enter their symptoms and receive immediate recommendation about whether they are allowed to work. this system also provides printable documentation to managers transmission-based precautions, the proportion of patients with delays in initiation of droplet and contact precautions or collection of mt swabs (each defined as more than hours from onset of symptoms) and the number of healthcare providers reporting sick to ohs. all laboratory and clinical data were obtained from laboratory reports and prospective ipac surveillance documentation. all healthcare provider illness reporting was obtained from ohs documentation. to account for any unintended consequences associated with these new processes, balancing measures were assessed including number of isolation days adjusted to total patient days, number of mt swabs processed by the microbiology laboratory and non-physician inpatient staff missed work hours due to illness adjusted to staff worked hours. the number of isolation days included any patient managed on precautions in the facility including patients with confirmed rv infection and those with suspected rv infection for whom mt swab results were pending. descriptive statistics were calculated for all variables of interest. continuous measures were summarised using means and sd, or median and iqr if they did not pass the test for normality. categorical measures were summarised using counts and percentages. the χ² or fisher's exact test were used to detect difference in proportions. p< . was considered statistically significant. data were analysed using spss statistics v. software (ibm, markham, ontario, canada). this study was deemed to be quality improvement within the mandate of the ipac programme and therefore formal research ethics board review was waived. the interdisciplinary stakeholder meeting did not include a patient or public representative, but patients and visitors were engaged in the project during the implementation of the process changes. patient input was received regarding sign location and automated telephone notification. the impact of the quality improvement study was presented to the organisation's quality committee that includes representation from the public. during implementation of the four process changes, % ( / ) of nursing staff were trained regarding criteria for initiation of transmission-based precautions, including % ( / ) of full-time staff. figure depicts the monthly proportion of patients placed on droplet and contact precautions and figure shows the monthly proportion tested with mt swabs for respiratory viruses greater than hours after onset of symptoms. a shift in practice was noted following training with significant reductions in delays in both initiation of droplet and contact precautions ( . % vs . %; p= . ) and viral testing ( . % vs . %; p< . ) in the intervention respiratory season and onward. table summarises the family of measures during the intervention and postintervention seasons compared with the baseline season. the number of bed closure days due to outreak adjusted for overall bed days dropped from . % to . % during the intervention season and was sustained at . % during the postintervention season (p< . ). staff reporting to ohs increased from to . per employees (p< . ). in terms of unintended consequences, earlier initiation of droplet and contact precautions did not lead to increased isolation days. in fact, the proportion of isolation days per patient days decreased during the intervention season as compared with baseline ( . % vs . %; p= . ). with regard to potential for increased absenteeism, there was no significant change in the number of missed work hours for employees ( . missed hours/ worked hours at baseline vs . missed hours / worked hours during intervention; p= . ). our rehabilitation centre reduced the number of bed closure days due to rv outbreaks to less than a third for two consecutive seasons through process changes that supported earlier initiation of transmission-based precautions for symptomatic patients, discouraged visitation by people with potentially infectious symptoms and made it easier for healthcare workers to stay home when potentially infectious. despite evidence supporting ipac practices to prevent nosocomial transmission of rv infection each rv season, the adoption of these practices following education alone is often suboptimal leading to preventable nosocomial outbreaks. there is a paucity of literature around using qi strategies to address these gaps and to our knowledge, none have been undertaken to prevent rv outbreaks in rehabilitation settings. in the paediatric population, nosocomial transmission has been shown to be prevented through screening of patients and cohorting nurses with positive children along with the use of transmission-based precautions. in a population of stem cell transplant patients, universal use of surgical masks by healthcare providers was associated with a greater than % reduction in nosocomial rv infection. rehabilitation settings are environments conducive to nosocomial rv transmission due to the nature of the patient population, which is being mobilised daily in common spaces. our approach was to better understand the barriers to adherence to ipac practices within the rehabilitation context. we used epidemiological data to identify important triggers of outbreaks and then drilled down to understand the main drivers. for example, delays in testing and initiation of droplet and contact precautions were occurring due to lack of clarity around syndromic criteria which was addressed through systematic training. lack of private rooms was an additional barrier noted by our staff, but our experience showed that earlier initiation of transmission-based precautions actually led to the same number of isolation-days presumably due to reduced nosocomial transmission. finally, we uncovered a number of system problems that made it easier for staff to work while sick rather than staying home. these included the perceived pressure from human resources attendance management and the challenge in accessing ohs. once these were addressed through open access redevelopment of an ohs electronic software reporting programme, better reporting of illness was seen. these examples underscore the impact of process changes that are linked to the specific barriers to best practice rather than relying on education alone. a striking finding in our study is that despite making it easier for staff to report to ohs, we observed no significant increase in the average number of missed work hours. one explanation for this finding is that the additional absences for staff staying home when potentially infectious was offset by a reduction in staff becoming infected while at work due to fewer encounters with infectious colleagues and fewer unprotected encounters with nosocomial rv cases. these data argue against the perception that staff staying home when symptomatic could increase staff shortages and should empower organisations to create similar models of care that make staying home when sick the easier thing to do. despite improvement in ipac practices, we continued to observe sporadic nosocomial transmission of rvs at our facility. one potential explanation is that increased viral testing resulted in ascertainment of more nosocomial cases even though there was reduced transmission through earlier use of droplet and contact precautions. another possibility is that our intervention could not fully prevent nosocomial transmission as visitors continued to enter with infectious symptoms since we could not monitor this practice accurately. finally, even though we reduced symptomatic visitation, either healthcare providers or visitors could have continued to transmit rv through asymptomatic viral carriage. some studies found limiting visits by children under the age of during the winter months, may reduce nosocomial transmission of viral respiratory infection. however, this approach may be a challenging and costly to operationalise as active screeners have to be strategically posted throughout the season. our study has several important limitations. we compared only three rv seasons where interyear differences could be explainable by differences in seasonality. however, the documented practice changes that coincided with the lower outbreak-days suggest that these improvements were related to the intervention. implementation of multiple strategies simultaneously made it difficult to assess the effectiveness of individual components, which would have been useful to direct resources more efficiently. on the other hand, the impact on prevention of rv outbreaks was close to predicted based on the individual drivers identified. our study highlights the impact of new processes of care that address barriers to following ipac practices on the prevention of nosocomial outbreaks in the rehabilitation setting. these strategies have the potential to improve both patient and staff safety across these institutions. nosocomial respiratory syncytial virus infections: the cost-effectiveness and costbenefit of infection control nosocomial respiratory syncytial virus infection: impact of prospective surveillance and targeted infection control nosocomial respiratory syncytial virus infections: prevention and control in bone marrow transplant patients risk of nosocomial respiratory syncytial virus infection and effectiveness of control measures to prevent transmission events: a systematic review prospective controlled study of four infection-control procedures to prevent nosocomial infection with respiratory syncytial virus ontario agency for health protection and promotion, provincial infectious diseases advisory committee. routine practices and additional precautions in all health care settings. rd edition. toronto, on: queen's printer for ontario infectious diseases protocol: appendix b: provincial case definitions for diseases of public health significance. disease: respiratory infection outbreaks in institutions and public hospitals universal mask usage for reduction of respiratory viral infections after stem cell transplant: a prospective trial advancing infection prevention and antimicrobial stewardship through improvement science working with symptoms of a respiratory infection: staff who care for high-risk individuals transmission of influenza: implications for control in health care settings respiratory virus infections after marrow transplant: the fred hutchinson cancer research center experience acknowledgements we would like to thank all staff at st. john's rehabilitation centre for their engagement in the development of these practice changes as well as the support from infection prevention & control, occupational health & safety, human resources, unit managers and the senior leadership team.contributors cc, ns, ta, wm, lr, lmdm and jal contributed to study concept and design. acquisition, analysis or interpretation of data performed by cc, vw, wm and jal. manuscript was drafted by cc, vw and jal. critical revision of the manuscript received from all authors.funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.competing interests none declared.patient consent for publication not required.provenance and peer review not commissioned; externally peer reviewed.data availability statement all data relevant to the study are included in the article or uploaded as supplementary information.open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. key: cord- - ylifqo authors: kelly, j. daniel; worden, lee; wannier, s. rae; hoff, nicole a.; mukadi, patrick; sinai, cyrus; ackley, sarah; chen, xianyun; gao, daozhou; selo, bernice; mossoko, mathais; okitolonda-wemakoy, emile; richardson, eugene t.; rutherford, george w.; lietman, thomas m.; muyembe-tamfum, jean jacques; rimoin, anne w.; porco, travis c. title: projections of ebola outbreak size and duration with and without vaccine use in Équateur, democratic republic of congo, as of may , date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: ylifqo as of may , , suspected, probable and confirmed cases of ebola virus disease (evd) had been reported in Équateur province, democratic republic of congo. we used reported case counts and time series from prior outbreaks to estimate the total outbreak size and duration with and without vaccine use. we modeled ebola virus transmission using a stochastic branching process model that included reproduction numbers from past ebola outbreaks and a particle filtering method to generate a probabilistic projection of the outbreak size and duration conditioned on its reported trajectory to date; modeled using high ( %), low ( %), and zero ( %) estimates of vaccination coverage (after deployment). additionally, we used the time series for prior ebola outbreaks from to to parameterize the thiel-sen regression model predicting the outbreak size from the number of observed cases from april to may . we used these techniques on probable and confirmed case counts with and without inclusion of suspected cases. probabilistic projections were scored against the actual outbreak size of evd cases, using a log-likelihood score. with the stochastic model, using high, low, and zero estimates of vaccination coverage, the median outbreak sizes for probable and confirmed cases were cases ( % prediction interval [pi]: , ), cases ( % pi: , ), and cases ( % pi: , ), respectively. with the thiel-sen regression model, the median outbreak size was estimated to be . probable and confirmed cases ( % pi: . , . ). among our three mathematical models, the stochastic model with suspected cases and high vaccine coverage predicted total outbreak sizes closest to the true outcome. relatively simple mathematical models updated in real time may inform outbreak response teams with projections of total outbreak size and duration. a a a a a on may , , the world health organization (who) announced the occurrence of an outbreak of ebola virus disease (evd) in the democratic republic of congo (drc). [ ] from april through may , suspected evd cases were reported in iboko and bikoro, Équateur province. on may , blood samples from five hospitalized patients had been sent to kinshasa for ebola-pcr testing, and two were confirmed pcr-positive. [ ] on may , vaccination of healthcare workers started. [ ] by may , the ring vaccination campaign was being rolled out as contacts and contacts of contacts were being actively monitored. six suspected, probable and confirmed evd cases had been reported, and ( %) of probable and confirmed evd cases had died. [ ] this outbreak had several features that were worrisome for widespread transmission. cases were reported over a -kilometer distance, including four confirmed cases in thẽ , , -inhabitant provincial capital of equateur, mbandaka, which is situated on the congo river and bordering congo-brazzaville. [ ] moreover, travel to kinshasa is frequent from mbandaka. given these risk factors, early epidemic growth profiles, [ ] and evidence of unreported infection from previous outbreaks, [ , ] the risk of a substantially larger outbreak could not be ignored. the factors causing epidemic growth to peak have been debated. delayed detection of evd outbreaks and resulting widespread distributions of evd have significantly contributed to epidemic growth. [ ] in addition to traditional burial practices, ebola treatment units with low quality care and/or high mortality rates have discouraged ebola suspects from presenting to care and contribute to community-based transmission. [ ] [ ] [ ] fragile, overwhelmed public health surveillance systems have also contributed to higher rates of unreported cases, who endanger urban communities, [ ] which potentially have had higher transmission rates than rural communities. [ ] change to subcritical transmission (reproduction number below ) tends to occur when ebola response organizations deploy control, prevention and care measures, [ , ] communities adopt more protective behaviors, [ , ] and/or transmission decreases in a social network. [ , ] scientific advances with rapid diagnostics and vaccines from the west africa outbreak were deployed in the april-july evd outbreak in drc and had the potential to limit ebola virus transmission. [ ] [ ] [ ] we used reported case counts during evd outbreak in drc and/or time series from prior outbreaks to estimate the total outbreak size and duration with and without the use of vaccines. these projections were intended to help organizations anticipate and allocate sufficient resources for the duration of the april-july evd outbreak. the following methods were used to generate projections: a stochastic branching process model, [ ] statistical regression based on prior outbreaks, and gott's law. [ ] on may , evd cases ( suspected, probable and confirmed) were reported in three locations (iboko, bikoro, and mbandaka) (fig ) . based on evd situation reports from drc, we assumed the ring vaccination program started the week of may , so we used may as the time point that vaccines were implemented in the model at high and low coverage levels. data on suspected, probable, and confirmed case counts were available from who situation reports in may and used as the basis for analysis. the published situation reports reflected data available up until may , , , , and , respectively. during the outbreak, the ebola response team tested suspected cases for evd and depending on positive or negative results, cases were classified as confirmed or not a case. the final outbreak case count was probable and confirmed cases (no suspected cases). [ ] due to this reporting process, probable and confirmed cases were used to parameterize the stochastic branching process model, regression models, and gott's law. we added suspected cases to create an additional projection, using stochastic branching process model. we modeled ebola virus transmission using a stochastic branching process model, parameterized by transmission rates estimated from the dynamics of prior evd outbreaks, and conditioned on agreement with reported case counts from the evd outbreak to date. we incorporated high and low estimates of vaccination coverage into this model. then we generated a set of probabilistic projections of the size and duration of simulated outbreaks in the current setting. to estimate the reproduction number r as a function of the number of days from the beginning of the outbreak, we included reported cases by date from thirteen prior outbreaks and excluded the first historical outbreak reported in those countries (e.g., outbreak in yambuko, drc) (s table) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] as there is a difference in the ebola response system as well as community sensitization to evd following a country's first outbreak, we employed this inclusion criterion to reflect the ebola response system in drc during what is now its ninth outbreak. the wallinga-teunis technique was used to estimate r for each case and therefore for each reporting date in the outbreak. [ ] the serial interval was defined as the interval between disease onset in an index case and disease onset in a person infected by that index case. the serial interval distribution used for this estimation was a gamma distribution with a mean of . days and a standard deviation of days, with intervals rounded to the nearest whole number of days, consistent with the understanding that the serial interval of evd cases ranges from to days with mean to days. [ , [ ] [ ] [ ] given that serial interval distribution, which we can denote as a probability w (t) of a t-day interval between given primary and secondary cases, wallinga-teunis estimation works by defining a relative likelihood p ij for each possible source j of a given case i: and then deriving from that an estimated reproduction number rj for each case: after using this technique to derive estimated reproduction numbers for each case in an outbreak, we use these estimated r values and cases' onset dates d to estimate an initial reproduction number r and quenching rate τ for each past outbreak by fitting an exponentially quenched curve: to each outbreak's r and d values (s fig) . transmission was modeled using a stochastic branching process model in which the number of secondary cases si caused by any given primary case i was drawn from a negative binomial distribution whose mean is the reproduction number r: [ , ] si � nbðr; kÞ; where r is reproduction number as a function of day, k is a dispersion parameter, and nb() denotes the negative binomial distribution. all transmission events were assumed to be independent. the serial interval between date of detection of each primary case and that of each of its secondary cases is assumed gamma distributed with mean . days and standard deviation days, rounded to the nearest whole number of days, as above. the pair of parameters r and τ estimated for the different past outbreaks used, and dispersion parameter k, were used in all possible combinations (with r and τ taken as a unit) to simulate outbreaks. this model generated randomly varying simulated outbreaks with a range of case counts per day. after the ministry of health and who conducted epidemiological investigations about the beginning of the evd outbreak in Équateur province, they concluded that the outbreak began on april , , with a single case. [ ] the simulation process occurs as follows: proposed epidemic trajectories are generated in an initial step based on the above branching process, and these are then subsequently filtered by discarding all but those whose cumulative case counts match the known counts of the april-july evd outbreak on known dates. the filtration accepts epidemics within a range of cases more or less than each recorded value. this one-step particle filtering technique produced an ensemble of model outbreaks, filtered on agreement with the recorded trajectory of the outbreak to date. this filtered ensemble is then used to generate projections of the eventual outcome of the outbreak. [ ] to model vaccination coverage with respect to total transmission (unreported and reported), we multiplied the estimate of vaccine effectiveness by low and high estimates of reported cases. in a ring vaccination study at the end of the west africa outbreak, the overall estimated rvsv-vectored vaccine efficacy was % and vaccine effectiveness was . % in protecting all contacts and contacts of contacts from evd in the randomized clusters, including unvaccinated cluster members. [ ] estimates of vaccine effectiveness were used in our stochastic model. the ring vaccination study found the vaccine to be effective against cases with onset dates days or more from the date of vaccine administration, so we modeled the vaccination program as a proportionate reduction in the number of new cases with onsets days or more after the program start date. then, past estimates of the proportion of unreported cases were used to estimate the proportion of exposed individuals not covered by the vaccination process. based on a sierra leonean study from the - outbreak, [ ] we estimated that the percentage of reported cases in drc would rise over time from a low of % to a high of %. given these low and high estimates of reported cases and the estimate of vaccine effectiveness ( . %), a low estimate of vaccination program coverage was % ( % multiplied by . %) and a high estimate of vaccination program coverage was % ( % multiplied by . %). the course of the outbreak with and without the vaccination program was modeled based on approximate dates available from situation reports. [ ] for simulation based on probable and confirmed cases, from , , simulated outbreaks, , were retained after filtering on approximate agreement with drc case counts. for simulation based on probable, confirmed, and suspected cases, from , , simulated outbreaks, , were retained after filtering. the simulated outbreaks that were retained after filtering were continued until they generated no further cases. this ensemble was used to derive a distribution of outbreak sizes and durations. mean and median values and % prediction intervals were calculated using the . and . percentiles of simulated outbreak size and duration. these analyses were conducted using r . . (r foundation for statistical computing, vienna, austria). for contrast with the stochastic model above, a simple regression forecast was conducted based solely on outbreaks of size or greater. time series for all such prior outbreaks were obtained, including seven prior ones from drc, dating back to (s table; the beginning of each outbreak was not reliably characterized; therefore, all time-series were aligned on the day they reached cases. in the april-july outbreak, we observed cases over the period from april to may (day to day ). may corresponded to day since reaching reported cases. for the prior outbreaks, linear interpolation was used to obtain the number of cases on day (after reaching cases). to reduce the influence of outliers and high leverage points, and to improve linearity, we calculated the pseudologarithm transform f(x) = arcsinh(x/ ), asymptotically logarithmic but well-behaved at . we used nonparametric theil-sen regression (r-package mblm) followed by calculation of the resulting prediction interval for a new observation. [ , ] finally, we reported the median and % central coverage intervals for the prediction distribution conditional on the value being no smaller than the observed value on day . sensitivity analysis was conducted using ordinary least squares regression. these analyses were conducted using r . . (r foundation for statistical computing, vienna, austria). gott' s law was used to estimate the outbreak size using data through may and may . we included a projection using data through may because we hypothesized that this method performs better when the first situation report is posted than at later in the outbreak period. [ ] then we included a projection with the regression models using data through may for comparison. with gott's law, we assume we have no special knowledge of our position on the epidemic curve. if we assume a non-informative uniform prior for the portion of the epidemic that still remains, the resulting probability distribution for the remaining number of cases y is: the median outbreak size was estimated, along with the two-sided % prediction interval. each of the above models assigned a probability to any possible value of the total outbreak size. the final outbreak size was probable and confirmed cases, so we identified the probability of this equivalent number ( ) from each model, as of may . probabilistic projections were scored using a log-likelihood (ignorance) score. [ ] as of may , , there were suspected, probable and confirmed evd cases. bikoko had ten confirmed cases, probable cases, and one suspected case. iboko had confirmed cases, two probable cases, and one suspected case. mbandaka had four confirmed cases and one suspected case (fig ) . with the stochastic model, we projected outbreak size and duration of probable and confirmed cases. in the absence of any vaccination program, the projected median outbreak size was . cases (mean . ; % prediction interval: . , . ). median duration of projected outbreaks was . days (mean . ; % prediction interval: . , . ). using a lower estimate of % vaccination coverage, the median outbreak size was . cases (mean . ; % prediction interval: . , . ) and median duration was . days (mean . ; % prediction interval: . , . ). using a higher estimate of % vaccination coverage, the median size was . evd cases (mean . ; % prediction interval: . , . ), and the median duration was . days (mean . ; % prediction interval: . , . ). these projections with the stochastic model were repeated to estimate suspected, probable and confirmed cases (table and table with the regression based on past outbreaks, the median outbreak size was estimated to be . probable and confirmed cases ( % prediction interval: . , . ), while use of ordinary least squares produced a median size of . probable and confirmed cases ( % prediction interval: . , . ). outbreak projections were also reported using data through may in table . gott's law suggests that given probable and confirmed cases, the median estimate of outbreak size was . cases ( % ci: . , . ). using the probable and confirmed cases as of may , the median estimate of outbreak size was . cases ( % ci: . , . ). of the mathematical models employed, the stochastic model that included suspected cases and high vaccination coverage had the best probabilistic score (log likelihood of - . ). likelihood scores of each model can be found in table . when we were conducting our projections in late may, this outbreak still had the potential to become the largest outbreak in drc since . vaccine use, regardless of coverage levels, was projected to prevent more than half of the total outbreak size. vaccines, however, were only part of concurrent prevention, control, and care strategies. [ , [ ] [ ] [ ] we also found that the stochastic model with vaccine use projected that rare, large outbreaks (tail of the distribution of the model without vaccinations) were prevented, suggesting that repeat epidemics such as the - west african outbreak may have been highly unlikely once vaccines were rolled out. multiple models were used to estimate total outbreak size. this study exemplified how mathematical models, including simple regressions, can be useful for advising real-time decision making because they provided rapid projections and similar estimates of r as compared to complex models, [ ] even though real-time modeling projections historically overestimated outbreak size and duration. [ , ] our projections that included suspected cases did not suggest that vaccines had as much of an impact as our model using only probable and confirmed cases. the trends associated with suspected cases were subject to several factors, including operational choices of response teams and maturity of the outbreak. nevertheless, suspected case counts may at times provide a better glimpse into the near future of an outbreak than the confirmed and probable case counts. in our case, use of the time series of confirmed, probable, and suspect cases yielded a forecast closer to the final outbreak size. however, as model projections can be highly sensitive to inclusion of suspected cases and use of exact case counts, particularly the last few counts in the available data, conclusions must be taken with caution. thus far, there had been a strong local and international response, and deployment of vaccines and rapid diagnostic tests (rdt) occurred early in response efforts. [ ] rdts were being used to screen ebola suspects while the vaccines are being administered to high-risk groups for evd, including healthcare workers, contacts, and contacts of contacts. to further limit epidemic growth from unreported cases, particularly those who have non-specific symptoms but table . distribution of projected outbreak size from stochastic branching process model. mean, median and % prediction interval of outbreak size, by proportion of vaccine coverage, using probable and confirmed cases with and without suspected cases. probable table . distribution of projected outbreak duration from stochastic branching process model. mean, median and % prediction interval of outbreak duration, by proportion of vaccine coverage, using probable and confirmed cases with and without suspected cases. there are limitations to our projections. projection distributions were right-skewed, with long tails (and we therefore reported the median instead of the mean). while there have been observed evd outbreaks with a case count greater than ten cases, we were unable to include all prior outbreaks in our estimates due to data availability. [ , ] note that the simple regression projection is based entirely on past outbreaks of evd (measured and reported in different ways), and cannot account for the improved control measures and vaccination in the way that a mechanistic model does. we included, however, as much real-time information into our estimates as possible, but situations such as the introduction of evd into a large urban population and implementation of rdts and vaccines are new to drc. we did not include vaccination of healthcare workers in the stochastic model. our estimates of vaccination effectiveness and reported cases were obtained from west africa because these estimates were not available for the evd outbreak in Équateur. these modeling assumptions may not have been consistent with estimates in drc and should be carefully considered prior to use in other evd outbreaks. a strength of our approach was the use of multiple methods to estimate the outbreak size, although we note that gott's law has not been validated for outbreak projections in other evd outbreaks. additional limitations of the models were that they did not include parameters to address spatial spread, urban settings, conflict zone, or other factors that may have influenced the accuracy of the predictions, particularly in the - evd outbreak in northeastern drc (ongoing in january ). while it can also be useful and achievable to use models of these kinds to make short-term forecasts for evaluation of model performance and to inform outbreak response, [ ] the present study was limited to projections of final outbreak size and duration. among our three mathematical models, the model that performed the best (stochastic model with suspected cases and high vaccine coverage) predicted total outbreak sizes close to the true outcome. when evd cases were introduced into mbandaka, there was concern that the total outbreak size could exceed most prior evd outbreaks in drc. indeed, our projections were consistent with this concern because models without vaccine coverage projected higher total outbreak sizes. in our stochastic model projections, vaccine use reduced mean total outbreak size by more than half, regardless of coverage levels (p< . , welch's t-test). as vaccine coverage was scaled up, an influx of support was warranted to support and bolster the evolving rapid response; however, continued efforts to strengthen the health system are equally as warranted so that we can respond to future outbreaks before they become epidemics. relatively simple mathematical models updated in real time may inform outbreak response teams with projections of total outbreak size and duration. supporting information s table. list of prior ebola outbreaks from to by time period, country, confirmed/probable reported and time series case count, outbreak inclusion into the regression and stochastic models. world health organization regional office for africa. health topics: ebola virus disease world health organization. emergencies preparedness, response excitement over use of ebola vaccine in outbreak tempered by real-world challenges mathematical models to characterize early epidemic growth: a review minimally symptomatic infection in an ebola 'hotspot': a cross-sectional serosurvey anatomy of a hotspot: chain and seroepidemiology of ebola virus transmission after ebola in west africa-unpredictable risks, preventable epidemics the ebola suspect's dilemma biosocial approaches to the - ebola pandemic ebola virus disease in west africa-clinical manifestations and management unreported cases in the - ebola epidemic: spatiotemporal variation, and implications for estimating transmission heterogeneity in district-level transmission of ebola virus disease during the - epidemic in west africa the impact of control strategies and behavioural changes on the elimination of ebola from lofa county dynamics and control of ebola virus transmission in montserrado, liberia: a mathematical modelling analysis risk communication and ebola-specific knowledge and behavior during - outbreak a theory-based socioecological model of communication and behavior for the containment of the ebola epidemic in liberia modeling household and community transmission of ebola virus disease: epidemic growth, spatial dynamics and insights for epidemic control ebola control: effect of asymptomatic infection and acquired immunity rapid antigen test for ebola. for use under emergency use authorization (eua) only efficacy and effectiveness of an rvsv-vectored vaccine in preventing ebola virus disease: final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola Ç a suffit!) ebola control: rapid diagnostic testing on the probability of the extinction of families implications of the copernican principle for our future prospects high-resolution global maps of st-century forest cover change report of a who/international study team ebola virus disease in southern sudan: hospital dissemination and intrafamilial spread ebola hemorrhagic fever outbreaks in gabon, - : epidemiologic and health control issues the reemergence of ebola hemorrhagic fever, democratic republic of the congo prise en charge des malades et des défunts lors de l'épidémie de fièvre hé morragique due au virus ebola d'octobre à décembre a limited outbreak of ebola haemorrhagic fever in etoumbi, republic of congo ebola virus disease in the democratic republic of congo filovirus outbreak detection and surveillance: lessons from bundibugyo different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures ebola virus disease in west africa-the first months of the epidemic and forward projections a systematic review of early modelling studies of ebola virus disease in west africa transmission dynamics and control of ebola virus disease (evd): a review comparing methods for estimating r from the size distribution of subcritical transmission chains superspreading and the effect of individual variation on disease emergence ebola virus disease in the democratic republic of the congo outbreak(s) of ebola haemorrhagic fever, congo and gabon potential for large outbreaks of ebola virus disease world health organization. weekly epidemiological record. abonnement annuel university of bergen dissertation for phd ebola virus disease outbreak in nigeria: transmission dynamics and rapid control ebola (ebola virus disease): history of ebola virus disease: - ebola outbreak in west africa: case counts estimates of the regression coefficient based on kendall's tau a rank-invariant method of linear and polynomial regression analysis. i, ii, iii. nederl akad wetensch, proc scoring probabilistic forecasts: the importance of being proper beyond vaccines: improving survival rates in the drc ebola outbreak food insecurity as a risk factor for outcomes related to ebola virus disease in kono district, sierra leone: a cross-sectional study the symbolic violence of 'outbreak': a mixed methods, quasiexperimental impact evaluation of social protection on ebola survivor wellbeing estimating the future number of cases in the ebola epidemic -liberia and sierra leone models overestimate ebola cases centers for disease control and prevention. outbreaks chronology: ebola hemorrhagic fever real-time projections of epidemic transmission and estimation of vaccination impact during an ebola virus disease outbreak in the eastern region of the democratic republic of congo we thank the ebola responders for their efforts in the evd outbreak in Équateur, democratic republic of congo. key: cord- - edzmj n authors: mitruka, kiren; wheeler, robert e. title: cruise ship travel date: - - journal: travel medicine doi: . /b - - - - . - sha: doc_id: cord_uid: edzmj n nan cruise ship travel has gained tremendous popularity over the last three decades. in , . million passengers sailed on north american cruises, representing a , % percent increase since . , a fleet of cruise ships, with , beds, sailed at % capacity that same year. surveys show that the top three reasons for passenger satisfaction with cruise vacations are being pampered, having the chance to visit several locations and fine dining. in fact, the modern-day cruise ship has evolved since the early s, when passenger ships were virtually the only means of crossing the ocean and when the focus was on efficient transatlantic transportation. the speed of jet air travel changed the focus of cruise ship travel to the pleasure of the voyage itself. cruise destinations such as the caribbean and mediterranean gained popularity due to climate as well as accessibility to many ports. over time cruise ships have come to resemble floating luxury resorts. the ever-expanding cruise itineraries, which include diverse ports of call, along with a growth in the number of embarkation ports and onboard amenities, provide travelers with convenient and comfortable means to sample different parts of the world in a short amount of time. with the growing popularity of recreational cruises, gastrointestinal (gi) and respiratory disease outbreaks have posed challenges for public health officials and the cruise industry to ensure a healthy cruise environment. many communicable diseases seen on board cruise ships are also on land. however, disease exposure and transmission aboard ships may be exacerbated by the densely populated, semiclosed cruise environment, which compels international passengers and crew to share many activities and resources. , , moreover, a ship can acquire new infectious disease reservoirs while in port through contaminated food and water or infected people. environmental contamination on cruise ships and infected crew and passengers who remain on board during successive voyages may result in protracted outbreaks on cruises. , an infectious disease acquired during the voyage may incubate in people disembarking from cruise ships and result in outbreaks in the travelers' home communities, especially in closed settings (such as nursing homes). therefore, the public health significance of illness aboard cruises lies not only in possible widespread illness onboard ships, but also the spread of diseases into communities all over the world. sanitation and disease surveillance programs developed through the cooperation of cruise industry and public health agencies have led to improved detection and control of communicable diseases. due to the potential impact on health, having knowledge about shipboard morbidity and illness prevention measures as well as cruise ship sanitation practices is important for embarking passengers and their health-care providers. understanding the most frequently reported diseases on cruise ships, their source and mode of transmission, prevention measures, and available ship medical care facilities can lead to better preparedness for a healthy cruise vacation. the north american cruise industry ships carrying or more passengers are considered to be passenger ships. they include sailboats, yachts, river cruise ships, and ocean cruise ships. sailboats and yachts are best known for niche travel, such as "eco-touring." river cruises are popular for providing an informal, intimate atmosphere while traveling to places such as the nile and the amazon. ocean cruises make up the greatest portion of ship-based leisure travel, with the north american cruise industry accounting for the major part of the global ocean cruise market. the north american cruise industry consists of cruise lines that primarily market cruises to north americans, but have embarkation ports all over the world. nevertheless, north american ports, particularly those in the united states, handle the vast majority ( % and %, respectively) of all global embarkations. the north american cruise industry provides significant benefits to the u.s. economy, creating , jobs and generating $ billion in . , during the same year, . million cruise passengers embarked on cruises from u.s. ports, with % of all cruise ship passengers sailing out of ports in florida. seaports in puerto rico and canada handled % each, and those in rest of the world (primarily europe and the mediterranean) had % of global embarkations in . , the caribbean remained the top cruise destination, followed by the mediterranean, other parts of europe, alaska, and mexico. depending on the type of cruise, the duration can range from a day (e.g. gambling cruises) to several months (e.g. round-the-world cruises). the average length of a cruise is days, and approximately % of cruising passengers choose -to -day cruises. the typical -day cruise allows passengers ample time to visit - ports and explore different locales and cultures. for many travelers the ship is a destination in itself, offering luxurious accommodation, a variety of food, exciting activities, and relaxation. over the last few years, the number of u.s. embarkation ports has steadily increased, allowing for lower costs and more convenience for u.s. residents wishing to take a cruise. data reported in by the cruise line international association (clia), the north american cruise industry's main marketing organization, indicate that up to million north americans might take a cruise within years. clia also notes that % of the u.s. population has already cruised once in their lifetime, with more than % of that number having been on a cruise more than once. in fact, % of all cruise passengers are u.s. residents. compared with u.s. resident noncruise vacationers (defined by those spending nights or more away from home for leisure trips), cruisers tend to be older ( % are over the age of years), have higher income levels, and be likely to plan a vacation - months in advance, allowing time for pretravel health preparation. a typical cruise ship will have a passenger-to-crew ratio of around : . , cruise ships employ crew members from all over the world; on average, nationalities will be represented in a crew of , . the origin of crew members will depend on the cruise line and the designated occupation on the ship. crew members may stay for months on successive voyages aboard a cruise ship, carrying out specialized tasks with the aim of achieving higher quality service. the international character of today's cruise industry is manifested not only by the variety of worldwide ports and the nationalities of passengers, crew members, and company ownership, but also by the flag status, or maritime registry, of the individual cruise ships. the flag or maritime registry administration is a regulatory agency that oversees the operational procedures, ship specifications, crew qualifications, practices, and conformity to laws of commercial vessels registered in a particular country. , , cruise lines may register their ships with maritime agencies in countries such as the netherlands, norway, the united kingdom, and the united states. they often choose to register their ships in the country of ownership of the cruise line or the site of the ship's production. some cruise lines opt to register their ships in countries that provide open maritime registration or "flags of convenience." panama, liberia, and the bahamas are three such countries that allow foreign vessel owners to register their ships through their respective flag administrations. together they account for more than % of the world's merchant fleet maritime registrations, including many cruise ships. the "flag of convenience" concept originated in panama just after world war i, when u.s. merchant and passenger vessel registrations began to be transferred to panama to take advantage of favorable tax incentives and to avoid restrictive prohibition laws. , the open maritime registrations continue to provide the respective countries with a substantial revenue flow and the registrants with significant financial advantages pertaining to tax, labor, and liability costs. each flag state, whether it provides open maritime registrations or the more traditional maritime state flag status, is required to be an international maritime organization (imo) member nation and abide by its maritime safety resolutions, conventions, and codes. cruise health, sanitation, and safety regulations the concept of monitoring health aboard ships emerged during the th century plague epidemic, when "black death," arrived from the east and swept across europe. to prevent the entry and spread of disease and protect commerce, venice enforced a mandatory -day anchor and observation of ships arriving from affected regions. this practice came to be known as "quarantine," derived from the italian word for (quaranta). thereafter, other global infectious disease outbreaks, such as the cholera epidemic during the mid- s, provoked multiple international treaties and conventions to develop world standards to prevent the spread of disease across borders. however, it was not until the world health organization (who) promulgated the international sanitary regulations (isr) in that such international standards were developed. the isr, renamed the international health regulations, were revised and updated in may to address emerging public health threats. , the overall goal of the revised ihr is to provide maximum security against the international spread of disease while avoiding unnecessary interference with international travel and trade. among other things, the ihr provide world standards for ship and port sanitation, surveillance, and response for infectious diseases that can have a serious public health impact globally. under the ihr, international ports and conveyance operators are required to take measures to ensure delivery of safe food or water, appropriate waste disposal, and vector control. in addition, the who guide to ship sanitation (referenced in the ihr) provides specific health requirements for ship construction and operation, and for sanitary measures on ships. it highlights the importance of applying control measures to reduce public health risks on ships. recently, these guidelines have been revised with a systematic review of documented outbreaks and diseases of public health significance aboard ships during the last three decades. the safety of cruise ship passengers and crew members is of paramount importance to cruise lines. safety regulations for international seagoing vessels, including cruise ships, are promulgated by the imo in its international convention for safety of life at sea (solas) and international safety management (ism) code. these regulations address a variety of issues pertaining to passenger and crew safety, including fire protection, lifesaving equipment and procedures, and radio communications. the primary responsibility for monitoring for compliance with the solas standards and other internationally recognized imo conventions lies with the ship's country of maritime registry or flag state. federal and state maritime agencies at ports of call, such as the united states coast guard for ships sailing in u.s. territorial waters, are provided with the legal authority to inspect vessels to ensure compliance with imo conventions. the centers for disease control and prevention (cdc) has responsibility for ensuring appropriate levels of sanitation and health aboard cruise ships arriving at u.s. ports. in , as a result of gastrointestinal outbreaks on cruise ships, cdc established the vessel sanitation program (vsp), in cooperation with the cruise industry, to minimize the risk of gastrointestinal diseases on cruise ships and establish comprehensive sanitation programs. in accordance with u.s. federal quarantine regulations, vsp requires all ships carrying or more passengers to report, at least hours before arrival at a u.s. port, the number of cases (including zero) of acute gastroenteritis (age). cdc defines age as three or more episodes of loose stool within chapter : cruise ship travel a -hour period, or vomiting plus one or more episodes of loose stool, fever, muscle aches, bloody stool, or headache. an epidemiologic and environmental investigation may be prompted if the cruise ship reports unusual cases, or at least % of the passenger or crew report symptoms of age. vsp posts summaries of recent and previous (since ) gastrointestinal outbreaks on its web site. those include the names of the associated cruise lines and cruise ships, sailing dates, illness symptoms, the percentage of passenger and crew affected, control measures, and causative agent, if known. in addition to monitoring and investigating gastrointestinal disease aboard cruise ships, vsp develops guidelines and provides consultation to help shipbuilders and renovators meet construction standards that protect public health. that guidance extends to facilities that could affect public health, such as food storage, ventilation systems, and pools or spas. vsp also conducts unannounced, biannual sanitation inspections of u.s.-bound cruise ships that have international itineraries. the cruise line pays the fee for this inspection, based on tonnage. ships are inspected for food and water sanitation, disinfection of spas and pools, personal hygiene and practices of employees, pest control, general cleanliness, the physical condition of the ship, surveillance for acute gastrointestinal disease, and other factors. a score of at least (out of ) is necessary for a ship to pass inspection. up-to-date sanitation inspection scores of cruise ships are available on the vsp web site and are published monthly in the "summary of inspections of international cruise ships" (green sheet). in general, lower inspection scores correlate with lower sanitation standards, but cannot provide an estimate for risk of acquiring gastrointestinal disease on the ships. other than age requirements, all international passenger conveyances bound for the united states are legally required to report, at least hours before arrival, onboard cases with certain febrile syndromes suggestive of a communicable disease, as well as any deaths. these reports are received and investigated by cdc's quarantine stations, located at major u.s. ports of entry or land border crossings, and operated by the cdc division of global migration and quarantine in atlanta, georgia. under federal quarantine regulations, the cdc quarantine stations have the authority to isolate, quarantine, and conduct medical surveillance of person(s) who are infected with, or exposed to, any of the communicable diseases listed in an executive order signed by the president of the united states. this list can be updated as new public health threats emerge. diseases on the list include cholera, diphtheria, infectious tuberculosis, plague, suspected smallpox, yellow fever, and viral hemorrhagic fever. recent additions include severe acute respiratory syndrome (sars) and influenza due to novel viruses with pandemic potential. although regulations provide an important framework for cruise health and sanitation, the cooperation of the cruise industry is crucial in establishing a safe and healthy environment on cruise ships. with this goal, clia, which recently merged with the international council of cruise lines, monitors and participates in domestic and international maritime policy development, and accordingly sets compliance standards among its member cruise lines (which represent the majority of the north america cruise industry). some of the clia's requirements of its member cruise lines include measures to ensure prevention of marine pollution, appropriate work environment for the crew, waste management, and ship safety and security. clia member cruise lines follow and exceed the "health care guidelines for cruise ship medical facilities," developed by the american college of emergency physicians (acep) section on cruise ship and maritime medicine. this acep section is composed of physicians actively involved in cruise ship medicine. their objective is to advance the capabilities of cruise ship medical facilities and the quality of medical care provided aboard cruise ships. the guidelines address standards for medical facility design, medical staff qualifications, diagnostic equipment, and formulary selection, with a goal of providing general and emergency medical services to passengers and crew. medical care aboard cruise ship is designed to provide cruise line passengers and crew members with timely access to comprehensive services for minor to severe illness and injury. the international maritime requirement to have a doctor aboard ship is actually determined by the size of the crew. only vessels with or more crew members on an international voyage of days or more are required to sail with a physician. no international maritime regulations require a doctor to be aboard ship specifically for passenger medical care. the availability of doctors and nurses aboard cruise ships for passenger medical care are a result of the maritime requirements for crew medical services. in reality, the provision of services to both crew members and passengers by medical staff has become the standard within the cruise industry to meet the needs and expectations of all people onboard the vessel. , cruise ship physicians are recruited from countries worldwide. employment by a particular cruise line may be dependent upon the doctor's nationality, as per the ship's flag state regulations, or the company's own hiring preferences. all physicians must meet the qualifications for appointment as a ship's medical officer. this typically includes an unrestricted medical license, medical board certification, years of clinical experience post medical school, competence in advanced life support and minor surgical skills, and fluency in the official language of the cruise line. cruise ship nurses have comparable requirements for employment. the number of medical staff aboard any particular ship is dictated primarily by the total number of people aboard ship. this can range from a lone doctor for a small ship of people to a medical staff of two physicians and five nurses for a mega-ship carrying more than , passengers and crew members. the medical facility aboard a modern cruise ship is designed to provide essential medical services within the space constraints of an ocean-going vessel (see infirmary photo). most of the medical conditions that arise aboard ship can be treated as they would be at a doctor's office or ambulatory care center at home. the infirmary is staffed several hours a day for routine medical evaluations. the medical staff is also available hours per day to respond to medical emergencies. more serious problems (such as myocardial infarction, respiratory distress, or cerebrovascular accidents) may require emergency evacuation to a fully staffed and equipped shore-side hospital after the patient is stabilized in the ship's medical facility. accordingly, one should view a ship's medical facility as an infirmary or sickbay and not a full-service hospital. basic specifications for medical equipment and drugs from the imo and the international labour organization require a "medicine chest" that includes the "international medical guide for ships" and the "list of essential drugs" published by who. , these regulations are aimed more toward the ship's master or other "medical person in charge" on smaller vessels without a doctor onboard. in addition, flag states may regulate supplemental equipment and supplies. however, the equipment and formulary found on a modern cruise ship are much more complex and comprehensive than the basic medicine chest, the result of an evolutionary process to optimize passenger and crew medical care. the specific needs of any particular ship are based on several factors, including the ship's size, total passenger and crew count, mean age, and baseline health status of those on board, and the destination and duration of the cruise. , the cruise lines have organized their medical departments on the basis of these factors and acep and other cruise industry guidelines. most modern cruise ships are equipped to perform a variety of laboratory tests (which may include complete blood count, blood sugar, electrolytes, chemistries, cardiac enzymes, pregnancy testing, and urinalysis), radiography, cardiac monitoring, and advanced life-support procedures. the ship's formulary includes medications for treating common medical problems and a variety of more serious conditions, including infections, injuries, respiratory distress, and cardiac disorders. the spectrum of illnesses occurring aboard cruise ships is broad and can vary depending on the demographics of passengers and crew on board. two studies involving retrospective reviews of cruise ship medical logs showed that about half of all passengers seeking care aboard cruise ships were older than age years. respiratory tract infection was the most common diagnosis, followed by injuries, nervous system problems (e.g. seasickness), and gastrointestinal illness. , about % of illnesses on cruise ships were not considered serious or life threatening, but of those which were, asthma, arrhythmia, angina, and congestive heart failure were among the most common. more than % of ill persons seen by the medical clinic were treated on board. the rest required either temporary or permanent disembarkation (before completion of the cruise) for shore-side medical care. , one study estimated that on an average cruise ship voyage, a medical facility can expect to encounter a potentially serious illness or injury four times and have a patient disembark for medical reasons once. antibiotics were the most frequently prescribed prescription medication on cruise ships. the risk of exposure to an infectious disease on a cruise is hard to quantify due to limited epidemiologic data and the wide range of environmental exposures that occur during cruise travel. documented outbreaks of infectious diseases abroad cruise ships have been most commonly related to gastrointestinal (norovirus) and respiratory infections (influenza, legionella). , clusters of illnesses related to vaccine-preventable diseases (other than influenza) such as rubella and varicella have also been reported in recent years. , upper respiratory tract infections are the most frequent diagnosis in cruise ship infirmaries, accounting for approximately % of passenger visits. the semiclosed and crowded environment of cruise ships may allow for increased person-to-person transmission of respiratory viruses. in addition, ship resources such as contaminated whirlpools or water supply, and even infected crew or passengers remaining on board for multiple voyages, may serve as reservoirs for respiratory pathogens, causing continuous transmission of illness on consecutive cruises. , the two most frequently documented etiologic agents of cruise ship-related pneumonia outbreaks are legionella and influenza viruses. , legionnaires' disease cruise travel-related legionnaires' disease may occur for several reasons. first, a large percentage of cruising passengers are of advanced age and may have underlying illnesses, placing them at a higher risk for this disease than the general population. second, cruise travel may involve high risk environmental exposures, such as potable water systems or cooling towers at ports of call in tropical climates. third, the ship's complex water system may fail in design, maintenance, or disinfection, leading to bacterial growth in the water supply, air conditioning, or whirlpools. , public health investigations often have difficulty linking a case of legionnaires' disease to a particular cruise ship due to delayed case detection and multiple exposures encountered during a cruise vacation. as a result of the long incubation period ( - days) of legionnaires' disease, cruise ship-associated clusters may go undetected because passengers may not develop symptoms until they have returned home. once symptoms do develop, physicians may not suspect or confirm the diagnosis of legionnaires' disease nor associate it with cruise travel. furthermore, even if a diagnosis is made, fewer than an estimated % of legionnaires' disease cases in the united states are reported to local or state public health departments, although reporting is legally required. upon case detection, public health investigators face several challenges in pinpointing the origin of travel-related legionnaires' disease. passengers on a particular cruise ship may have been exposed to multiple pathogen reservoirs, such as hotel showers, during port stops, as well as before and after cruise travel. moreover, firm linkage to a source requires isolation of the pathogen both from the suspected environment and from clinical specimens, which may no longer be available at the time of the public health investigation. the first passenger ship-associated case of legionnaires' disease was reported in . since then approximately incidents involving about cases were documented as of . in about % of these outbreaks, the ship's infectious source was not determined or reported. the most commonly established causes of the outbreaks included contamination of ship's water supply, air conditioning system, or spa pool. , the largest documented culture-confirmed cruise ship outbreak of legionnaires' disease occurred in . it involved a total of passengers during nine separate sailings of the same ship. illness due to infection through bacteria-laden aerosols generated by the spas was associated with immersion in, and spending time around, the whirlpool. the risk increased by % for every hour spent in the spa water and % for every hour spent around the spa. the same strain of legionella pneumophila serogroup was isolated from the sand filters of the whirlpool spas and a clinical respiratory specimen, pointing to inadequate bromination of the ships' three whirlpool spas as the cause for the outbreak. no cases were discovered in the crew, most likely due to their lack of exposure to the spas and younger age. this outbreak was detected months after it began, when a new jersey physician notified the state health department that three hospitalized patients with atypical pneumonia had been on the same cruise ship, which highlights the delay in detection of cruise-associated legionnaires' disease. in another, smaller, outbreak, three cases of legionnaires' disease were detected on two separate voyages of one ship in the autumn of and . a hot water supply contaminated with l. pneumophila serogroup was found to be the outbreak source. past cruise ship outbreaks of legionnaires' disease and better knowledge about legionella ecology have led to improvements in cruise ship prevention measures: design optimization of water-containing equipment, and standardization of disinfection, as well as maintenance, of spas and water supplies reduce the risk of bacterial growth and colonization. clinicians can also play an important role in the control of cruise travel-related legionnaires' infection through rapid case detection among pneumonia patients by ▪ inquiring about travel history, including cruise travel; ▪ performing appropriate diagnostic tests (both rapid and culturebased tests); and ▪ promptly reporting cases to state and local health departments. influenza influenza a and b outbreaks among cruise ships crew and passengers can occur throughout the year, even when seasonal influenza activity is absent in the region of the cruise. , the convergence and intermingling of international crew and passengers from parts of the world where influenza is in circulation, can lead to the introduction and rapid spread of influenza aboard ships. substantial morbidity may result from cruise influenza outbreaks due to the presence of a large percentage of elderly and chronically ill passengers, both of whom are at higher risk for complications and death due to influenza infection. , in september , an influenza outbreak occurred among passengers and crew aboard a cruise ship during several sailings between new york and montreal. the associated acute respiratory illness (ari: cough and/or sore throat) affected % of the crew ( of ) and % of , surveyed passengers, % ( ) of whom were age years or older and % ( ) had chronic health conditions. investigators found that the number of persons who sought treatment for respiratory illnesses from the ship's infirmary greatly underestimated the true magnitude of the outbreak. although this cruise was in the northern hemisphere, the isolated influenza a (h n ) strain was thought to have been introduced by travelers from the southern hemisphere, where influenza was in season and the implicated strain was circulating. this outbreak was contained through surveillance, isolation of cases, vaccination of crew member, antiviral prophylaxis and treatment of both crew and passengers, and other public health control measures. a more sustained outbreak occurred among land-and sea-based tourists to alaska and the yukon during the summer of , when % of an estimated . million tourists entered the region by cruise ship. some of these passengers also participated in overland tours. tour operators and returning travelers alerted public health officials about the increased risks of acquiring ari and pneumonia. reviews of cruise ship passenger medical logs revealed ari rates two to three times the rate of . visits per , passengers. this led to intense public health surveillance at multiple sites, including local hospitals, clinics, and cruise ship infirmaries. the surveillance ultimately revealed , cases of ari, including , influenza-like illness (ari and fever of ° f or . ° c or self-reported fever) and cases of pneumonia. most cases were among tourists and tourism workers (representing and countries, respectively), and only a small percentage were among alaska residents. the isolated influenza a (h n ) virus was the predominant circulating strain during the previous influenza season in the united states and canada. it was unclear if the virus was still circulating among alaskan residents and infected susceptible tourists or if infected tourists from the southern hemisphere (where the influenza season was ongoing) introduced this outbreak. despite control measures, the outbreak lasted for months due to a large weekly influx of susceptible overland and cruise ship tourists, ending only after the completion of tourism season. during the summer of , an increase in ari again occurred among tourists to the same region, prompting year-long surveillance. it also resulted in cdc's releasing the "preliminary guidelines on prevention, surveillance and control of influenza-like illness (ili) aboard cruise ships," compliance with which is voluntary for cruise lines. influenza b outbreaks have occurred more recently. in one outbreak during the summer of , a baltic cruise from the united kingdom carrying passengers primarily from the united states had a much greater ari attack rate among the crew ( % of ) than the passengers ( % of , ) . , confirmed cases initially tested negative by rapid influenza testing (designed to detect a and b strains). the final diagnosis of influenza b was made by viral culture and immunofluorescence antibody of nasopharyngeal specimens. the index case was found to be a passenger who boarded the ship ill and remained in her cabin except for meals, passing on the infection to both her cabin and dining room stewards. other crew members became infected by socializing or sharing cabins with the ill crew members, leading to the higher attack rate among crew than among passengers. this outbreak demonstrates the potential for person-to-person transmission of the influenza virus between passenger and crew. it also highlights the importance of appropriate isolation of ill persons and use of infection control precautions in preventing and controlling outbreaks, especially in crowded and confined settings such as cruise ships. prevention of influenza outbreaks aboard cruise ships involves joint efforts from the cruise industry, public health agencies, and the traveling public. cdc guidelines suggest that cruise lines should ensure yearly influenza vaccination of at least % of crew per ship. in addition, to ensure early recognition of an outbreak, ships should conduct surveillance for ari and ili, perform appropriate rapid influenza testing, expeditiously report suspected outbreaks to public health authorities, and implement control measures such as isolation, infection control, and treatment with antiviral medications, if warranted. clinicians can also play an important role in preventing influenza and other respiratory disease outbreaks aboard ships by ▪ asking travelers to refrain from traveling while ill and if illness develops during the trip, to practice respiratory hygiene and minimize contact with other people, including the cruise staff; and ▪ providing vaccination (or rarely, antiviral medications) as prevention, especially to high-risk populations as well as their close contacts, and those traveling in large tour groups, even if travel occurs during summer. the estimated likelihood of contracting gastroenteritis aboard a -day cruise is less than %. , gastrointestinal (gi) disease accounts for fewer than % of passenger visits to the ship's infirmary. cruise outbreaks of gastroenteritis due to bacterial and viral pathogens, particularly noroviruses (nov), are well recognized. , as a matter of fact, the number of outbreaks of gastroenteritis on cruise ships has increased significantly in recent years due to nov. acute gastroenteritis (age) outbreaks per cruises increased almost tenfold from to ( . to . ). a recent who review documented shipassociated food and waterborne outbreaks from to . data from outbreaks revealed , ill persons, hospitalizations, and deaths. however, these reported outbreaks were thought to underestimate the true incidence of gastrointestinal illness aboard cruises due to underdetection of cases. ill passengers may not seek care in the ship's infirmary for fear of ruining a vacation or other impositions, and ill crew may not present themselves due to concerns of losing income during isolation or premature disembarkation. a review of data from cruise ship waterborne diseases outbreaks during the period - showed that enterotoxigenic escherichia coli (etec) and nov are the two pathogens most frequently linked to cruise ship waterborne gi outbreaks. consumption of ice from contaminated water bunkered by cruise ships at non-u.s. ports, with subsequent onboard water treatment failure have resulted in number of etec outbreaks. in addition, factors such as crosscontamination of potable water with bilge water and ice machine contamination from failure of backflow prevention devices have resulted in nov gi outbreaks. more commonly, however, nov may not be implicated in waterborne disease outbreaks because of the difficulty in detecting nov in environmental samples. moreover, nov are more resistant to chlorination than enteric bacteria and require higher levels of residual chlorine levels to prevent outbreaks. other organisms that may cause waterborne gi outbreaks on cruise ships include salmonella spp, shigella sp, cryptoporidium sp, and giardia intestinalis. however, the specific cause cannot be identified in about one quarter of outbreaks. an outbreak of brainerd diarrhea was associated with consumption of unbottled water, ice, and raw sliced fruit and vegetables aboard a cruise to the galapagos islands in . deficiencies in the ship's water handling and chlorination may have contributed to this outbreak of chronic diarrhea among passengers. cruise ships can prevent waterborne disease outbreaks by ensuring that water is obtained from safe and reliable sources at ports and stored safely; loading water properly at ports to avoid cross contamination; conducting extra disinfection treatments of water if it is suspected to be contaminated; monitoring residual disinfectants in distribution systems; and ensuring performance of regular inspections and maintenance of the ship's potable water systems. an epidemiologic review of cruise ship foodborne disease outbreaks that occurred from through showed that % were caused by bacterial pathogens and the rest by viruses, parasites, or unknown sources. salmonella spp was the most common etiologic agent of cruise ship foodborne outbreaks, causing more than one quarter of the outbreaks. other common pathogens included enterotoxigenic e. coli (etec) ( % of outbreaks), shigella spp ( %), vibrio parahaemolyticus spp ( %), and nov ( %). outbreaks have resulted more rarely from staphylococcus aureus, vibrio cholerae, clostridium perfringens, trichinella spiralis, and cyclospora spp. seafood (causing % of outbreaks) has been the most commonly implicated food vehicle, followed by salads, poultry, eggs, and red meat. however, a contributing factor could be identified in fewer than half of all outbreaks. those identified factors most frequently included inadequate temperature control, infected food handlers, and contaminated raw ingredients. cruise dining typically offers elaborate meals consisting of a large assortment of foods, which usually involve preparation by multiple food handlers and in many steps, resulting in an increased chance of food mishandling and contamination. furthermore, meals are served to a large population in a short time, likely leading to a time gap between the preparation and serving. inadequate temperature control of foods during this time can allow bacteria to grow. for example, in a s. aureus gastrointestinal illness outbreak aboard a caribbean cruise ship, the suspected food was pastries, which were believed to have been contaminated during preparation. the same strain of s. aureus was detected from several food handlers and cases. additionally, possible subsequent storage of the pastries at warm temperatures led to the production of enterotoxin, which caused illness among passengers. to reduce the risk of foodborne outbreaks cruise ships should ensure that food (especially shellfish) is thoroughly cooked, use pasteurized eggs, cater shore-side meals rather than using local sources, and exclude ill food handlers from food preparation. norovirus from to , the incidence of outbreak-related diarrheal disease cases on cruise ships decreased from . cases per , passenger days to . cases per , . this decline was associated with improved sanitation aboard ships, as vsp inspection failure rates dropped from almost % in to about % in . however, during the period to , despite good environmental health standards on cruise ships, the incidence of outbreak-related diarrheal disease rose to cases per , passenger days. in fact, the total number of reported gi outbreaks on cruise ships increased from in to in . this increase in gi outbreaks as well as the frequency of age cases on cruise ships was attributed to noroviruses (nov). outbreaks of nov typically occur during the fall and winter months. however, during the summer of , the incidence of nov outbreaks peaked with the emergence of a previously unidentified strain called "farmington hills" (genogroup ii cluster nov). this was also the predominant circulating strain on land, causing % of the outbreaks. , this strain caused gi outbreaks on as many as six consecutive cruises, despite sanitation measures. it even resulted in a nursing home outbreak linked to an infected resident who returned from cruise travel. nov are the most common cause of viral gastroenteritis on cruise ships and age in the united states, with million cases yearly. nov are transmitted by fecal-oral route, directly person to person, from contaminated food and water, or by contact with contaminated surfaces or objects. aerosolized vomit has also been suspected as a mode of transmission. during cruise nov outbreaks, the original source of infection may be an infected person or food. further spread, resulting in large numbers of illnesses, mainly occurs by person-toperson transmission of the virus. most nov outbreaks can be characterized by having high attack rates, high prevalence of vomiting, short duration of illness, and an absence of identifiable pathogen on culture. recurrences of nov cases on consecutive cruises are common due to the virus' low infective dose, combined with its persistent reservoir; cruise staff remaining onboard during multiple voyages; and a contaminated cruise environment, which is difficult to disinfect with routine sanitary measures. , , furthermore, studies to identify effective disinfectants are difficult due to the lack of a nov culture system, making efficient decontamination even more challenging for the cruise industry. the key to controlling the spread of nov on cruise ships is the rapid implementation of control measures at the first signs of an age outbreak. in fact, each cruise line has detailed operational directives, based on cdc-recommended control measures, on how to deal with a pending or actual gastrointestinal outbreak. for example, routine cleaning is conducted when age affects fewer than % of passengers or crew. if the percentage affected reaches % or more (outbreak likely or in progress) or there are six or more cases in one day, the captain is notified immediately and a decision may be made to escalate sanitation measures. some examples of cdc-recommended nov control measures include strict application of food and water sanitation measures; prompt disinfection with suitable disinfectants (e.g. chlorine solutions at concentrations of at least , ppm, phenol-based compounds, and accelerated hydrogen peroxide products); and isolation of ill passengers and crew for - hours after clinical recovery. typically, the captain gives printed instructions to the passengers about illness prevention and control measures to be followed. these may include hand washing tips and a recommendation to seek medical care in the ship's infirmary as soon as gi symptoms develop. this letter also lists sanitation measures being undertaken by the ship, such as frequent cleaning of common areas, staterooms, elevator buttons, and hand rails. in addition to influenza, cruise ships have had outbreaks of other routine vaccine-preventable diseases (vpd), such as rubella and varicella. most often, such illnesses are traced to crew originating from countries in which immunity to routine vpd may be low. for example, susceptibility rates to rubella range from % to % in countries without a routine rubella vaccination program. the densely populated environment of cruise ships and the social interactions among crew and passengers allow for person-to-person spread of vpd among susceptible persons. in the united states an estimated % of women of childbearing age are susceptible to rubella. of the pregnant women infected during the first weeks of gestation, up to % of the infants will be born with congenital rubella syndrome (crs); the rate of crs for infants born to women infected during the first weeks of pregnancy is %. hence, women of childbearing age (i.e. - years), particularly pregnant women, along with other potentially susceptible groups of cruise travelers, such as the elderly, immunosuppressed, and children, need to check their immune status to routine vpd before travel. in , the cdc investigated two outbreaks of rubella among crew members on two cruise ships sailing from florida to the bahamas. in one outbreak, ( %) of crew members tested were found to have a positive igm for rubella. of these sixteen crew members with an acute rubella infection, % were asymptomatic. an additional % of tested crew members proved to be susceptible to infection. approximately % of crew members were born outside the united states (representing more than different countries), and % had no known immunity to rubella or had a negative antibody result on testing. although no cases appeared among passengers in either outbreak, a survey of , passengers on one of the cruise ships found % to be u.s.-born, % to be of childbearing age, and . % to be pregnant (half being in the first trimester), demonstrating the susceptibility of passengers to rubella. this outbreak was controlled by administration of measles-mumps-rubella (mmr) vaccine to crew members without documented immunity to rubella, active surveillance aboard the cruise ship for new rubella cases, and notification of all passengers at risk for exposure to rubella on the cruise ship. another outbreak of varicella aboard a cruise ship in revealed similar trends in vpd risk among the crew, with % being infected or susceptible, most being foreign-born (especially from tropical countries). persons are immune once they develop varicella, so the risk of infection decreases with age. in tropical areas, however, varicella typically occurs among adults, who are at risk of developing more severe disease. special attention should be given to immunocompromised persons among susceptibles, and they who should receive specific varicella-zoster immune globulin (or intravenous immune globulin if specific ig is not available) within hours of exposure. the cdc quarantine stations receive case reports from u.s.-bound ships of other communicable diseases (mostly among crew) such as measles, mumps, tuberculosis, typhoid, and hepatitis a and b. after respiratory infection, injuries are the second most common reason for passengers to seek medical care aboard cruise ships, accounting for % of infirmary visits. the most common injuries seen are sprains, contusions, and superficial wounds. reported cruise-related injuries most frequently occur on decks and stairs, in passengers' own cabins, or ashore during port calls. most cruise itineraries tend to be in the calm waters of the caribbean or the mediterranean. modern cruise ships are also constructed with roll stabilizers, which minimize turbulence. even so, sea sickness is a common concern of many cruise travelers and is among the top four reasons for infirmary visits. some passengers are sensitive to motion and require pharmacologic prevention and treatment with antihistamines, antimuscarinic, or antidopaminergic agents. alternative medicines may also help some individuals (for more information on sea sickness, see chapter ). the association between passenger cabin location and risk of motion sickness is controversial, but common perception persists that central cabins are the least sea sickness-inducing. a recent study found that cabin location is only associated with the risk of sea sickness when the passenger is seated or standing. passengers who are able to readily lie down can reduce their risk for motion sickness irrespective of their cabin location. pre-travel health preparation for cruise travel can be challenging because of planned visits to multiple countries and participation in a variety of shipboard and shore-side activities. in making health risk assessments, health-care providers should consider a broad range of issues. these include the travelers' health condition and immunity to routine vpd including influenza, the need for special immunizations and chemoprophylaxis based on the cruise ship's itinerary, and health-related risk behaviors during cruise travel. , , (see table during pre-travel counseling, clinicians should carefully review the traveler's medical conditions to assess if the person can endure the stress of travel and whether the person has any special health needs, for example, wheelchair access, oxygen, or dialysis. , cruise travel can expose travelers to infectious agents, pollutants, changes in diet, physical exertion, extremes of weather, and other conditions that can exacerbate chronic medical conditions. however, cruise tours are available that provide care by onboard specialists, such as pulmonologists and nephrologists, for persons with certain physical impairments, such as chronic obstructive pulmonary disease (copd) and renal failure requiring hemodialysis. travelers with medical conditions should be advised to contact and make arrangements with the cruise line about their specific medical needs before departure. , cruise ships built during the past years generally have cabins designed to accommodate wheelchairs. information regarding wheelchair access can be obtained from the individual cruise lines or the clia web site. , depending on the medical condition, some cruise lines may require that the traveler have a travel companion. cruise travelers can also verify a cruise ship's sanitation level and learn about ongoing or recent gi outbreaks through the cdc's vsp web site. , medical facilities on most modern cruise ships are comparable to those of a community urgent care center. however, limitations and variability exist between cruise lines and individual ships -and at shore-side hospitals during port stops -in the level of care available. , for this reason and to protect the health of others on board, passengers with acute medical complaints or those who acquire an infectious disease before travel should be encouraged to postpone travel and call the cruise lines to discuss alternatives. regardless of age and underlying medical conditions, all passengers should be up-to-date for routine age-appropriate vaccinations (see table . ). , given previous cruise ship outbreaks of vpd such as rubella, chickenpox, and influenza, immunity to these diseases should be ensured, especially in high-risk populations (e.g. elderly, immunosuppressed, or pregnant women). , , consideration for influenza vaccination should be given, especially to travelers at high risk for complications from influenza infections and their close contacts, or those who will be traveling with a large group (any time of the year) or visiting the tropics or the southern hemisphere during april to september. however, influenza vaccine may be largely unavailable in north america during the summer months. therefore, clinicians may consider prescribing a recommended antiviral medication for treatment or prophylaxis of influenza for high-risk patients. the traveler's planned itinerary -which countries will be visited, duration of stay, and shore-side excursions and activities -provides crucial insights for determining the need for special immunizations (such as typhoid, rabies, yellow fever, japanese encephalitis, and meningococcal) and chemoprophylaxis (e.g. for malaria and influenza). if warranted by location of shore-side stays and outdoor activities, travelers should be advised to include mosquito and sun protection in their travel kit (for more information on travel kits, see chapter ). travelers, especially those with known health conditions, should carry a written summary of essential health information which would facilitate their care on board or at a shore-side hospital during a medical emergency. this personal medical information sheet (sample available in reference ) should include information on the traveler's demographics, allergies, chronic conditions, blood type, medication list, contact information of the physician and next of kin, and medical and travel insurance information. , important laboratory information, such as an ecg or chest radiograph, if abnormal, should also be attached to the medical information sheet. , all prospective cruise travelers should be strongly advised to contact their health insurance carriers in advance of travel and to consider purchase of additional insurance to cover reimbursement for medical evacuation and health services in foreign countries. , , often, gaps in regular coverage require the additional travel insurance, which can often be found in a travel package offered by cruise lines, usually costing %- % of the total package price. however, if only supplemental medical evacuation insurance is needed, the cost can be as low as $ per person for year of coverage. clinicians should remind cruise travelers to exercise health-conscious behavior during their journey. travelers should use caution in selecting the food and water they consume and should practice good hygiene (wash hands, cover coughs and sneezes, etc.) to reduce their risk of getting ill from an infectious disease (see table . ) . , passengers should ensure that food they consume is thoroughly cooked, inquire if pasteurized eggs were used for foods requiring a large number of eggs as ingredients (e.g. custards or flan), and evaluate the risks of eating food off the ship at ports. they should be encouraged to follow the rule of "boil it, peel it, cook it, or forget it." during shore-side excursions, pre-packaged foods should not be kept for long hours at unsuitable temperatures, and passengers should drink bottled water. , practicing good hand and respiratory hygiene is important in preventing illnesses that are transmitted from person to person, either by direct contact, by respiratory routes, or through contaminated environments. , after travel passengers should be urged to follow up with their health-care provider for any fever or flu-like illness that develops up to a year after travel. clinicians should inquire about cruise travel in all cases of pneumonia, other respiratory illnesses, gastrointestinal illnesses, or suspected communicable disease. appropriate diagnostic testingboth rapid and culture-based-better enables public health investigations to link an illness to a source. viral isolation (via nasopharyngeal specimens) is essential to identify new and unusual imported strains of influenza and other respiratory pathogens. , clinicians can help enhance surveillance and characterization of cruise ship-associated illnesses by identifying and reporting notifiable diseases or conditions and possible clusters of diseases to public health agencies. insect repellent (based on itinerary and shore-side activities) (same resources as above) adequate supply of all medication written personal medical information (include patient demographics, health and travel insurance, contact information of health-care provider and next of kin, medical history, current medications and pertinent lab data (ekg) routine immunizations, if not up-to-date other immunizations if indicated (based on itinerary) malaria prophylaxis if indicated (based on itinerary) influenza antiviral medication (based on risk assessment) guidance about mosquito prevention guidance about sun protection travel advice -pre-travel health preparation, during travel healthy habits, and after travel follow-up (table . ) conclusion since , the north american cruise industry has seen an average annual passenger growth rate of . %. and the popularity of cruise travel is expected to continue to grow, reaching an estimated . million cruising passengers in . the occurrence of shipboard illnesses and outbreaks related to gastrointestinal, respiratory, and vaccine-preventable diseases has led to improved infectious diseases surveillance and control strategies by the cruise industry and public health agencies. , , pre-travel health preparations and knowledge of available medical care aboard cruise ships are important for cruise travelers, especially given that approximately one third are senior citizens who may have chronic illnesses or who may be at greater risk for some infectious diseases. because medical facilities aboard cruise ships are designed to provide basic emergency medical care, travelers should be encouraged to consult their health insurance provider regarding extra coverage while away from their home country and for medical evacuation. during travel (while on cruise and on-shore): to prevent getting food-and water-borne diseases ensure all food consumed is thoroughly cooked inquire about use of pasteurized eggs for foods with eggs as main ingredient (e.g. flan, omelets) evaluate the risks of eating any food, especially off the ship ensure correct temperature of cold and hot foods ensure pre-packaged food for shore-side excursions is stored at appropriate temperature to prevent spread of germs follow good hand hygiene: wash hands frequently with soap and water if soap and water not available, alcohol-based disposable wipes or gel sanitizers containing at least % alcohol may be used follow good respiratory hygiene: cover mouth and nose with tissue when coughing or sneezing if tissue not available, cough or sneeze into upper sleeve, not hands put used tissue in waste basket avoid close contact with people who are sick be sure to report illness to cruise staff if they are unaware stay well hydrated by drinking water get plenty of rest avoid excessive alcohol intake report to doctor for illnesses especially with fever or respiratory or symptoms new york: cruise lines international association (us) london: passenger shipping association brief history of the passenger ship history travelers' health: yellow book. health information for international travelers available from: www .ncid.cdc.gov/travel/yb/utils/ybget. asp?section=transportation&obj=cruise.htm&cssnav=browsecyb infectious diseases on cruise ships cruise ships: high-risk passengers and the global spread of new influenza viruses outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominant circulating strain of norovirus-united states norovirus transmission on cruise ship outbreak of legionnaires' disease among cruise ship passengers exposed to a contaminated whirlpool spa outbreaks of gastrointestinal diseases on cruise ships: lessons from three decades of progress international convention for the safety of life at sea (solas) available from: www.imo.org./home.asp?flash=false the contribution of the north american cruise industry to the us economy in business research and economic advisors for international council of cruise lines (us) the cruise industry economic summary cruise lines international association (former international council of cruise lines) (us); [date unknown travel health at sea: cruise ship medicine cdc vessel sanitation program regulation, representation and the flag market top merchant fleets of the world, flag registry united states department of transportation maritime administration investigation and management of infectious diseases on international conveyances (airplanes and cruise ships) international infectious disease law-revision of the world health organization's international health regulations sanitation on ships: compendium of outbreaks of foodborne and waterborne disease and legionnaire's disease associated with ships cruise industry source book- edition virginia): cruise lines international association national center for environmental health. vessel sanitation program atlanta: centers for disease control and prevention, department of health and human services (us) health care guidelines for cruise ship medical facilities american college of emergency physicians, section on cruise ship and maritime medicine ilolex: database of international labour standards ilo convention (no. ): health protection and medical care for seafarers evaluation of emergency air evacuation of critically ill patients from cruise ships descriptive epidemiology of injury and illness among cruise ship passengers anatomy of a world cruise sea, wind and pneumonia legionellosis associated with ships: to . comm dis public health legionnaire's disease on a cruise ship linked to the water supply system: clinical and public health implications a large outbreak of influenza a and b on a cruise ship causing widespread morbidity large summertime influenza a outbreak among tourists in alaska and the yukon territory preliminary guidelines for the prevention and control of influenza-like illness among passengers and crew members on cruise ships influenza b virus outbreak on a cruise ship-northern europe epidemiology of gastroenteritis on cruise ships epidemiology of diarrheal disease outbreaks on cruise ships a review of outbreaks of waterborne disease associated with ships: evidence for risk management traveler's diarrhea at sea: three outbreaks of waterborne enterotoxigenic escherichia coli on cruise ships an outbreak of brainerd diarrhea among travelers to the galapagos islands a review of outbreaks of foodborne disease associated with passenger ships: evidence for risk management staphylococcal food poisoning on a cruise ship the vessel sanitation program inspection team. diarrheal disease on cruise ships current trends vessel sanitation scores. mmwr outbreaks of gastroenteritis associated with noroviruses on cruise ships-united states epidemiologic notes and reports gastroenteritis outbreaks on two cruise ships. mmwr dealing with gastrointestinal illness on a cruise ship. part : description of sanitation measures. part : an isolation study rubella among crew members of commercial cruise ships-florida, . mmwr control and prevention of rubella: evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital rubella infecton effect of climatic factors and population density on varicella zoster virus epidemiology within a tropical country division of global migration and quarantine, national center for preparedness, detection, and control of infectious disease cabin location and the likelihood of motion sickness in cruise ship passengers atlanta: centers for disease control and prevention cruise ship accommodations for passengers with physical limitations due to disability or age new york: cruise lines international association (us) prevention and control of influenza. recommendations of the advisory committee on immunization practices. mmwr keep health needs in mind atlanta: centers for disease control and prevention, department of health and human services stopping the spread of germs at home, work & school [online]. atlanta: centers for disease control and prevention, department of health and human services key: cord- - y uyf authors: vashishtha, vipin m.; john, t. jacob; pothapregada, sriram title: correspondence date: - - journal: indian pediatr doi: . /s - - - sha: doc_id: cord_uid: y uyf nan however, the academy is capable of going much beyond merely reporting of the cases. we have the expertise to lead investigations and offer solutions regarding diagnosis and management of these 'mystery illnesses'. already, few iap members are involved in the investigations of the ongoing recurring outbreaks in muzaffarpur in their own individual capacity. the infectious disease chapter of iap should come forward and contribute to ongoing investigations. it can organize brain storming sessions on the problem involving all the stakeholders, including state and central agencies. the local pediatricians, usually the iap members, are keys to the success of this endeavor. in fact, the government of india is short of technical advice on many issues pertaining to outbreak investigations and usually depends on multiple agencies -some of their own and some from outsides -for solving the mystery and instituting preventive measures, which ultimately do not go beyond recommending mass vaccination against japanese encephalitis in affected areas [ ] . outbreak investigation in india is in a dismal state. once an outbreak is spotted, usually by the media, the regional and central investigating teams arrive, carry out field survey, collect few biological samples, perform virological investigations, and if no organism is identified, label the outbreak to be caused by an unidentified viral agent [ ] . the problem is each team starts with a fixed mindset and looks for some infective pathology behind every outbreak. there is lack of coordination and synchronization of efforts, and ultimately they waste their energy either duplicating the efforts of others or pursuing a different approach unmindful of other's accomplishment. individual experts start investigating these outbreaks according to their own areas of interests. for example, in an outbreak of aes amongst children in andhra pradesh, india in , the virology group concluded it to be an outbreak of acute encephalitis caused by chandipura virus [ ] and the neurology team claimed the outbreak was caused by a neurovascular stroke called as "epidemic brain attack", not by any encephalitis [ ] . similarly, in muzaffarpur outbreaks, one group claimed it to be caused by heat stroke, and another hinted towards a toxin contained in the litchi, a locally grown fruit [ ] . the current scenario is bit murky and resembles like five blind people describing an elephant. the need of the hour is to adopt a fresh systematic approach with an open mindset. every effort must be made to characterize the clinical entity, whether it is an encephalopathy, encephalitis or a multisystem disease. thorough clinical, biochemical, histopathological and microbiological investigations, and autopsies must be performed to reach at a correct clinico-pathological diagnosis. second stage of investigations should consist of proper epidemiological investigations to identify any risk factor. based on these investigations, further studies that may include detailed toxicology can also be planned. the team should include epidemiologists, pathologists, neurologists, toxicology experts, public health experts and pediatricians. they should report to one designated authority spearheading all these teams. it is definitely possible to crack the mystery behind these recurring outbreaks and put an end to the prolonged ordeal of innocent children. history repeats in bihar, as pointed out by iap president [ ] . the 'mystery disease' recurred annually for decades in the north-western districts, during premonsoon months; it was called 'muzaffarpur encephalitis' first and later acute encephalitis syndrome, as icmr/ncdc failed to find viral etiology. again, a volunteer team (t jacob john, arun shah and mukul das facilitated by nk sinha and guided by maya thomas) investigated the problem. we diagnosed hypoglycemic encephalopathy and have advised bihar health ministry how to investigate etiology and to mitigate the risk factor of undernutrition [ ] . these non-infectious encephalopathy cases can be prevented or treated. in up, public education that cassia occidentalis is poisonous was enough to prevent the disease [ ] . in bihar, early infusion of % dextrose saved lives [ ] . in healthcare, incorrect diagnosis or treatment is medical negligence. in public health, incorrect management is public health negligence -consequent deaths amount to homicide by public health negligence [ ] . state officials believe that outbreak investigation is the responsibility of the central government. in delhi, the view is that health is state subject; states are responsible for diagnosis and prevention. the unfortunate victims are people without voice. india's health management system lacks organization with clear lines of command and is in need of review and repair. iap can serve as advocate, advisor and guide in this regard. we read with interest, the recently published article on the atypical manifestation of dengue fever in children [ ] . the authors have highlighted the occurrence of atypical manifestations like splenomegaly, neurological abnormalities, acute respiratory distress syndrome (ards), disseminated intravascular coagulopathy (dic), diarrhea and myopathy. in this context, we would like to share our experience of the atypical manifestations during the epidemic of dengue fever at puducherry in - . during the dengue fever epidemic, atypical manifestations were seen in children ( . %) and out of them splenomegaly ( . %), biphasic fever ( . %) and diarrhea ( . %) was the most common; . % of children with severe dengue infection had bleeding. the common mode of presentation of severe dengue infection was with features of peripheral circulatory failure ( . %) and hypotension ( . %) without bleeding. ards, myocarditis and dic were seen in four children, five children had encephalopathy and refractory shock, and three children had myositis. ultrasound abdomen showed gall bladder wall edema in % of cases. there were six deaths; common causes for poor outcome were ards, multiorgan failure, dic and refractory shock. since many children of dengue hemorrhagic fever had features of peripheral circulatory failure without volume __ november , correspondence spontaneous bleed, we found it difficult to classify them according to the dengue hemorrhagic fever guidelines given by world health organization in [ ] . our clinical experience suggests a need to relook at the classification of dengue fever and its management guidelines. with recent epidemics showing the changing pattern of presentation, atypical manifestations occur more often than previously reported [ ] . the awareness regarding atypical manifestations of dengue fever is lacking among the health care personnel at primary health centers from where these cases are more often referred. since the case fatality rate in children with severe dengue infection is high, pediatricians have a very important role to play to reduce the disease burden, and the minimum we can do is to update the health care personnel and community at various forums, about the various atypical manifestations of dengue for prompt recognition and management. puducherry, india. psriram_ped@yahoo.co.in misery of mystery of muzaffarpur indian health ministry orders encephalitis vaccination in select districts after more than deaths inadequate research facilities fail to tackle mystery disease a large outbreak of acute encephalitis with high fatality rate in children in andhra pradesh role of chandipura virus in an "epidemic brain attack cassia occidentalis poisoning causes fatal coma in children in western uttar pradesh misery of mystery of muzaffarpur recurrent outbreaks of hypoglycaemic encephalopathy in muzaffarpur disappearance of a deadly disease, acute hepatomyoencephalopathy syndrome, from saharanpur homicide by neglect? uncontrolled pediatric infectious diseases atypical manifestations of dengue fever dengue hemorrhagic fever: diagnosis, treatment, prevention and control. nd edn. geneva: world health organization dengue viral infection in children -a perspective key: cord- -gyilma h authors: shaffer, loren; funk, julie; rajala-schultz, päivi; wallstrom, garrick; wittum, thomas; wagner, michael; saville, william title: early outbreak detection using an automated data feed of test orders from a veterinary diagnostic laboratory date: journal: intelligence and security informatics: biosurveillance doi: . / - - - - _ sha: doc_id: cord_uid: gyilma h disease surveillance in animals remains inadequate to detect outbreaks resulting from novel pathogens and potential bioweapons. mostly relying on confirmed diagnoses, another shortcoming of these systems is their ability to detect outbreaks in a timely manner. we investigated the feasibility of using veterinary laboratory test orders in a prospective system to detect outbreaks of disease earlier compared to traditional reporting methods. idexx laboratories, inc. automatically transferred daily records of laboratory test orders submitted from veterinary providers in ohio via a secure file transfer protocol. test products were classified to appropriate syndromic category using their unique identifying number. counts of each category by county were analyzed to identify unexpected increases using a cumulative sums method. the results indicated that disease events can be detected through the prospective analysis of laboratory test orders and may provide indications of similar disease events in humans before traditional disease reporting. prompt detection of outbreaks might provide for earlier intervention efforts that result in minimizing their overall impact [ ] , [ ] , [ ] , [ ] . some animals are susceptible to infection from many of the same pathogens as humans, sometimes showing signs of disease earlier [ ] , [ ] . therefore, animals might be used as sentinels and provide for earlier recognition of disease outbreaks that could affect humans. as pet animals share much of the same environment as their human owners, they especially might prove to be valuable outbreak sentinels [ ] . most of the current disease surveillance systems used for animal populations are considered inadequate for detecting outbreaks of emerging disease, potential acts of bioterrorism, or outbreaks resulting from pathogens for which the system was not specifically designed for in a timely manner [ ] , [ ] , [ ] , [ ] . such functionality in animal-based systems has been considered important to our overall bioterrorism and disease outbreak preparedness capabilities [ ] , [ ] , [ ] , [ ] , [ ] , [ ] , [ ] . syndromic surveillance methods utilize population health indicators to warn of potential outbreaks earlier than reports of confirmed diagnoses. although many sources of data have been investigated for syndromic surveillance in humans, there is paucity in the literature describing similar studies in animals [ ] . laboratories are recognized as important sources of data for disease surveillance in animals as well as humans [ ] . test orders for specimens submitted to commercial medical laboratories have been utilized as one of the data sources for syndromic surveillance in humans [ ] , [ ] . most of the private veterinary practitioners in the united states also submit specimens to commercial laboratories for diagnostic testing [ ] . through the utilization of data from these commercial laboratories, we might possibly achieve the benefit of the aggregation of many veterinary providers across a wide geographic area. such centralized aggregation of data may be important in detecting certain outbreaks [ ] . the results of a previous investigation conducted by us demonstrated the representation of companion animals in select veterinary diagnostic laboratory (vdl) data and indicated the potential for identifying clusters of cases through analysis of the aggregated orders [ ] . although laboratory analyses are not as frequently a part of the veterinary care of pet animals compared to the medical care of humans [ ] , we hypothesize that the consistency of test orders over time is such that increases in cases of disease will result in detectable increases in the number of test orders submitted by veterinarians that can be identified using prospective analysis. we conducted a prospective study of laboratory orders submitted to idexx laboratories, inc. (westbrook, maine) for specimens originating from veterinary clinics in ohio between september , and november , . idexx transferred once daily to a server located at the real-time outbreak and disease surveillance (rods) laboratory (university of pittsburgh, pennsylvania), via secure file transfer protocol, an automatically generated text file containing records of laboratory orders for specimens received within the previous -hour period. each record included the accession number assigned by idexx to the specimen, date and time that idexx received the specimen, -digit zip code of the clinic submitting the specimen, species of animal, and numerical code/s of the laboratory product/s ordered. we distributed a list of product descriptions ordered during a -week period to ten small and large animal veterinarians asking them to consider the diseases that they might use each product to confirm or rule out during the diagnostic process. the veterinarians then assigned each product to syndromic categories based on the expected presentation of these diseases. eight categories were considered initially: respiratory, gastrointestinal, neurologic, behavioral, dermal, reproductive, non-specific, and sudden death. seven of the ten surveyed veterinarians returned the categorized lists (table ). the behavioral and sudden death categories were subsequently removed based on zero responses from the surveyed veterinarians for these categories. in addition to the surveyed veterinarians, two idexx laboratorians also reviewed the list of products. based on their input and advice, five categories were added to further describe many of those products that had been classified into the non-specific category. these additional categories were endocrine, hepatic, infectious, febrile, and renal. records were mapped to syndromic category based on the identifying number for the laboratory product ordered and appropriately classified as the server received them. we used frequency analysis to describe the representation of species groups and distribution of accessions by day of the week. the percentage of the total daily records included in the dataset for each -hour period was used to describe availability of records. a cumulative sums (cusum) method was used to analyze category counts, as records were received, for each ohio county, as determined by the zip code. the value of the cusum was calculated as ( ) where t x was the observed count at time t, t μ the expected count (baseline), and t σ the standard deviation of the counts used to determine the baseline. daily analysis was performed automatically using the count from the current and previous six days for the observed value. a moving -day period was chosen to reduce the anticipated day-of-week effect in the data. the expected value was calculated by averaging the weekly counts for the previous -week period. we defined alerts as instances when the cusum value equaled or exceeded five. an alert period was defined as at least two consecutive days where the cusum value exceeded the threshold. by using this two-in-a-row rule we were able to somewhat reduce the impact of single-day increases on weekly counts. using this rule has been shown to increase the robustness of cusum methods [ ] . alerts were considered for all syndromic categories except non-specific, which was mostly comprised of general screening tests such as blood chemistries. we investigated alerts by identifying the specific laboratory product or products involved and contacting select veterinarians located in the same area as the alert asking about their impressions of disease activity. veterinarians may or may not have been idexx clients. during the pilot, the daily transfer of data from idexx laboratories was interrupted twice. the first interruption began on september and continued through september . this interruption in data transfer occurred because the workflow involved in the transfer had been unscheduled and the job was mistakenly shut down. the second interruption occurred october through october for unknown reasons. the interruptions affected the transfer of , ( . %) records. idexx forwarded records that were created during these times of interruption once the data feed was re-established providing for a complete time-series. the pilot system relied upon transfer of data from idexx that was being queued in a test environment. the reliability of this environment was knowingly not as stable as a production environment would be. the interruptions experienced during this pilot would not be expected in a more stable production platform. during the study period, idexx transferred records for , accessions. specimens originated throughout ohio and appeared to correlate with the population of each area. accessions displayed an obvious and predictable day-of-week effect ( figure ) with sundays, mondays, and days following holidays representing days with the lowest volume. species represented by the accessions included canine ( . %), feline ( . %), and equine ( . %). an important consideration for the designers of any syndromic surveillance system is the timely availability of data [ ] , [ ] . earlier detection being the overall goal, the system must receive records, with the appropriate information for analysis, within a period that provides for improved timeliness of detection compared to traditional reporting systems. excluding the accessions that occurred during the interruption periods (n= , ), on average, % of daily records were received with the next day's dataset ( figure ). almost all ( . %) records were received by the fourth -hour period. the system identified nine alert periods during the study period using the cusum detection method as previously described. all of the alerts involved canines and/or felines. the number of accessions generating the alerts ranged from eight to . no cause could be determined for three of the nine ( . %) alert periods and two ( . %) were possibly related to breeding operations that existed in the area (e.g. screening of litters for pathogens). two ( . %) others were potentially the result of provider interest. one veterinary practice located in an area where a gastrointestinal alert occurred reported being especially interested in educating clients about the risks from parasite ova. another provider in an area where an endocrine alert occurred had recently been ordering an increased number of thyroid tests that were unrelated to increases in clinical disease. the remaining two ( . %) alert periods were linked to verified disease activity in the pet population during the time of the alert. september , to inquire about a number of clients that had brought their pets presenting with vomiting and diarrhea (nancy niehaus, lake county health department, personal communication). these clients had shared with the local veterinarian that they also were experiencing diarrhea. the lake county health department reported on october , that they were investigating "a cluster of diarrheal illness in humans and their associated pet dogs." the primary purpose of this study was to explore the feasibility of using prediagnostic data from a vdl in a prospective manner to detect unexpected increases in the number of disease cases that might indicate an outbreak. we evaluated the feasibility by first determining the stability of electronic records and the success of automatically transferring them from the vdl for analysis, measured in terms of the percentage of complete records received in a timely manner. we then considered the representation of the records both by species of animal and geographic distribution. finally, we investigated the alerts generated by the pilot system to validate if they might be associated with increases of disease. while no single data source provides the capability to detect all outbreaks that may occur, veterinary providers may be desirable sources to include in surveillance activities for bettering our capabilities of detecting those outbreaks that result from emerging pathogens and potential bioweapon agents [ ] , [ ] , [ ] , [ ] , [ ] . the change in the number of laboratory orders submitted by veterinary providers may be a valuable proxy to measure the number of individual cases they are treating. an increase in the number of these individual cases may result from an outbreak, detection of which may be possible through the analysis of aggregated laboratory orders counts from several providers in the outbreak area. there are inherent biases to consider with using laboratory data. laboratory testing in veterinary medicine is not as frequently used as in human medicine [ ] . severity of clinical disease and cost benefit are two factors that influence the use of laboratory testing for animals [ ] . severity of clinical disease as an influence on testing may provide for increased specificity since only animals with true disease/condition are included. as demonstrated in this study, the interests of the providers may also contribute to the potential biases encountered. the consistency of the veterinarians' ordering behavior may help to control some bias by recognizing the effects in the counts over time and how they contribute to the normal baseline (i.e. expected number of test orders). the results of this study demonstrated the stability and timely availability of test order data for companion animals and how those data might be used in a prospective surveillance to detect disease outbreaks. a significant number of daily records were received within the first -hour period following their creation. using pre-existing data, generated by routine workflow, minimizes any additional burden for providers. employing an automated data transfer protocol further reduces burden and is an essential benefit to support a sustained surveillance effort [ ] , [ ] , [ ] . this system also achieved the benefit of obtaining provider-level data from a wide geographic area through a single source, creating no additional work for the veterinary providers and minimal work to establish and maintain the automated transfer mechanism for records from the vdl. the results from this study also indicated that increases in the number of test orders submitted by veterinarians can be detected in a timely manner using prospective analysis. the development of the syndrome categories and the detection method used most likely influenced the alerts generated by this pilot system. we described two alerts that linked unexpected increases in test orders to increased incidence of disease. one of these alerts may also have provided warning of human cases of disease. the number of true and verifiable outbreaks of disease that occur limits determining the performance of an outbreak detection system [ ] , [ ] . we lacked such a gold standard in this study. therefore, we considered attempting any estimates of sensitivity, specificity, or positive predictive value to be inappropriate. additional investigation, following refinement of the syndrome categories, might be beneficial for better evaluating the potential of such a system to detect outbreaks of disease. the results support the continued consideration of vdl data by demonstrating the quality of data available, the ability to transfer and analyze the data in a timely manner, and the potential for detecting real disease events in the surveillance population. the true measure of a surveillance system lies in its usefulness [ ] . additional benefits from this method of surveillance may exist that contribute intangible value to the system [ ] , [ ] . previous studies found that regular reports of conditions were considered beneficial by data providers [ ] , [ ] . while prospective analysis of orders includes methods designed to detect aberrant increases, reports of area syndromic trends may be valuable to veterinarians when treating individual animals as part of their practice. the addition of test results might also provide reports beneficial for veterinarians while potentially improving the specificity of outbreak detection. input from all potential end users should be considered when further developing the utility of this type of surveillance system to ensure its maximum benefit. early detection of possible bioterrorist events using sentinel animals pet dogs as sentinels for environmental contamination development of a computerized dairy herd health data base for epidemiologic research the national capitol region's emergency department syndromic surveillance system: do chief complaint and discharge diagnosis yield different results? implementation of a national early event detection and situational awareness system framework for evaluating public health surveillance systems for early detection of outbreaks modern epidemiology syndromic surveillance and bioterrorism-related epidemics review of efforts to protect the agricultural sector and food supply from a deliberate attack with a biological agent, a toxin or a disease directed at crops and livestock the emergence of zoonotic diseases: understanding the impact on animal and human health how outbreaks of infectious disease are detected: a review of surveillance systems and outbreaks the abcs of bioterrorism for veterinarians, focusing on category a agents monitoring and surveillance for rare health-related events: a review from the veterinary perspective surveillance system for emerging diseases. the value of an "early warning" surveillance system for emerging diseases purdue university-banfield national companion animal surveillance program for emerging and zoonotic diseases surveillance for early detection and monioring of infectious disease outbreaks associated with bioterrorism microbial threats to health: emergence, detection, and response a new method for investigating nontraditional biosurveillance data: studying behaviors prior to emergency department visits the economic impact of a bioterrorist attack: are prevention and postattack intervention programs justifiable? strengthening safeguards against disease outbreaks improvements in methodologies for tracking infectious disease needed. the newsbulletin counted data cusum's integrated human-animal disease surveillance biological terrorism in the united states: threat, preparedness, and response animal health at the crossroads: preventing, detecting, and diagnosing animal diseases passive animal disease surveillance in canada: a benchmark evaluation of microbiology orders from two veterinary diagnostic laboratories as potential data sources for early outbreak detection handbook of biosurveillance draft framework for evaluating syndromic surveillance systems value of icd- -coded chief complaints for detection of epidemics. proceedings of the amia annual symposium detecting emerging diseases in farm animals through clinical observations availability and comparative value of data elements required for an effective bioterrorism detection system electronic surveillance system for the early notification of community-based epidemics (essence) population biology of emerging and re-emerging pathogens acknowledgments. the authors wish to thank dr. bill wallen, gary watson, and robert ledford at idexx laboratories, inc. for granting access to use these data and for their technical advice and assistance in establishing the transfer mechanism. key: cord- - gka h authors: timpka, toomas; spreco, armin; gursky, elin; eriksson, olle; dahlström, Örjan; strömgren, magnus; ekberg, joakim; pilemalm, sofie; karlsson, david; hinkula, jorma; holm, einar title: intentions to perform non-pharmaceutical protective behaviors during influenza outbreaks in sweden: a cross-sectional study following a mass vaccination campaign date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: gka h failure to incorporate the beliefs and attitudes of the public into theoretical models of preparedness has been identified as a weakness in strategies to mitigate infectious disease outbreaks. we administered a cross-sectional telephone survey to a representative sample (n = ) of the swedish adult population to examine whether self-reported intentions to improve personal hygiene and increase social distancing during influenza outbreaks could be explained by trust in official information, self-reported health (sf- ), sociodemographic factors, and determinants postulated in protection motivation theory, namely threat appraisal and coping appraisal. the interviewees were asked to make their appraisals for two scenarios: a) an influenza with low case fatality and mild lifestyle impact; b) severe influenza with high case fatality and serious disturbances of societal functions. every second respondent ( . %) reported high trust in official information about influenza. the proportion that reported intentions to take deliberate actions to improve personal hygiene during outbreaks ranged between – %, while less than % said that they intended to increase social distancing. multiple logistic regression models with coping appraisal as the explanatory factor most frequently contributing to the explanation of the variance in intentions showed strong discriminatory performance for staying home while not ill (mild outbreaks: area under the curve [auc] . ( % confidence interval . ; . ), severe outbreaks auc . ( % ci . ; . )) and acceptable performance with regard to avoiding public transportation (auc . ( . ; . ), auc . ( . ; . )), using handwash products (auc . ( . ; . ), auc . ( . ; . )), and frequently washing hands (auc . ( . ; . ), auc . ( . ; . )). we conclude that coping appraisal was the explanatory factor most frequently included in statistical models explaining self-reported intentions to carry out non-pharmaceutical health actions in the swedish outlined context, and that variations in threat appraisal played a smaller role in these models despite scientific uncertainties surrounding a recent mass vaccination campaign. although encouraging the public to undertake specific protective behaviors has proved useful in containing outbreaks of infectious disease [ ] , more research has been called for examining the social, demographic, and cultural factors that influence these efforts [ ] . this is particularly important to understanding people's hesitations to heed official advice, particularly in the absence of clear scientific evidence regarding the disease outbreak [ ] . the as -adjuvanted pandemrixh was the most commonly used vaccine in response to the influenza a(h n )pdm outbreak in europe [ ] ; finland and sweden recommended this vaccine to their entire populations. in august reports of a possible association between exposure to the vaccine and occurrence of narcolepsy in children and adolescents emerged in both the latter countries, which led to a review of the vaccine by the european medicines agency (ema). subsequently, increased narcolepsy diagnoses associated with the start of the campaign have been confirmed [ ] . in sweden, scientific uncertainty regarding the safety of this mass vaccination was both publicly discussed [ ] and questioned by researchers [ ] . beliefs that the interventions suggested are effective and safe [ ] , that the illness has severe consequences [ ] , and that there is a high likelihood of exposure [ ] have been associated with compliance with behavioral recommendations. it has also been pointed out that behavioral research in epidemics should not only identify determinants of individual and population behavioral responses, but also clarify the mechanisms underpinning these [ ] . protection motivation theory (pmt) [ , ] posits that an intention to perform protective activities is determined by perceptions of threat and the ability to cope. in addition to intentions and preceptions, a recent review concluded that protective behavior needs to be investigated with regard to sociodemiograpic characteristics in order to identify the ''contagious'' effect and contextual nature of perceptions and mediating mechanisms [ ] . for instance, coping appraisals are made in interaction with environmental resources, which vary in availability across population subgroups. protective behavior associated with influenza outbreaks has also been investigated with regard to general estimates of health status [ ] , but few studies have used validated measures of self-rated health as a means for the sub categorization. at present, several such measures are available for use in population-based research [ ] . to provide a snapshot of intended self-protective behaviors during a period when scientific uncertainty pervaded public discussions addressing infectious disease control, we carried out a cross-sectional telephone survey of a demographically representative sample of the swedish population. the specific aim was to examine to what extent self-reported intentions to improve personal hygiene and increase social distancing during influenza outbreaks can be explained by perceptions of threat and the ability to cope as outlined in pmt, self-reported assessments of health, trust in official information, and sociodemiographic factors. the study used a cross-sectional design to analyze associations between intended protective behaviors during influenza outbreaks and items in a theoretical model of explanatory factors [ , ] . a random sample of , persons ranging between - years of age was drawn from the swedish national population register. a combined telephone and questionnaire survey was carried out during the first quarter of . the study was conducted according to the world medical association's declaration of helsinki from regarding ethical principles for medical research involving human subjects, revised in . potential study sample participants were informed about the study by letter via postal mail and invited to participate in a telephone survey on protective behaviors during influenza outbreaks. those agreeing to participate returned their consent in writing. all collected data were managed confidentially and analyzed anonymously. the study design was approved by the institutional (ethics) review board at umeå university (dnr - - Ö ). a hypothetical explanatory model was constructed to inform the analysis of the main research question; i.e. to what extent selfreported intentions to perform protective behaviors during influenza outbreaks can be explained by perceptions of threat and the ability to cope as outlined in the pmt, self-assessments of health status, trust in official information, and sociodemiographic factors. in this model, protective behaviors during outbreaks are restricted to two categories: increased personal hygiene (use of disinfectants and other handwash products; frequent washing of hands when having touched common objects, such as door knobs) and social distancing (staying home from work or school; avoiding use of public transportation). the intentions to carry out a protective behavior are assessed by asking whether the respondent would try to perform the behavior during a mild and severe influenza outbreak, respectively. both outbreak scenarios described personal risk of infection as high (i.e., in people infected). the mild influenza description details moderate health consequences (less than in infected people dying) and a minor lifestyle impact (services mainly operating normally). the severe scenario describes serious health consequences ( in - infected people dying) and services no longer being able to operate normally. the first set of explanatory factors concerned perceptions of threat and the ability to cope. based on the notion of subjective expected utility [ ] , which postulates that people's choices are a product of assessments of probability and utility of options, healthrelated methodologies such as the pmt and the health belief model [ ] have included formally quantified models of subjective health risk perceptions, i.e., as the likelihood of contracting a disease multiplied by disease severity. together with different types of cost-benefit valuations and self-efficacy expectations, these perceptions of risk are presumed to determine health-protective behaviors. in the present study, the collection and analysis of data on protection motivation in relation to influenza outbreaks are structured according to the pmt. this theory suggests that threat appraisal will generate an intention to act, while coping appraisal determines the type of action. threat appraisal is in this study characterized in its three dimensions [ , [ ] [ ] : -perceived relative risk of catching influenza; measured by one item assessing personal likelihood of infection, if no preventative action was taken, -anxiety about catching mild and severe influenza; measured by one item for each influenza type, and -perceived severity of the consequences of catching mild and severe influenza; measured by one item for each influenza type. coping appraisal is also represented in its three dimensions: -response efficacy; assessed by one item asking about protecting oneself from influenza by employing enhanced personal hygiene and one item asking about social distancing, -self-efficacy; measured by two items asking whether the respondent felt it is possible to carry out protective behaviors by social distancing and increased personal hygiene, respectively, and whether they were confident they could carry out these actions if they so desired [ ] , and -response costs; defined as the estimated efforts needed to overcome perceived barriers on carrying out protective actions. for social distancing, this dimension was assessed by asking for 'work concerns', i.e. guilt and anxiety about not completing work. response costs for increased personal hygiene were assessed through items asking for concerns associated with acquiring adequate soaps and disinfectants (handwash products) and learning the correct techniques to use them. self-reported health assessments have in epidemiological studies been found to be valid indicators of health status as measured by prediction of future physician contacts and all-cause mortality [ ] . in this study, self-reported health is measured by the sf- tm -hour recall questionnaire in order to examine associations with intentions to carry out protective behaviors. this general selfreported health instrument contains eight health-related questions that, in turn, can be summarized in two overall measures of physical and mental health: physical component summary (pcs) and mental component summary (mcs), respectively [ ] . it is derived from the sf- for the purposes of yielding comparable scores for the health dimensions and summary measures of the sf- with minimal respondent burden. trust in government information during influenza outbreaks has in previous studies been found to be associated with greater self-efficacy and personal hygiene [ ] . trust in official information was therefore included in the explanatory model, asking for agreement with a single statement about trust in government information during outbreaks. the sociodemiographic factors included in the model were marriage status, number of children living at home, formal education, employment status, and ethnicity. prior to the telephone call, the subjects were asked to complete a paper-based survey, querying for sociodemiographic data and data elements from the sf- tm . the remaining data were collected in the telephone interview. to catalyze their considerations about the research topics, each subject was presented with brief scenarios of mild and severe influenza outbreaks. interview data were derived from open statements, and the respondents were asked to score their agreement along a seven-point scale from (strongly disagree) to (strongly agree). the collection of data on perceptions associated with precautionary behaviors was structured in accordance with the pmt (text s ). to assess trust in official information in this study, the single statement ''for information during influenza outbreaks i do rely on government sources'' was used. we conducted a drop-out analysis based on the demographic variables available for the entire sample, i.e. gender, age and place of residence. all collected data were first subjected to descriptive statistics, i.e. mean, median and standard deviation for continuous data and frequency and proportions (%) for categorical data. the primary end points for the ensuing analyses were intentions to increase social distancing (staying home while not ill; avoid public transportation), and enhance personal hygiene (use of handwash; frequent washing of hands after touching common objects) during mild and severe influenza outbreaks, respectively. the theoretical model of potential explanatory factors was used as the basis for the analysis. for each endpoint, logistic regression analyses were applied using the items in the model as explanatory variables. these included trust in official information; variables corresponding to pmt items (the threat appraisal items of perceived personal risk, emotional response (worry), perceived severity; and the coping appraisal items of general response efficacy, self-efficacy, and response costs); variables representing the sf- summary items (pcs and mcs); and sociodemographic characteristics (age, gender, educational level, living with partner, living with child, and employment). when used as response variables, ordinal variables were dichotomized (agree/do not agree). to contrast expected perceptions against other perceptions, the variables were converted with the agreement scores in the expected extreme as one category. for threat appraisal, agreement scores in the low extreme were contrasted against other opinions, except for the estimates of the severity of the consequences of getting infected where the scores in the high extreme were contrasted against the other opinions. regarding coping appraisal, the personal hygiene scores in the high extreme were contrasted against other opinions for response efficacy and self-efficacy and in the low extreme for response costs. for social distancing, agreement scores in the low extreme were contrasted against other opinions for response efficacy and in the high extreme for self-efficacy and response costs. the area under the roc curve (auc) was used as model performance indicator and nagelkerke r to estimate the determination level for each model. the limits for interpreting the auc (or c-statistic) were set to . , . , and . , denoting very strong (outstanding), strong (excellent), and acceptable discriminatory performance, respectively [ ] . all tests were twosided and p, . was regarded as statistically significant. all calculations were done using spss version or higher. two-hundred and fifty-four persons in the total population sample (n = , ) could not be reached by a telephone call. of the persons reached, provided a complete response, leading to a % response rate to the telephone survey and a % participation rate with regard to the total sample. the age category - years was slightly over-represented ( % response rate) among the study participants when compared to the total population sample (p = . ). however, the effect size of this difference in participation was small (cramer's v = . ). thus, while elderly individuals were overrepresented in our data, the impact of this deviation from the reference population was of a small magnitude. in terms of place of residence, those living in small labor market regions (with a total population of less than , inhabitants) exhibited the highest participation rates: %, compared to % in large regions (with a population greater than , inhabitants). the basic sociodemiographic characteristics of the final study participants are displayed in table . the general level of health in the study population as measured by sf- scores was above the reference values for all items except for physical functioning and vitality (lower scores) and general health (equal scores) ( table ). there was no statistically significant difference between men and women regarding the mean scores of any sf- item or summary component. every second respondent ( . %) reported high or very high trust (scores - ) in information about influenza provided by official sources (mean score . ; median . ; standard deviation (sd) . )). neither age, education, employment nor any component of self-rated health was associated with trust in official information about influenza. however, the level of trust was associated with gender, with men reporting lower trust levels than women (p = . ; odds ratio (or) . ( % confidence interval (ci) . ; . )). regarding social distancing measures, % of the respondents scored strong (strong or very strong) agreement with the stated intention to stay home when not ill during mild influenza outbreaks, and % of the respondents scored strong agreement with this intent during severe outbreaks. more than twice as many respondents ( %) scored strong agreement with avoiding use of public transportation during a mild outbreak, while % of the respondents scored strong agreement with this intention during a severe outbreak. regarding measures related to personal hygiene, % of the respondents scored strong agreement with the stated intention to use handwash products during mild outbreaks, while % of the respondents scored strong agreement with this intention during severe outbreaks. regarding the intention to frequently engage in handwashing, % reported strong agreement in association to mild influenza outbreaks and % in association to severe outbreaks. a model describing the intention to stay home without being ill during a mild influenza outbreak included eight significant variables and displayed a strong discriminative performance (auc . ( % ci . ; . )) ( table ). this self-reported intention was strongly associated with coping appraisal; low perceived response costs associated with staying home and selfefficacy with regard to social distancing; and, interestingly, to a disbelief in the general efficacy of social distancing as an infectious disease control measure. planning to stay home was also strongly associated with male gender and, with a weaker association, to being unemployed and living with a partner. the intention was also associated with threat appraisal, although with a weaker strength; with worry about getting infected and high perceived severity of the influenza threat. in comparison, the intention to stay home without being ill during a severe outbreak was represented by a model including only four significant variables, but that also displayed a strong discriminative performance (auc . (( % ci . ; . )). as for the mild outbreak scenario, this intention was strongly associated with coping appraisal; to response costs and perceived self-efficacy with regard to social distancing. however, staying home during a severe outbreak was also strongly associated with threat appraisal related to concerns about getting infected. regarding sociodemographic factors, this intention was only associated with not having employment. the intention to avoid using public transportation during a mild influenza outbreak was represented by a model including six significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )) ( table ). this self-reported intention was, also, strongly associated with coping appraisal; to perceived response costs associated with avoiding public transportation and to self-efficacy with regard to social distancing. the intention was also strongly associated with threat appraisal in terms of worry about getting infected. in addition, avoiding use of public transportation was associated with a lower level of formal education, living with a partner, and high trust in official information. in contrast, the intention to avoid public transportation during a severe influenza outbreak was described by a model including four significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )). as for the mild outbreak scenario, avoiding public transportation during severe outbreaks was strongly associated with coping appraisal; to response costs; and, with weaker strength, to perceived self-efficacy with regard to personal social distancing. with regard to threat appraisal, avoiding public transportation during a severe outbreak was associated with worry about getting infected and a high perceived severity of the influenza threat. planning to use handwash products during a mild influenza outbreak was described by a model including three significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )) ( table ). planning to use handwash was strongly associated with female gender. this intention was, for mild outbreaks, also explained by self-efficacy with regard to personal hygiene and trust in official information. for the severe outbreak scenario, planning to use handwash products was represented by a model including four significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )). this intention was, too, strongly associated with female gender. in addition, it was strongly associated with coping appraisal; to a belief in the general efficacy of increased personal hygiene; and low response costs associated with acquiring of suitable products. contrary to any of the other intended behaviors studied, the intention to use handwash products during severe outbreaks was associated with low self-rated physical health. an intention to frequently engage in handwashing after having touched common objects during a mild influenza outbreak was represented by a model including four significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )) ( table ). the intention was strongly associated with coping appraisal in terms of self-efficacy with regard to personal hygiene. it was also associated with female gender, higher age, and lower education. in comparison, planning to frequently wash hands during a severe outbreak was represented by a model including three significant variables and an acceptable discriminative performance (auc . ( % ci . ; . )). similar to the mild influenza scenario, it was strongly associated with coping appraisal in terms of a high self-efficacy with regard to personal hygiene. the intention was also associated with female gender and being born in the country. despite the fact that the safety of the mass vaccination during the a(h n )pdm outbreak had been questioned by national mass media in a campaign-like manner, two years after the outbreak every second respondent in a representative sample of the swedish adult population reported high trust in official information about influenza. while the proportion of persons reporting intentions to improve personal hygiene during influenza outbreaks ranged between - %, the proportion reporting intentions to increase social distancing did not exceed %. this pattern can generally be explained by the notion that the initial behavioral changes during an influenza outbreak are more likely to resemble familiar reactions and well-known routines [ ] , such as increasing personal hygiene, rather than changes that require deductive planning, such as increasing social distancing. the explanatory models developed in this study showed statistical associations ranging from strong (staying home without being ill) to acceptable (avoiding public transportation and increasing personal hygiene). among the explanatory factors considered, coping appraisal was the factor most frequently showing associations (as displayed by odds ratios) with the reported intentions. in a validation analysis (data not shown), we fitted each model fully (including all terms in the five explanatory factors categories trust of information, threat appraisal, coping appraisal, sociodemographic factors, and self-rated health) and calculated the proportion of correctly classified cases for these full models for all eight scenarios. then we left the terms from one of the five categories out separately, and calculated the proportion of correctly classified cases for each of these subset models. we found that the proportion of correctly classified cases without coping appraisal was lower than the corresponding proportion for all full models and lower or equal to the corresponding proportion for of the models excluding one of the other four categories. we interpret these observations combined as indicative evidence that of the explanatory factors considered, coping appraisal was the factor strongest associated with the reported intentions. analogous to our results, a recent british web-based survey of university employees found that coping appraisal was the principal predictor of variability in protective intentions during pandemics [ ] , and response costs have been reported as the largest predictor for emergency nurses not reporting to work during an influenza pandemic [ ] . a contributing influence to the lesser relative importance of threat appraisal suggested by our results may be a scandinavian tendency to perceive risks lower than in other countries [ ] [ ] [ ] . one of the explanations for this tendency is that the media in scandinavia appear to report more about risks abroad with less attention to risk inside the country [ ] . in contrast to our results, self-efficacy during the a(h n )pdm outbreak in hong kong was found to be only weakly associated with social distancing [ ] . however, hong kong residents are limited in their ability to avoid crowds, and the relatively mild impact of the outbreak could have led to the notion that people saw no reason to jeopardize their economic well-being and curtail other social activities. a socio-geographic theory of protective behaviors during infectious disease outbreaks suggested that efficacy beliefs of chinese living in the uk and the netherlands were comparable to those of native uk and dutch residents during the sars outbreak in [ ] , indicating that country of residence is more important than ethnicity or country and culture of origin in determination of protective behaviors. however, with coordinated regional disease control efforts and increasing influence from social media, this may change. gender was the sociodemiographic characteristic that showed the strongest association with the observed variation in reported intentions. as also found in a norwegian study from the same time table . simple and multiple logistic regression models of explanatory factors for the intention to avoid using public transport displayed by influenza outbreak scenario. period [ ] , the swedish women in this study were more disposed to enhance their protective behaviors related to personal hygiene than were men. one explanation of this finding could be an interaction with concerns about the consequences of getting infected. a recent study from the u.s. reported that women were more worried than men about getting seriously ill or even dying during a severe influenza outbreak [ ] . however, no gender differences with regard to threat appraisal were reported from the norwegian study [ ] . originally, we did not include interaction terms in our statistical analyses. a secondary analysis (data not shown) did not reveal any statistically significant interaction between gender and any threat or coping appraisal item such that omitting the interaction from the model would disturb the estimation of the main effects. therefore, an alternative explanation of our findings is that the female respondents were more disposed to enhance their protective behaviors related to personal hygiene than the male respondents because swedish women purchase and use hygiene products more often than men [ ] , and, in consequence, were more confident about the practical handling of handwash and liquid soap. conversely, men were more inclined to stay home without being ill during influenza outbreaks. this could be explained by the fact that fewer of the employed swedish men ( %) than women ( %) were at the time of the study working in caring or educational occupations that require physical presence at the workplace, such as nursing, child care, and teaching [ ] . in other words, a larger proportion of men could consider the possibility of staying home while continuing to work during an ongoing influenza outbreak, which was not an option for many women. these findings indicate that more research is needed to understand gender-related differences in protective behavior during influenza outbreaks. the main strengths of this study are its foundation on a current theoretical model [ ] and a relatively large representative sample of the swedish population. however, the study has also important limitations that must be taken into consideration when interpreting the results. the demographic characteristics available may not be the most important factors biasing the results. for instance, it is possible that individuals with low trust in official information about influenza were under-represented, and anxious individuals worrying about disease risks were over-represented, among the participants. moreover, interpreting cross-sectional data on protective behaviors is difficult because they confound the motivation and accuracy-associated aspects regarding the causaltemporal relationship between perception and behavior [ ] . the motivational hypothesis assumes that high perceived risk leads people's intention to adopt protective behaviors, while the accuracy hypothesis suggests that people who act in a more risky way should also feel more at risk. as an example, individuals having physical contact with many people through their occupation may have been aware of that daily routines are associated with a higher risk for getting infected. accordingly, a negative correlation may indicate accurate relative risk perceptions, i.e. that people are aware of their risk status [ , ] . further longitudinal studies of protective behaviors during influenza outbreaks are thereby warranted [ ] . another limitation is that we assessed self-reported intentions rather than objectively measured behavior. nevertheless, intentions are a well-validated proxy for behavior predicting a moderate amount ( - %) of the variance in actual behavior across a wide range of contexts [ , ] . moreover, proponents of dual-process health behavior models have suggested that analytic central and emotional-heuristic processes work in concert to select decisions [ ] , and under certain circumstances emotions may even be the dominant force [ ] . while the pmt used in this study does include an emotional component, it still represents a cognitive appraisal model in assuming that cognitive risk assessment determines experience of fear. such a model is naturally applicable for the study of behaviors aimed at fending off long-term disease, where fear is likely to be less imminent and therefore secondary to more rational reflections about gains and losses related to protective behavior. however, in an acute threat situation, like a severe influenza outbreak, emotional aspects might gain more immediate importance. this would even be more likely during periods of scientific uncertainty, when fewer facts are available. it is in this context interesting to note that coping appraisal in this study was found to be the motivation factor that contributed most to the discriminatory performance despite the fact that threataffect was included in the general model, although indirectly through cognitive assessment. however, what role affect-or emotion-based judgments play in interaction with threat and coping appraisals is still an issue in need of clarification. finally, it should be noted that there were relatively small differences between the reported intended behaviors associated to the mild and severe scenarios, respectively. one explanation of this observation can be the fact that the a(h n )pdm outbreak was relatively mild in sweden, and that the respondents, wrongfully, related the severe scenario to their recent personal experience rather than the scenario description. however, the lack table . simple and multiple logistic regression models of explanatory factors for the intention to wash hands after touching common objects displayed by influenza outbreak scenario. of difference can also be seen as a sign of its own, i.e. that the swedish population may not be fully aware of the seriousness of a full influenza pandemic. failure to monitor the beliefs and attitudes of the public has recently been identified as a weakness in preparedness strategies against infectious disease outbreaks [ ] . we examined how items in a general explanatory model of intended health behavior were associated with personal hygiene and social distancing practices following a questioned mass vaccination campaign against influenza in the swedish population. we observed a relatively high trust in official recommendations and a higher proportion of intentions to improve personal hygiene than those used to increase social distancing. among the explanatory factors considered, coping appraisal was the factor most frequently included in models explaining self-reported intentions. variations in threat appraisal played a smaller role in these models despite the uncertainties surrounding the mass vaccination during the a(h n )pdm outbreak. the results also show that not just from a third world perspective [ ] it is necessary to consider that not all population sub groups have the same predispositions to enact specific behaviors to protect their health. for instance, they suggest that further studies are needed of gender differences in protective behaviors during influenza outbreaks. we conclude that developing interventions that support the general population's efforts to perform self-protective behaviors during influenza outbreaks and longitudinal studies of such interventions across several influenza seasons are warranted also in european countries. text s interview guideline for collection of data on perceptions associated with precautionary behaviors. 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testing for breast cancer susceptibility: influences of cancer worry and risk perceptions developing pandemic preparedness in europe in the st century: experience, evolution and next steps delivering interventions to reduce the global burden of stillbirths: improving service supply and community demand item specific for intention to wash hands after touching common objects. formal education past high school/secondary school. doi: . /journal.pone. .t key: cord- -btaxvmsr authors: di paola, nicholas; sanchez-lockhart, mariano; zeng, xiankun; kuhn, jens h.; palacios, gustavo title: viral genomics in ebola virus research date: - - journal: nat rev microbiol doi: . /s - - - sha: doc_id: cord_uid: btaxvmsr filoviruses such as ebola virus continue to pose a substantial health risk to humans. advances in the sequencing and functional characterization of both pathogen and host genomes have provided a wealth of knowledge to clinicians, epidemiologists and public health responders during outbreaks of high-consequence viral disease. here, we describe how genomics has been historically used to investigate ebola virus disease outbreaks and how new technologies allow for rapid, large-scale data generation at the point of care. we highlight how genomics extends beyond consensus-level sequencing of the virus to include intra-host viral transcriptomics and the characterization of host responses in acute and persistently infected patients. similar genomics techniques can also be applied to the characterization of non-human primate animal models and to known natural reservoirs of filoviruses, and metagenomic sequencing can be the key to the discovery of novel filoviruses. finally, we outline the importance of reverse genetics systems that can swiftly characterize filoviruses as soon as their genome sequences are available. infections with viruses of the mononegaviral family filoviridae (in particular, members of the genera ebolavirus and marburgvirus) are an increasing threat to mankind. until recently, the infrequent spillover of these viruses into humans and the fact that spillover often occurred in remote locations, coupled with a limited knowledge of non-human reservoir hosts, the use of low-output genomic sequencing, and biosafety and bio security restrictions on filovirus research, contributed to the paucity of publicly available data on filovirus genome sequences . in december , complete genome sequences for only ebolaviruses and marburgviruses were available despite the fact that outbreaks of natural filovirus disease had been recorded . since december , atypically extensive filovirus disease outbreaks, from to in western africa and from to present in the democratic republic of the congo, have profoundly impacted public health systems. at least , fatalities from filovirus disease were reported between december and april , (refs , ). by leveraging the continued development and improvement of next-generation sequencing technology, > complete filovirus genome sequences and over , draft genomes (that is, genomes with > % coverage) across classified and unclassified filovirus family members have become available since (ref. ). indeed, among high-consequence, risk group viruses, the genomic diversity of filoviruses is arguably becoming the best characterized. the impact and importance of genomics in pathogen characterization is routinely demonstrated, but the rapid prediction of, response to and mitigation of outbreaks requires more detailed genomic information than virus consensus-genome sequencing. indeed, as predicted , metagenomic sequencing has become a powerful tool for identifying novel viruses and, crucially, for predicting pathogen emergence . targeted or unbiased sequencing of individual clinical samples aids in the identification of outbreaks, the determination of outbreak aetiology and the definition of virus transmission chains by identifying chain-defining single nucleotide polymorphisms (snps). furthermore, field transcriptomics improves our understanding of host responses to virus infection and will be important in deciphering the differences between asymptomatic and symptomatic disease states and in predicting whether patients with acute and chronic disease will survive . functional genomics is becoming the tool of choice for the rapid characterization of patient-specific viruses that have not been isolated in culture or that cannot be equitably shared among laboratories across borders . finally, the genomic analysis of patient-specific viruses also enables precision medicine by predicting the efficacy of available medical countermeasures (mcms) against these individual viruses. here, we review how recent advances in genomic technologies have shaped past and current responses to outbreaks of ebola virus disease (evd), including insights into filovirus diversity and evolution. we emphasize the importance of accurate and rapid large-scale data generation and its implications for the development of mcms and outbreak response. we also examine the phenomena of ebola virus (ebov) persistence in human hosts and provide an overview of recent genomic advances in threat characterization, vaccine development a collection of continuously evolving technologies and techniques that allow for the digitalization of genomic material. the sequencing of genetic material recovered directly from an environmental or clinical sample that allows the identification of all organisms and mobile genetic elements represented in the sample. and immunotherapy. although we focus primarily on ebov, these practices can apply to all pathogenic filoviruses and other high-consequence viruses capable of sustaining human-to-human transmission. although the global distribution and diversity of filoviruses remains largely undefined, metagenomic sequencing is becoming a valuable tool for identifying filovirus reservoirs. until , disease outbreaks owing to infection by ebolaviruses (including ebov, sudan virus (sudv) and marburgviruses (including marburg virus (marv) and ravn virus (ravv)) had only been recorded on the african continent ( fig. ). as the natural reservoir hosts of all of these viruses remained unidentified, despite extensive ecological studies, filoviruses were thought to be african viruses . this view changed after , when reston virus (restv; of the genus ebolavirus) was discovered and repeatedly identified as a lethal pathogen of captive crab-eating macaques (macaca fascicularis) in non-human primate (nhp) breeding facilities in the philippines - ( fig. ). however, although restv can infect humans, it appears to be apathogenic . restv was subsequently considered to be an asian anomaly to the african filovirus dogma. classical filovirus-targeted genome sequencing and, later, unbiased broad-scale metagenomic sequencing, shed new light on filovirus ecology. in , the sequencing of samples obtained from egyptian rousettes (rousettus aegyptiacus) in africa revealed that these bats, which are cavernicolous and frugivorous pteropodids, are natural reservoir hosts of both marv and ravv. coding-complete or complete genomic sequences of both viruses were repeatedly obtained from egyptian rousette populations in uganda, sierra leone and south africa [ ] [ ] [ ] [ ] , and genomic fragments of these viruses were also detected in populations of these bats in the democratic republic of the congo and in zambia . around and after , sequence-based evidence obtained using a range of techniques began to support the hypothesis that restv is an asian virus. restv genome sequences were obtained from captive dome stic pigs (sus scrofa domesticus) in the philippines and china , , and restv genome fragments were sequen ced from samples from molossid, pteropodid and vespertilionid bats in the philippines . next-generation sequencing further enabled the discovery of a highly divergent filovirus, lloviu virus (llov, genus cuevavirus), in deceased schreibers's long-fingered bats (miniopterus schreibersii) in hungary and in spain . the ebolavirus genus was expanded owing to the discovery (via next-generation sequencing) of bombali virus (bomv) in molossid little free-tailed bats (chaerephon pumilus) and angolan free-tailed bats (mops condylurus) in guinea, kenya and sierra leone [ ] [ ] [ ] in short, genomics has clarified that highly divergent filoviruses, frequently with unknown pathogenic potential, are likely to be distributed widely over the african, asian and european continents in highly diverse host reservoirs ( fig. , box ). furthermore, expanded animal sampling and unbiased host virome sequencing is likely to enable this diversity and distribution to be described in more detail. of note, the natural host reservoirs of three ebolaviruses that are human pathogens, namely bundibugyo virus (bdbv), sudv and taï forest virus (tafv), are still unclear. furthermore, although bats are suspected to be hosts of ebov owing to the detection of short ebov genomic fragments and/or antibodies to ebov in certain bats , no complete ebov genome has yet been sequenced from any bat sample. the genomic investigation of archived or newly acquired samples could also support or refute the often-repeated hypothesis that middle african central chimpanzee (pan troglodytes troglodytes), duiker (cephalophus spp.) and western lowland gorilla (gorilla gorilla gorilla) populations are frequently decimated by ebov infection [ ] [ ] [ ] . thus, genomics may enable the prevention of future filovirus disease outbreaks by identifying filovirus natural hosts and by limiting host-human contacts as well as the initial introduction of filoviruses into the human population. identifying and characterizing outbreaks genomics-based techniques have been central in the identification and characterization of filovirus disease outbreaks. the largest known filovirus disease outbreak occurred from to in western africa and was caused by a novel ebov variant, makona (ebov/mak) ( fig. ). genomic sequencing efforts during this evd outbreak showcased various platforms and strategies to characterize thousands of human clinical samples containing ebov/mak . early efforts relied on exporting positive samples to high-complexity genomic centres abroad , (box ). however, in december , ebov/mak genome sequencing using benchtop sequencers, such as the miseq system (illumina) and the ion torrent system nature reviews | microbiology r e v i e w s (thermo fisher scientific) in-country (namely, in liberia and sierra leone), became standard practice [ ] [ ] [ ] . in addition, field laboratories used the iseq (illumina), a portable bench-top sequencer with low error rates that can be transported in a suitcase, to obtain complete ebov genome sequences to determine virus transmission in the democratic republic of the congo , . use of the portable nanopore sequencing technology minion (oxford nanopore technologies) markedly reduced the time required to obtain the genome sequence from patient samples and enabled the reintroduction of ebov into guinea and sierra leone to be rapidly confirmed . similarly, the ebov variants causing the Équateur province evd (ebov/"tum") and the ongoing nord-kivu/sud-kivu/ituri province evd outbreak caused by ebov/"itu" in the democratic republic of the congo were quickly identified by the use of minion , . the timing and establishment of in-country genomic sequencing capabilities determine which information can be captured and disseminated during an evd outbreak. early sequencing efforts can provide an informative 'snapshot' of the genomic epidemiology of ebov during the initial phase of the outbreak . the extent of the genomic diversity of the virus at the beginning of an outbreak can be used to determine whether single or multiple virus spillover events have occurred and to provide a crude estimate of the time at which a virus emerged in a human population , , , . highly accurate genomic data have been used to characterize intra-host ebov populations and genetic drift and even to evaluate, in silico and in real time, the available diagnostic measures and mcms , , . as an outbreak progresses and the sampling size increases, phylodynamic and spatiotemporal analyses reveal broader trends in the intra-outbreak evolutionary rate of the virus, its geographical migration and factors contributing to virus transmission, disease outcome and virus-host adaptation , [ ] [ ] [ ] [ ] [ ] [ ] . ideally, the viral agent is initially identified using highly portable sequencing platforms on site. after this identification, considerations other than sequencing speed (for example, sequencing accuracy and processivity) become paramount in determining virus transmission networks and in detecting changes in the viral genome (between cases in the current outbreak and between the current and previous outbreaks) that could subvert mcms. however, whereas unbiased sequencing approaches using high fidelity platforms can lead to the discovery of co-infections and reveal important clinical considerations during the treatment of patients near the point of need, targeted methods of pathogen characterization using the portable sequencing platforms iseq and miseq (which use bait-enrichment techniques) and minion (which uses amplicon sequencing) can still provide useful genomic data albeit with a lower sequencing output (that is, a lower number of reads) than unbiased sequencing. sequencing only a single target during an enduring and large outbreak of evd may result in the detection of co-infections and/or superinfections being missed. the earliest evidence of an ebov co-infection was obtained in gabon in , where a patient with evd also tested positive for human immunodeficiency virus (hiv- ; a lentivirus of the retroviridae family) the change in the frequency of an existing gene variant (allele) in a population owing to the occurrence of random mutations. of the family hepadnaviridae) and epstein-barr virus (a lymphocryptovirus of the family herpesviridae) were reported [ ] [ ] [ ] . additionally, ebov infections in patients with a gram-negative septicaemia or with bacterial translocation have been described [ ] [ ] [ ] . moreover, an extensive infectious disease due to one particular virus could plausibly conceal a simultaneous outbreak caused by a different pathogen . notoriously, there have been outbreaks of cholera, plague, measles and malaria, and sporadic cases of monkeypox and yellow fever, alongside the -present evd outbreak in the north-eastern region of the democratic republic of the congo. detecting and characterizing co-infections during a disease outbreak can provide clinicians with crucial point-of-care information and identify differences in patient outcomes that may result from co-occurring infections. the characterization of unexpected, co-circulating viruses during large-scale viral outbreaks requires established and reliable sequencing strategies that can be applied without knowledge of which virus is present. the discovery of novel viruses is ideally facilitated by metagenomic sequencing, which often relies on the pre-processing of clinical samples by depleting host-derived genomic material, followed by single or random primer amplification by pcr and deep sequencing [ ] [ ] [ ] . however, metagenomic sequencing is limited by the requirement for computational and bioinformatics resources, which are not always readily available under field conditions. instead, target-enrichment approaches using a wide breadth of bait probes for known pathogenic viruses, including filoviruses, have led to the successful characterization of known viruses in clinical samples from patients with disease of unknown etiology [ ] [ ] [ ] . moreover, target-enrichment sequencing is more cost-effective than metagenomic approaches. the percentage of sequencing data matching the target pathogen or pathogens can range from % to % with target enrichment, whereas with metagenomics approaches often < % of sequencing data matches the target , . punctual and highly accurate sequencing efforts have revealed the molecular genomic epidemiology of disease and thus enabled the characterization of pathogen transmission during disease outbreaks . the first application of in-country, real-time genomic epidemiology started well into the evd outbreak of - in western africa; portable sequencing was performed and data were analysed in tangent with up-to-date public health data . the abundance of ebov genome sequences determined during recent large-scale evd outbreaks (including the - outbreak and the -present outbreak in the democratic republic of the congo) enabled real-time and retrospective investigations, using median-joining haplotype network establishment and phylodynamic inferences, to reveal cryptic human ebov transmission chains in humans , , , . in coordination with classical epidemiological data (for example, that obtained by manual contact tracing), individual virus transmission events identified by genomic analysis such as median-joining haplotype networks can be temporally and spatially linked to determine likely transmission pathways, including the mode of virus diffusion and the identification of 'superspreaders' (as reviewed in ref. as the quality and quantity of avail able, complete genome sequences improves, new methods identifying intra-host snps may provide more granular analyses of person-to-person transmission than previous techniques . such snps can distinguish between almost identical consensus sequences of two or more patients . however, acute infections resulting from direct contact with a recently infected and symptomatic individual, and for which primary infection occurred < days before the onset of symptoms, is not the only route for sustained person-to-person transmission during filovirus disease outbreaks. ebov initially infects monocyte-derived macrophages and dendritic cells, which disseminate the virus through the circulatory system to all main target organs, including the liver, spleen and kidneys. after infecting and damaging the vascular endothelia, ebov infiltrates the parenchymata of these organs, resulting in focal necroses and inflammation. such damage can eventually lead to multi-organ dysfunction syndrome and ultimately death , . however, in some cases, the intrinsic, innate and adaptive immune responses can contain viral replication and dissemination, resulting in the survival of the patient . until recently, it was hypothesized that survivors of filovirus diseases effectively abolished filovirus infection. however, new evidence indicates that ebov can persist in certain sites of the body in the absence of viraemia and that this persistence could cause disease flare-ups (for example, see ref. ). some of these sites, including the brain, eyes and testes, are immune-privileged box | endogenous filovirus elements the bioinformatic analysis of higher animal genome sequences, the number of which is steadily increasing, reveals that a marked percentage of these sequences are derived from ancient retroviruses . many animal genomes are mosaics that are likely to have evolved through the accidental integration of retroviral genes or gene fragments into germ cell genomes and the subsequent inheritance of this genetic material by descendants. in some cases, these sequences were positively selected for and were (or are still) expressed and their functions were exapted by hosts for novel functions . a famous example of exaptation is the use of the human endogenous retrovirus w-derived syncytin, which was once a retrovirion surface glycoprotein that mediated virion host cell entry but is now essential for placental morphogenesis in pregnant women . during the past decade, scientists have been increasingly aware that such 'viral fossils' or 'paleoviruses' can derive from viruses other than retroviruses. indeed, non-retroviral integrated rna viruses (nirvs; also known as endogenous viral elements) were derived from the ancestors of numerous extant virus families . prominent examples of negative-sense rna virus-derived nirvs are bornavirus sequences, which are found in the genomes of bats, fish, hyraxes, marsupials, primates, rodents, ruminants and elephants , , and rhabdovirus sequences, which are found in the genomes of crustaceans, mosquitoes, ticks and plants , . interestingly, filovirus-derived nirvs also appear to be widespread as they have been located in the genome of afrosoricids, bats, eulipotyphlans, marsupials and rodents , , . the function of these stably inherited filovirus sequences remains to be determined. however, the existence of nirvs indicates that filoviruses are at least several million years old and that highly divergent mammals were exposed to, and at least occasionally infected by, these viruses and perhaps by the descendants of these viruses that exist today. the novel use of an evolved trait for a different function. a minimum spanning tree analysis of recombinant-free genomic sequences that infers ancestry-descendant relationships using haploid genotypes that can be visualized in a single unrooted, reticulate network. the study of how evolutionary processes interact with epidemiological and immunological factors to influence phylogenetic estimations. because they are physically separated from tissues and cells that are under immune surveillance ( fig. ) . thus, foreign antigens such as ebov particles are tolerated within these sites without eliciting an inflammatory immune response . prior to the outbreak of evd in western africa, evidence of persistent ebov infection had been sparse probably owing to the small number of spillover events arising from this persistence ( fig. ). nevertheless, infectious ebov and marv and/or filoviral rna had been detected in the eyes and semen of convalescent survivors prior to this outbreak [ ] [ ] [ ] [ ] . the large pool of survivors following the - outbreak of evd (specifically, , individuals) was different. disease flare-ups or re-emergences were reported in at least nine individuals and attributed to sexual transmission or breast-feeding . sexual transmission of persistent ebov was implicated in the initiation of new ebov transmission chains , , [ ] [ ] [ ] . genomic analyses revealed that the evolutionary rate of ebov persisting in testes during convalescence is reduced relative to the rates of ebov persisting in blood and plasma , . all these observations prompted a notable number of studies of the long-term effects of persistent ebov infection in evd survivors. indeed, ebov persistence can be accompanied by various sequelae, colloquially often referred to as 'post-ebola [virus] syndrome' . studies of ebov persistence in humans and experimentally in nhps have revolutionized our understanding of ebov infection and changed the guidelines of clinical operation as well as the recommendations of the world health organization for evd survivors. the impact of genomics on understanding the persistence of ebov is broader than next-generation sequencing; advances have also revolutionized the field of pathology by allowing the rapid exploration of transcriptional expression in a chosen site of filovirus infection. the development of multi-labelled and targeted 'probes' that allow multiplex immunopathological hybridizations in sites of interest have also boosted our knowledge of ebov persistence. indeed, studies using novel histopathological tools have benefited genomic research in immune-privileged and non-immune-privileged sites. immune-privileged sites. various neurological complications have been noted in survivors of evd . in experimentally infected rhesus monkeys (macaca mulatta), encephalitic ebov persistence is always accompanied by various degrees of encephalitis or meningoencephalitis . persistent infection of ebov in the brain may lead to evd relapse and late-onset encephalitis in human survivors several months after acute disease , . in experimentally infected nhps, ebov enters the brain by breaking down the blood-brain barrier by directly infecting and damaging endothelial cells (fig. a) . interestingly, ebov primarily infects and persists in microglia . ocular complications, including uveitis, are some of the most common findings during evd convalescence , and persistent ebov and persistent marv have been isolated from the aqueous humour of human survivors with uveitis , . in experimentally infected nhps, ebov infects blood vessels during the acute phase of infection and later infects parenchymal eye tissues. however, in rhesus monkeys surviving the experimental infection of ebov with various degrees of uveitis, retinitis and vitritis, ebov only persisted in cd + cells (monocytes or macrophages) in the vitreous chamber and in the inner limiting membrane of the retina to which it is adjacent (fig. b ). whether ebov isolated from the aqueous humour of human survivors originates from the vitreous chamber and its adjacent structures, as appears to be the case in nhps, remains unknown . the first recorded sexual transmission of a filovirus occurred in , when a male survivor of marburg virus disease transmitted marv to his wife . ebov genomic rna was repeatedly detected in the semen of evd survivors up to months after acute infection , , , [ ] [ ] [ ] , and infectious ebov was isolated from a few semen samples . ebov infects the seminiferous tubules of both human and nhps ( fig. c) , which are the immune-privileged sites of sperm production, during the acute phase of disease . persistent ebov infection was detected in the epididymis of a single rhesus monkey survivor with epididymitis, whereas marv persistence in seminiferous tubules was multifocal in of crab-eating macaques that survived , . recent studies indicate that testicular persistence is not restricted to filoviruses, as potential cases of the sexual transmission of crimean-congo haemorrhagic fever virus (cchfv; an orthonairovirus of the family nairoviridae) and uveitis inflammation of the uvea (the pigmented layer between retina and the fibrous layer composed of sclera and cornea of the eye). over the past two decades, high-throughput benchtop platforms (for example, sequencing (roche), miseq, nextseq and hiseq (illumina), sequel and rs (pacbio) and ion torrent (thermo fisher)) have been the backbone of metagenomics and targeted sequencing approaches for pathogen identification . genomic centres generally had to allocate a notable portion of space to house and maintain sequencers and transporting sequencers was impractical. for example, miseq, which is the smallest of the sequencers, weighs kg and occupies ~ , cm . recently, 'capacity building' efforts have established on-site genomics centres in low-resource settings , . however, the international shipping of oversized sequencers that rely on precise optical alignments for functionality can be challenging and cost-prohibitive and may cause irreparable damage to the sequencer. the maintenance and repair of internationally shipped sequencers may also be challenging as they do not come with in-country service contracts from the manufacturers. moreover, in low-resource settings, trained local staff may not be permanent, and they will periodically require guidance and retraining in sample handling and storage and in how to ensure the continued service and activity of the sequencers. the technological improvements in, and practicality of, portable sequencing technologies have been embraced in recent viral disease outbreaks, including in the -present ebola virus disease outbreak in the democratic republic of the congo and a lassa fever outbreak in nigeria. the iseq (illumina) and minion (oxford nanopore) platforms both conform to on-site field requirements as they are miniature, rapid and easy to use. the zibra zika virus (zikv; a flavivirus of the family flaviviridae) sequencing project in brazil also demonstrated the feasibility of a 'trailer laboratory', but produced limited complete genome sequences owing to the small amounts of zikv rna in clinical samples . several commercialized mobile laboratories incorporated into trucks or trailers shield equipment and temperature-sensitive reagents from austere conditions while providing ample power and laboratory workspace for sequencing. within such mobile laboratories, smaller pcr thermocyclers, such as the programmable mini thermal cycler with a smartphone (minipcr bio™), and miniature centrifuges further bolster portability and ease space requirements. other innovations that limit the need of a 'cold chain' for supplies will greatly improve on-site sequencing in hot climates and remote communities that are prone to outbreaks of ebola virus disease. arenaviridae) have been reported [ ] [ ] [ ] . sertoli cells, the supporting cells of spermatogenesis, are the main cellular reservoir of testicular marv and cchfv persistence in experimentally infected nhps , , and they may also be the reservoir of testicular lasv. the majority of cases of filovirus persistence have been associated with immuneprivileged sites. however, in several evd flare-ups originating from asymptomatic survivors of evd that were persistently infected with ebov, identifying the exact sites of viral persistence in the index cases was not possible , . thus, it is expected that sites of ebov persistence that are not immune-privileged will be discovered. ebov can be detected in breastmilk of female survivors of evd and in various tissues, including the blood and liver, of laboratory mice that have been experimentally infected with ebov and have partial immunity up to days post-exposure , . persistence in sites that are not immune-privileged has also been recently reported for cchfv and lasv , . interestingly, cchfv persists within granulomas of nhp survivors with latent tuberculosis . lasv persists in the smooth muscle cells of blood vessels with vasculitis in both crab-eating macaque and domesticated guinea pig survivors , , suggesting that a local altered immunological environment may sustain viral persistence. genomics is uniquely suited to study the pattern of transmission from patients who are asymptomatic or paucisymptomatic. genomic studies of persistent infections revealed distinct evolutionary dynamics that might result in patterns that can when viral diversity cannot be explained by spillover and spatial-temporal estimations, a secondary spillover may be possible (top left). persistent infections through sexual transmission present with low genetic diversity (that is, with a slow evolutionary rate) over periods (bottom right) that are much longer than expected for acute reintroduction at the expected evolutionary rate (top right). a similar analysis was performed during the first discovery of sexual transmission during the - western african evd outbreak , and a theoretical example is shown (bottom right). this example indicates the number of days after the initial presentation of symptoms at which an acutely infected male is sampled (day ) and the day at which he recovers (day ). on day , the sexual partner of this male becomes symptomatic owing to a very similar ebov genotype, confirmed with epidemiological information and visualized using a median-joining haplotype network. help identify the source of the flare-ups . during the - evd outbreak, an unexpectedly low genetic diversity and complementary epidemiological data provided the first evidence of ebov sexual transmission , . recent pathogenesis studies elucidated the persistent infection of ebov and marv in seminiferous tubules , and epididymides , but niche-specific genomic studies (or single-cell sequencing efforts) have yet to be reported. certain ebov mutations may be tissue-specific and may therefore be required to establish persistence; genomics will be key in identifying these mutations. for instance, the sequencing of ebov genomes present in the plasma and cerebrospinal fluid of a patient with evd during a relapse revealed that only two non-coding changes to the genome had occurred compared to the originally obtained ebov genomes sequenced from plasma during the acute phase of disease . multiple or even single nucleotide changes may permit ebov to transverse the blood-brain barrier by directly infecting endothelial cells and microglia cells and establishing a persistent infection . although ebov and marv have been detected and isolated from the aque ous humour of evd survivors with uveitis , and in breastmilk of survivors , genomic studies have not yet investigated the evolutionary dynamics in these niches. in nature, diverse biotic communities constantly interact and evolve within an ecosystem in response to environmental factors. microorganisms, pathogenic or not, participate in these relationships and constantly react and evolve to changes within the environment. in highly complex organisms such as mammals, immune responses against viruses are inherently complex and involve humoural and intracellular mediators and diverse cell types. in turn, viruses such as ebov evolve sophisticated and diverse strategies to evade the host immune response. by studying host-pathogen interactions, we may improve our understanding of the mechanisms that govern infection, immunity and immune evasion. even though ebov is highly virulent and lethal in humans, some individuals survive infection. furthermore, some individuals who were exposed to ebov or who tested seropositive for the virus never reported disease. the seroprevalence rate of these individuals, categorized as asymptomatic or paucisymptomatic, has been reported to be > % throughout africa [ ] [ ] [ ] [ ] [ ] [ ] . transcriptomics offer insight as to why certain factors, such as the source, viral load, and infectivity of ebov or host genetics, contribute to the range of disease severity and survivorship in patients. host 'immune gene signatures' in patients infected with ebov/mak have been associated with clinical prognosis , . indeed, data generated from patients infected with ebov/mak ( survivors and fatal cases) revealed that interferon response-related genes and acute-phase responses were dysregulated in patients who did not survive . however, natural killer cell populations were increased in evd survivors, suggesting a crucial role for natural killer cells in controlling ebov infection. furthermore, low levels of inflammation and robust t cell responses with an upregulation of cytotoxic t lymphocyte-associated protein (ctla ) and programmed cell death (pd ) expression in t cells also correlated with survival from evd . additional transcriptomic studies focusing on the population dynamics of ebov in infected humans and possibly in naive nhps will complement earlier characterization of host responses to evd and provide a greater understanding of the mechanisms of evd pathogenesis and disease outcome. bringing transcriptomics tools to the field, facilitated by our ability to perform genomic sequencing in outbreak areas, will allow the promises of precision medicine to be realized in an outbreak setting. the genomic characterization of an outbreak pathogen is only the first step in characterizing a threat, a process that can be facilitated by reverse functional genomics. classical reverse genetics has focused on the virus rescue of filoviruses based on cloning a reference (that is, a consensus) filovirus sequence or using a replicating filovirus isolate to clone filovirus sequences , . however, synthetic reverse genomics can rapidly rescue individual virus haplotypes or genotypes from a virus population in the absence of replicating isolates, using gene and genome synthesis based on sequence information alone. these rescued viruses can be used to evaluate the functional aspects of individual filovirus genome mutations. thus, functional genomics can facilitate the rapid and precise functional characterization of a newly emerging filovirus or filovirus mutant. given that natural filovirus isolates must be studied while fulfilling strict biosafety and biosecurity requirements that are frequently not available in areas of filovirus disease outbreaks, the availability of in-country and field-deployable sequencing platforms increases the ability of researchers to gather crucial information about the virus without the need to export biological specimens across national borders. to succeed, field sequencing needs to produce highly accurate finished filovirus genome sequences (for example, sequences that include the complete genomic leader and trailer regions of the virus) from a variety of sample sources , , . filoviruses rescued from synthetic reverse genetics systems can then be used to study host adaptation and attenuation as well as the efficacy of therapeutics - . the de novo generation of ebov from the ongoing evd outbreak in the democratic republic of the congo (that is, of ebov/"itu") demonstrates the value of synthetic reverse genetics (fig. ). after the development of modular reverse genetic systems that are even more efficient than those available today, even high-throughput phenotypical characterizations of large numbers of minimally divergent filoviruses are likely to be possible even in the absence of a biological isolate. multiple mcms against ebov infection have been developed, including small molecules, monoclonal antibodies (mabs), antibody cocktails and vaccines , and clinical trials have yielded promising results. however, the population dynamics and evolution of ebov are influenced by mutations in rna, rna recombination rates, virus population bottlenecks, natural selection and fitness (including diversifying and purifying selection), host range and mode of transmission . these traits re-adjust depending on the environment in a natural host, a naive accidental host, a previously exposed accidental host (owing to infection or vaccination) or an accidental host that received an mcm. therapeutic pressures will force the selection of individual ebov genotypes, and thereby adaption, to ensure virus survival or persistence. highly accurate genomic data can be used to evaluate available mcms in silico prior to in vitro and in vivo testing and to characterize host responses to specific therapeutic interventions in real time. the erosion of genetic diversity and concomitant reduction in individual fitness and evolutionary potential. for example, accurate sequencing data from ebov/"itu" allowed for the rapid in silico assessment of the ability of the mab (national institutes of health) and zmapp (mapp biopharmaceutical) mabs to bind to the receptor-binding domain of the ebov spike glycoprotein gp , , predicting that these mabs should be effective against circulating ebov/"itu" . using genomic approaches to understand how mcms influence ebov population dynamics and to identify mutant viruses that escape mcms could augment future therapeutic designs and filovirus-targeting strategies. correlates of protection for different vaccines and vaccination regimens against ebov have not been fully determined. however, both humoural and cellular immunity independently correlate with the protection of nhps from ebov infection and disease , . the use of a recombinant vesicular stomatitis indiana virus vaccine expressing ebov gp , , rvsvΔg-zebov-gp (sold under the brand name ervebo), the first ebov vaccine to be approved by the fda , , diminished evd case fatality rates in a limited ring-vaccination trial performed in guinea in (ref. ) and it is currently administered to people living in the area of the current evd outbreak. however, unfortunately, some vaccinated individuals still present with clinical signs of mild evd. the exact reasons for these 'breakthrough cases' are not completely understood; however, they are thought to result from ebov infection within the first days after vaccination. a breakthrough could be due to the individual having an insufficient immune response to control the virus (that is, when the vaccine induces a low titre of anti-ebov antibodies and/or scarce effector cells) or to ebov adapting to escape the immunological pressures produced by the vaccine. the characterization of the genomic ebov population in patients who developed evd after vaccination could help address these questions. immunotherapy has also been successfully used as a therapy for evd, most notably during the ongoing outbreak in the democratic republic of the congo . the pamoja tulinde maisha (palm) randomized controlled trial recently evaluated four investigational therapeutics (zmapp, remdesivir (gilead sciences, inc.), mab and regn-eb (regeneron pharmaceuticals)) in the treatment of evd . mab (a single mab) and regn-eb (a cocktail of three mabs) were significantly more effective than zmapp (a cocktail of three mabs) reverse functional genomics facilitates external support in the response to outbreaks of ebola virus disease (evd) that occur in remote areas that lack in-house resources to test available medical countermeasures. rapid, high accuracy , complete genome sequences determined in-country are shared with out-of-country collaborators to evaluate key genomic and proteomic changes in ebola virus (ebov) that may affect the efficacy of available therapeutics (part a). for example, changes in the double-stranded rna (dsrna)-binding site of the ebov polymerase cofactor viral protein (vp ), a protein targeted by several therapeutics, can be identified from the sequencing data obtained for a new ebov isolate. changes in this region of vp may compromise the efficacy of treatments. indeed, if two available therapeutic agents (hypothetical treatment a and hypothetical treatment b) target vp , reverse genetic systems can produce replicative ebovs de novo that contain the changes identified in vp (part b). these replicative ebovs can then be used for the in vitro and in vivo therapeutic evaluation of both hypothetical treatments; data obtained using this approach can inform on which treatment is potentially more efficacious against the ebov isolate causing the outbreak. in treating evd (p = . and p = . , respectively) and were also more effective than remdesivir (a nucleoside analogue); the effect of zmapp and remdesivir on evd was not significantly different. mab , obtained from a evd survivor from the democratic republic of the congo, is one of several recently identified ebolavirus-neutralizing antibodies that are being developed as therapeutics for evd [ ] [ ] [ ] [ ] . this mab protected nhps from ebov-induced disease and death, even when administered days after inoculation with ebov . as mab binds to the ebov glycoprotein gp , , the risk of escape mutants arising might be constrained by viral fitness. regn-eb also showed promising results in ebov-exposed nhps, and no mutant viruses were reported to escape this mcm , . by contrast, ebov mutants that escape zmapp have been characterized . a mutation in amino acid residue of ebov gp , abrogated its binding to two of the mabs within zmapp, and a mutation in amino acid residue of ebov gp , abrogated its binding to the third mab . moreover, epitope mapping of ebov gp , using an alanine-scanning assay identified several residues that are crucial for antibodies to bind to ebov gp , , although none of these mutations was tested for fitness. ( ) . as ebov continually replicates, expanding intra-host diversity can create heterogeneous subpopulations ( , blue circles). once exposed to treatment ( , dashed line), ebov intra-host populations may be countered and eliminated, demonstrating an effective treatment without further intra-host replication or diversification (green circles). however, a small subpopulation surviving the therapeutic bottleneck may allow escape mutants to subvert treatment ( ) and continue diversifying into novel, treatment-resistant genotypes ( , red circles). (~ - ) reduces the analytical power of comparative virus-host interactions and inter-host population-level genomics. in addition, experiments aimed at understanding the appearance of antiviral resistance are restrictive; precise protocols to measure and evaluate ebov and the host immune response to infection without violating established policies are urgently required. furthermore, the possibility that a more virulent or less treatable virus may evolve during such experiments and be accidently released is a concern, which is why institutional biosafety committees are cautious in approving experiments aimed at creating such viruses. additionally, concerns may arise from other nations that are parties of the biological weapons and toxins convention. convincing national rivals that experiments resulting in ebov strains that are resistant to mcms were actually intended to strengthen mcms, and not to deliberately create biological weapons, is not straightforward. the advancement of targeted and unbiased genomic sequencing has profoundly impacted our biological knowledge of, epidemiological preparedness for, and response strategies to known and unknown high-consequence filovirus infections. greater investments in in-country genomic infrastructure and mobile sequencing platforms have reduced the time from sample to viral genome sequence and simultaneously informed local clinicians, epidemiologists and public health officials of genome-guided information on the virus responsible for a current outbreak. advances in large-scale and timely data generation encourage future genomic studies to go beyond consensus-level pathogen genome sequencing during an outbreak. for example, persistent infections in immune-privileged sites of survivors can be characterized using single-cell sequencing technologies. additionally, an increased focus on host responses in an infected individual and the contribution of host genome characteristics to disease outcome and transmission would potentially further benefit the development of mcms and improve the outbreak response. complete pathogen-host genomic investigations could be applied to infected individuals, nhps and known natural host reservoirs of filoviruses. the successful integration of current and future genomic tools will rely on the establishment of new long-term partnerships between government, academia and public health agencies and on maintaining in-country genomic capabilities where the threat of filovirus outbreaks is imminent. in silico modelling using the three-dimensional structure of ebov gp , was used to predict which mutations in ebov would enable it to escape antibody binding , . initially, mab kz was analysed, followed by mab , mab and mab f - - . a list of mutations predicted to interfere with kz -ebov gp , binding was expanded to mutations predicted to disrupt the binding of other mabs to ebov gp , . three of the predicted mutations were found in ebovs infecting humans or experimental animals , , showing that viruses may escape current mcms under investigation. despite the proven efficacy of two therapeutics assessed in the palm trial, namely mab and regn-eb , none of the treatments achieved complete protection against evd . we hypothesize that the characterization of the ebov population in individuals who did not benefit from treatment in the palm trial might help elucidate the reasons for this failure. a clear demonstration of the power of genomics for this purpose was the investigation of two nhps that succumbed to experimental ebov exposure despite experimental treatment with mb- , a cocktail of three mabs. two clusters of genomic mutations (a cluster of five non-synonymous changes in one animal and a cluster of four non-synonymous changes in the other) reduced the binding of the three mabs to ebov gp , ( fig. ). viral isolates obtained after mb- treatment recapitulated the observed 'escape' phenotype. the mutations, all located in the ebov glycoprotein (gp) gene, abrogated antibody binding to gp , . although this study was restricted in size, it highlights mechanisms by which ebov can evade immuno therapies. first, adaptation to a selection pressure can occur rapidly. second, methods to monitor the appearance and phasing of viral mutants that can escape immunotherapies are crucial. third, with the use of reverse genetics systems, scientists can acquire pertinent information on the therapeutic efficacy of sequence-based mcms during an ongoing outbreak of evd (fig. ). for example, phenotypical changes resulting from clade-defining non-synonymous mutations (for example, alanine to histidine substitution at residue in nucleoprotein or isoleucine to methionine substitution at residue in viral protein , both in ebov/"itu") or positively selected non-synonymous mutations identified in the ongoing outbreak can be investigated. unfortunately, not many studies have investigated the resistance of ebov to candidate vaccines or to mcm. cost is a consideration, but 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ancient and integrated into mammalian genomes sequence-based evidence of a long co-evolutionary history of filoviruses and mammalian filovirus hosts clinical metagenomic next-generation sequencing for pathogen detection establishment and cryptic transmission of zika virus in brazil and the americas we thank laura bollinger (nih/niaid integrated research facility at fort detrick, frederick, md, usa) for critically editing the manuscript and william discher (usamriid, fort detrick, frederick, md, usa) for the diagram used in fig. . in no event shall any of these entities have any responsibility or liability for any use, misuse, inability to use or reliance upon the information contained herein. the us departments do not endorse any products or commercial services mentioned in this publication. these authors researched data for the article, contributed to the writing and discussion of the content, and reviewed and edited the manuscript prior to submission, focusing on the following sections: introduction (n.d., j.h.k. and g.p.); identifying filovirus reservoirs (j.h.k.); identifying and characterizing outbreaks (n.d., j.h.k., g. p. and x.z.); genomics in threat characterization (n.d. and g.p.); and genomics in prevention and therapy (m.s.-l. and g.p.). all of the authors contributed to the conclusions. all authors declare no competing interests. nature reviews microbiology thanks miles carroll and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. fda news release on the first fda-approved vaccine for the prevention of ebola virus disease: https://www.fda.gov/ news-events/press-announcements/first-fda-approvedvaccine-prevention-ebola-virus-disease-marking-criticalmilestone-public-health key: cord- -jk ej c authors: qian, hua; miao, te; liu, li; zheng, xiaohong; luo, danting; li, yuguo title: indoor transmission of sars-cov- date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: jk ej c background: by early april , the covid- pandemic had infected nearly one million people and had spread to nearly all countries worldwide. it is essential to understand where and how sars-cov- is transmitted. methods: case reports were extracted from the local municipal health commissions of prefectural cities (municipalities) in china, not including hubei province, between january and february . we identified all outbreaks involving three or more cases and reviewed the major characteristics of the enclosed spaces in which the outbreaks were reported and associated indoor environmental issues. results: three hundred and eighteen outbreaks with three or more cases were identified, involving confirmed cases in prefectural cities. we divided the venues in which the outbreaks occurred into six categories: homes, transport, food, entertainment, shopping, and miscellaneous. among the identified outbreaks, . % involved three cases, . % involved four cases, and only . % involved ten or more cases. home outbreaks were the dominant category ( of outbreaks; . %), followed by transport ( ; . %; note that many outbreaks involved more than one venue category). most home outbreaks involved three to five cases. we identified only a single outbreak in an outdoor environment, which involved two cases. conclusions: all identified outbreaks of three or more cases occurred in an indoor environment, which confirms that sharing indoor space is a major sars-cov- infection risk. in less than months, sars-cov- has rapidly spread to nearly all countries worldwide and by april it had infected more than a million people, and killed nearly , people. understanding where and how sars-cov- is transmitted from an infected person to a susceptible person is essential for effective intervention. the once-in-a-century covid- pandemic occurred right in the age of artificial intelligence and big data. many clusters/outbreaks were identified via contact tracing by local health authorities in china and elsewhere using both traditional and new technologies. the identification of these clusters allowed the health authorities to quarantine close contacts for effective intervention and provided an opportunity to study the characteristics of where and how these clusters occurred. the first covid- patient was identified in wuhan in december , and the largest number of confirmed chinese cases occurred in hubei province, of which wuhan is the provincial capital. since january , the local health authorities of cities outside hubei have reported online the details of most identified cases of infections. in this study, we identified the outbreaks from these case reports from the local municipal health commissions of prefectural cities (municipalities) in china, not including hubei province, between january and february and reviewed the major characteristics of the enclosed areas in which these outbreaks were determined to have occurred and associated indoor environment issues. we collected descriptions of each confirmed case from the local municipal health commission website of prefectural cities in mainland china, not including hubei province. each local municipal health commission announced a description of the confirmed cases each day. the case descriptions generally included age, sex, venue of infection, symptoms, date of symptom onset, hospitalisation, and confirmation and history of exposure. many described cases also included the individual trajectory and relationship with other confirmed cases, and quite often clusters had already been identified. we consulted the websites nationwide except for those of cities in hubei province and collected all available data up to february . data from a few major cities -beijing, shanghai, and guangzhouwere not included in our analysis due to insufficient case descriptions. case descriptions from hong kong, macao, and taiwan were collected from their health authorities. we input the data into a database in a unified format and conducted crossvalidation to ensure data reliability. a total of cases with the minimum required descriptions (i.e., the information listed above) were found; these accounted for . % of the , confirmed non-hubei cases in china by february . in this study, we defined a cluster as an aggregation of three or more cases that appears to be linked to the same infection venue (e.g., an apartment, an office, a school or a train) during a sufficiently close period. we defined an outbreak as a cluster in which a common index patient is suspected, and we excluded tertiary and highergeneration infections in counting the number of cases involved. we also excluded outbreaks that involved only two cases to exclude possible spouse-to-spouse transmission and to reduce the workload due to the large number of clusters or outbreaks with two cases. we also identified the index patient(s) of the identified outbreaks and their date of symptom onset. we divided the identified outbreaks into categories for further analysis. first, six categories of infection venues were considered: homes (apartments and villas), transport (train, private car, high-speed rail, bus, passenger plane, taxi, cruise ship, etc.), restaurants and other food venues, entertainment venues (gyms, mahjong, cards, tea houses, and barbershops) and shopping venues (shopping malls and supermarkets), with an additional miscellaneous venue (hospitals, hotel rooms, unspecified community, thermal power plants, etc.) . second, four categories of infected individuals were considered based on their relationship: family members, family relatives, socially connected and socially non-connected. the funding bodies had no such involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. the corresponding authors also confirms that they had full access to all the data in the study and had final responsibility for the decision to submit for publication. we identified outbreaks involving , infected individuals in cities. the top three cities (table s ) were shenzhen, guangdong ( outbreaks, · %; cases, · %), chongqing ( outbreaks, · %; cases, · %) and bozhou, anhui (nine outbreaks, · %; , · %). the average number (sd) of cases per outbreak was ·  · . among the identified outbreaks, more than half ( ; · %) involved three cases, more than a quarter ( ; · %) involved four cases, and only five ( · %) outbreaks involved ten or more cases. table s briefly describes four outbreaks, including the largest outbreak in a shopping mall in tianjin ( cases). among the outbreaks, involved only family members, involved family relatives, involved socially connected individuals, involved socially non-connected, and only three involved multiple relationships. in addition to family members, family relatives and socially connected individuals constituted a large proportion of the infected cases ( figure a ). eighty-three of the identified outbreaks had multiple possible venues, which means either that the exact venue of infection cannot be identified or that more than one venue was involved in the infection. if we double-or triple-count these venues, we have a total of infection venues for outbreaks ( figure b ). among the outbreaks, ( · %) occurred in a home (one in a villa; all others in apartments), ( · %) in transport, at a restaurant or other food venue, seven at an entertainment venue, and seven at a shopping venue (shopping mall and supermarket), with an additional at a miscellaneous venue (e.g., hospital, hotel room, unspecified community, and thermal power plant). most of the home outbreaks included three to five cases ( with three cases, with four cases, and with five cases). the average number of cases was · for the home outbreaks, · for transport, · for food venues, · for entertainment venues, · for shopping venues, and · for miscellaneous venues. the proportion of large outbreaks was high for shops and food venues, possibly because more susceptible individuals were present in these venues than in homes. shopping and entertainment venues were each associated with only seven outbreaks. this seems to suggest the difficulty of implementing preventive measures in places with large numbers of susceptible individuals. between december and january , we also identified outbreaks with known start and end dates of the suspected infectious period (figure a ). the identified outbreaks peaked between and january (figure a ), which coincides with the celebration period of the chinese new year (cny). cny lasted from new year's eve on january to the lantern festival (i.e., the th of lunar january) on february. the official holiday in mainland china was from to january . the peak date for the number of transport outbreaks was to days earlier than that for the home outbreaks as people travelled home for cny. because home outbreaks dominated, the changes in the temporal profile of the number of cases ( figure a ) closely follows that of the home outbreaks ( figure b ). however, for outbreaks with more than six cases, no particular pattern was identified over time, which suggests a sporadic nature. among the outbreaks with a known suspected infectious period, included a known date of symptom onset for the index patient ( figure ). we further divided those outbreaks into two subgroups according to the index patient's symptom-onset date: on or before january ( outbreaks) and after january ( outbreaks). the average time from symptom onset to the ending infectious date was · ± · days for those on and before january and · ± · days for those afterward. the first salient feature of the identified outbreaks that involved three or more cases is that they all occurred in indoor environments. although this finding was expected, its significance has not been well recognised by the community and by policy makers. indoors is where our lives and work are in modern civilisation. the transmission of respiratory infections such as sars-cov- from the infected to the susceptible is an indoor phenomenon. the emergence of homes as the most common covid- outbreak venue in china is not surprising. during the covid- epidemic in mainland china, homes became temporary quarantine places. our estimated home dominance of · % is close to the official estimate of % of the so-called household clusters among the nearly clusters (not outbreaks) defined by the china national health commission. after wuhan announced its city lockdown on january, the warning message spread throughout the country. people in provinces outside hubei also began to stay at home. most chinese families have one child, and some families may also include grandparents. the relatively low number of cases in these home outbreaks might be considered an advantage of compulsory home quarantine because transmission was limited to the small number of family members. similar stay-athome policies have now been implemented elsewhere during the pandemic. the rising trend shown before the peak period in figure was probably due to the introduction of imported cases due to the spring festival travel season (chunyun in chinese), a period around cny during which many people leave cities in which they work to visit their rural families. the chunyun brought people from the epicentre wuhan to their home all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/ . / . . . doi: medrxiv preprint cities before wuhan's lockdown on january. social and family gatherings continued after january in most cities outside hubei. interventions such as contact tracing and confinement of estates, villages, and individual buildings were implemented gradually in most cities outside hubei immediately after cny, which explains the sharp declining curve after january. our study does not rule out outdoor transmission of the virus. however, among our , identified cases in china with sufficient descriptions, only one outdoor outbreak involving two cases occurred in a village in shangqiu, henan. a -year-old man had a conversation outdoors with an individual who had returned from wuhan on january and had the onset of symptoms on february. the second salient feature of the identified outbreaks is the relatively small number of outbreaks that involved or more cases. the largest outbreak occurred in a tianjin shopping mall and involved cases, although wu et al. reported that cases were involved (table ) . this feature contrasts with the sars-cov epidemic, during which major super-spreading events in hong kong and singapore alone were identified to involve as many as cases, and super-spreading events dominated the epidemic. the occurrence of many small outbreaks (in number of cases) in the covid- pandemic suggests a different transmission pattern from that of the sars-cov epidemic. some virus, epidemiological, and environmental factors could have contributed to this observed difference between the sars-cov epidemic and the current covid- pandemic. we cannot pinpoint the exact transmission routes from these identified outbreaks. most health authorities advised that the covid- virus is transmitted mainly by close contact and via the fomite route (e.g., china nhc and cdc ). the china nhc also suggested that longrange aerosol transmission may occur when certain conditions are met, such as in crowded enclosures or spaces with poor ventilation. frequent close contact occurs and high touch surfaces exist in buildings. - we do not have data on the hygiene conditions and human density of the infection venues of the outbreaks studied here. the exact location of the infection venues and the necessary parameters such as the floor area or the number of occupants were not provided in the case reports. instead, we reviewed the current design standards of thermal and ventilation conditions, occupant density and close contact behaviour in the various indoor environments discussed here (table s ). the required ventilation rates vary significantly among homes, offices, trains, and buses. for example, the required ventilation rate is only · l/s per person in shopping malls and · l/s per person in public buses, whereas a ventilation rate of to l/s is required for good indoor air quality. an international systematic review showed that a rate as high as l/s per person may be needed. many existing buildings are crowded, poorly ventilated, and unhygienic. a comprehensive review of ventilation conditions in chinese indoor environments by ye et al. showed that the co concentration can reach , ppm in some buildings. the design and operation of buildings have also been under pressure to reduce energy use and increase human productivity. balancing the need for energy efficiency, indoor environment, and health in both urban planning and building design has not been easy. the quality of indoor environments might be sacrificed by putting a greater focus on cost than on health. this study has limitations. we only studied outbreaks in china, where very strict intervention measures were implemented. we relied fully on the case reports of the local health authorities in each city, and variation exists in the details and the quality of their original epidemiological investigations. we also made no attempt to access any of the infection venues, and the details of each of these indoor spaces remains unknown. this study shows that the individual indoor environments in which we live and work are the most common venues in which the virus of the once-in-a-century-pandemic is transmitted among us. an individual infected in one building may infect others in the building(s) that he or she later visits. people are in constant contact as they move from one indoor space or building to another, which creates an indoor contact network through which a virus can spread. the buildings and transport cabins in various parts of the world are thus connected and facilitated the spread of the covid- pandemic virus. the association between crowding and infection has been known since pringle. the most dramatic example might be in the cruise ship outbreak on the crowded diamond princess, of which the peak basic production number was predicted to be or · before quarantine and much higher elsewhere. the world's first statutory housing policy, the artisans and labourers dwellings act was developed following th century empirical evidence that crowding led to a high incidence of infectious disease. a recent systematic review by the world health organization also found an association between crowding and infection. a lancet editorial in declared '[t]he right to a healthy home'. one who meeting also declared that 'everyone has the right to breathe healthy indoor air' and that 'the provision of healthy indoor air should not compromise global or local ecological integrity, or the rights of future generations'. we hope that in the post-pandemic future, mankind will reflect deeply on the need for a healthy indoor environment. all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/ . / . . . doi: medrxiv preprint the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/ . / . . . doi: medrxiv preprint (a) (b) all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/ . / . . . doi: medrxiv preprint (c) figure s . two hundred and thirty-one outbreaks with known starting and ending dates of suspected infectious period, arranged by (a) starting date of suspected infectious period, (b) ending date, and (c) median date. all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi. org/ . org/ . / all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi. org/ . org/ . / the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi. org/ . org/ . / figure s . provincial distribution of the identified outbreaks and number of cases involved in these outbreaks. table s . brief summary of outbreaks with to cases. shop ( ), liaocheng, shangdong between january and february, workers from the zhenhua supermarket (振华量贩聊城闸口店) were confirmed to be infected. seven of them worked in the f shopping area. six other secondary infections were reported (five family members of the two cases and one close contact of the third case). local health authorities identified close contacts by february, and a free check and test were offered to all customers who visited the shop from to jan. based on our collected data, cases were involved. according to news reports (wenzhou news network, ), a total of cases were involved in this outbreak, including administrators, shopping assistants or cleaners, and customers of wenzhou intime department store (温州银泰百货商场). the patient with the earliest onset of symptoms was a female cleaner ( january) and the last was a female customer ( february). the first case was identified on january. the mall was closed on january. the local health authority traced more than , people who visited the mall or nearby for minutes or more, including , workers in the mall and nearby residents. the mall was opened again on march. ( ), tianjin based on our collected data, cases were involved. according to wu et al. ( ) , cases were involved. six shop workers and nine customers in a shopping centre were infected, with onset dates between january (a shop assistant) and february (a customer). the shopping complex was built in , with a , m shopping area, mainly on the first and second floors. there were workers including shop assistants. people were purchasing clothes and gifts before cny, so the shop was very crowded with at least , visitors to the venue during the possible infectious periods. the outbreak mainly occurred on the first floor, where clothes, shoes, jewellery, and small appliances are sold. the building was closed on january. all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/ . / . . . doi: medrxiv preprint 宁夏 ningxia table s . characteristics of indoor environments as required by standards where covid- clusters occurred. all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is in general, we tried to review the chinese standards/studies of chinese buildings and cited international standards or studies elsewhere if needed. who, a. coronavirus disease (covid- ) situation reports. situation report - by air infiltration rates in the bedrooms of residences and estimated parametric infiltration rate distribution in guangzhou air change rates in urban chinese bedrooms patterns of human social contact and contact with animals in shanghai social mixing patterns in rural and urban areas of southern china preferred interpersonal distances: a global comparison hou et al. ( ) stated 'the result is that in approximately % of chinese bedrooms, regardless of climate region or season, the only outdoor air entering bedrooms is by infiltration the authors are grateful to shengqi wang, xiaoxue cheng, luping ma, ya lei, siying mei, ziying zhou, yiran lu, mengjie duan, yifan li, qionglan he and ziang xi, who helped collect the original data. the authors declare no conflict of interest.h. qian, t. miao, and y. li contributed equally. y. li and h. qian contributed to study design, hypothesis formulation, and coordination. l. liu, x. zheng and d. luo contributed to data collection and initial data analyses. h. qian and t miao contributed to major data analyses. y. li wrote the first draft of the paper, and h. qian and t. miao contributed to major revision. all of the other authors contributed to revision.all of the authors approved the submitted version and have agreed to be personally accountable for their own contributions. key: cord- -gd phncm authors: chuo, hsin-you title: theme park visitors’ responses to the sars outbreak in taiwan date: - - journal: nan doi: . /s - ( ) - sha: doc_id: cord_uid: gd phncm the purpose of this study is to examine empirically different characteristics between theme park visitors who did and did not visit theme parks during the sars outbreak period in taiwan. the data consisting of , respondents were obtained from visitors to the five leading theme parks. discriminant analysis was used to analyze respondents’ characteristics such as age, benefit sought, product involvement, and risk perception to examine significant differences between the two categories of respondents. results of this study showed that younger or more frequent visitors more likely continued to visit theme parks during the sars outbreak. besides, visitors who continued to visit theme parks perceived greater infectious risk than those who did not visit theme parks during the sars outbreak. severe acute respiratory syndrome (sars), caused by the previously unrecognized coronavirus (sars-cov), is a highly contagious febrile respiratory illness and also associated with a high mortality rate. it is the first severe and readily transmissible new disease to emerge in the st century. dr. carl urbani, a advances in hospitality and leisure, volume , - copyright r by elsevier ltd. all rights of reproduction in any form reserved issn: - /doi: . /s - ( ) - world health organization (who) epidemiologist working in vietnam, submitted a report to the wto, an affiliation of the united nations, and identified/named this unknown disease ''sars'' initially in march for the cases with the onset in february of (who, a , however, the health authority in china named the disease ''atypical pneumonia'' (or feidian, the shortened version of its full chinese name) instead (wang, ) . the first cases of sars are now known to have emerged in mid-november in guangdong province, china. on february , , an infected medical doctor (dr. liu) left guangdong province and visited hong kong for attending a wedding reception. dr. liu stayed at the metropole hotel in hong kong and infected a number of tourists from several parts of the world (who, b) . subsequently, the disease began spreading around the world along international air travel routes. a few days later, hospitals in hong kong, vietnam, and singapore began reporting cases. by late february , sars was considered an emerging disease (who, a) . from sars' appearance in november to july , , when the who declared that owing to the outbreak more than , individuals were infected by and victims died from the disease (who, c) . most sars cases have occurred in mainland china, hong kong, taiwan, and canada. mainland china reported the largest number of sars infections ( , ) and deaths ( ), followed by hong kong ( , ; ) and taiwan ( ; ) (cdc, ; who, c) . consequently, sars caused considerable social disruption and public anxiety, even in area well beyond the outbreak sites (who, d) . in terms of the number of sars infections and deaths, the severity of the outbreak might seem to be overstated and people's responses might look like over-reacting. in contrast to tuberculosis ( , people infected and , dead per year), or car accidents ( , people injured and killed in the first months of ), sars killed ''only'' patients in taiwan (chen, jang, & kim, ) . accordingly, some scholars (e.g., chen et al., ; mckercher & chon, ) point out that people were over-reacting to the sars epidemic and tourism suffered unnecessary damage. however, it seems more interesting and necessary to realize factors out of the cumulative number of fatal cases that caused an enormous panic -which subsequently resulted in the over-reactions. the sars epidemic has been characterized by its rapid spread. hsieh, chen, and hsu ( ) synthesize official reports and describe the rapid spread of the sars outbreak in taiwan in detail. the who reported , probable sars cases with deaths worldwide on april , ; china, hong kong, singapore, vietnam, and toronto, canada, had the most cases. taiwan, meanwhile, had probable cases and no deaths. seventyeight percent of the cases were imported. the growth of the numbers of sars infections seemed to be a typical minor outbreak at that time. on that day, a new cluster of seven infections in hoping hospital in taipei was reported and it started a chain of local transmissions that cumulated in probable cases and deaths in the following two weeks. by mid-may, the numbers grew to probable cases and deaths. subsequently, by june , it expanded into probable cases and deaths. in a period of less than one month, more than a sixfold increase in the numbers of sars infections and victims was erupted rapidly in taiwan. the rapid increase rates of reported probable sars case-patients and deaths undoubtedly would cause a panic nationwide in taiwan. in addition to the rapid increase rate of reported probable sars casepatients, the nationwide panic in taiwan might also be resulted from a sense of the endless and uncontrolled expansion of the outbreak. as the disease was spreading so rapidly, the health authority in taiwan enforced many stringent measures in order to contain the outbreak. in addition to thermal scanning arrivals from abroad to check for signs of fever induced by sars, hsieh et al. ( ) indicate two of the most important stressed measures. one measure was reporting, admitting, and hospitalizing all susceptible patients. the other was the house quarantine of people either those with contacts to the suspected case-patients or arrivals from the affected areas abroad. however, on the first hand, hospitals in taiwan were initially unprepared for and unprotected from the sars disease. the patient quarantine rooms, personal protective equipments for health care workers, and general infection control, etc., which had been improved and well prepared professionally later (esswein et al., ) , were relatively insufficient at the beginning of the outbreak. since frequent unprotected or inadequately protected patient-to-health care worker interactions and grouping large numbers of ill persons can greatly amplify intrahospital transmission (gopalakrishna et al., ) , almost percent of all traceable infections in taiwan occurred in hospital settings (hsieh et al., ) . it caused inevitably a panic among all medical professions on the frontline in the battle against sars. on the other hand, the home quarantine of a number of susceptible people was frequently broken (hsieh et al., ) . just as the acquired immune deficiency syndrome (aids), it cannot be considered quarantineable not only because of medical but also because of ethical and legal issues (gensini, yacoub, & conti, ) . accordingly, a sense of uncontrollability was emerged publicly at the beginning of the sars outbreak. furthermore, the local sensationalist media accelerated and amplified the resulted panic from the sense of uncontrollability successfully by focusing their attention on some intrahospital transmission and out-of-supervised quarantine cases. this phenomenon was consistent with mason, grabowski, and du's ( , p. ) description of the global media that the media were much less interested in providing accurate information and more concerned with selling copies of their publication through sensationalist but inaccurate stories. aside from the domestic factors, i.e., the rapid increase rate of sarsinfected cases and a sense of out-of-control, it should be noted that there was an international factor as well. the international factor played a significant role in the enforcement of not only a nationwide panic in taiwan but also a worldwide panic to the sars epidemic. in order to minimize the global spread of sars, the who issued a series of specific travel advisories -recommending travelers to postpone all but essential travel to designated areas where the risk of exposure to sars was considered high -against hong kong, china, toronto, and taiwan, respectively from april to may and especially a ''general travel advisory'' to potential travelers on march , (who, d . the travel advisories did trigger a chain reaction of public anxiety even in areas well beyond the outbreak sites. the announcements were unprecedented in the who's almost -year history, for this was the first time that the organization had issued advisories for specific geographical areas due to an outbreak of an epidemic (wttc, ) . although the recommendations were respectively removed by the who from all the designated areas to which they had applied as the sars outbreak was successfully curtailed in late june, the hospitality and tourism industry in asia had been severely hit by the outbreak of the sars epidemic. while it must be praised for the who's substantial actions in controlling the sars outbreak, strong criticism from authorities of the ''off-limits'' areas, tourism industry, and scholars was directed at the organization. mckercher and chon ( ) indicate that the who's travel advisories criticism was instrumental in triggering the almost complete eradication of tourism in asia. based on the costs of canceled travel and decreased investment in asia, the economic costs have been estimated ranging from us$ , million to us$ , (who, d) . it is even estimated to produce costs that might rival the asian financial crisis of the mid- s (de lisle, ) . lakshmanan ( ) (as cited by mckercher & chon, ) well describes the very unusual feature of the sars outbreak by a statement that ''a panic spread faster than the disease itself.'' most likely, it was partly contributed by the participation of the global media as a role of accelerators and amplifiers in the spread of the worldwide panic. since the who publicized its message about sars and travel warning by using the global media, however, it could not write word-for-word the article or website commentary, the organization could hardly control the tone or precise nature of any media communication. accordingly, mason et al. ( ) point out that the way the who's global health alert was reported by the world's media is also likely to have contributed to the feeling of worldwide panic. tourism industry is still threatened by the possibility of the recurrence of the infectious disease since the who has warned that sars might recur. besides, there will be new biological threats whether sars reappears or not. therefore, during the post-outbreak period, one of the most significant recovery efforts that marketing managers in the tourism industry can make is to know what kind of customers continued to patronize their services during the outbreak period. from customers' different patronage decisions in response to the sars outbreak, they can learn valuable lessons and develop a plague survival strategy for possible emerging epidemic outbreaks in the future. particularly, if customers who continued to patronize a hospitality/ tourism service during the sars outbreak can be distinguished and identified from those who did not, marketing managers may be able to increase their efforts to attract the most potential customers in case the sars or similar biological crises emerge someday. drawing on insights from crisis management literature, not only the proactive, strategic, holistic approaches to the issue of crises have been proposed and discussed (e.g., ritchie, ) , but generic or specific models for analyzing and developing management strategies have also been proposed (e.g., faulkner, ; huang & min, ) . aside from the underlying efforts, various crisis cases have been explored, investigated, analyzed, and discussed. chen ( ) examined asian outbound travelers' consumption patterns after the asian economic crisis and provided marketing strategies for international tourism practitioners. blake and sinclair ( ) examined policy responses to the september terrorist attacks in the united states and suggested some ways of handling the situation to policymakers. page, yeoman, munro, connell, & walker ( ) illustrated complex issues associated with a flu pandemic qualitatively via a case study of scenario planning exercise. to the impacts of the sars outbreak, a number of researchers devoted efforts to the formulation of proactive and recovery management in the tourism industry. while some (e.g., chen et al., ; dombey, ; mckercher & chon, ; pine & mckercher, ) revealed the impacts of the sars effects on diverse aspects of the managerial functions, on various sectors of the industry, and/or on different geographical areas, some others (e.g., chien & law, ; henderson & ng, ; tse, so, & sin, ) suggested substantial processes to set up contingency and recovery arrangements for hotel and restaurant management specifically. the purpose of this study is to examine empirically different characteristics between theme park visitors who did and did not visit theme parks during the sars outbreak period in taiwan. significant differences between the two categories of respondents on their characteristics such as age, patronage frequency in the last year, benefit sought, product involvement, and risk perception were examined. accordingly, the following four research questions were developed: . can a significant discriminant function be developed to interpret the differences between respondents who did and did not visit theme parks during the sars outbreak period in taiwan on the basis of their personal characteristics? . which characteristics contribute to most of the inter-group differences? . how accurately can respondents be classified into the two categories by the developed discriminant function? . what marketing implications can be derived from theme park visitors' different patronage decisions in response to the sars outbreak? the target population for this study was visitors to the five leading theme parks in taiwan (i.e., jenfusan, leofoo, yamay, formosan aboriginal culture village, and window on china). quota sampling technique was employed to select elements of the research sample from the sampling population based on the official report (tourism bureau, ) on annual attendance to domestic theme parks in taiwan in . in order to minimize respondents' recall errors, the field survey for data collection was conducted during the period between june and july in since the who extended its travel recommendation to include taiwan on may and removed it from the list of postpone-travel areas on june . junior students from a local university were trained as interviewers for data collection. interviewers stationed near the exit gates of the five parks invited departing visitors to participate in this study. all subjects were selected based on their willingness to volunteer their personal information on site. a structured-undisguised questionnaire was developed for data collection. in addition to the information of respondents' general demographics, their patronage frequency in the last year and whether they visited theme parks in the period of the sars outbreak, the question content also consisted of scale items to measure ''benefit sought,'' ''product involvement,'' and ''risk perception.'' ten individual benefit scale items were derived from pearce's ( ) leisure ladder model for theme park visitors. respondents were asked to rate each of the benefit items from '' '' to '' '' to indicate the extent to which the benefit motivated them to make the current visits. in the specific interests of this study, mcquarrie and munson's ( ) eight scale items for the measurement of consumers' ''enduring involvement'' with a product were modified to measure respondents' product involvement with theme parks in this study. the ''many factors'' described in the seventh scale item ''i usually take many factors into account before purchasing this product'' were replaced by ''admission fee'' and ''the distance a theme park is from my home,'' respectively. as a result, nine involvement measure items with a five-point likert scale were designed in the questionnaire. finally, respondents were asked to subjectively estimate the probability a person will be infected with sars in each of the three given scenarios, respectively. the given scenarios were: ( ) right now in the theme parks which they had just departed from; ( ) participating in outdoor recreational activities if the who should again extend its postpone-travel recommendation to include taiwan; and ( ) visiting a theme park in the same period of time described in the second scenario. respondents were asked to rate the sars-infected possibility in each of the scenarios in terms of percentage (from '' '' to '' ''). in order to develop a meaningful discriminant function, possible correlations between respondents' personal characteristics had to be avoided or eliminated first. accordingly, variables representing each of the respondents' personal characteristics were condensed into factors by the technique of principal components analysis. internal consistency reliability of the variables contained in each of the factors was assessed. a value of cronbach's alpha coefficient greater than . generally indicates satisfactory internal consistency reliability (malhotra, ) . mean of respondents' ratings to consistent variables contained in each of the factors served as the input score of the factor in the process of discriminant analysis. thus, on the one hand, whether or not the respondents visited theme parks during the sars outbreak was adopted to be the dependant (criterion) variable; on the other, respondents' age, their patronage frequency in the last year, and the factors condensed from scale items of respondents' risk perception, benefit sought, and product involvement were adopted to be the independent variables (predictors) in the developing discriminant function. the significance and validity of the function were assessed based on wilks' l test and the percentage of cases correctly classified, respectively. spss was utilized for data processing and the level of significance of . was accepted for all statistic tests in this study. by using quota sampling technique, a research sample consisting of , respondents was obtained from visitors to the five leading theme parks. table shows that the distribution patterns of the respondents' demographics were consistent with the practical observation of theme park visitors' characteristics in the real world. respondents' age ranged from to years, with the mean age of . years (s.d. ¼ . ). they had been to the five theme parks ranging from to times and for an average of . times (s.d. ¼ . ) in the last year. the correlation matrices of the benefit and involvement scale items in the procedure of principal components analysis were examined by bartlett's test of sphericity. to the benefit scale items, the approximate w statistic was . with degrees of freedom, which is of . significance. besides, the value of the kmo statistic (. ) was also large (>. ). to the involvement scale items, the approximate w statistic was . with degrees of freedom, which is also of . significance and the value of the kmo statistic was . . therefore, the procedure of principal components analysis was considered an appropriate technique for analyzing the data in this study. in order to differentiate between the two categories of respondents, a discriminant function was developed in this study. at first, seven independent variables for the subsequent discriminant analysis were identified through the analytical procedures of principal components analysis and cronbach's alpha test. tables and show the results of principal components analysis. ten benefit scale items and nine involvement scale items were condensed into two benefit factors and two involvement factors, were examined to ensure satisfactory internal consistency reliability and then accepted into the discriminant analysis. as a result, the developed standard canonical discriminant function was: where if di>. , classify individual i as belonging to ''visitors who did visit theme parks during the sars outbreak''; otherwise classify individual i as belonging to the other category. the eigenvalue associated with this function is . , and it accounts for percent of the explained variance. the canonical correlation associated with this function is . . it indicates that the variance in the dependent variable is not largely explained by this model. however, the wilks' l associated with the function is . , which transforms to a w of . with degrees of freedom. this is significant beyond the . level. in other words, the discriminant function is statistically significant. therefore, it is meaningful to interpret the results of the discriminant analysis. table shows the primary results of the discriminant analysis. the significance of the univariate f ratios indicates that when the independent variables are considered individually, only the respondents' age, their patronage frequency, and risk perception were significant predictors in discriminating between the groups. besides, the pooled within-groups correlation matrix indicates low correlations between the independent variables. in this case, multicollinearity was unlikely to be a problem. given low intercorrelations between the independent variables in table , independent variables with relatively large standardized coefficients contribute more to the discriminating power of the function, as compared with independent variables with smaller coefficients. therefore, respondents' age and their patronage frequency in the last year contribute to most, while respondents' risk perception also contributes to some, of the inter-group differences. the signs of the coefficients associated with the significant predictors suggest that younger age and more experience in visiting theme parks were more likely to result in the respondents visiting theme parks during the sars outbreak. meanwhile, individuals who visited theme parks during the sars outbreak were also associated with higher risk perception. table shows the classification results based on the developed discriminant function. the percentage of cases correctly classified is . percent. the function seems to be of deficient validity if one expects the function to distinguish individuals who had been to theme parks during the sars outbreak from those who had not, since the predictability of the function is only percent greater than that obtained by chance (i.e., / ¼ . or percent). generally speaking, in this study, a statistically significant discriminant function was successfully developed to interpret the differences between respondents who did and did not visit theme parks during the sars outbreak period in taiwan on the basis of their personal characteristics. among the seven adopted characteristics, respondents' age and their patronage frequency in the last year contributed to most of the inter-group differences. moreover, individuals who visited theme parks during the sars outbreak were also associated with higher risk perception. substantial marketing implications can be explored based on the results of the discriminant analysis, although the function seems to be of deficient validity in terms of predictability. first of all, in case the sars or similar biological crises emerge in the future, younger and/or frequent consumers should be the focused targets of theme park managers' primary marketing efforts because they are more likely to continue to visit theme parks during the period of epidemic outbreak. accordingly, a plague survival strategy can be developed with the goal of attracting consumers from the targets. since the benefits sought by theme park visitors played only a trivial role in their patronage decisions during the sars outbreak, contents of the promotion projects may not be associated with or restricted to particular benefits of visiting theme parks. instead, a series of sales promotions, such as special promotional prices for the admission of large teen groups, cross-promotions with firms providing other products or services to young consumers, or discounted season passes for potential heavy-users, may help theme parks survive the period of epidemic outbreak. one of the results of this study indicates that individuals who continued visiting theme parks during the sars outbreak were associated with higher risk perception in comparison with those who did not visit theme parks. it is interesting to note that grobe and douthitt ( ) also obtained similar findings from their research regarding milk consumers' risk perception of the recombinant (synthetic) bovine growth hormone (rbgh). their findings indicated that consumers who purchase more milk perceive a greater risk than those who purchase less (p. ). however, they did not explain the findings of their research. in fact, the theme park visitors' continued patronage or the milk purchasers' greater consumption resulted in, rather than resulted from, their greater risk perception. in detail, the consistent theme park patronage during the sars outbreak and milk consumption under the purchasers' psychological resistance to the rbgh injection seem to be caused by individuals' relatively inelastic demands for theme parks or milk. in order to build lasting customer relationships, managers should compensate the customers with inelastic demands for their consistent patronage rather than take advantage of them since there are usually a couple of brands or selections for a particular product. therefore, in case the sars or similar biological crises emerge in the future, the present seems to be the perfect time to build up a valuable database consisting of the customers with inelastic demands for particular hospitality and tourism services. thus, service providers may continuously benefit from the database. the finding that visitors' risk perception of the sars infection did not largely contribute to their patronage decisions during the sars outbreak provides indirect evidence that theme park visitors' ''risk attitude'' dominated their ''risk perception'' in their risk response behavior to the sars epidemic. pennings, wansink, and meulenberg ( ) proposed that the behavior of consumers in a crisis situation can be explained by a combination of risk perception and risk attitude. whereas risk attitude deals with consumers' interpretation of the content of the risk, the seriousness of adverse consequences, or the extent of risk aversion toward a particular crisis, risk perception instead deals with consumers' interpretation of the chance of being exposed to the content of the risk. since individuals with greater risk perception were the ones who continued to visit theme parks while those with lower risk perception tended to avoid the patronage, risk perception does not seem to be the dominant motivator of theme park visitors. suppose that risk attitude is the true motivator behind theme park visitors' responses to the sars outbreak. in such a case, pennings et al. suggest that even if the probabilities of being exposed to the risk are small, effectively communicating these probabilities will have little influence on consumer behavior. instead, marketers will have to focus on ways to eliminate the risk. chien and law ( ) suggested substantial processes to minimize hotel employees and guests' possibility of sars infection and to contain the potential spread of viruses on the hotel property. the processes can also be well utilized by other businesses or services in the hospitality and tourism industry. in addition to actually implementing the processes of risk elimination, it is equally important that management should make efforts to let the potential consumers know and let the customers see, smell, hear, and feel the processes of risk elimination on the property. based on the findings and limitations of this study, several recommendations for further research can be drawn. first, the roles that both risk perception and risk attitude play in people's responses to severe epidemics or similar biological crises can be further explored. extended from the existing related literature, the following research might be expected to establish a theoretical model -consisting risk perception, risk attitude, and other significant variables -of people's responses to disease outbreaks. second, although the significant role of the media in the sars outbreak has been well discussed in mason et al. ( ) in terms of the amount of media attention given to the outbreak along the five stages of hall's ( ) ''issue-attention cycle,'' given a strong averse risk attitude toward particular epidemics or pandemics, issues regarding how and what the media can communicate effectively to the public to have significant influence on their responses to the disease outbreak can be further investigated by the following research. however, it might be even more important to know how to allure or encourage the media to cease rather than amplify social panic by the above approaches. the singapore case -a well-trusted institute (e.g., tourist board) coordinates related media and tourism sectors to establish a taskforce and working with the national health authority to produce guidelines and to have a hold over the social panic -indicated in henderson ( ) might not work applicably in elsewhere, however, it did provide a sample of possible domestic problem-solving mechanism. based on the basic framework, a possible international cooperation mechanism might be further discussed and developed. it is clear that the international hospitality and tourism industry will always benefit from researchers' continuing efforts to confront any possible emerging industry crises in the future. the efforts provide effective suggestions to either the management practitioners or the public policymakers during and after a certain crisis emergence in the industry. tourism crisis management: us response to use of quarantine to prevent transmission of severe acute respiratory syndrome: taiwan examining asian outbound travelers' consumption patterns after the asian economic crisis the impact of the sars outbreak on taiwanese hotel stock performance: an event-study approach the impact of the severe acute respiratory syndrome on hotels: a case study of hong kong atypical pneumonia and ambivalent law and politics: sars and the response to sars in china the effects of sars on the chinese tourism industry environmental and occupational health response to sars towards a framework for tourism disaster management the concept of quarantine in history: from plague to sars sars transmission and hospital containment consumer acceptance of recombinant bovine growth hormone: interplay between beliefs and perceived risks travel safety and the media: the significance of the issue-attention cycle managing a health-related crisis: severe acute respiratory syndrome (sars) in singapore responding to crisis: severe acute respiratory syndrome (sars) and hotels in singapore sars outbreak earthquake devastation and recovery in tourism: the taiwan case hong kong's fear of sars spreading faster than the disease itself: % residents wearing surgical masks marketing research: an applied orientation severe acute respiratory syndrome, tourism and the media the over-reaction to sars and the collapse of asian tourism a revised product involvement inventory: improved usability and validity a case study of best practice-visit scotland's prepared response to an influenza pandemic fundamentals of tourist motivation a note on modeling consumer reactions to a crisis: the case of the mad cow disease the impact of sars on hong kong's tourism industry chaos, crises and disasters: a strategic approach to crisis management in the tourism industry report on tourism statistics crisis management and recovery: how restaurants in hong kong responded to sars china's response to sars severe acute respiratory syndrome (sars): status of the outbreak and lessons for the immediate future severe acute respiratory syndrome (sars): report by the secretariat (provisional agenda item . , eb / ) singapore and vietnam reports). london: world travel and tourism council this study reveals that younger or more frequent visitors more likely continued to visit theme parks during the sars outbreak period. in addition to the substantial suggestions on possible adjustments of marketing mix, some implications can be emerged from the findings and discussion of this study. it should be firstly noted that, during a plague outbreak, the impact against tourism industry is primarily generated by the panic resulted from the plague rather than by the plague itself. the dominant determinant in the formulation of the plague-resulted panic tends to be the magnitude of people's aversion (risk attitude) to the plague rather than the perceived possibility to be infected by the plague (risk perception). by the back-up of the media, the scale and spread of possible emerged panic tends to be amplified and accelerated extensively. if a panic has been prevailed, it might be an inevitable outcome that people tend to over-react in their responses to a plague outbreak. people's over-reactions might be represented by decreasing the amount of consumption or even the collapse of regional tourism. according to the subsequence of a plague-outbreak crisis emerging from the discovery and identification of an epidemic to possible damages suffered by tourism industry, several critical points between different stages of the crisis progression can be found. in terms of crisis management, if the critical points can be well monitored and managed, the situation will be substantially better off. key: cord- -fqy sm authors: huremović, damir title: brief history of pandemics (pandemics throughout history) date: - - journal: psychiatry of pandemics doi: . / - - - - _ sha: doc_id: cord_uid: fqy sm intermittent outbreaks of infectious diseases have had profound and lasting effects on societies throughout history. those events have powerfully shaped the economic, political, and social aspects of human civilization, with their effects often lasting for centuries. epidemic outbreaks have defined some of the basic tenets of modern medicine, pushing the scientific community to develop principles of epidemiology, prevention, immunization, and antimicrobial treatments. this chapter outlines some of the most notable outbreaks that took place in human history and are relevant for a better understanding of the rest of the material. starting with religious texts, which heavily reference plagues, this chapter establishes the fundamentals for our understanding of the scope, social, medical, and psychological impact that some pandemics effected on civilization, including the black death (a plague outbreak from the fourteenth century), the spanish flu of , and the more recent outbreaks in the twenty-first century, including sars, ebola, and zika. given to ways plagues affected the individual and group psychology of afflicted societies. this includes the unexamined ways pandemic outbreaks might have shaped the specialty of psychiatry; psychoanalysis was gaining recognition as an established treatment within medical community at the time the last great pandemic was making global rounds a century ago. there is a single word that can serve as a fitting point of departure for our brief journey through the history of pandemics -that word is the plague. stemming from doric greek word plaga (strike, blow), the word plague is a polyseme, used interchangeably to describe a particular, virulent contagious febrile disease caused by yersinia pestis, as a general term for any epidemic disease causing a high rate of mortality, or more widely, as a metaphor for any sudden outbreak of a disastrous evil or affliction [ ] . this term in greek can refer to any kind of sickness; in latin, the terms are plaga and pestis (fig. . ). perhaps the best-known examples of plagues ever recorded are those referred to in the religious scriptures that serve as foundations to abrahamic religions, starting with the old testament. book of exodus, chapters through , mentions a series of ten plagues to strike the egyptians before the israelites, held in captivity by the pharaoh, the ruler of egypt, are finally released. some of those loosely defined plagues are likely occurrences of elements, but at least a few of them are clearly of infectious nature. lice, diseased livestock, boils, and possible deaths of firstborn likely describe a variety of infectious diseases, zoonoses, and parasitoses [ ] . similar plagues were described and referred to in islamic tradition in chapter of the qur'an (surat al-a'raf, v. ) [ ] . throughout the biblical context, pandemic outbreaks are the bookends of human existence, considered both a part of nascent human societies, and a part of the very ending of humanity. in the apocalypse or the book of revelation, chapter , seven bowls of god's wrath will be poured on the earth by angels, again some of the bowls containing plagues likely infectious in nature: "so the first angel went and poured out his bowl on the earth, and harmful and painful sores came upon the people who bore the mark of the beast" (revelation : ). those events, regardless of factual evidence, deeply shaped human history, and continue to be commemorated in religious practices throughout the world. as we will see, the beliefs associated with those fundamental accounts have been rooted in societal responses to pandemics in western societies and continue to shape public sentiment and perception of current and future outbreaks. examined through the lens of abrahamic spiritual context, serious infectious outbreaks can often be interpreted as a "divine punishment for sins" (of the entire society or its outcast segments) or, in its eschatological iteration, as events heralding the "end of days" (i.e., the end of the world). throughout known, predominantly western history, there have been recorded processions of pandemics that each shaped our history and our society, inclusive of shaping the very basic principles of modern health sciences. what follows is an outline of major pandemic outbreaks throughout recorded history extending into the twenty-first century. the athenian plague of b.c. the athenian plague is a historically documented event that occurred in - b.c. during the peloponnesian war, fought between city-states of athens and sparta. the historic account of the athenian plague is provided by thucydides, who survived the plague himself and described it in his history of the peloponnesian war [ ] . the athenian plague originated in ethiopia, and from there, it spread throughout egypt and greece. initial symptoms of the plague included headaches, conjunctivitis, a rash covering the body, and fever. the victims would then cough up blood, and suffer from extremely painful stomach cramping, followed by vomiting and attacks of "ineffectual retching" [ ] . infected individuals would generally die by the seventh or eighth day. those who survived this stage might suffer from partial paralysis, amnesia, or blindness for the rest of their lives. doctors and other caregivers frequently caught the disease, and died with those whom they had been attempting to heal. the despair caused by the plague within the city led the people to be indifferent to the laws of men and gods, and many cast themselves into self-indulgence [ ] . because of wartime overcrowding in the city of athens, the plague spread quickly, killing tens of thousands, including pericles, athens' beloved leader. with the fall of civic duty and religion, superstition reigned, especially in the recollection of old oracles [ ] . the plague of athens affected a majority of the inhabitants of the overcrowded city-state and claimed lives of more than % of the population [ ] . the cause of the athenian plague of b.c. has not been clearly determined, but many diseases, including bubonic plague, have been ruled out as possibilities [ ] . while typhoid fever figures prominently as a probable culprit, a recent theory, postulated by olson and some other epidemiologists and classicists, considers the cause of the athenian plague to be ebola virus hemorrhagic fever [ ] . while hippocrates is thought to have been a contemporary of the plague of athens, even possibly treating the afflicted as a young physician, he had not left known accounts of the outbreak [ ] . it was another outbreak that occurred a couple of centuries later that was documented and recorded by contemporary physicians of the time. the outbreak was known as the antonine plague of - ad and the physician documenting it was galen; this outbreak is also known as the plague of galen [ ] . the antonine plague occurred in the roman empire during the reign of marcus aurelius ( - a.d.) and its cause is thought to be smallpox [ ] . it was brought into the empire by soldiers returning from seleucia, and before it abated, it had affected asia minor, egypt, greece, and italy. unlike the plague of athens, which affected a geographically limited region, the antonine plague spread across the vast territory of the entire roman empire, because the empire was an economically and politically integrated, cohesive society occupying wide swaths of the territory [ ] . the plague destroyed as much as one-third of the population in some areas, and decimated the roman army, claiming the life of marcus aurelius himself [ ] . the impact of the plague on the roman empire was severe, weakening its military and economic supremacy. the antonine plague affected ancient roman traditions, leading to a renewal of spirituality and religiousness, creating the conditions for spreading of new religions, including christianity. the antonine plague may well have created the conditions for the decline of the roman empire and, afterwards, for its fall in the west in the fifth century ad [ ] . the justinian plague was a "real plague" pandemic (i.e., caused by yersinia pestis) that originated in mid-sixth century ad either in ethiopia, moving through egypt, or in the central asian steppes, where it then traveled along the caravan trading routes. from one of these two locations, the pestilence quickly spread throughout the roman world and beyond. like most pandemics, the justinian plague generally followed trading routes providing an "exchange of infections as well as of goods," and therefore, was especially brutal to coastal cities. military movement at the time also contributed to spreading the disease from asia minor to africa and italy, and further to western europe. described in detail by procopius, john of ephesus, and evagrius, the justinian epidemic is the earliest clearly documented example of the actual (bubonic) plague outbreak [ ] . during the plague, many victims experienced hallucinations prior to the outbreak of illness. the first symptoms of the plague followed closely behind; they included fever and fatigue. soon afterwards, buboes appeared in the groin area or armpits, or occasionally beside the ears. from this point, the disease progressed rapidly; infected individuals usually died within days. infected individuals would enter a delirious, lethargic state, and would not wish to eat or drink. following this stage, the victims would be "seized by madness," causing great difficulties to those who attempted to care for them [ ] . many people died painfully when their buboes gangrened; others died vomiting blood. there were also cases, however, in which the buboes grew to great size, and then ruptured and suppurated. in such cases, the patient would usually recover, having to live with withered thighs and tongues, classic aftereffects of the plague. doctors, noticing this trend and not knowing how else to fight the disease, sometimes lanced the buboes of those infected to discover that carbuncles had formed. those individuals who did survive infection usually had to live with ''withered thighs and tongues'', the stigmata of survivors. emperor justinian contracted the plague himself, but did not succumb [ ] . within a short time, all gravesites were beyond capacity, and the living resorted to throwing the bodies of victims out into the streets or piling them along the seashore to rot. the empire addressed this problem by digging huge pits and collecting the corpses there. although those pits reportedly held , corpses each, they soon overflowed [ ] . bodies were then placed inside the towers in the walls, causing a stench pervading the entire city. streets were deserted, and all trade was abandoned. staple foods became scarce and people died of starvation as well as of the disease itself [ ] . the byzantine empire was a sophisticated society in its time and many of the advanced public policies and institutions that existed at that time were also greatly affected. as the tax base shrank and the economic output decreased, the empire forced the survivors to shoulder the tax burden [ ] . byzantine army suffered in particular, being unable to fill its ranks and carry out military campaigns, and ultimately failing to retake rome for the empire. after the initial outbreak in , repetitions of the plague established permanent cycles of infection. by , it is possible that the population of the empire had been reduced by %. in the city of constantinople itself, it is possible that this figure exceeded % [ ] . at this point in history, christian tradition enters the realm of interpreting and understanding the events of this nature [ ] . drawing on the eschatological narrative of the book of revelations, plague and other misfortunes are seen and explained as a "punishment for sins," or retribution for the induction of "god's wrath" [ ] . this interpretation of the plague will reappear during the black death and play a much more central role throughout affected societies in europe. meanwhile, as the well-established byzantine empire experienced major challenges and weakening of its physical, economic, and cultural infrastructure during this outbreak, the nomadic arab tribes, moving through sparsely populated areas and practicing a form of protective isolation, were setting a stage for the rapid expansion of islam [ , ] . the black death "the plague" was a global outbreak of bubonic plague that originated in china in , arrived in europe in , following the silk road. within years of its reign, by , [ ] it reduced the global population from million to below million, possibly below million, with the pandemic killing as many as million. some estimates claim that the black death claimed up to % of lives in europe at that time [ ] . starting in china, it spread through central asia and northern india following the established trading route known as the silk road. the plague reached europe in sicily in . within years, it had spread to the virtually entire continent, moving onto russia and the middle east. in its first wave, it claimed million lives [ ] . the course and symptoms of the bubonic plague were dramatic and terrifying. boccaccio, one of the many artistic contemporaries of the plague, described it as follows: in men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg...from the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. as the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves [ ] . indeed, the mortality of untreated bubonic plague is close to %, usually within days, while the mortality of untreated pneumonic plague approaches %. treated with antibiotics, mortality drops to around % [ ] . at the time, scientific authorities were at a loss regarding the cause of the affliction. the first official report blamed an alignment of three planets from for causing a "great pestilence in the air" [ ] . it was followed by a more generally accepted miasma theory, an interpretation that blamed bad air. it was not until the late xix century that the black death was understood for what it was -a massive yersinia pestis pandemic [ ] . this strain of yersinia tends to infect and overflow the guts of oriental rat fleas (xenopsylla cheopis) forcing them to regurgitate concentrated bacteria into the host while feeding. such infected hosts then transmit the disease further and can infect humans -bubonic plague [ ] . humans can transmit the disease by droplets, leading to pneumonic plague. the mortality of the black death varied between regions, sometimes skipping sparsely populated rural areas, but then exacting its toll from the densely populated urban areas, where population perished in excess of , sometimes % [ ] . in the vacuum of a reasonable explanation for a catastrophe of such proportions, people turned to religion, invoking patron saints, the virgin mary, or joining the processions of flagellants whipping themselves with nail embedded scourges and incanting hymns and prayers as they passed from town to town [ ] . the general interpretation in predominantly catholic europe, as in the case of justinian plague, centered on the divine "punishment for sins." it then sought to identify those individuals and groups who were the "gravest sinners against god," frequently singling out minorities or women. jews in europe were commonly targeted, accused of "poisoning the wells" and entire communities persecuted and killed. non-catholic christians (e.g., cathars) were also blamed as "heretics" and experienced a similar fate [ ] . in other, non-christian parts of the world affected by the plague, a similar sentiment prevailed. in cairo, the sultan put in place a law prohibiting women from making public appearances as they may tempt men into sin [ ] . for bewildered and terrified societies, the only remedies were inhalation of aromatic vapors from flowers or camphor. soon, there was a shortage of doctors which led to a proliferation of quacks selling useless cures and amulets and other adornments that claimed to offer magical protection [ ] . entire neighborhoods, sometimes entire towns, were wiped out or settlements abandoned. crops could not be harvested, traveling and trade became curtailed, and food and manufactured goods became short. the plague broke down the normal divisions between the upper and lower classes and led to the emergence of a new middle class. the shortage of labor in the long run encouraged innovation of labor-saving technologies, leading to higher productivity [ ] . the effects of such a large-scale shared experience on the population of europe influenced all forms of art throughout the period, as evidenced by works by renowned artists, such as chaucer, boccaccio, or petrarch. the deep, lingering wake of the plague is evidenced in the rise of danse macabre (dance of the death) in visual arts and religious scripts [ ] , its horrors perhaps most chillingly depicted by paintings titled the triumph of death (fig. . ) [ ] . the plague made several encore rounds through europe in the following centuries, occasionally decimating towns and entire societies, but never with the same intensity as the black death [ ] . with the breakdown of societal structure and its infrastructures, many professions, notably that of medical doctors, were severely affected. many towns throughout europe lost their providers to plague or to fear thereof. in order to address this shortage in times of austere need, many municipalities contracted young doctors from whatever ranks were available to perform the duty of the plague doctor (medico della peste) [ ] . venice was among the first citystates to establish dedicated practitioners to deal with the issue of plague in . their principal task, besides taking care of people with the plague, was to record in public records the deaths due to the plague [ ] . in certain european cities like florence and perugia, plague doctors were the only ones allowed to perform autopsies to help determine the cause of death and managed to learn a lot about human anatomy. among the most notable plague doctors of their time were nostradamus, paracelsus, and ambrois pare [ ] . the character of the plague doctor was drawing from experiences from ancient cultures that had dealt with contagious diseases, medieval societies observed the connection between the passage of time and the eruption of symptoms, noting that, after a period of observation, individuals who had not developed symptoms of the illness would likely not be affected and, more importantly, would not spread the disease upon entering the city. to that end, they started instituting mandatory isolation. the first known quarantine was enacted in ragusa (city-state of dubrovnik) in , where all arrivals had to spend days on a nearby island of lokrum before entering the city. this period of days (trentine) was later extended to days (quarenta giorni or quarantine) [ ] . the institution of quarantine was one of the rarely effective measures that took place during the black death and its use quickly spread throughout europe. quarantine remains in effect in the present time as a highly regulated, nationally and internationally governed public health measure available to combat contagions [ ] . the spanish flu pandemic in the first decades of the twentieth century was the first true global pandemic and the first one that occurred in the setting of modern medicine, with specialties such as infectious diseases and epidemiology studying the nature of the illness and the course of the pandemic as it unfolded. it is also, as of this time, the last true global pandemic with devastating consequences for societies across the globe [ ] . it was caused by the h n strain of the influenza virus, [ ] a strain that had an encore outbreak in the early years of the twenty-first century. despite advances in epidemiology and public health, both at the time and in subsequent decades, the true origin of spanish flu remains unknown, despite its name. as possible sources of origin, cited are the usa, china, spain, france, or austria. these uncertainties are perpetuated by the circumstances of the spanish flu -it took place in the middle of world war i, with significant censorships in place, and with fairly advanced modes of transportation, including intercontinental travel [ ] . within months, the deadly h n strain of influenza virus had spread to every corner of the world. in addition to europe, where massive military movements and overcrowding contributed to massive spread, this virus devastated the usa, asia, africa, and the pacific islands. the mortality rate of spanish flu ranged between % and %. with over a quarter of the global population contracting that flu at some point, the death toll was immense -well over million, possibly million dead. it killed more individuals in a year than the black death had killed in a century [ ] . this pandemic, unusually, tended to mortally affect mostly young and previously healthy individuals. this is likely due to its triggering a cytokine storm, which overwhelms and demolishes the immune system. by august of , the virus had mutated to a much more virulent and deadlier form, returning to kill many of those who avoided it during the first wave [ ] . spanish flu had an immense influence on our civilization. some authors (price) even point out that it may have tipped the outcome of world war i, as it affected armies of germany and the austrian-hungarian empire earlier and more virulently than their allied opponents (fig. . ) [ ] . many notable politicians, artists, and scientists were either affected by the flu or succumbed to it. many survived and went on to have distinguished careers in arts and politics (e.g., walt disney, greta garbo, raymond chandler, franz kafka, edward munch, franklin delano roosevelt, and woodrow wilson). many did not; this pandemic counted as its victims, among others, outstanding painters like gustav klimt and egon schiele [ ] , and acclaimed poets like guillaume apollinaire. it also claimed the life of sigmund freud's fifth child -sophie halberstadt-freud. this pandemic was also the first one where the longlingering effects could be observed and quantified. a study of us census data from to found that the children born to women exposed to the pandemic had more physical ailments and a lower lifetime income than those born a few months earlier or later. a study in the journal of political economy found that "cohorts in utero during the pandemic displayed reduced educational attainment, increased rates of physical disability, lower income, lower socioeconomic status, and higher transfer payments compared with other birth cohorts" [ ] . despite its immense effect on the global civilization, spanish flu started to fade quickly from the public and scientific attention, establishing a precedent for the future pandemics, and leading some historians (crosby) to call it the "forgotten pandemic" [ ] . one of the explanations for this treatment of the pandemic may lie in the fact that it peaked and waned rapidly, over a period of months before it even could get adequate media coverage. another reason may be in the fact that the pandemic was overshadowed by more significant historical events, such as the culmination and the ending of world war i. a third explanation may be that this is how societies deal with such rapidly spreading pandemicsat first with great interest, horror, and panic, and then, as soon as they start to subside, with dispassionate disinterest. hiv/aids is a slowly progressing global pandemic cascading through decades of time, different continents, and different populations, bringing new challenges with every new iteration and for every new group it affected. it started in the early s in the usa, causing significant public concern as hiv at the time inevitably progressed to aids and ultimately, to death. the initial expansion of hiv was marked by its spread predominantly among the gay population and by high mortality, leading to marked social isolation and stigma. hiv affects about million people globally (prevalence rate: . %) and has killed almost the same number of people since [ ] . it causes about one million deaths a year worldwide (down from nearly two million in ) [ ] . while it represents a global public health phenomenon, the hiv epidemic is particularly alarming in some sub-saharan african countries (botswana, lesotho, and swaziland), where the prevalence tops % [ ] . in the usa, about . million people live with hiv and about , die every year (down from over , per year in the late s). hiv in the usa disproportionately affects gay population, transgendered women, and african-americans [ ] . being a fairly slowly spreading pandemic, hiv has received formidable public health attention, both by national and by international administrations and pharmaceuticals. advances in treatment (protease inhibitors and anti-retrovirals) have turned hiv into a chronic condition that can be managed by medications. it is a rare infectious disease that has managed to attract the focus of mental health which, in turn, resulted in a solid volume of works on mental health and hiv [ ] . by studying the mental health of hiv, we can begin to understand some of the challenges generally associated with infectious diseases. we know, for example, that the lifetime prevalence rate for depression in hiv individuals is, at %, more than twice the prevalence rate in general population [ ] . we understand how depression in hiv individuals shows association with substance abuse and that issues of stigma, guilt, and shame affect the outlook for hiv patients, including their own adherence to life-saving treatments [ ] . we know about medical treatments of depression in hiv and we have studies in psychotherapy for patients with hiv. some of those approaches can be very useful in treating patients in the context of a pandemic. given the contrast between the chronicity of the hiv and the acuity of a potential pandemic, most of those approaches cannot be simply translated from mental health approach to hiv and used for patients in a rapidly advancing outbreak or a pandemic. smallpox was a highly contagious disease for which edward jenner developed the world's first vaccine in . caused by the variola virus, it was a highly contagious disease with prominent skin eruptions (pustules) and mortality of about %. it may have been responsible for hundreds of millions of fatalities in the twentieth century alone. due to the wellcoordinated global effort starting in under the leadership of donald henderson, smallpox was eradicated within a decade of undertaking the eradication on a global scale [ ] . the smallpox outbreak in the former yugoslavia in was a far cry from even an epidemic, let alone a pandemic, but it illustrated the challenges associated with a rapidly spreading, highly contagious illness in a modern world. it started with a pilgrim returning from the middle east, who developed fever and skin eruptions. since a case of smallpox had not been seen in the region for over years, physicians failed to correctly diagnose the illness and nine healthcare providers ended among cases infected by the index case and first fatality [ ] . socialist yugoslavia at the time declared martial law and introduced mandatory revaccination. entire villages and neighborhoods were cordoned off (cordon sanitaire is a measure of putting entire geographic regions in quarantine). about , individuals who may have come into contact with the infected were placed in an actual quarantine. borders were closed, and all non-essential travel was suspended. within weeks, the entire population of yugoslavia was revaccinated (about million people at the time). during the outbreak, cases were identified, with fatalities. due to prompt and massive response, however, the disease was eradicated and the society returned to normal within months [ ] . this event has proven to be a useful model for working out scenarios ("dark winter") [ ] for responses to an outbreak of a highly contagious disease, both as a natural occurrence [ ] and as an act of bioterrorism [ ] . severe acute respiratory syndrome (sars) was the first outbreak in the twenty-first century that managed to get public attention. caused by the sars corona virus (sars-cov), it started in china and affected fewer than , individuals, mainly in china and hong kong, but also in other countries, including cases in canada (toronto) [ ] . the severity of respiratory symptoms and mortality rate of about % caused a global public health concern. due to the vigilance of public health systems worldwide, the outbreak was contained by mid- [ ] . this outbreak was among the first acute outbreaks that had mental health aspects studied in the process and in the aftermath, in various part of the world and in different societies, yielding valuable data on effects of an acute infectious outbreak on affected individuals, families, and the entire communities, including the mental health issues facing healthcare providers [ ] . some of the valuable insights into the mental health of patients in isolation, survivors of the severe illness, or psychological sequelae of working with such patients were researched during the sars outbreak. "swine flu" or h n / pandemic the h n pandemic was a reprise of the "spanish flu" pandemic from , but with far less devastating consequences. suspected as a re-assortment of bird, swine, and human flu viruses, it was colloquially known as the "swine flu" [ ] . it started in mexico in april of and reached pandemic proportions within weeks [ ] . it began to taper off toward the end of the year and by may of , it was declared over. it infected over % of the global population (lower than expected), with a death toll estimated varying from , to over , [ ] . although its death rate was ultimately lower than the regular influenza death rates, at the time it was perceived as very threatening because it disproportionately affected previously healthy young adults, often quickly leading to severe respiratory compromise. a possible explanation for this phenomenon (in addition to the "cytokine storm" applicable to the h n outbreak) is attributed to older adults having immunity due to a similar h n outbreak in the s [ ] . this pandemic also resulted in some valuable data studying and analyzing the mental health aspects of the outbreak. it was among the first outbreaks where policy reports included mental health as an aspect of preparedness and mitigation policy efforts. this outbreak of h n was notable for dissonance between the public sentiment about the outbreak and the public health steps recommended and undertaken by who and national health institutions. general public sentiment was that of alarm caused by who releases and warnings, but it quickly turned to discontent and mistrust when the initial grim outlook of the outbreak failed to materialize [ ] . health agencies were accused of creating panic ("panicdemic") and peddling unproven vaccines to boost the pharmaceutical companies (in , some extra $ , billion worth of h n vaccines were purchased and administered in the usa) [ ] . this outbreak illustrated how difficult it may be to gauge and manage public expectations and public sentiments in the effort to mobilize a response. it also demonstrated how distilling descriptions of the impact of a complex public health threat like a pandemic into a single term like "mild," "moderate," or "severe" can potentially be misleading and, ultimately, of little use in public health approach [ ] . ebola virus, endemic to central and west africa, with fruit bats serving as a likely reservoir, appeared in an outbreak in a remote village in guinea in december . spreading mostly within families, it reached sierra leone and liberia, where it managed to generate considerable outbreaks over the following months, with over , cases and over , fatalities. a very small number of cases were registered in nigeria and mali, but those outbreaks were quickly contained [ ] . ebola outbreak, which happened to be the largest outbreak of ebola infection to date, gained global notoriety after a passenger from liberia fell ill and died in texas in september of , infecting two nurses caring for him, and leading to a significant public concern over a possible ebola outbreak in the usa [ ] . this led to a significant public health and military effort to address the outbreak and help contain it on site (operation united assistance) [ , ] . zika virus was a little known, dormant virus found in rhesus monkeys in uganda. prior to , the only known outbreak among humans was recorded in micronesia in . the virus was then identified in brazil in , after an outbreak of a mild illness causing a flat pinkish rash, bloodshot eyes, fever, joint pain and headaches, resembling dengue. it is a mosquitoborne disease (aedes aegypti), but it can be sexually transmitted. despite its mild course, which initially made it unremarkable form the public health perspective, infection with zika can cause guillain-barre syndrome in its wake in adults and, more tragically, cause severe microcephalia in unborn children of infected mothers (a risk of about %) [ ] . in brazil, in , for example, there were birth defects and infant deaths due to suspected zika infection [ ] . zika outbreak is an illustrative case of the context of global transmission; it was transferred from micronesia, across the pacific, to brazil, whence it continued to spread [ ] . it is also a case of a modern media pandemic; it featured prominently in the social media. in early , zika was being mentioned times a minute in twitter posts. social media were used to disseminate information, to educate, or to communicate concerns [ ] . its presence in social media, perhaps for the first time in history, allowed social researchers to study the public sentiment, also known as the emotional epidemiology (ofri), in real time [ ] . while both public health institutions and the general public voiced their concern with the outbreak, scientists and officials sought to provide educational aspect, while concerned public was trying to have their emotional concerns addressed. it is indicative that out of posts on zika on social media were accurate; yet, those that were "trending" and gaining popularity were posts with inaccurate content (now colloquially referred to as the "fake news") [ ] . this is a phenomenon that requires significant attention in preparing for future outbreaks because it may hold a key not only to preparedness, but also to execution of public health plans that may involve quarantine and immunization. since , zika has continued to spread throughout south america, central america, the caribbean, and several states within the usa. it remains a significant public health concern, as there is no vaccine and the only reliable way to avoid the risk for the offspring is to avoid areas where zika was identified or to postpone pregnancy should travel to or living in affected areas be unavoidable [ ] . disease x disease x is not, as of yet, an actual disease caused by a known agent, but a speculated source of the next pandemic that could have devastating effects on humanity. knowing the scope of deleterious effects a pandemic outbreak can have on humankind, in the wake of the ebola outbreak, the world health organization (who) decided to dedicate formidable resources to identifying, studying, and combating possible future outbreaks. it does so in the form of an r&d blueprint, though devising its global strategy and preparedness plan that allows the rapid activation of r&d activities during epidemics [ ] . r&d blueprint maintains and updates a list of so-called identified priority diseases. this list is updated at regular intervals and, as of , it includes diseases such as ebola and marburg virus diseases, lassa fever, middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome (sars), nipah and henipa virus diseases, zika, and others [ ] . for each disease identified, an r&d roadmap is created, followed by target product profiles (i.e., immunizations, treatment, and regulatory framework). those efforts are important to help us combat a dangerous outbreak of any of the abovementioned diseases, but also to fend off disease x. since disease x is a hypothetical entity, brought by a yet unknown pathogen that could cause a serious international pandemic, the r&d blueprint explicitly seeks to enable cross-cutting r&d preparedness that is also relevant for both existing culprits and the unknown future "disease x" as much as possible. who utilizes this r&d blueprint vehicle to assemble and deploy a broad global coalition of experts who regularly contribute to the blueprint and who come from several medical, scientific, and regulatory backgrounds. its advisory group, at the time, does not include mental health specialists [ ] . the black death: the greatest catastrophe ever the great leveler: violence and the history of inequality from the stone age to the twenty-first century. chapter : the black death mortality risk and survival in the aftermath of the medieval black death an epidemiologic analysis of the ten plagues of egypt the noble qur'an surah thucydides' description of the great plague the plague of athens: epidemiology and paleopathology the thucydides syndrome: a new hypothesis for the cause of the plague of athens the thucydides syndrome: ebola déjà vu? 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of risk perception, communication and management summary of probable sars cases with onset of illness from was sars a mental health catastrophe? gen hosp psychiatry geographic dependence, surveillance, and origins of the influenza a (h n ) virus in new theory, swine flu started in asia, not mexico. the new york times estimated global mortality associated with the first months of pandemic influenza a h n virus circulation: a modelling study risk factors for hospitalisation and poor outcome with pandemic a/ h n influenza: united kingdom first wave assessing the severity of the novel influenza a/ h n pandemic doctors rake in billions battling h n flu by dalia fahmy. abc news reflections on pandemic (h n ) and the international response the emergence of ebola as a global health security threat: from 'lessons learned' to coordinated multilateral containment efforts overview, control strategies, and lessons learned in the cdc response to the - ebola epidemic ebola outbreak in west africa military ebola mission in liberia coming to an end zika: the origin and spread of a mosquito-borne virus the microcephaly epidemic and zika virus: building knowledge in epidemiology propagating and debunking conspiracy theories on twitter during the - zika virus outbreak the emotional epidemiology of h n influenza vaccination spreading the (fake) news: exploring health messages on social media and the implications for health professionals using a case study who: r&d blueprint, about the r&d blueprint who: r&d blueprint, scientific advisory group members key: cord- -zhmnfd w authors: straif-bourgeois, susanne; ratard, raoult title: infectious disease epidemiology date: journal: handbook of epidemiology doi: . / - - - - _ sha: doc_id: cord_uid: zhmnfd w the following chapter intends to give the reader an overview of the current field of applied infectious disease epidemiology. prevention of disease by breaking the chain of transmission has traditionally been the main purpose of infectious disease epidemiology. while this goal remains the same, the picture of infectious diseases is changing. new pathogens are identified and already known disease agents are changing their behavior. the world population is aging; more people develop underlying disease conditions and are therefore more susceptible to certain infectious diseases or have long term sequelae after being infected. the following chapter intends to give the reader an overview of the current field of applied infectious disease epidemiology. prevention of disease by breaking the chain of transmission has traditionally been the main purpose of infectious disease epidemiology. while this goal remains the same, the picture of infectious diseases is changing. new pathogens are identified and already known disease agents are changing their behavior. the world population is aging; more people develop underlying disease conditions and are therefore more susceptible to certain infectious diseases or have long term sequelae after being infected. infectious diseases are not restricted to certain geographic areas anymore because of the increasing numbers of world travelers and a worldwide food distribution. the fear of a bioterrorist attack adds a new dimension in infectious disease epidemiology, and health departments enhance their surveillance systems for early detection of suspicious disease clusters and for agents used as weapons of mass destruction. improvements in laboratory techniques and mapping tools help to expand the knowledge of transmission of disease agents and enhanced surveillance techniques are feasible as a result of software progress and reporting of diseases via secure internet sites. surveillance and outbreak investigations remain the major responsibilities in public health departments. epidemiologic methods and principles are still the basis for these tasks but surveillance techniques and outbreak investigation are changing and adapting to improvements and the expanded knowledge. conducting surveys is a useful way to gather information on diseases where surveillance data or other data sources are not available, especially when dealing with emerging or re-emerging pathogens. program evaluation is an important tool to systematically evaluate the effectiveness of intervention or prevention programs for infectious diseases. infectious diseases are a major cause of human suffering in terms of both morbidity and mortality. in , out of an estimated total of million deaths, million were due to infectious diseases (who a,b) . the most common cause of infectious disease deaths were pneumonia ( million), diarrhea ( million) followed by tuberculosis, malaria, aids and hepatitis b. not surprisingly, there is a large imbalance in diseases between developing and industrialized countries (see table . ). morbidity due to infectious diseases is very common in spite of the progress accomplished in recent decades. even in industrialized countries, the prevalence of infection is very high for some infectious agents. serologic surveys found that by young adulthood the prevalence of antibodies was % against herpes simplex virus type , - % against type , % against human herpes virus, % against hepatitis a, % against hepatitis c, - % against hepatitis b, and % against chlamydia pneumoniae (american academy of pediatrics ; mandell et al. ) . annually, approximately , , episodes of diarrhea leading to , hospitalizations and deaths occur among adults in the united states (mounts et al. ). the center for disease control and prevention (cdc) estimates that each year million people in the us get sick, more than , are hospitalized and die as a result of foodborne illnesses (cdc ) . every year influenza circulates widely, infecting from % to % of the world population. the importance of infectious disease epidemiology for prevention it is often said that epidemiology is the basic science of preventive medicine. to prevent diseases it is important to understand the causative agents, risk factors and circumstances that lead to a specific disease. this is even more important for infectious disease prevention, since simple interventions may break the chain of transmission. preventing cardiovascular diseases or cancer is much more difficult because it usually requires multiple long term interventions requiring lifestyle changes and behavior modification, which are difficult to achieve. in , the american commission of yellow fever, headed by walter reed, was sent to cuba. the commission showed that the infective agent was transmitted by the mosquito aedes aegypti. this information was used by the then surgeon general of the us army william gorgas, to clean up the year old focus of yellow fever in havana by using mosquito proofing or oiling of the larval habitat, dusting houses with pyrethrum powder and isolating suspects under a mosquito net. this rapidly reduced the number of cases in havana from in to in (goodwin ) . a complete understanding of the causative agent and transmission is always useful but not absolutely necessary. the most famous example is that of john snow who was able to link cholera transmission to water contamination during the london cholera epidemic of by comparing the deaths from those households served by the southwark & vauxhall company versus those served by another water company. john snow further confirmed his hypothesis by the experiment of removing the broad street pump handle (wills a ). over the past three decades, more than new pathogens have been identified, some of them with global importance: bartonella henselae, borrelia burgdorferi, campylobacter, cryptosporidium, cyclospora, ebola virus, escherichia coli :h , ehrlichia, hantaan virus, helicobacter, hendra virus, hepatitis c and e, hiv, human herpesvirus and , human metapneumovirus, legionella, new variant creutzfeldt-jakob disease agent, nipah virus, parvovirus b , rotavirus, severe acute respiratory syndrome (sars) etc.. while there are specific causative agents for infectious diseases, these agents may undergo some changes over time. the last major outbreak of pneumonic plague in the world occurred in manchuria in . this scourge, which had decimated humans for centuries, is no longer a major threat. the plague bacillus cannot survive long outside its animal host (humans, rodents, fleas) because it lost the ability to complete the krebs cycle on its own. while it can only survive in its hosts, the plague bacillus also destroys its hosts rapidly. as long as susceptible hosts were abundant, plague did prosper. when environmental conditions became less favorable (lesser opportunities to sustain the host to host cycles), less virulent strains had a selective advantage (wills b) . the influenza virus is the best example of an agent able to undergo changes leading to renewed ability to infect populations that had been already infected and immune. the influenza virus is a single stranded rna virus with a lipophilic envelope. two important glycoproteins from the envelope are the hemagglutinin (ha) and neuraminidase (na). the ha protein is able to agglutinate red blood cells (hence its name). this protein is important as it is a major antigen for eliciting neutralizing antibodies. antigenic drift is a minor change in surface antigens that result from point mutations in a gene segment. antigenic drift may result in epidemics, since incomplete protection remains from past exposures to similar viruses. antigenic shift is a major change in one or both surface antigens (h and|or n) that occurs at varying intervals. antigenic shifts are probably due to genetic recombination (an exchange of a gene segment) between influenza a viruses, usually those that affect humans and birds. an antigenic shift may result in a worldwide pandemic if the virus can be efficiently transmitted from person to person. in the past three decades throughout the world, there has been a shift towards an increase in the population of individuals at high risk for infectious diseases. in industrialized nations, the increase in longevity leads to higher proportion of the elderly population who are more prone to acquiring infectious diseases and developing life threatening complications. for example, a west nile virus (wnv) infection is usually asymptomatic or causes a mild illness (west nile fever); rarely does it cause a severe neuro-invasive disease. in the epidemic of west nile in louisiana, the incidence of neuro-invasive disease increased progressively from . per , in the to age group to per , in the to year old age group and jumped to per , in the age group and older. mortality rates showed the same pattern, a gradual increase to . per , in the to age group with a sudden jump to per , for the oldest age group of and older. improvement in health care in industrialized nations has caused an increase in the number of immune-deficient individuals, be it cancer survivors, transplant patients or people on immuno-suppressive drugs for long term auto-immune diseases. some of the conditions that may increase susceptibility to infectious diseases are: cancers, particularly patients on chemo or radiotherapy, leukemia, lymphoma, hodgkin's disease, immune suppression (hiv infection), long term steroid use, liver disease, hemochromatosis, diabetes, alcoholism, chronic kidney disease and dialysis patients. for example persons with liver disease are times more likely to develop vibrio vulnificus infections than are persons without liver disease. some of these infections may be severe, leading to death. in developing countries a major shift in population susceptibility is associated with the high prevalence of immune deficiencies due to hiv infections and aids. in botswana which has a high prevalence of hiv (sentinel surveillance revealed hiv seroprevalence rates of % among women presenting for routine antenatal care), tuberculosis rates increased from per , in to per , in (lockman et al. ) while before the hiv|aids epidemics, rates above were very rare. changes in lifestyles have increased opportunities for the transmission of infectious disease agents in populations previously at low risk. intravascular drug injections have increased the transmission of agents present in blood and body fluids (e.g. hiv, hepatitis b and c). consumption of raw fish, shell fish and ethnic food expanded the area of distribution of some parasitic diseases. air travel allows people to be infected in a country and be half-way around the globe before becoming contagious. by the same token, insects and other vectors have become opportunistic global travelers. aedes albopictus, the asian tiger mosquito, was thus imported in to houston, texas inside japanese tires. subsequently, it has invaded us states. with the advent of nucleic acid tests, it has become possible to detect the presence of infectious disease agents in the air and environmental surfaces. for example, the use of air samplers and polymerase chain reaction analysis has shown that bordetella pertussis dna can be found in the air surrounding patients with b. pertussis infection, providing further evidence of airborne spread (aintablian et al. ) and thus leading to re-evaluate the precautions to be taken. however the presence of nucleic acids in an environmental medium does not automatically mean that transmission will occur. further studies are necessary to determine the significance of such findings. infectious disease agents, when used in bioterrorism events, have often been reengineered to have different physical properties and are used in quantities not usually experienced in natural events. there is little experience and knowledge about the human body's response to large doses of an infectious agent inhaled in aerosol particles that are able to be inhaled deep into lung alveolae. during the anthrax letter event, there was considerable discussion about incubation period, recommended duration of prophylaxis, and minimum infectious dose. this lack of knowledge base has led to confusion in recommendations being made. although the basics of infectious disease epidemiology have not changed and the discipline remains strongly anchored on some basic principles, technological developments such as improved laboratory methods and enhanced use of informatics (such as advanced mapping tools, web based reporting systems and statistical analytical software) have greatly expanded the field of infectious disease epidemiology. molecular techniques are being used more and more as a means to analyze epidemiological relationships between microorganisms. hence the term molecular epidemiology refers to epidemiologic research studies made at the molecular level. the main microbial techniques used, target plasmids and chromosomes. more specifically, plasmid fingerprinting and plasmid restriction endonuclease (rea) digestion, chromosomal analysis including pulse field gel electrophoresis (pfge), restriction fragment length polymorphism (rflp), multi-locus sequence type (mlst) and spa typing to name a few of these techniques. polymerase chain reaction (pcr) is used to amplify the quantity of genomic material present in the specimen. real-time pcr detection of infectious agents is now possible in a few hours. these techniques are becoming more widely used, even in public health laboratories for routine investigations. it is beyond the scope of this text to describe these methods in more detail. applications of molecular epidemiology methods have completely changed the knowledge about infectious disease transmission for many microorganisms. the main application is within outbreak investigations. being able to characterize the nucleic acid of the microorganisms permits an understanding of how the different cases relate to each other. molecular epidemiology methods have clarified the controversy about the origin of tuberculosis cases: is it an endogenous (reactivation) or exogenous (reinfection) origin? endogenous origin postulates that mycobacterium tuberculosis can remain alive in the human host for a lifetime and can start multiplying and producing lesions. on the other hand exogenous origin theory postulates that reinfection plays a role in the development of tuberculosis. the immunity provided by the initial infection is not strong enough to prevent another exposure to mycobacterium tuberculosis and a new infection leads to disease. in countries with low tuberculosis transmission, for example the netherlands, most strains have unique rflp fingerprints. each infection is unique and there are hardly any clusters of infections resulting from a common source. most cases are the result of reactivation. this is in contrast with areas of high endemicity where long chains of transmission can be identified with few rflp fingerprinting patterns (alland et al. ) . in some areas, up to % of tuberculosis cases are the result of reinfection. numerous new immunoassays have been developed. they depend on an antigenantibody reaction, either using a test antibody to detect an antigen in the patient's specimen or using a test antigen to detect an antibody in the patient's specimen. an indicator system is used to show that the reaction has taken place and to quantify the amount of patient antigen or antibody. the indicator can be a radioactive molecule (radioimmunoassay [ria]), a fluorescent molecule (fluorescent immunoassay [fia]), a molecule with an attached enzyme that catalyzes a color reaction (enzyme-linked immunoassay [elisa or eia]), or a particle coated with antigen or antibody that produces an agglutination (latex particle agglutination [la] ). the reaction can be a simple antigen|antibody reaction or a "sandwich" immunoassay where the antigen is "captured" and a second "read out" antibody attaches to the captured antigen. the antibody used may be polyclonal (i.e. a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope) or monoclonal (i.e. immunoglobulin molecules of single-epitope specificity that are secreted by a clone of b cells). it may be directed against an antigen on an epitope (i.e. a particular site within a macromolecule to which a specific antibody binds). plotting diseases on a map is one of the very basic methods epidemiologists do routinely. as early as john snow, suspecting water as a cause of cholera, plotted the cases of cholera in the districts of golden square, st. james and berwick, in london. the cases seemed to be centered around the broad street pump and less dense around other pumps. the map supplemented by other observations led to the experiment of removing the handle on the broad street pump and subsequent confirmation of his hypothesis (snow ) . geographical information systems (gis) have been a very useful tool in infectious disease research. gis are software programs allowing for integration of a data bank with spatial information. the mapping component includes physical layout of the land, towns, buildings, roads, administrative boundaries, zip codes etc. data may be linked to specific locations in the physical maps or to specific aggregates. a gis system includes tools for spatial analysis. climate, vegetation and other data may be obtained through remote sensing and combined with epidemiologic data to predict vector occurrence. however, these tools should be used with caution. they can be useful to generate hypotheses and identify possible associations between risk of disease and environmental exposures. because of potential bias, mapping should never be considered as more than an initial step in the investigation of an association. "the bright color palettes tend to silence a statistical conscience about fortuitous differences in the raw data" (boelaert et al. ) . for statistical methods in geographical epidemiology see chap. ii. of this handbook. web based reporting, use of computer programs and developments of sophisticated reporting and analytical software have revolutionized epidemiologic data collection and analysis. these tools have provided the ability to collect large amounts of data and handle large databases. however this has not been without risks. it remains crucial to understand the intricacies of data collected to avoid misinterpretation. for example, one should be aware that diseases and syndromes are initially coded by a person who may not be very software proficient, using shortcuts and otherwise could enter data of poor quality. what are the questions to be answered? too often one sees epidemiologists and statisticians preparing questionnaires, carrying out surveys, gathering surveillance information, processing data and producing reports, tables, charts and graphs in a routine fashion. epidemiology describes the distribution of health outcomes and determinants for a purpose. it is important to question the goals and objectives of all epidemiologic activities and tailor these activities to meet these objectives. the description of disease patterns includes analysis of demographic, geographical, social, seasonal and other risk factors. age groups to be used differ depending on the disease e.g. diseases affecting young children should have numerous age groups among children; sexually transmitted diseases require detailed age groups in late adolescence and early adulthood. younger age groups may be lumped together for diseases affecting mainly the elderly. gender categorization, while important for sexually transmitted diseases and other diseases with a large gender gap (such as tuberculosis), may not be important for numerous other diseases. geographical distribution is important to describe diseases linked to environmental conditions but may not be so useful for other diseases. surveillance, both active and passive, is the systematic collection of data pertaining to the occurrence of specific diseases, the analysis and interpretation of these data, and the dissemination of consolidated and processed information to contributors to the program and other interested persons (cdc b). in a passive surveillance system the surveillance agency has devised and put a system in place. after the placement, the recipient waits for the provider of care to report. passive case detection has been used for mortality and morbidity data for decades. it is almost universal. most countries have an epidemiology section in the health department that is charged with centralizing the data in a national disease surveillance system collecting mortality and morbidity data. in theory, a passive surveillance system provides a thorough coverage through space and time and gives a thorough representation of the situation. practically, compliance with reporting is often irregular and incomplete. in fact, the main flaws in passive case detection are incomplete reporting and inconsistencies in case definitions. the main advantages are the low cost of such a program and the sustained collection of data over decades. the purpose is to produce routine descriptive data on communicable diseases, generate hypotheses and prompt more elaborate epidemiologic studies designed to evaluate prevention activities. some conditions must be met to maximize compliance with reporting: . make reporting easy: provide easy to consult lists of reportable diseases, provide pre-stamped cards for reporting, provide telephone or fax reporting facilities. . do not require extensive information: name, age, sex, residence, diagnosis. some diseases may include data on exposure, symptoms, method of diagnosis etc. . maintain confidentiality and assure reporters that confidentiality will be respected. . convince reporters that reporting is essential: provide feedback; show how the data are used for better prevention. confidentiality of data is essential, particularly for those reporting health care providers who are subject to very strict confidentiality laws. any suspicion of failure of maintaining secure data would rapidly ruin a passive surveillance program. in an active surveillance system, the recipient will actually take some action to identify the cases. in an active surveillance program, the public health agency organizes a system by searching for cases or maintaining a periodic contact with providers. regular contacting boosts the compliance of the providers. providers are health agencies but also as in passive case detection, there may be day care centers, schools, long term care facilities, summer camps, resorts, and even public involvement. the agency takes the step to contact the health providers (all of them or a carefully selected sample) and requests reports from them at regular intervals. thus no reports are missing. active surveillance has several advantages: it allows the collection of more information. a provider sees that the recipient agency is more committed to surveillance and is therefore more willing to invest more time her|himself. it allows direct communication and opportunities to clarify definitions or any other problems that may have arisen. active surveillance provides much better, more uniform data than passive case detection but active case detection is much more expensive (see tables . and . ). active surveillance systems are usually designed when a passive system is deemed insufficient to accomplish the goals of disease monitoring. this type of surveillance is reserved for special programs, usually when it is important to identify every single case of a disease. active surveillance is implemented in the final phases of an eradication program: smallpox eradication, poliomyelitis eradication, guinea worm eradication and malaria eradication in some countries. active surveillance is also the best approach in epidemic or outbreak investigations to elicit all cases. in the smallpox eradication program, survey agents visited providers, asking about suspected cases and actually investigating each suspected case. in polio eradication programs, all cases of acute flaccid paralysis are investigated. in malaria eradication programs and some malaria control programs, malaria control agents go from house to house asking who has fever or had fever recently (in the past week or month for example). a blood smear is collected from those with fever. a case register is a complete list of all the cases of a particular disease in a definite area over a certain time period. registers are used to collect data on infections over long periods of time. registers should be population based, detailed and complete. a register will show an unduplicated count of cases. they are especially useful for long term diseases, diseases that may relapse or recur and diseases for which the same cases will consult several providers and therefore would be reported on more than one occasion. case registers contain identifiers, locating information, disease, treatment, outcome and follow-up information as well as contact management information. they are an excellent source of information for epidemiologic studies. in disease control, case registers are indispensable tools for follow up of chronic infections disease such as tuberculosis and leprosy. the contents and quality of a case register determine its usefulness. it should contain patient identifiers with names (all names), age, sex, place and date of birth, complete address with directions on how to reach the patient, name and address of a "stable" relative that knows the patient's whereabouts, diagnosis information with disease classification, brief clinical description (short categories are better than detailed descriptions), degree of infectiousness (bacteriological, serological results), circumstances of detection, initial treatment and response with specific dose, notes on compliance, side effects, clinical response, follow-up information with clinical response, treatment regimen, compliance, side effects, locating information; for some diseases contact information is also useful. updating a register is a difficult task. it requires cooperation from numerous persons. care must be taken to maintain the quality of data. it is important to only request pertinent information for program evaluation or information that would remind users to collect data or to perform an exam. for example, if compliance is often a neglected issue, include a question on compliance. further details concerning the use of registries in general are given in chap. i. of this handbook. sentinel disease surveillance for sentinel disease surveillance, only a sample of health providers is used. the sample is selected according to the objectives of the surveillance program. providers most likely to serve the population affected by the infection are selected, for example child health clinics and pediatricians should be selected for surveillance of childhood diseases. a sentinel system allows cost reduction and is combined with active surveillance. a typical surveillance program for influenza infections includes a selected numbers of general practitioners who are called every week to obtain the number of cases presented to them. this program may include the collection of samples for viral cultures or other diagnostic techniques. such a level of surveillance would be impossible to maintain on the national level. surveillance systems are evaluated on the following considerations (cdc b): usefulness: some surveillance systems are routine programs that collect data and publish results; however it appears that they have no useful purpose -no conclusions are reached, no recommendations are made. a successful surveillance system would provide information used for preventive purposes. sensitivity or the ability to identify every single case of disease is particularly important for outbreak investigations and eradication programs. predictive value positive (pvp) is the proportion of reported cases that actually have the health-related event under surveillance. low pvp values mean that non-cases might be investigated, outbreaks may be exaggerated or pseudo outbreaks may even be investigated. misclassification of cases may corrupt the etiologic investigations and lead to erroneous conclusions. unnecessary interventions and undue concern in the population under surveillance may result. representativeness ensures that the occurrence and distribution of cases accurately represent the real situation in the population. simplicity is essential to gain acceptance, particularly when relying on outside sources for reporting. flexibility is necessary to adapt to changes in epidemiologic patterns, laboratory methodology, operating conditions, funding or reporting sources. data quality is evaluated by the data completeness (blank or unknown variable values) and validity of data recorded (cf. chap. i. of this handbook). acceptability is shown in the participation of providers in the system. timeliness is more important in surveillance of epidemics. stability refers to the reliability (i.e., the ability to collect, manage and provide data properly without failure) and availability (the ability to be operational when it is needed) of the public health surveillance system. the major elements of a surveillance system as summarized by who are: mortality registration, morbidity reporting, epidemic reporting, laboratory investigations, individual case investigations, epidemic field investigations, surveys, animal reservoir and vector distribution studies, biologics and drug utilization, knowledge of the population and the environment. traditional surveillance methods rely on counting deaths and cases of diseases. however, these data represent only a small part of the global picture of infectious disease problems. mortality registration was one of the first elements of surveillance implemented. the earliest quantitative data available on infectious disease is about mortality. the evolution of tuberculosis in the us for example, can only be traced through its mortality. mortality data are influenced by the occurrence of disease but also by the availability and efficacy of treatment. thus mortality cannot always be used to evaluate the trend of disease occurrence. reporting of infectious diseases is one of the most common requirements around the world. a list of notifiable diseases is established on a national or regional level. the numbers of conditions vary; it ranges usually from to conditions. in general, a law requires that health facility staff, particularly physicians and laboratories, report these conditions with guaranteed confidentiality. it is also useful to have other non-health related entities report suspected communicable diseases such as day care centers, schools, restaurants, long term care facilities, summer camps and resorts. regulations on mandatory reporting are often difficult to enforce. voluntary compliance by the institution's personnel is necessary. reporting may be done in writing, by phone or electronically in the most advanced system. since most infectious diseases are confirmed by a laboratory test, reporting by the laboratory may be more reliable. the advantage of laboratory reporting is the ability to computerize the reporting system. computer programs may be set up to automatically report a defined set of tests and results. for some infectious diseases, only clinical diagnoses are made. these syndromes may be the consequences of a large number of different microorganisms for which laboratory confirmation is impractical. when public or physician attention is directed at a specific disease, reporting may be biased. when there is an epidemic or when the press focuses on a particular disease, patients are more prone to look for medical care and physicians are more likely to report. reporting rates were evaluated in several studies. in the us, studies show report rates of % for viral hepatitis, hemophilus influenzae %, meningococcal meningitis % and shigellosis %. it is important to have a standardized set of definitions available to providers. without standardized definitions, a surveillance system may be counting different entities from one provider to another. the variability may be such that the epidemiologic information obtained is meaningless. most case definitions in infectious disease epidemiology are based on laboratory tests, however some clinical syndromes such as toxic shock syndrome do not have confirmatory laboratory tests. most case definitions include a brief clinical description useful to differentiate active disease from colonization or asymptomatic infection. some diseases are diagnosed based on epidemiologic data. as a result many case definitions for childhood vaccine preventable diseases and foodborne diseases include epidemiologic criteria (e.g., exposure to probable or confirmed cases of disease or to a point source of infection). in some instances, the anatomic site of infection may be important; for example, respiratory diphtheria is notifiable, whereas cutaneous diphtheria is not (cdc ) . cases are classified as a confirmed case, a probable or a suspected case. an epidemiologically linked case is a case in which ) the patient has had contact with one or more persons who either have|had the disease or have been exposed to a point source of infection (including confirmed cases) and ) transmission of the agent by the usual modes is plausible. a case may be considered epidemiologically linked to a laboratory-confirmed case if at least one case in the chain of transmission is laboratory confirmed. probable cases have specified laboratory results that are consistent with the diagnosis yet do not meet the criteria for laboratory confirmation. suspected cases are usually cases missing some important information in order to be classified as a probable or confirmed case. case definitions are not diagnoses. the usefulness of public health surveillance data depends on its uniformity, simplicity and timeliness. case definitions establish uniform criteria for disease reporting and should not be used as the sole criteria for establishing clinical diagnoses, determining the standard of care necessary for a particular patient, setting guidelines for quality assurance, or providing standards for reimbursement. use of additional clinical, epidemiological and laboratory data may enable a physician to diagnose a disease even though the formal surveillance case definition may not be met. surveillance programs collect data on the overt cases diagnosed by the health care system. however these cases may not be the most important links in the chain of transmission. cases reported are only the tip of the iceberg. they may not at all be representative of the true endemicity of an infectious disease. there is a continuous process leading to an infectious disease: exposed, colonized, incubating, sick, clinical form, convalescing, cured. even among those who have overt disease there are several disease stages that may not be included in a surveillance system: some have symptoms but do not seek medical attention some do get medical attention but do not get diagnosed or get misdiagnosed some get diagnosed but do not get reported cases reported cases diagnosed but not reported cases who seek medical attention but were not diagnosed cases who were symptomatic but did not seek medical attention cases who were not symptomatic infectious disease cases play different roles in the epidemiology of an infectious disease; some individuals are the indicators (most symptomatic), some are the reservoir of microorganisms (usually asymptomatic, not very sick), some are amplifiers (responsible for most of the transmission), some are the victims (those who develop severe long term complications). depending on the specific disease and the purpose of the surveillance program, different disease stages should be reported. for example in a program to prevent rabies in humans exposure to a suspect rabid animal (usually a bite) needs to be reported. at the stage where the case is a suspect, prevention will no longer be effective. for bioterrorism events, reporting of suspects is of paramount importance to minimize consequences. waiting for confirmation causes too long of a delay. in the time necessary to confirm cases, opportunities to prevent co-infections may be lost and secondary cases may already be incubating, depending on the transmissibility of the disease. surveillance for west nile viral infections best rests on the reporting of neuroinvasive disease. case reports of neuro invasive diseases are a better indicator than west nile infection or west nile fever cases that are often benign, go undiagnosed and are reported haphazardly. for gonorrhea, young males are the indicators because of the intensity of symptoms. young females are the main reservoir because of the high proportion of asymptomatic infections. females of reproductive age are the victims because of pelvic invasive disease (pid) and sterility. a surveillance program for hepatitis b that only would include symptomatic cases of hepatitis b could be misleading. a country with high transmission of hepatitis b from mother to children would have a large proportion of infected newborn becoming asymptomatic carriers and a major source of infection during their lifetime. typically in countries with poor reporting of symptomatic hepatitis, the reporting of acute cases of hepatitis b would be extremely low in spite of high endemicity which would result in high rates of chronic hepatitis and hepatic carcinoma. most morbidity reporting collects data about individual cases. reporting of individual cases includes demographic and risk factor data which are analyzed for descriptive epidemiology and for implementation of preventive actions. for example, any investigation leading to contact identification and prophylaxis requires a start from individual cases. however, identification of individuals may be unnecessary and aggregate data sufficient for some specific epidemiologic purposes. monitoring an influenza epidemic for example, can be done with aggregate data. obtaining individual case information would be impractical since it would be too time consuming to collect detailed demographics on such a large number of cases. aggregate data from sentinel sites consists of a number of influenza-like illnesses by age group and the total number of consultants or the total number of 'participants' to be used as denominators. such data is useful to identify trends and determine the extent of the epidemic and geographic distribution. collection of aggregate data of the proportion of school children by age group and sex is a useful predictive tool to identify urinary schistosomiasis endemic areas (lengeler et al. ) without having to collect data on individual school children. epidemics of severe diseases are almost always reported. this is not the case for epidemics of milder diseases such as rashes or diarrheal diseases. many countries do not want to report an outbreak of disease that would cast a negative light on the countries. for example, many countries that are tourism dependent do not report cholera or plague cases. some countries did not report aids cases for a long time. case investigations are usually not undertaken for individual cases unless the disease is of major importance such as hemorrhagic fever, polio, rabies, yellow fever, any disease that has been eradicated and any disease that is usually not endemic in the area. outbreaks or changes in the distribution pattern of infectious diseases should be investigated and these investigations should be compiled in a comprehensive system to detect trends. while the total number of infectious diseases may remain the same, changes may occur in the distribution of cases from sporadic to focal outbreaks. for example the distribution of wnv cases in louisiana shifted from mostly focal outbreaks the first year the west nile virus arrived in the state in , to mostly sporadic cases the following year in (see fig. . ) . surveys are a very commonly used tool in public health, particularly in developing countries where routine surveillance is often inadequate (cf. chap. iv. of this handbook). survey data needs to be part of a comprehensive surveillance database. one will acquire a better picture from one or a series of well constructed surveys than from poorly collected surveillance data. surveys are used in control programs designed to control major endemic diseases: spleen and parasite surveys for malaria, parasite in urine and stools for schistosomiasis, clinical surveys for leprosy or guinea-worm disease and skin test surveys for tuberculosis. surveillance of microbial strains is designed to monitor, through active laboratory based surveillance, the bacterial and viral strains isolated. examples of these systems are: in the us, the pulsenet program is a network of public health laboratories that performs dna fingerprinting of bacteria causing foodborne illnesses (swaminathan et al. ). molecular sub-typing methods must be standardized to allow comparisons of strains and the building of a meaningful data bank. the method used in pulsenet is pulse field gel electrophoresis (pfge). the use of standardized subtyping methods has allowed isolates to be compared from different parts of the country, enabling recognition of nationwide outbreaks attributable to a common source of infection, particularly those in which cases are geographically separated. the us national antimicrobial resistance monitoring system (narms) for enteric bacteria is a collaboration between cdc, participating state and local health departments and the us food and drug administration (fda) to monitor antimicrobial resistance among foodborne enteric bacteria isolated from humans. narms data are also used to provide platforms for additional studies including field investigations and molecular characterization of resistance determinants and to guide efforts to mitigate antimicrobial resistance (cdc ) . monitoring of antimicrobial resistance is routinely done by requiring laboratories to either submit all, or a sample of their bacterial isolates. surveillance for zoonotic diseases should start at the animal level, thus providing early warning for impending increases of diseases in the animal population. rabies surveillance aims at identifying the main species of animals infected in an area, the incidence of disease in the wild animals and the prevalence of infection in the asymptomatic reservoir (bats). this information will guide preventive decisions made when human exposures do occur. malaria control entomologic activities must be guided by surveillance of anopheles population, biting activities, plasmodium infection to biting acivities and plasmodium infection rates in the anopheles population. surveillance for dead birds, infection rates in wild birds, infection in sentinel chickens and horse encephalitis are all part of west nile encephalitis surveillance. these methods provide an early warning system for human infections. the worldwide surveillance for influenza is the best example of the usefulness of monitoring animals prior to spread of infection in the human population. influenza surveillance programs aim to rapidly obtain new circulating strains to make timely recommendations about the composition of the next vaccine. the worldwide surveillance priority is given to the establishment of regular surveillance and investigation of outbreaks of influenza in the most densely populated cities in key locations, particularly in tropical or other regions where urban markets provide opportunities for contacts between humans and live animals (snacken et al. ). the rationale for selecting infectious diseases and an appropriate surveillance method is based on the goal of the preventive program. outbreaks of acute infectious diseases are common and investigations of these outbreaks are an important task for public health professionals, especially epidemiol-ogists. in , a total of foodborne outbreaks with , cases involved were reported in the us (cdc ) with norovirus being the most common confirmed etiologic agent associated with these outbreaks (see table . ). outbreaks or epidemics are defined as the number of disease cases above what is normally expected in the area for a given time period. depending on the disease, it is not always known if the case numbers are really higher than expected and some outbreak investigations can reveal that the reported case numbers did not actually increase. the nature of a disease outbreak depends on a variety of circumstances, most importantly the suspected etiologic agent involved, the disease severity or case fatality rate, population groups affected, media pressure, political inference and investigative progress. there are certain common steps for outbreak investiga-tions as shown in table . . however, the chronology and priorities assigned to each phase of the investigation have to be decided individually, based on the circumstances of the suspected outbreak and information available at the time. another way to detect an increase of cases is if the surveillance system of reportable infectious diseases reveals an unusually high number of people with the same diagnosis over a certain time period at different health care facilities. outbreaks of benign diseases like self-limited diarrhea are often not detected because people are not seeking medical attention and therefore medical services are not aware of them. furthermore, early stages of a disease outbreak are often undetected because single cases are diagnosed sporadically. it is not until a certain threshold is passed, that it becomes clear that these cases are related to each other through a common exposure or secondary transmission. depending on the infectious disease agent, there can be a sharp or a gradual increase of number of cases. it is sometimes difficult to differentiate between sporadic cases and the early phase of an outbreak. in the st. louis encephalitis (sle) outbreak in louisiana, the number of sle cases increased from to between week one and two and then the numbers gradually decreased over the next weeks to a total of cases (jones et al. ) . . after the initial report is received, it is important to collect and document basic information: contact information of persons affected, a good and thorough event description, names and diagnosis of hospitalized persons (and depending on the presumptive diagnosis their underlying conditions and travel history), laboratory test results and other useful information to get a complete picture and to confirm the initial story of the suspected outbreak. it also might be necessary to collect more biological specimens such as food items and stool samples for further laboratory testing. . based on the collected information the decision to investigate must be made. it may not be worthwhile to start an investigation if there are only a few people who fully recovered after a couple of episodes of a self-limited, benign diarrhea. other reasons not to investigate might be that this type of outbreak occurs regularly every summer or that it is only an increase in number of reported cases which are not related to each other. on the other hand, however, there should be no time delay in starting an investigation if there is an opportunity to prevent more cases or the potential to identify a system failure which can be caused, for example, by poor food preparation in a restaurant or poor infection control practices in a hospital or to prevent future outbreaks by acquiring more knowledge of the epidemiology of the agent involved. additional reasons to investigate include the interest of the media, politicians and the public in the disease cluster and the pressure to provide media updates on a regularly basis. another fact to consider is that outbreak investigations are good training opportunities for newly hired epidemiologists. sometimes lack of data and lack of sufficient background information make it difficult to decide early on if there is an outbreak or not. the best approach then is to assume that it is an outbreak until proven otherwise. . prevention of more cases is the most important goal in outbreak investigations and therefore a rapid evaluation of the situation is necessary. if there are precautionary measures to be recommended to minimize the impact of the outbreak and the spread to more persons, they should be implemented before a thorough investigation is completed. most likely control measures implemented by public health professionals in foodborne outbreaks are: recall or destruction of contaminated food items, restriction of infected food handlers from food preparation, correction of any deficiency in food preparation or conservation. . after taking immediate control measures, the next step is to know more about the epidemiology of the suspected agent. the most popular books for public health professionals include the "red book" (american academy of pediatrics ), the "control of communicable diseases manual" from the american public health association (apha ) or other infectious disease epidemiology books as well as the cdc website (www.cdc.gov). if the disease of interest is a reportable disease or a disease where surveillance data are available, baseline incidence rates can be calculated. then a comparison is made to determine if the reported numbers constitute a real increase or not. furthermore, the seasonal and geographical distribution of the disease is important as well as the knowledge of risk factors. many infectious diseases show a seasonal pattern such as rotavirus or neisseria meningitides. for example in suspected outbreaks where cases are associated with raw oyster consumption, the investigator should know that in the us gulf states vibrio cases increase in the summer months because the water conditions are optimal for the growth of the bacteria in water and in seafood. this kind of information will help to determine if the case numbers show a true increase and if it seems likely to be a real outbreak. . for certain diseases, numbers are not important. depending on the severity of the disease, its transmissibility and its natural occurrence, certain diseases should raise a red flag for every health care professional and even a single case should warrant a thorough public health investigation. for example a single confirmed case of a rabid dog in a city (potential dog to dog transmission within a highly populated area), a case of dengue hemorrhagic fever or a presumptive case of smallpox would immediately trigger an outbreak investigation. . sometimes an increase of case numbers is artificial and not due to a real outbreak. in order to differentiate between an artificial and a natural increase in numbers, the following changes have to be taken into consideration: alterations in the surveillance system, a new physician who is interested in the disease and therefore more likely to diagnose or report the disease, a new health officer strengthening the importance of reporting, new procedures in reporting (from paper to web based reporting), enhanced awareness or publicity of a certain disease that might lead to increased laboratory testing, new diagnostic tests, a new laboratory, an increase in susceptible population such as a new summer camp. . it is important to be sure that reported cases of a disease actually have the correct diagnosis and are not misdiagnosed. is there assurance that all the cases have the same diagnosis? is the diagnosis verified and were other differential diagnoses excluded? in order to be correct, epidemiologists have to know the basis for the diagnosis. are laboratory samples sufficient? if not, what kind of specimens should be collected to ascertain the diagnosis? what are the clinical signs and symptoms of the patient? in an outbreak of restaurant associated botulism in canada only the th case was correctly diagnosed. the slow progression of symptoms and misdiagnosis of the dispersed cases made it very difficult to link these cases and identify the source of the outbreak (cdc (cdc , . . the purpose of a case definition is to standardize the identification and counting of the number of cases. the case definition is a standard set of criteria and is not a clinical diagnosis. in most outbreaks the case definition has components of person, place and time, such as the following: persons with symptoms of x and y after eating at the restaurant z between date and date . the case definition should be broad enough to get most of the true cases but not too narrow so that true cases will not be misclassified as controls. a good method is to analyze the data, identify the frequency of symptoms and include symptoms that are more reliable than others. for example, diarrhea and vomiting are more specific than nausea and headache in the case definition of a food related illness. . what kind of information is necessary to be collected? it is sufficient to have a simple database with basic demographic information such as name, age, sex and information for contacting the patient. more often, date of reporting and date of onset of symptoms are also important. depending on the outbreak and the potential exposure or transmission of the agent involved further variables such as school, grade of student or occupation in adults might be interesting and valuable. . during an outbreak investigation it is important to identify additional cases that may not have been known or were not reported. there are several approaches: interview known cases and ask them if they know of any other friends or family members with the same signs or symptoms, obtain a mailing list of frequent customers in an event where a restaurant is involved, set up an active surveillance with physicians or emergency departments, call laboratories and ask for reports of suspected and confirmed cases. another possibility is to review surveillance databases or to establish enhanced surveillance for prospective cases. occasionally it might be worthwhile to include the media for finding additional cases through press releases. however the utility of that technique depends on the outbreak and the etiologic agent; the investigator should always do a benefit risk analysis before involving the media. . after finding additional cases, entering them in the database and organizing them, the investigator should try to get a better understanding of the situation by performing some basic descriptive epidemiology techniques such as sorting the data by time, place and person. for a better visualization of the data, an epidemic or "epi" curve should be graphed. the curve shows the number of cases by date or time of onset of symptoms. this helps to understand the nature and dynamic of the outbreak as well as to get a better understanding of the incubation period if the time of exposure is known. it also helps to determine whether the outbreak had a single exposure and no secondary transmission (single peak) or if there is a continuous source and ongoing transmission. figures . and . show "epi" curves of two different outbreaks: a foodborne outbreak in a school in louisiana, and the number of wnv human cases in louisiana in the outbreak, respectively. sometimes it is useful to plot the cases on a map to get a better idea of the nature and the source of an outbreak. mapping may be useful to track the spread by water (see john snow's cholera map) or by air or even a person to person transmission. if a contaminated food item was the culprit, food distribution routes with new cases identified may be helpful. maps, however, should be taken with caution and carefully interpreted. for example, wnv cases are normally mapped by residency but do not take into account that people might have been exposed or bitten by an infective mosquito far away from where they live. for outbreak investigations, spot maps are usually more useful than rate maps or maps of aggregate data. depending on the outbreak it might be useful to characterize the outbreak by persons' demographics such as age, sex, address and occupation or health status. are the cases at increased susceptibility or at high risk of infection? these kinds of variables might give the investigator a good idea if the exposure is not yet known. for typical foodborne outbreaks however, demographic information is not very useful because the attack rates will be independent of age and sex. more details on methods used in descriptive epidemiology are given in chap. i. of this handbook. . based on the results of basic descriptive epidemiology and the preliminary investigation, some hypotheses should be formulated in order to identify the cause of the outbreak. a hypothesis will be most likely formulated such as "those who attended the luncheon and ate the chicken salad are at greater risk than those who attended and did not eat the chicken salad". it is always easier to find something after knowing what to look for and therefore a hypothesis should be used as a tool. however, the epidemiologist should be flexible enough to change the hypothesis if the data do not support it. if data clues are leading in another direction, the hypothesis should be reformulated such as "those who attended the luncheon and ate the baked chicken are at greater risk than those who attended and did not eat the baked chicken". to verify or deny hypotheses, measures of risk association such as the relative risk (rr) or the odds ratio (or) have to be calculated (as described in chaps. i. , i. , and i. of this handbook). the cdc has developed the software program 'epiinfo' which is easy to use in outbreak investigations, and, even more importantly, free of charge. it can be downloaded from the cdc website (http:||www.cdc.gov|epiinfo|). measures of association, however, should be carefully interpreted; even a highly significant measure of association can not give enough evidence of the real culprit or the contaminated food item. the measure of association is only as good and valid as the data. most people have recall problems when asked what they ate, when they ate and when their symptoms started. even more biases or misclassifications of cases and controls can hide an association. a more confident answer comes usually from the laboratory samples from both human samples and food items served at time of exposure. agents isolated from both food and human samples that are identified as the same subtype, in addition to data results supporting the laboratory findings, are the best evidence beyond reasonable doubt. . as the last step in an outbreak investigation, the epidemiologist writes a final report on the outbreak and communicates the results and recommendations to the public health agency and facilities involved. in the us, public health departments also report foodborne outbreaks electronically to cdc via a secure web based reporting system, the electronic foodborne outbreak reporting system (efors). the "traditional" foodborne outbreak the "traditional" foodborne outbreak is usually a small local event such as family picnic, wedding reception, or other social event and occurs often in a local restaurant or school cafeteria. this type of outbreak is highly local with a high attack rate in the group exposed to the source. because it is immediately apparent to those in the local group such as the group of friends who ate at the restaurant or the students' parents, public health authorities are normally notified early in the outbreak while most of the cases are still symptomatic. epidemiologists can start early on with their investigation and therefore have a much better chance to collect food eaten and stool samples of cases with gastroenteritis for testing and also to detect the etiologic agent in both of them. in a school outbreak in louisiana, eighty-seven persons (sixty-seven students and twenty faculty members) experienced abdominal cramps after eating at the school's annual "turkey day" the day before. stool specimens and the turkey with the gravy were both positive for clostridium perfringens with the same pulse field gel electrophoresis (pfge) pattern (merlos ) . the inspection of the school cafeteria revealed several food handling violations such as storing, cooling and reheating of the food items served. other than illnesses among food handlers, these types of improper food handling or storage are the most common causes of foodborne outbreaks. a different type of outbreak is emerging as the world is getting smaller. in other words persons and food can travel more easily and faster from continent to continent and so do infectious diseases with them. foodborne outbreaks related to imported contaminated food items are normally widespread, involving many states and countries and therefore are frequently identified. in , a large outbreak of cyclospora cayetanensis occurred in us states and ontario, canada and was linked to contaminated raspberries imported from south america. several hundred laboratory confirmed cases were reported, most of them in immunocompetent persons (cdc ) . a very useful molecular tool to identify same isolates from different geographic areas is sub-typing enteric bacteria with pfge. in the us, the pulsenet database allows state health department to compare their isolates with other states and therefore increase the recognition of nationwide outbreaks linked to the same food item (swaminathan et al. ) . in a different scenario, a widely distributed food item with low-level contamination might result in an increase of cases within a large geographic area and therefore might be not get detected on a local level. this kind of outbreak might only be detected by chance if the number of cases increased in one location and the local health department alerts other states to be on the lookout for a certain isolate. another type of outbreak is the introduction of a new pathogen into a new geographic area as it happened in when vibrio cholerae was inadvertently introduced in the waters off the gulf coast of the united states. in the u.s., however, most cases are usually traced back to people who traveled to areas with a high cholera risk or to people who ate food imported from cholera-risk countries and only sporadic vibrio cholerae cases are associated with the consumption of raw or undercooked shellfish from the gulf of mexico (cdc b). food can not only be contaminated by the end of the food handling process i.e. by infected food handlers but also can be contaminated by any event earlier in the chain of food production. in , an ice cream outbreak of salmonella enteritidis in a national brand of ice cream resulted in , illnesses. the outbreak was detected by routine surveillance because of a dramatic increase of salmonella enteritidis in south minnesota. the cause of the outbreak was a basic failure on an industrial scale to separate raw products from cooked products. the ice cream premix was pasteurized and then transported to the ice cream factory in tanker trucks which had been used to haul raw eggs. this resulted in the contamination of the ice cream and subsequent salmonella cases (hennessey et al. ) . surveys are useful to provide information for which there is no data source or no reliable data source. surveys are time consuming and are often seen as a last choice to obtain information. however, too often unreliable information is used because it is easily available. for example, any assessment of the legionella problem using passive case detection will be unreliable due to under-diagnosis and under-reporting. most cases of legionellosis are treated empirically as community acquired pneumonias and are never formally diagnosed. in developing countries, surveys are often necessary to evaluate health problems since data collected routinely (disease surveillance, hospital records, case registers) are often incomplete and of poor quality. in industrialized nations, although many sources of data are available, there are some circumstances where surveys may be necessary. prior to carrying out surveys involving human subjects, special procedures need to be followed. in industrialized countries, a human subject investigation review board has to evaluate the project's value and ethics. in developing countries, however, such boards may not be formalized but it is important to obtain permission from medical, national and local political authorities before proceeding. surveys of human subjects are carried out by mail, telephone, personal interviews, and behavioral observations. in infectious diseases, the collection of biological specimens in humans (i.e. blood for serologic surveys) or the collection of environmental samples (food, water, environmental surfaces) is very common. personal interviews and specimen collection require face to face interaction with the individual surveyed. these are carried out in offices or by house to house surveys. non-respondents are an important problem for infectious disease surveys. those with an infection may be absent from school, may not answer the door or may be unwilling to donate blood for a serologic survey, thus introducing a systematic bias into the survey results. since surveys are expensive, they cannot be easily repeated. all field procedures, questionnaires, biological sample collection methods and laboratory tests should be tested prior to launching the survey itself. feasibility, acceptability and reliability can be tested in a small scale pilot study. more details on survey methods are to be found in chap. i. of this handbook. sampling . . since surveys are labor intensive, they are rarely carried out on an entire population but rather on a sample. to do a correct sampling, it is necessary to have a sampling base (data elements for the entire population) from which to draw the sample. examples of sampling bases are population census, telephone directory (for the phone subscriber population), school roster or a school list. in developing countries such lists are not often available and may have to be prepared before sampling can start. more information on sampling designs can be found in chap. iv. of this handbook. community surveys (house to house surveys) . . most community surveys are carried out in developing countries because reliable data sources are rare. the sampling base often ends up to the physical layout of the population. a trip and geographical reconnaissance of the area are necessary. the most common types of surveys undertaken in developing countries are done at the village level; they are based on maps and a census of the village. in small communities, it is important to obtain the participation of the population. villagers are often wary of government officials counting people and going from door to door. to avoid misinterpretations and rumors, influential people in the community should be told about the survey. their agreement is indispensable and their help is needed to explain the objectives of the survey and particularly its potential benefits. increasing the knowledge about disease, disease prevention and advancing science are abstract notions that are usually poorly understood or valued by villagers who are, in general, very practical people. if a more immediate benefit can be built into the survey, there will be an increase in cooperation of the population. incentives such as offering to diagnose and treat an infection or drugs for the treatment of common ailments such as headaches or malaria enhance the acceptance of the survey. in practically all societies the household is a primary economic and social unit. it can be defined as the smallest social unit of people who have the same residency and maintain a collective organization. the usual method for collecting data is to visit each household and collect samples or administer a questionnaire. medical staff may feel left out or even threatened whenever a medical intervention (such as a survey) is done in their area. a common concern is that people will go to their medical care provider and ask questions about the survey or about specimen collection and results. it is therefore important to involve and inform local medical providers as much as practical. a rare example of a house to house survey in an industrialized nation was carried out in slidell, louisiana for the primary purpose of determining the prevalence of west nile infection in a southern us focus. since the goal was to obtain a random sample of serum from humans living in the focus, the only method was a survey of this type. a cluster sampling design was used to obtain a representative number of households. the area was not stratified because of its homogeneity. census blocks were grouped so that each cluster contained a minimum of households. the probability of including an individual cluster was determined by the proportion of houses selected in that cluster and the number of persons participating given the number of adults in the household. a quota sampling technique was used, with a goal of enlisting participating households in each cluster. inclusion criteria included age (at least years of age) and length of residence (at least years). the household would be included only if an adult household resident was present. a standardized questionnaire was used to interview each participant. information was collected on demographics, any recent febrile illness, knowledge, attitudes, and behaviors to prevent wnv infection and potential exposures to mosquitoes. a serum sample for wnv antibody testing was drawn. in addition, a second questionnaire regarding selected household characteristics and peridomestic mosquito reduction measures was completed. informed consent was obtained from each participant, and all participants were advised that they could receive notification of their blood test results if they wished. institutional review board approvals were obtained. logistics for specimen collection, preservation and transportation to the laboratory were arranged. interpretation of serologic tests and necessary follow up were determined prior to the survey and incorporated in the methods submitted to the ethics committee. sampling weights, consisting of components for block selection, householdwithin-block selection, and individual-within-household participation, were used to estimate population parameters and % confidence intervals (ci). statistical tests were performed incorporating these weights and the stratified cluster sampling design. in this survey, households were surveyed (a % response rate), including participants. there were igm seropositive persons, for a weighted seroprevalence of . % (with a % confidence interval of . %- . %) (vicari et al. ). program evaluation is a systematic way to determine if prevention or intervention programs for the infectious disease of interest are effective and to see how they can be improved. it is beyond the scope of this chapter to explain program evaluation in detail however there is abundant information available i.e. the cdc's framework for program evaluation in public health (cdc a) as well as text books on program evaluation (fink ) . most importantly, evaluators have to understand the program such as the epidemiology of the disease of interest, the program's target population and their risk factors, program activities and resources. they have to identify the main objectives of the control actions and determine the most important steps. indicators define the program attributes and translate general concepts into measurable variables. data are then collected and analyzed so that conclusions and recommendations for the program are evidence based. evaluating an infectious disease control program requires a clear understanding of the microorganism, its mode of transmission, the susceptible population and the risk factors. the following example of evaluation of tuberculosis control shows the need to clearly understand the priorities. most of tuberculosis transmission comes from active pulmonary tuberculosis cases who have positive sputum smear (confirmed as tuberculosis mycobacteria on culture). to a lesser extent, smear negative culture positive pulmonary cases are also transmitting the infection. therefore priority must be given to find sputum positive pulmonary cases. the incidence of smear positive tuberculosis cases is the most important incidence indicator. incidences of active pulmonary cases and of all active cases (pulmonary and extra-pulmonary) are also calculated but are of lesser interest. the following proportions are used to detect anomalies in case finding or case ascertainment: all tuberculosis cases who are pulmonary versus extra-pulmonary, smear positive, culture positive, pulmonary cases versus smear negative, culture positive, pulmonary cases, culture positive, pulmonary cases versus culture negative, pulmonary cases. poor laboratory techniques or low interest in obtaining sputa for smears or cultures may result in underestimating bacteriological confirmed cases. excessive diagnosis of tuberculosis with reliance on chest x-rays on the other hand may overestimate unconfirmed tuberculosis cases. once identified, tuberculosis cases are placed under treatment. treatment of infectious cases is an important preventive measure. treatment efficacy is evaluated by sputum conversion (both on smear and culture) of the active pulmonary cases. after months of an effective regimen, % of active pulmonary cases should have converted their sputum from positive to negative. therefore the rate of sputum conversion at months becomes an important indicator of program effectiveness. this indicator must be calculated for those who are smear positive and with a lesser importance for the other active pulmonary cases. to ensure adequate treatment and prevent the development of acquired resistance, tuberculosis cases are placed under directly observed therapy (dot). this measure is quite labor intensive. priority must therefore be given to those at highest risk of relapse. these are the smear positive culture proven active pulmonary cases. dot on extra-pulmonary cases is much less important from a public health standpoint. the same considerations apply to contact investigation and preventive treatment in countries that can afford a tuberculosis contact program. a recently infected contact is at the highest risk of developing tuberculosis the first year after infection; hence the best preventive return is to identify contacts of infectious cases. those contacts are likely to have been recently infected. systematic screening of large population groups would also identify infected individuals but most would be 'old' infections at lower risk of developing disease. individuals infected with tuberculosis and hiv are at extremely high risk of developing active tuberculosis. therefore the tuberculosis control program should focus on the population at high risk of hiv infection. often, program evaluation is performed by epidemiologists who have not taken the time to understand the dynamics of a disease in the community. rates or proportions are calculated, no priorities are established and precious resources are wasted on activities with little preventive value. for example, attempting to treat all tuberculosis cases, whether pulmonary or not with dot, investigating all contacts regardless of the bacteriologic status of the index case, would be wasteful. today the world is smaller than ever before, international travel and a worldwide food market make us all potentially vulnerable to infectious diseases no matter where we live. new pathogens are emerging such as the sars or spreading through new territories such as wnv. wnv introduced in the us in , became endemic in the us over the next years. hospital-associated and community-associated methicillin resistant staphylococcus aureus (mrsa) and resistant tuberculosis cases and outbreaks are on the rise. public health professionals are concerned that a novel recombinant strain of influenza will cause a new pandemic. but not only the world and the etiologic agents are changing, the world population is changing as well. in industrialized countries, the life expectancy is increasing and the elderly are more likely to acquire a chronic disease, cancer or diabetes in their lifetime. because of underlying conditions or the treatment of these diseases, older populations also have an increased susceptibility for infectious diseases and are more likely to develop life-threatening complications. knowledge in the field of infectious disease epidemiology is expanding. while basic epidemiological methods and principles still apply today, improved laboratory diagnoses and techniques help to confirm cases faster, see how cases are related to each other and therefore can support the prevention of spread of the specific disease. better computers can improve the data analysis and internet allows access to in depth disease specific information. computer connectivity improves disease reporting for surveillance purposes and the epidemiologist can implement faster preventive measures if necessary and is also able to identify disease clusters and outbreaks on a timelier basis. the global threat of bioterrorism adds a new dimension. the intentional release of anthrax spores, and the infection and death of persons who contracted the disease created a scare of contaminated letters in the us population. with all these changes, there is renewed emphasis on infectious disease epidemiology and makes it a challenging field to work in. detection of bordetella pertussis and respiratory syncytial virus in air samples from hospital rooms transmission of tuberculosis in new york city. an analysis by dna fingerprinting and conventional epidemiologic methods report of the committee on infectious diseases in: chin j (ed) control of communicable diseases manual, th edn geographical information system (gis), gimmick or tool for health district management update: international outbreak of restaurant-associated botulism -vancouver epidemiologic notes and reports restaurant associated botulism from mushrooms bottled in-house -vancouver outbreaks of cyclospora cayetanensis infection -united states case definitions for infectious conditions under public health surveillance cdc ( a) framework for program evaluation in public health summary of infections reported to vibrio surveillance system (http:||www.cdc.gov|ncidod|dbmd|diseaseinfo|files|vibcste web.pdf) accessed norowalk-like viruses": public health consequences and outbreak management updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group outbreaks of gastroenteritis associated with noroviruses on cruise ships -united states diagnosis and management of foodborne illnesses: a primer for physicians and other health care professionals epiinfo (http:||www.cdc.gov|epiinfo|) accessed evaluation fundamentals: guiding health programs, research and policy yellow fever. in: cox cr (ed) the wellcome trust illustrated history of tropical diseases a national outbreak of salmonella enteritidis infections from ice cream encephalitis outbreak in louisiana in simple school questionnaires can map both schistosoma mansoni and schistosoma haematobium in the democratic republic of congo molecular and conventional epidemiology of mycobacterium tuberculosis in botswana: a population-based prospective study of pulmonary tuberculosis patients dolin r (eds) ( ) mandell, douglas, and bennett's principles and practice of infectious diseases epidemiology, principles and methods. little, brown and company an uninvited guest at "turkey day trends in hospitalizations associated with gastroenteritis among adults in the united states the next influenza pandemic: lessons from hong kong on the mode of communication of cholera pulsenet: the molecular subtyping network for foodborne bacterial disease surveillance, united states late-breaker report presented at the cdc "annual epidemic intelligence service conference http:||www.who.int|whr | | archives|index.htm) accessed statistical annex. (http:||www.who.int| whr | |archives| |en|pdf|statisticalannex.pdf) accessed cholera, the black one. in: yellow fever black goddess, the coevolution of people and plagues four tales from the new decameron. in: yellow fever black goddess, the coevolution of people and plagues key: cord- -i tacj authors: nan title: empfehlung zur prävention nosokomialer infektionen bei neonatologischen intensivpflegepatienten mit einem geburtsgewicht unter g: mitteilung der kommission für krankenhaushygiene und infektionsprävention beim robert koch-institut date: - - journal: bundesgesundheitsblatt gesundheitsforschung gesundheitsschutz doi: . /s - - - sha: doc_id: cord_uid: i tacj nan ein neugeborenes wird als solches bis zum . lebenstag bezeichnet. es handelt sich um ein frühgeborenes, wenn das gestationsalter (ga) bei geburt -gerechnet vom ersten tag der letzten normalen regelblutung -kleiner ist als vollendete wochen (< tage) . je nach geburtsgewicht (gg) werden des weiteren unterschieden . < g: untergewichtige neugeborene (lbw), - % der lebendgeborenen, . - g: sehr untergewichtige neugeborene (vlbw), , - , % aller lebendgeborenen, . < g: extrem untergewichtige neugeborene (elbw), , - , % aller lebendgeborenen. ausgehend von einem anteil an allen lebendgeborenen von , % für die frühgeborenen sowie von , % für vlbw-und , % für elbw-neugeborene ergeben sich als mittelwert für die jahre - folgende kalkulationen für deutschland: die absolute zahl der lebendgeborenen in der jeweiligen gruppe pro jahr beträgt im median frühgeborene kinder, frühgeborene unter g geburtsgewicht kinder, vlbw frühgeborene (geburtsgewicht - g) kinder, elbw frühgeborene (geburtsgewicht - g) kinder. entsprechend verteilen sich die im rahmen des neo-kiss surveillanceprojektes dokumentierten patienten (n= ) folgendermaßen: < g , %, - g %, - g , % (http://www.nrzhygiene.de/surveillance/neo.htm). f bis zur verwendung ist der inkubator mind. h bei laufendem motor zu belüften; siehe auch angaben der hersteller (kategorie ib). f nach der aufbereitung muss der inkubator in einem "reinen" und abgetrennten bereich (nicht auf dem stationsflur) vor kontamination geschützt werden (kategorie ib). f die patientenseitige desinfektion eines belegten inkubators ist nicht möglich, da eine schädigung des frühgeborenen durch exposition gegenüber marktüblichen flächendesinfektionsmitteln nicht auszuschließen ist (kategorie ib). f die reinigung der innenseite des belegten inkubators kann mit wasser von trinkwasserqualität erfolgen (siehe oben), wobei für jeden inkubator (patientenbezogen) ein frisches, keimarmes tuch verwendet werden muss (kategorie ib). f alle außen gelegenen handkontaktflächen am inkubator (inklusive steu-erungstastaturen) müssen arbeitstäglich wischdesinfiziert werden (kategorie ib). f die frage, in welchen abständen ein patient einen frisch aufbereiteten inkubator bekommen muss, wurde bisher nicht untersucht und ist daher ungelöst (kategorie iii). während in speziellen situationen, z. b. im verlauf einer sanierungsbehandlung bei mrsa-besiedlung, ein täglicher wechsel im rahmen der grundpflege erforderlich ist, spricht bei stabilen kindern, die zumindest einmal täglich mit frischer wäsche versorgt werden, nichts gegen einen wöchentlichen inkubatorwechsel. in einigen neonatologischen intensivbehandlungseinheiten ist es üblich, die abgepumpte muttermilch für sehr unreife frühgeborene in regelmäßigen intervallen mikrobiologisch zu untersuchen und je nach ergebnis freizugeben oder zu verwerfen. im rahmen von ausbruchsuntersuchungen wurden in der muttermilch e. [ , , , ] (kategorie ii). die Überbelegung einer station, die definitionsgemäß mit einem mangel an angemessen ausgebildeten schwestern, pflegern und Ärzten einhergeht, korreliert mit einem erhöhten risiko nosokomialer infektionen [ , , , ] . zahlreiche studien aus der neonatologie und aus anderen fachdisziplinen bestätigen dies übereinstimmend [ , , , , , , , , ] . sie beweisen, dass bei gleich bleibendem personalbestand eine Überbelegung das risiko nosokomialer infektionen erhöht bzw., dass eine bessere austattung mit fachschwestern-/pflegern das risiko von nosokomialen infektionen senkt [ ] . jedoch kann auch eine quantitativ ausreichende personalausstattung nosokomiale infektionen nicht verhindern, wenn das vorhandene personal schlecht ausgebildet oder mit den arbeitsabläufen und den hygienestandards vor ort nicht ausreichend vertraut ist [ ] . f es ist wissenschaftlich gesichert, dass eine nicht angemessene ausstattung der nips mit qualifiziertem und vor ort eingearbeitetem personal das risiko nosokomialer infektionen erhöht (kategorie ia). f die empfehlung der gesellschaft für neonatologie und pädiatrische intensivmedizin (zur personalausstattung) [ ] ist diesbezüglich wegweisend (kategorie ib). die postnatale reinigung der haut bei frühgeborenen < g erfolgt je nach allgemeinzustand und hautbeschaffenheit. hierzu benötigte pflegeutensilien und -mittel sind patientenbezogen einzusetzen (zur mikrobiologischen wasserqualität siehe oben), da sie zum ausgangspunkt nosokomialer ausbrüche werden können [ ] . f in der besonders vulnerablen phase (erste lebenswoche) nach der geburt sollte bei extrem unreifen frühgeborenen (< . ssw) aufgrund der erhöhten permeabilität und verletzlichkeit der haut nur so viel wie unbedingt nötig manipuliert werden (z. b. antisepsis vor invasiven prozeduren, körperwaschung) (kategorie ib). entsprechende studien liegen für level und nips nicht vor (kategorie iii). vor jeder durchtrennung der haut (z. b. blutentnahmen, injektionen, punktionen) muss ein hautantiseptikum aufgetragen und die deklarierte einwirkzeit eingehalten werden (haut trocknen lassen). es empfiehlt sich die begrenzung auf präparate mit möglichst geringem resorptivem risiko [ , ] . polyvidoniod % (pvp-iod) hat den nachteil der systemischen jodresorption und ist daher bei extrem unreifen frühgeborenen primär kontraindiziert [ , , ] (kategorie ib). chlorhexidin kann bei extrem unreifen frühgeborenen lokale unverträglichkeitsreaktionen auslösen, die einer zweitgradigen verbrühung ähneln [ , ] . es weist wirkungslücken im gramnegativen bereich auf [ , ] , was bei kontamination der lösung nosokomiale epidemien zur folge haben kann [ ] . es hat zytotoxische und im tierversuch mutagene eigenschaften [ ] . seit wurde über mehr als durch chlorhexidin ausgelöste, zum teil lebensbedrohliche anaphylaktoide reaktionen berichtet, so dass die u.s.-amerikanische food and drug administration sich zu einem speziellen warnhinweis veranlasst sah [ ] . f chlorhexidin wird aufgrund von wirkungslücken, ungünstiger beeinflussung der wundheilung, potenzieller mutagenität und der klinisch relevanten gefahr von Überempfindlichkeitsreaktionen nicht zur hautdesinfektion empfohlen (kategorie ib). octenidinhydrochlorid ( , %) in kombination mit % phenoxyethanol (octenispet®) ist ein farbloses, nicht mutagenes haut-und schleimhautantiseptikum mit breiterem wirkungsspektrum als chlorhexidin und guter lokaler verträglichkeit [ ] . es gibt inzwischen eine reihe klinischer anwendungsbeobachtungen u. a. auch in der kinderurologie und bei extrem unreifen frühgeborenen [ ] . die sicherheit des präparats in der anwendung bei extrem unreifen frühgeborenen kann jedoch nicht allein aus dem nachweis des abbauproduktes phenoxyessigsäure im urin geschlussfolgert werden. f aus toxikologischen gründen wird eine hautdesinfektion bei frühgeborenen mit octenidin , % ohne phenoxyethanol empfohlen (kategorie ii). der hersteller von octenisept® bietet klinikapotheken octenidin als grundsubstanz zur eigenen herstellung einer gebrauchsfertigen lösung (zielkonzentration , %) nach einer arzneirezeptur an. vor blasenkatheterisierung soll ein antiseptikum mit sterilem, satt getränkten tupfer aufgetragen und von der harnröhre nach dorsal abgewischt werden (einwirkzeit min). octenisept® ist wegen der resorption des zusätzlich enthaltenen phenoxyethanols problematisch [ ] . f zur schleimhautantiseptik bei frühgeborenen < g ist octenidin , % ohne phenoxyethanol mittel der wahl (kategorie ib), (s. o.). eine evidenzbasierte empfehlung zur mundhöhlenantiseptik bei apparativer beatmung ist nicht möglich (kategorie iii). spezielle indikationen zur antiseptischen hautwaschung können bei frühgeborenen bestehen, die mit mrsa besiedelt sind oder unter der geburt/sectio äußerlich durch das blut der mutter mit he- unmittelbar postnatal wird die nabelschnur nach anlegen einer sterilen kunststoffklemme durchtrennt und mit einer sterilen kompresse abgedeckt. dabei wird die kompresse unter der nabelklemme durchgezogen, um den kontakt des nabelschnurstumpfes mit der bauchhaut und mit urin zu verhindern. sofern der nabelstumpf nicht verunrei nigt ist, oder als zugang für intravaskuläre katheter genutzt wird, ist eine antiseptik nicht erforderlich (der nabelstumpf wird nicht als wunde angesehen, stellt jedoch eine potenzielle eintrittspforte für sekundärinfektionen dar). bei lokalen entzündungszeichen insbesondere bei einer rötung des nabelrings ist nach entnahme eines abstrichs zur erregerdiagnostik ein antiseptikum indiziert (siehe hautantiseptik). die verhinderung des hustenreflexes, die reizung/verletzung des trachealepithels, die leitschiene für die mikroaspiration von bakterien des mund-und rachenraumes und die kunststoffoberfläche, auf der sich ein mikrobieller biofilm bildet, machen den intratrachealen tubus zum wichtigsten risikofaktor der vap [ , ] . intrinsische faktoren des beatmungspflichtigen frühgeborenen kommen hinzu, wie der oft kritische und katabole allgemeinzustand, eine zelluläre oder humorale immundefizienz sowie die an-tibiotische vorbehandlung. das beatmete frühgeborene ist einer vielzahl von faktoren in seiner belebten und unbelebten umgebung ausgesetzt, durch die eine infektion begünstigt wird [ ] (. tabelle ). die diagnostik der vap bei frühgeborenen ist schwierig, was bei der beurteilung entsprechender studien berücksichtigt werden muss [ , , ] . risikofaktoren für eine vap bei frühgeborenen sind: . [ , ] ist auch bei frühgeborenen möglich. ebenso ist eine intermittierende bauchlagerung zur besseren ventilation und sekretdrainage der basalen lungenabschnitte in der regel zu empfehlen. die erstversorgung geht in aller regel mit invasiven maßnahmen einher und findet oft räumlich angrenzend an den gynäkologischen operationssaal statt. vor dem hintergrund der besonderen infektionsgefährdung bei extrem unreifen frühgeborenen ergeben sich folgende empfehlungen: die derzeit verfügbaren beatmungsfilter zur passiven befeuchtung des systems [ , ] sind für frühgeborene nicht geeignet, da sie für diese patienten nicht validiert sind und durch totraumerhöhung zu einer kritischen co -retention führen könnten (kateorie iii). wegen der hochgradigen immundefizienz wird für fg < g geburtsgewicht zusätzlich zur thermischen desinfektion in einem automaten eine definiert geschützte (geschlossene) lagerung von beatmungszubehör empfohlen (kategorie ii in einer prospektiven studie mit vs. beatmeten neugeborenen < g gg [ ] traten in beiden gruppen (geschlossene absaugung vs. offene konventionelle absaugung) je vap-episoden auf. unabhängig von der methode des absaugens (offen oder geschlossen) muss die spülflüssigkeit steril sein. f wenn durch entsprechende maßnahmen flüssigkeits-und sekretrückstände im geschlossenen absaugsystem vermieden werden, ist das system als bestandteil des beatmungssystems zu betrachten und kann tage am patienten verbleiben [ , ] . studien zu dieser frage bei frühgeborenen fehlen (kategorie iii). f eine empfehlung zum infektionspräventiven einsatz und zum wechselintervall geschlossener absaugsysteme bei frühgeborenen kann nicht ausgesprochen werden (kategorie iii). f wenn der patient endotracheal mit multiresistenten krankheitserregern besiedelt ist, wird eine geschlossene absaugung zur verringerung der umgebungskontamination empfohlen (kategorie ib). es ist bisher unbekannt, ob spezielle maßnahmen der schleimhauthygiene, die sich in zahlreichen studien bei erwachsenen intensivpatienten als effektiv in der vap-prävention erwiesen haben [ ] , die kolonisation der schleimhäute bei frühgeborenen günstig beeinflussen und die vap-inzidenz vermindern können. vor allem wurden die entsprechenden studien bei erwachsenen mit chlorhexidin oder oralen antibiotika durchgeführt, deren einsatz bei sehr unreifen frühgeborenen nicht empfohlen werden kann. f mit antibiotika behandelte, sehr unreife frühgeborene sollten eine lokale prophylaxe mit nystatin-oder amphotericin b (cave: hohe osmolarität von am-phomoronal®) erhalten [ ] (kategorie ii). f eine prophylaktische antibakterielle chemotherapie bei beatmeten frühgeborenen wird nicht empfohlen [ ] (kategorie ia). das gleiche gilt für eine prophylaktische substitution von immunglobulinen zur prävention der vap [ ] (kategorie ia). f Über die passive immunisierung mit palivizumab zur prävention der rsv-pneumonie bei hochrisikofrühgeborenen, die während der rsv-saison noch stationär behandelt werden, sollte im einzelfall entschieden werden [ , , , , ] (kategorie ib). zentrale venenkatheter werden bei frühgeborenen < g in der regel als nabelkatheter oder als perkutane zentrale venenkatheter (peripherally-inserted central catheter, "silastik"-katheter, picc) angewendet [ f die indikation zum gebrauch eines picc muss täglich geprüft werden; er muss so früh wie möglich entfernt werden (kategorie ib). f piccs müssen nicht routinemäßig gewechselt werden (kategorie ib). [ , ] . bei kindern im neugeborenenalter wurden bei , % lokalinfektionen beschrieben [ ] . studien bei frühgeborenen < g wurden bisher nicht publiziert. periphere arterienkatheter bei frühgeborenen werden gewöhnlich in die a. radialis oder die a. tibialis post. gelegt [ , ] . eine bevorzugte insertionsstelle aus infektiologischen/hygienischen gründen konnte bisher in studien und insbesondere bei frühgeborenen < g nicht gezeigt werden. obwohl keine daten zu den hygienischen maßnahmen während der insertion peripherer arterienkatheter vorliegen, sollten alle maßnahmen eingehalten werden, die bei der insertion peripherer venenverweilkanülen getroffen werden, und darüber hinaus sterile handschuhe getragen werden, da in der regel auch während der punktion die palpation des arterienpulses notwendig sein kann. f eine empfehlung zur wahl der insertionsstelle von peripheren arterienkathetern aus infektiologischer sicht kann nicht gegeben werden (kategorie iii hinsichtlich verband und verbandswechsel sollen periphere arterienkatheter wie periphere venenverweilkanülen behandelt werden. f eine punktionsnahe applikation von unsterilen pflasterstreifen ist zu vermeiden (kategorie ib). f es können sowohl transparente als auch gazeverbände verwendet werden (kategorie ib). f die verbände müssen täglich inspiziert werden (kategorie ib). f transparentverbände müssen nicht routinemäßig, sondern nur bei bedarf (verschmutzung, ablösung, durchfeuchtung, infektionsverdacht) gewechselt werden (kategorie ib). f gazeverbände müssen tgl. gewechselt werden (kategorie ib). f es ist eine hygienische händedesinfektion vor und nach verbandswechsel erforderlich (kategorie ib). f der verbandswechsel erfolgt mittels no-touch-technik oder mit sterilen handschuhen (kategorie ib). f die insertionsstelle wird mit steriler , % nacl-lösung und sterilem stieltupfer gereinigt (kategorie ib). da infektionen mit gram-negativen stäbchenbakterien bei verwendung von mehrwegdruckmesssystemen beschrieben wurden, sind einwegartikel, wie heute auch allgemein üblich, den mehrwegsystemen vorzuziehen [ , , , ] . auch bei neonatologischen patienten wurden infektionen über das messsystem beschrieben, insbesondere mit candida parapsilosis aber auch gram-negativen bakterien [ , , ] . als druckmesssysteme sollten geschlossene systeme ohne dreiwegehahn verwendet werden. die gesamten systeme sollten alle stunden gewechselt werden [ , , ] . die blutentnahme kann aus solchen systemen über eine durchstichmembran mit einer geeigneten sterilen nadel/spritze nach vorheriger alkoholischer wischdesinfektion der membran erfolgen [ ] . grundsätzlich sollten die anzahl der manipulationen, insbesondere blutabnahmen so niedrig wie möglich gehalten werden [ , ] . f es sollen einmalartikel als druckmesssysteme verwendet werden (kategorie ib). f es sollen geschlossene druckmesssysteme eingesetzt werden (kategorie ib). f die handhabung der nicht konnektierten druckmesssysteme muss im bereich der verbindungsstücke unter aseptischen kautelen erfolgen (kategorie ib). f druckmesssysteme müssen alle stunden gewechselt werden (kategorie ib). f bei blutabnahmen über eine gummimembran mit einer sterilen nadel/ spritze muss vorher eine alkoholische wischdesinfektion der membran erfolgen (kategorie ib). wie bei peripheren venenverweilkanülen nimmt die kolonisationsrate bei längerer liegedauer zu [ , , , , ] . zusammenfassend sind die infektionsraten auch bei längerer liegedauer niedrig, sodass keine empfehlung für einen routinemäßigen wechsel gegeben werden kann [ , ] . wegen der begünstigung einer bakteriellen oder mykotischen besiedlung des systems sollten keine glukosehaltigen spüllösungen verwendet werden [ , , ] . die zugabe von , - u/ ml heparin führt zu einer verlängerten nutzungsdauer auch bei kindern und neonatalen patienten [ , , ] . eine metaanalyse von randolph et al. kommt deshalb zu der allgemeinen empfehlung, der arteriellen spüllösung heparin zuzusetzen [ ] . aus infektiologischer sicht existieren keine daten, die einen nutzen für die kontinuierliche heparingabe zur prophylaxe der katheter-assoziierten infektionen zeigen. f periphere arterienkatheter können in situ belassen werden, solange eine klinische indikation besteht bzw. keine komplikation aufgetreten ist (kategorie ib). f ein routinemäßiger wechsel peripherer arterieller katheter ist nicht notwendig (kategorie ib). f die indikation muss täglich neu geprüft werden (kategorie ib). f katheter sind bei sichtbarer entzündung an der eintrittsstelle sofort zu entfernen (kategorie ib). f glukosehaltige spüllösungen dürfen nicht verwendet werden (kategorie ib). f eine empfehlung zur verwendung von heparin kann aus infektiologischen gründen nicht gegeben werden (kategorie iii). speziell geschulte katheterteams und personalschulungen können die rate katheter-assoziierter infektionen signifikant reduzieren. studien, die dies für die anlage und pflege von nvk/nak untersucht haben, fehlen jedoch. der einfluss verschiedener kathetermaterialien wurde im hinblick auf infektions-präventive effekte für nabelkatheter nicht untersucht [ , ] . katheter aus polyurethan oder silikon sollten bevorzugt verwendet werden, da in-vitro-daten eine schlechtere adhäsion von mikroorganismen an diesen materialien im vergleich zu polyvinylchlorid oder polyethylen zeigen [ ] . mehrlumige nabelvenenkatheter sind im vergleich mit einlumigen kathetern nicht mit einer erhöhten infektionsrate assoziiert [ , , ] . die position (hohe vs. tiefe position) des nabelarterienkatheters wurde hinsichtlich katheter-assoziierter infektionen nicht untersucht. hinsichtlich der entwicklung einer nec (s. u.) zeigte sich kein signifikanter unterschied [ ] . f es können handelsübliche nvk/ nak aus silikon oder polyurethan verwendet werden (kategorie iii). f es können sowohl einlumige als auch mehrlumige katheter zum einsatz kommen (kategorie ib). f eine empfehlung für die hohe oder tiefe position beim nak kann nicht ausgesprochen werden (kategorie iii). es existieren keine studien, in denen der einfluss bestimmter hygienemaßnahmen bei der insertion auf die infektionsrate von nabelkathetern untersucht wurde. die anlage von nabelkathetern erfolgt in steriler technik unter maximalem barriereschutz. zur desinfektion des nabelstumpfes sollte wie bei den piccs und den peripheren venen-und arterienkathetern in der patientengruppe < g gg octenidin , % verwendet werden. f katheter können im kreißsaal, op oder auf der station gelegt werden (kategorie ib). weitere empfehlungen sind: f hygienische händedesinfektion vor der anlage (kategorie ia), f haut-und nabelstumpfdesinfektion mit octenidin , % unter beachtung der einwirkzeit von mind. min (kategorie ib), f anlage von sterilen einmalhandschuhen, sterilen schutzkitteln, mund-nasen-schutz und haube, großflächige abdeckung der punktionsstelle mit sterilem lochtuch (kategorie ia), f durchtrennung der nabelschnur und präparation der nabelgefäße mit sterilem instrumentarium (kategorie ib), f insertion unter aseptischen bedingungen (kategorie ia). die nabelgefäßkatheter können mit hilfe einer annaht am nabelstumpf fixiert werden. der nabelstumpf kann mit einem gazeverband verbunden werden. transparentverbände eignen sich hierfür nicht. nicht-transparente gazeverbände müssen täglich erneuert werden, um eine inspektion der eintrittsstelle durchzuführen. dem vorteil eines verbandes der nabelregion (z. b. schutz vor verunreinigungen aus der perianalregion) stehen die nachteile der schlechteren beurteilbarkeit der einführtiefe des nabelgefäßkatheters gegenüber. ob eine offene nabelpflege (ohne pflasterverband) zu einem höheren risiko für katheter-assoziierte infektionen führt, wurde nicht untersucht. die reinigung der insertionsstelle sollte mit sterilen tupfern und nacl , % und die lokale antisepsis mit octenidin , % erfolgen. daten über die anwendung von antimikrobiellen salben auf der insertionsstelle bei nabelgefäßkathetern existieren nicht. f eine aussage zur notwendigkeit eines pflasterverbandes bei liegendem nabelkatheter ist nicht möglich (kategorie iii). empfohlen wird eine f lokale antiseptik mit octenidin , % (kategorie ib), f und keine routineapplikation von antibakteriellen substanzen an der nabelöffnung bei liegenden nabelgefäßkathetern (kategorie iii). in einer kontrollierten studie konnte unter antibiotischer prophylaxe zwar eine reduktion der kolonisierung der nak, jedoch keine reduktion von klinischen infektionen beobachtet werden [ , ] . gleiches gilt für nvk [ , ] . f die prophylaktische gabe systemischer antibiotika zur prophylaxe nabelkatheter-assoziierter infektionen wird nicht empfohlen (kategorie ib). es gibt keine studien, welche den einfluss eines routinemäßigen wechsels bzw. eine entfernung von nabelkathetern nach einer definierten liegedauer untersucht haben. der systemwechsel erfolgt analog zu dem bei piccs (siehe dort). f ein routinemäßiger wechsel bzw. eine routinemäßige entfernung von nabelkathetern nach einem bestimmten zeitpunkt wird nicht empfohlen (kategorie iii). f nabelkatheter müssen bei zeichen einer omphalitis (eitrige sekretion, rötung der periumbilikalregion) sofort entfernt werden (kategorie ib). die durchgängigkeit von nak wird durch den kontinuierlichen zusatz von heparin zur infusionslösung ("arterienspülung") günstig beeinflusst und damit die liegedauer verlängert [ , ] . ob der heparinzusatz zu einer geringeren infektionsrate führt, ist nicht untersucht. f intermittierende spülungen können, falls notwendig, mit steriler , % nacl-lösung erfolgen (kategorie ib). f eine empfehlung zum einsatz von heparin als kontinuierliche infusion zum erhalt und zur infektionsprävention bei nak kann nicht gegeben werden (kategorie iii). f siehe entsprechender abschnitt zu den arterienkathetern [ , , ] , ciprofloxacin [ , , ] oder linezolid [ , ] . in bezug auf den gesamten verbrauch von glycopeptiden entfällt in pädiatrischen behandlungszentren ca. ein drittel auf die nips ( % bei [ ] ). bei der überwiegenden mehrzahl der so behandelten episoden ( % bei [ ] ) wird vancomycin empirisch ohne den nachweis eines methicillin-resistenten erregers in der blutkultur eingesetzt [ , ] . aufgrund der hohen anwendungsrate breit wirksamer antibiotika bei früh-geborenen < g geburtsgewicht ist der selektionsdruck für erreger mit speziellen resistenzen und multiresistenzen besonders hoch [ ] . die anwendung bestimmter antibiotika korreliert mit der selektion von resistenten erregerspezies [ , , ] . zum beispiel begünstigt der einsatz von cephalosporinen der gruppe iii die selektion von cephalosporin-resistenten enterobacter spp. [ ] , von klebsiella spp. [ ] und aufgrund der primären wirkungslücken auch die von enterokokken und clostridium difficile [ ] . der empirische einsatz von vancomycin erhöht den selektionsdruck für glycopeptid-resistente erreger, wie vancomycin-oder teicoplanin-resistente koagulase-negative staphylokokken [ , , , ] oder vancomycin-resistente enterococcus faecium [ , , , , ] . bis zu % der bei neonatologischen intensivpatienten isolierten koagulasenegativen staphylokokken (cons) sind meca gen-positiv und damit phänotypisch meist methicillin-resistent [ , ] . der frühe empirische einsatz von vancomycin beruht somit auf der befürchtung, das akut erkrankte kind könnte ohne ein glycopeptid durch eine unwirksame therapie gefährdet werden. eine signifikant höhere letalität bei inadäquater initialer antimikrobieller therapie ist in dieser patientengruppe z. b. für candida-infektionen in einer multivariaten analyse beschrieben [ ] . einige studien zur late-onset-sepsis deuten jedoch darauf hin, dass -im unterschied zu gram-negativen bakterien und systemischen candidainfektionen [ ] -die letalität von cons-infektionen sehr gering ist (maximal , %- von episoden bei karlowicz et al. [ ] ). somit besteht vor allem beim empirischen einsatz von vancomycin in der neonatologie -wie in vielen anderen fachdisziplinen auch [ ] -offensichtlich ein erhebliches einsparpotenzial, solange in einer abteilung nicht ein relevanter anteil der s.aureus methicillin-resistent ist [ ] . der selektionsdruck der glycopeptide könnte durch den gezielten und restriktiven einsatz von vancomycin reduziert werden [ , , , , ] . toxinbildende clostridium difficile werden vorübergehend von mehr als der hälfte aller mit antibiotika behandelten frühgeborenen ausgeschieden, sind in dieser altersgruppe jedoch als krankheitserreger von untergeordneter bedeutung [ , ] . erhebliche probleme durch nosokomiale Übertragung können daraus resultieren, dass ältere kinder mit neugeborenen auf der gleichen intensivstation betreut werden [ , ] . neonatologische intensivpatienten mit kompliziertem verlauf und langem aufent halt können durch eine persistierende besiedlung der atemwege oder von dauerhaft eingesetzten hilfsmitteln (tubus, tracheostoma, magensonde, peg) zu einem bedeutsamen "reservoir" der nosokomialen ausbreitung multiresistenter infektionserreger werden [ , , , ] . hier sind besonders gramnegative erreger wie acinetobacter spp. [ , , , ] , enterobacter spp. [ , , , , , ] , klebsiella spp. [ , , ] im folgenden wird nur in stark komprimierter form auf eine begrenzte auswahl übertragbarer krankheitserreger eingegangen. zur weiteren vertiefung wird auf die zitierte literatur verwiesen. frühgeborene sind u. a. aufgrund der fehlenden kolonisationsresistenz und der häufigen anwendung breit wirksamer antibiotika besonders empfänglich für eine kolonisation mit nachfolgender infektion durch multiresistente nosokomiale infektionserreger. methicillin-resistente s.aureus (mrsa) [ , , , , ] und vancomycin-resistente enterokokken (vre) [ , , , , , ] weisen unter den gram-positiven erregern die größte bedeutung auf, da sie ein erhebliches epidemisches potential haben. zum teil haben aus der kolonisation hervorgehende epidemische infektionen auch dann, wenn das frühgeborene überlebt, schwerwiegende langzeitfolgen, wie etwa bei der meningoencephalitis mit ausgedehnten hirnabszessen verursacht durch serratia marcescens [ , ] . zu gram-negativen bakterien finden sich zahlreiche berichte über ausbrüche durch multiresistente klebsiella spp. [ , , ] , acinetobacter spp. [ , , , ] , serratia spp. [ , , , , , , , , , , ] oder zu solchen isolaten, die in vitro durch die produktion von betalaktamasen mit erweitertem wirkungsspektrum (esbl) eine resistenz gegen cephalosporine der gruppe iii aufweisen [ , , , ] . vor allem für die gram-negativen erreger dieser auflistung [ , ] , jedoch auch für vre und mrsa [ , , , , , ] , ist die besiedlung des gastrointestinaltraktes von epidemiologischer bedeutung [ , , ] . bei intubierten kindern sind oft auch die atemwege mit multiresistenten isolaten besiedelt [ , ] . alle können über die hände des behandlungsteams (und der eltern) sowie durch kontaminierte gegenstände und pflegemittel von kind zu kind übertragen werden [ , ] . acinetobacter baumanii nimmt eine sonderstellung unter den gram-negativen hospitalkeimen ein, weil diese spezies resistent ist gegen trocknungsschäden [ , , ] zusätzlich zu den bakteriellen nosokomialen infektionserregern treten bei frühund neugeborenen virale erkrankungen auf, die sich aufgrund der fehlenden immunität auf seiten der patienten (z. b. fehlender nestschutz durch mütterliche an-tikörper) [ ] [ ] . zur prävention der influenza [ ] ist v. a. die immunität aller kontaktpersonen des fg entscheidend. f das gesamte behandlungsteam einer nips und alle angehörigen von fg sollten (jährlich) gegen influenza aktiv immunisiert werden [ ] bei herpes labialis muss von den eltern oder vom personal ein mund-nasen-schutz getragen werden (tröpfcheninfektion) und sehr sorgfältig auf die durchführung der hygienischen händedesinfektion vor jedem patientenkontakt (Übertragung über kontaminierte hände) geachtet werden. die läsion sollte abgedeckt sein und nicht während der arbeit mit den händen berührt werden. da das cytomegalovirus (cmv) von infizierten frühgeborenen über monate im urin ausgeschieden wird, ist eine nosokomiale Übertragung z. b. durch ungeschützten handkontakt mit "sauberen" windeln oder cmv in muttermilchproben und fehlende händedesinfektion möglich [ , , ] . auch nicht-immunes personal (bis zu % in abhängigkeit vom lebensalter und den lebensumständen) kann auf diesem wege cmv-infektionen bis hin zur akuten cmv-encephalitis erwerben [ , ] . f in der pflege cmv-ausscheidender fg sind strikt befolgte standardhygienemaßnahmen zur vermeidung einer nosokomialen Übertragung ausreichend (kategorie ib). f dem behandlungsteam sollte der eigene cmv-serostatus bekannt sein (kategorie ii). f augenärztliche vorsorgeuntersuchungen müssen mit desinfizierten händen und mit sterilisiertem oder mit einem umfassend viruzid wirksamen mittel desinfizierten instrumentarium erfolgen, weil sonst die gefahr einer Übertragung von adenoviren bzw. einer epidemischen keratokonjunktivitis besteht [ , , , , ] (kategorie ib) . das humane parvovirus b (erreger der ringelröteln) kann über tröpfcheninfektion (auch kontaminierte gegenstände) nosokomiale epidemien auslösen, wozu v. a. seine hohe tenazität und unempfindlichkeit gegenüber handelsüblichen desinfektionsmitteln beiträgt [ , , , ] . der serostatus der mitarbeiter sollte diesen bekannt sein, insbesondere, wenn es sich um frauen mit kinderwunsch handelt (gefahr des hydrops fetalis bei infektion in der frühschwangerschaft) [ , , , , , ] . eine exposition gegenüber masernvirus [ , , , , , , , ] in einer nips erfordert die passive immunisierung aller nicht durch maternale antikörper geschützten frühgeborenen mit standardimmunglobulin und die Überprüfung des serostatus (ggf. die auffrischimpfung) des behandlungsteams. unter den viralen erregern der gastroenteritis sind v. a. rotavirus [ , , , , , ] insbesondere in 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authors: gharavi, erfaneh; nazemi, neda; dadgostari, faraz title: early outbreak detection for proactive crisis management using twitter data: covid- a case study in the us date: - - journal: nan doi: nan sha: doc_id: cord_uid: ad avzd during a disease outbreak, timely non-medical interventions are critical in preventing the disease from growing into an epidemic and ultimately a pandemic. however, taking quick measures requires the capability to detect the early warning signs of the outbreak. this work collects twitter posts surrounding the covid- pandemic expressing the most common symptoms of covid- including cough and fever, geolocated to the united states. through examining the variation in twitter activities at the state level, we observed a temporal lag between the rises in the number of symptom reporting tweets and officially reported positive cases which varies between to days. "starting the new year off right with a cough and fever!" "starting the new year off right, sick as a dog with a high fever and a nasty cough. craptastic." "starting with a fever and flu like symptoms is not how i pictured this decade starting" "my ribs hurt when i cough so i don't want to cough but i have to cough i hate it here" these are only few examples of many twitter messages (known as tweets) that people have posted in early in the united states, complaining about intense flu-like symptoms such as dry cough and fever, later on, were recognized as the most common symptoms of covid- . sars-cov- , the virus that causes covid- , is thought to have first transmitted from an animal host to humans in wuhan, china in late . on march , , after the rapid increase of the cases outside china, the world health organization (who) eventually declared the covid- as a pandemic (who ). as of april , it is officially reported that more than three million people are infected by this virus in countries and territories around the world and international conveyances (worldometer ) . during a pandemic with a high infection rate, prompt mitigatory actions play a crucial role in decelerating the spread and preventing the new hotspots of the disease. though, taking immediate actions requires the capability to detect the early warning signs of the outbreak and to characterize the dynamic of the spread in a near real-time fashion. in the case of covid- pandemic, delay in developing the test kits, the limited number of kits, complicated bureaucratic health care systems, and lack of transparency in data collection procedures are the major origins of postponement of effective preventive interventions and mitigatory (washington post; achrekar et al. ). lai et. al. could have been conducted one week, two weeks, or three weeks earlier in china, cases would have been reduced by %, %, and %, respectively, together with significantly reducing the number of affected areas (lai et al. ) . to fill this gap, epidemic intelligence (ei) is being used to explore alternative mostly informal sources of data to gather information regarding disease activity, early warning, and infectious disease outbreak (de quincey and kostkova ) . human activities and interactions on the web are one of these informal sources. for instance, google flu trends exploits web search queries to estimate flu activity ("google flu trends" ). social media content is another powerful tool that provides invaluable crowd-sourced near realtime data for sensing health trends. twitter is a microblogging service with around million monthly active users that let users communicate through short messages (tweets) (salman aslam ). twitter permits third parties to explore tweets and collect data about posters and their locations. it provides the opportunity to harness tweets data to detect early signs of outbreaks which can ultimately support decision-makers in taking more informed actions (grover and aujla ) . in this paper, we explore twitter data right before and during covid- pandemic across the united states at the state level, for the most common symptoms of covid- including cough and fever. to offer a framework for outbreak early detection, the result of analysis on twitter data are compared to the formal dataset provided by john hopkins university which is openly available to the public for educational and academic research purposes . the rest of this paper is organized as follows: section reviews the related literature that harness the twitter data to analyze, detect and predict the outbreaks. in section , we present our methodology for extracting relevant information from twitter and preprocessing and analyzing the collected data. elaborated results for six states are presented in section . in section , we will discuss the results, key findings and potential application, limitations and further steps of this study. finally, we conclude in section . several studies have been conducted on the use of the twitter data to explore the outbreak trends aiming to develop models for disease outbreak prediction. achrekar et al. present a framework that monitors messages posted on twitter with a mention of flu indicators to track and predict the emergence and spread of an influenza epidemic in a population (achrekar et al. ) . similarly, chen et al. , propose an approach to aggregate users' states in a geographical region for a better estimation of the flu trends (chen et al. ) . smith et al. , offer a method to distinguish between personal flu infection tweets versus general awareness tweets (i.e. expressing concern regarding flu outbreak) (smith et al. ) . the twitter content during the h n outbreak is analyzed by (chew and eysenbach ) . besides flu, tweeter data has been also leveraged to analyze other epidemies like malaria, zika virus, dengue, ebola and so on. for instance, masri et al. , utilize in this study, we propose a conceptual framework for investigating the temporal trends in the twitter users' posts. this framework has three main modules including data collection, data preprocessing and data analysis. the framework schema is depicted in figure . in the following section, we will further elaborate each module. we use getoldtweets python package to retrieve historical tweets. by employing this package, the query can be restricted to get tweets containing determined keywords, during a particular time frame and within a specific region. we collect tweets containing keywords fever or cough, as the main symptoms of coronavirus, from the beginning of september to april- , . the query limits the retrieved tweets to be within -mile radius distance of kansas city that covers all the states in america. then, we use twitter api (application programming interfaces) to retrieve the corresponding tweets using the given ids to access the precise geographical information of the user. the statistics of the number of tweets per state is shown in figure . the data is available on our github data repository . to compare the results with the formal cases we use time series data of covid - cases, reported by john hopkins university. the data is reported from january to april , . during the preprocessing, all the variations of the location name in twitter data within a state are integrated into a unique token with the following format: "state_name, usa". it is the same naming format as in john hopkin's dataset. the number of confirmed cases in john hopkins dataset were reported separately for different counties within a state. the data has been aggregated over all counties in each state. for data preparation, a continuous time-series of the daily number of tweets and confirmed cases are calculated for each state. the data analysis steps are illustrated by figure on colorado state data as an example. step : to compare the time series of the tweets containing covid- symptoms and the number of confirmed cases, we plot the data from the beginning of december. we assign zero to all the dates before january , for the case data that was not available in the johns hopkins dataset. step : the date of the formal outbreak is defined as the date where the number of confirmed cases in a state exceeds (hartfield and alizon ) . we refer to this date as the beginning of the outbreak in a given state and show it with a vertical red line. as illustrated in figure , the formal outbreak date at colorado state was on march . step : for colorado state and all other states, tweet time series shows a linear growth trend from the beginning of december up to march th, followed by an exponential growth. to model the temporal trend, a regression-based estimator is fitted on the tweet data during this period which is represented by the black line. step : finally, we detect the date of the informal outbreak, defined as the beginning of the exponential growth phase in tweets containing symptoms key words, by estimating the initial nonlinearity on tweet time series. vertical green line represents the informal outbreak on figure . in this section, we present the results for six highly affected states. as explained in section . , these plots (figure ) exhibit the number of tweets over time compared to the number of confirmed cases. the specified formal outbreak and the estimated informal outbreak are also shown for these states. this figure shows that there is a time lag between the estimated informal outbreak and formal outbreak which varies across the states. table summarizes the time lags observed for the six states shown in figure . the longest and shortest time lags were detected as and days for maryland and new york respectively. for most of the states the lag length is estimated around two weeks. based on the epidemic models, usually in the early stages of an epidemic we expect an exponential growth trend in the number of the cases of disease (martcheva ) . however, it is difficult to monitor the growth trends of the infection in real-time and detect the outbreak without significant delay. this delay is often caused by the time-consuming and bureaucratic procedures of diagnosis including test development, test processing time, and reporting time (rong et al. ) . in this study we examined the possibility to fill this gap by detecting the early signs of an outbreak using twitter content. we collected tweets containing the common symptoms of covid- , right before and after the formal outbreak. a challenging issue in analyzing this data is to differentiate between general public concerns regarding the outbreak, and personal infection by covid- to detect any anomaly in tweets' trend. to address this issue, smith et al. , use nlp to classify flu-related tweets into two categories of personal infection tweets that express an awareness of influenza. they show the temporal trends of these two categories are very different (smith et al. ) . in this study, we assume that the general awareness tweets, prior to an outbreak in a given state, increases linearly, following the increase in the volume of the epidemic-related news of other countries or other states. on the other hand, we expect to observe exponential growth in the volume of the personal infection tweets, when an outbreak is happening in the given state, even prior to the official detection of the outbreak by formal medical procedures. looking into the temporal trends in the twitter data in states of the us, prior to the official detection of the epidemic outbreak in any of the given states, as expected, we observe linear growth in the number of tweets following the news media reporting on the outbreak in china and later in western europe. however, for each state there is a tipping point that happens before any official reports of the outbreak in those states where the growth trends change from linear to exponential, implying that the number of personal infection tweets not only dominate the general awareness tweets, but also define the growth behavior of the aggregate number of the tweets (implying that an outbreak is happening on top of a general awareness growth.) in the case of covid- pandemic, lai et. al. , show if non-pharmaceutical interventions were conducted one week, two weeks, or three weeks earlier in china, cases would have been reduced by %, %, and %, respectively, together with significantly reducing the number of affected areas (lai et al. ) . the observations of the current study, as a proof of concept, suggest that the behavioral patterns of an epidemic outbreak emerges in the temporal trends of the informal data streams like twitter data, as an early sign of an outbreak in local level. in sum, this approach has potential to be used further as a decision support system to inform the policy makers deploying the intervention policies in a timely manner. for future work, we suggest to validate the results of this study using a classifier to better differentiate the relevant from irrelevant tweets to exclude tweets containing 'baby fever' or 'cough cough'. moreover, a model can be trained to monitor the fluctuation of symptom keyword usage and predict the pandemic in advance. in this paper, we investigated the possibility of using twitter content to detect and track covid- outbreak in each state across the united states. we used a simple analysis of temporal trends of the relevant tweets. our results have shown that the trend of tweets containing the common covid- symptoms such as cough and fever, are highly correlated with the official cdc dataset. although, a significant temporal lag, between to days, was observed between the exponential growth phase of tweets and the confirmed cases which could be related to inherent delays in the testing and diagnosis procedures. therefore, we conclude that twitter data provides a near real time assessment of an outbreak which can be utilized as an early warning system to increase the public awareness. it also can be used as a decision support system to inform policy maker in taking timelier mitigatory and preventive actions. predicting flu trends using twitter data syndromic surveillance of flu on twitter using weakly supervised temporal topic models pandemics in the age of twitter: content analysis of tweets during the h n outbreak google flu trends prediction model for influenza epidemic based on twitter data introducing the outbreak threshold in epidemiology effect of non-pharmaceutical interventions for containing the covid- medrxiv, . . use of twitter data to improve zika virus surveillance in the united states during the epidemic malaria epidemic prediction model by using twitter data and precipitation volume in nigeria early warning and outbreak detection using social networking websites: the potential of twitter effect of delay in diagnosis on transmission of covid- twitter by the numbers: stats, demographics & fun facts towards real-time measurement of public epidemic awareness: monitoring influenza awareness through twitter a timeline of coronavirus testing in the u.s. -the washington post rolling updates on coronavirus disease (covid- ) coronavirus update (live): , , cases and , deaths from covid- virus pandemic key: cord- -mhmvc kq authors: sy, charlle; bernardo, ezekiel; miguel, angelimarie; san juan, jayne lois; mayol, andres philip; ching, phoebe mae; culaba, alvin; ubando, aristotle; mutuc, jose edgar title: policy development for pandemic response using system dynamics: a case study on covid- date: - - journal: process integr optim sustain doi: . /s - - -x sha: doc_id: cord_uid: mhmvc kq the coronavirus disease (covid- ) outbreak has burdened several countries. its high transmissibility and mortality rate have caused devastating impacts on human lives. this has led countries to implement control strategies, such as social distancing, travel bans, and community lockdowns, with varying levels of success. however, a disease outbreak can cause significant economic disruption from business closures and risk avoidance behaviors. this paper raises policy recommendations through a system dynamics modeling approach. the developed model captures relationships, feedbacks, and delays present in a disease transmission system. the dynamics of several policies are analyzed and assessed based on effectiveness in mitigating infection and the resulting economic strain. the ongoing covid- pandemic is raising unprecedented global health concerns because of its high infection and mortality potential. since the first case reported on december , , the number of confirmed cases worldwide has grown at an alarming exponential rate (huang et al. ) , reaching hundreds of thousands being infected in different countries. as such, the world health organization (who) declares covid- a public health emergency at an international level . this spurred immediate action to identify, prevent, and control the transmission of this virus. similar precautions and strategies are suggested by experts for combatting covid- . sohrabi et al. ( ) propose immediate diagnosis and isolation for patients with contact to the virus. xiao and torok ( ) similarly suggest limiting human-human interaction, identifying and isolating persons with exposure, and providing immediate care to those who have been infected. globally, each country has put up their own efforts against covid- . china, as well as many other countries, imposed travel bans and community lockdowns, especially to and from the epicenter of the outbreak wuhan, china (hua and shaw ) . their strict governance has allowed them to "flatten the curve"; however, a second wave is expected because of their premature lifting of the lockdowns and travel ban . nonetheless, late detection allowed their people to travel internationally, leading to a global spread of the virus. singapore and south korea, although the latter initially saw a significant spike in cases because of virus transmission during religious gatherings, effectively address this issue through strict screening, contact tracing, and quarantine measures (gilbert et al. ). on the other hand, europe has become a hotspot for the covid- virus; infection and mortality cases soar in italy, spain, germany, and france, with case counts reaching hundreds of thousands per country. this may be attributed to delayed response, lack of rapid testing, and the high mobility of tourists around europe (the lancet ). for the same reasons, the united states of america (usa) has the most number of cases worldwide, having reached over , cases as of april , (who ). in south east asia, the philippines has the second most number of cases at confirmed cases as of april , , closely following malaysia. as a response to covid- , the philippine government implemented a travel ban of foreigners and a gradual implementation of enhanced community quarantine (comparable with lockdowns implemented in other countries). there have also been efforts to increase testing and quarantine capacities (department of health ). although vaccination is seen as an effective pharmaceutical-based mitigation strategy, existing vaccines may be ineffectual against novel virus strains (araz ) , such as the case in covid- . unfortunately, effective vaccines and treatment for this virus are still under research and development . the persistence of an influenza pandemic can have a significant negative impact on an economy's productive capacity because of its crippling effect on labor supply depending on its morbidity and mortality rate. fundamental economic theory establishes that labor is required in conjunction with capital and natural resources for the production of valuable goods. additionally, this triggers a domino effect, wherein the loss in productivity of one sector would inevitably result in the succeeding customer sector to fail to meet their targets and orders. moreover, government policies, such as school closures and discouraging workers to attend their workplace, can increase worker absenteeism. however, this could be offset by the availability of informal care arrangements and the ability of the parents to work from home (keogh-brown ). due to the novelty of the situation, there had yet to be any formal evaluation of the success of online platforms for work in maintaining productivity. based on the performance of global supply chains, it is apparent that online platforms will fail to sustain the volume of commercial activity prior to the outbreak (ivanov ) . variations in the methods for delivering online education also indicate that universities have yet to converge on a best approach for this scenario, with some universities suspending classes completely and others persisting with online lectures. prior studies on using technology to deliver the online lectures cite difficulties due to lack of reliable internet connection, promoting student initiative and autonomy in learning, and the learning delays of adjusting to the technology (jowsey et al. ; cuaca dharma et al. ) . these indicate that, although quarantine is necessary to some extent to control the situation, extended quarantine is not an appropriate solution. furthermore, despite its unpredictability, there is evidence that suggests externalities such as fear-driven behavioral changes could potentially be the largest contributor to the economic costs of disease outbreaks. from the onset of an outbreak until a considerable period after events stabilize, people are likely to take precautionary actions on top of lockdowns and quarantines imposed, such as avoiding public transportation and international travels, avoiding congregative and entertainment events, and limiting shopping to essentials that would all aggregate to an increase in gdp loss in the first year of about % of gdp (keogh-brown ). thus, although public health is of highest priority, there is also the need to minimize the negative economic impact of pandemic outbreak responses (xiao and torok ) . mathematical and statistical models have been used to gain a better understanding of disease outbreaks and aid in emergency preparedness and response decision-making. these models have been integral in providing insights necessary for developing risk management strategies that minimize the transmission of disease outbreaks and other negative impacts, such as shortages in essential resources and economic declines. one particular methodology, system dynamics (sd) has been employed in disease outbreaks such as influenza. it is a simulation and modeling technique that is established in the application of strategic planning. it is a comprehensive systems perspective approach to map relationships present within complex systems and capturing any nonlinearities, feedback loops, and delays. all of this may provide useful insights towards designing and developing policy interventions (edaibat et al. ) . safarishahrbijari et al. ( ) combined system dynamics with particle filtering approach to predict future influenza outbreaks. their results outlined the improved accuracy and robustness of the prediction of future influenza outbreak, thus proposing the development of standardized guidelines to control and regulate the potential outbreak. araz ( ) proposed an integrated framework joining system dynamics with analytic hierarchy process (ahp) a decision-making tool for the assessment of public health strategies in an influenza outbreak capturing multiple stakeholder preferences. the results are aimed to aid the decision-makers on health strategies in the event that an influenza pandemic outbreak. vincenot and moriya ( ) adopted an integrated concept of system dynamics and individual-based modeling on the impact of resurgence of influenza pandemic. the results highlighted the behavior of spread over different scenarios outlining the significance of spatial disaggregation during outbreaks. currently, no studies have been found in the application of system dynamics on the covid- outbreak. to address this gap, this research is aimed to demonstrate the viability of system dynamics as a framework to understand and develop response strategies for disease pandemics such as covid- . the general objective of the study is to develop a system dynamics model of covid- for different scenarios aiming to equip decision-makers with evidence-based judgment in the control of the outbreak. alternatives to the extended community quarantine are proposed using the sd framework. healthcare capacity, community control policies, and individual human behavior, among the other factors to be considered in this study, vary greatly in the magnitude and nature of their impact to the situation. yet, it is evident they are critical to pandemic response. under the sd framework, the relationships between these factors are organized into feedback loops, then are simulated as stocks and flows. however, it is important to note that the numbers or values obtained from sd are not predictive. instead, sd is used to demonstrate the trend and behavior of problem variables over time as influenced by feedbacks present in the system. the sd model developed in this study builds upon the basic susceptible-infectious-recovered (sir) model originally proposed by grassly and fraser ( ) . capturing the natural infection process, the number of infected persons, divided into the asymptomatic and symptomatic, will increase the amount of people exposed as shown in the causal loop diagram presented in fig. . the values of these variables are influenced by actions taken to control the situation, such as through the quarantine of those infected, social distancing, travel bans, and personal isolation and protection strategies. conversely, the magnitude of the problem at various points in time will also influence the magnitude of the response to control the situation. likewise, a tendency for relaxation is encouraged by negative economic performance. hypothetical and literature-based data were used during model implementation, especially because data is not always available and accurate to represent soft variables and highlevel relationships. sd framework was followed, wherein the model is validated against a reference model for the problem variable. the sd model is used to model and simulate the impact of various policies. as a preliminary study, effectiveness will be evaluated in terms of the number of infected people in a population, as this roughly reflects the duration that a country is experiencing a pandemic. figure a and b show some of the common responses to the pandemic. the construction of additional hospitals and quarantine centers is one of the primary responses to a pandemic. while some increase in healthcare capacity is necessary, this will only address infection by a limited extent, and is infeasible for developing countries. another common policy is to encourage social distancing through either education, publicity, or the closure of establishments (fig. b) . this not only reduces the peak levels of infection but also extends the duration that a country is affected by the pandemic. some consideration may need to be given for the economy or out of necessity, by allowing for certain industries to continue their operations. even if we yield to economic pressures, overall infection under social distancing will be less than the baseline (fig. c) . similarly, by relaxing the social distancing measures for low-risk demographics, overall infection will still be less than the baseline (fig. d) . community quarantine is intended to starve the virus, by preventing the spread of the disease between households. depending on the duration of the quarantine period, this can merely delay the peak of the pandemic without significantly lowering overall infection (fig. e) . gradual quarantine lifting, i.e., reducing the stringency of quarantine over time, gives an opportunity for the economy to recover faster while keeping the potential for infection under control (fig. f) . as a final note, the policies may be implemented together with varying degrees of potency according to the resources and disposition of a particular community. the sd framework made it possible to see the interactions between policies in elemental form. this gives the policymaker more room to modify and improve the pre-existing methods for handling pandemics. first, it answers the question of which policies can be implemented together efficiently. some policies are complementary. precautionary measures, for instance, will reduce the chance for infection without introducing new consequences to the economy. there are also policies that are inefficient when implemented in basic form, yet have great potential after being modified. in particular, the gradual lifting of quarantine limits infection and also reduces the impairment of the economy resulting from complete quarantines. rather than investing much in a single policy, multiple policies can leverage on one another to improve the state of a country under the pandemic. from this point, further analysis can be conducted to identify the best parameters for implementation. impactful parameters include quarantine duration, additional healthcare capacity, and decisions on the quantity and characteristics of low-risk citizens, among other specifics that need to be defined when implementing a policy. by understanding the dynamics of the system, it becomes possible to fine-tune the solution through the parameters, without being too dependent on these values for impact. the covid- outbreak has proven to be a complex problem with effects rooted in public health and economics among some. it is crucial that deeper analysis and assessment frameworks are developed to support decision-making for risk management strategies and transmission control interventions that account for the interactions between participating sectors. based on initial modeling, the most effective strategies focus on avoiding exposure to the virus from happening in the first place; focusing on increasing healthcare capacities only delays the inevitable system collapse as its effectiveness assumes people getting infected first. system dynamics may also be utilized to gain better understanding of other aspects of the system, such as the management of healthcare operations in the face of an influenza pandemic. furthermore, other modeling techniques, such as optimization modeling, may be employed for resource allocation, especially in the face of scarce essential commodities and medical supplies. it may also be used to select between feasible policy alternatives and to operationalize their implementation based on various, and even conflicting, stakeholder objectives. conflict of interest the authors declare that they have no conflicts of interest. integrating complex system dynamics of pandemic influenza with a multi-criteria decision making model for evaluating public health strategies basic japanese grammar and conversation e-learning through skype and zoom online application ) covid daily testing capacity increases, numbers to improve further to k system dynamics simulation modeling of health information exchange (hie) adoption and policy intervention: a case study in the state of maryland preparedness and vulnerability of african countries against importations of covid- : a modelling study mathematical models of infectious disease transmission infodemic" and emerging issues through a data lens: the case of china clinical features of patients infected with novel coronavirus in predicting the impacts of epidemic outbreaks on global supply chains: a simulation-based analysis on the coronavirus outbreak (covid- /sars-cov- ) case blended learning via distance in pre-registration nursing education: a scoping review macroeconomic effect of infectious disease outbreaks. ency health econ transmission dynamics and evolutionary history of -ncov predictive accuracy of particle filtering in dynamic models supporting outbreak projections world health organization declares global emergency: a review of the novel coronavirus (covid- ) covid- : learning from experience impact of the topology of metapopulations on the resurgence of epidemics rendered by a new multiscale hybrid modeling approach world health organization ( ) coronavirus disease (covid- ) situation report taking the right measures to control covid- beware of the second wave of covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -xzfo jjq authors: todd, ewen c. d. title: foodborne disease in the middle east date: - - journal: water, energy & food sustainability in the middle east doi: . / - - - - _ sha: doc_id: cord_uid: xzfo jjq food safety is a concern worldwide and according to the world health organization, developing countries are probably more at risk of foodborne illness because many of these, including those in the middle east, have limited disease surveillance and prevention and control strategies. specifically, the middle east and north africa (mena) region has the third highest estimated burden of foodborne diseases per population, after the african and south-east asia regions. however, it is difficult to determine what the burden is since little is published in peer-reviewed journals or government reports for public access. this chapter reviews autonomous nations, namely, afghanistan, bahrain, egypt, iran, iraq, israel, palestine, kuwait, lebanon, oman, pakistan, qatar, saudi arabia (ksa), syrian arab republic (syria), united arab emirates (uae) and yemen. countries range in size from bahrain with . million inhabitants to pakistan with a population of million. agriculture and local food production is much influenced by water availability for irrigation. water shortages are most severe in the gulf countries which rely on aquifers, desalination, and recycled waste water for most of their water supplies. this means that most food is imported which is expensive if not subsidized through petrodollars. this impacts food security which is a particular concern in countries under conflict, particularly, syria, yemen and iraq. gastrointestinal infections are frequent in this region from salmonella typhi and other salmonella spp., shigella spp., campylobacter jejuni and c. coli, rotavirus, hepatitis a virus, parasites, and more rarely from aeromonas, yersinia enterocolitica, brucella spp., and middle east respiratory syndrome coronavirus (mers-cov). reports indicate that children are the most susceptible and that many isolates are multidrug resistant. chemical contamination of water supplies and crops are probably more of a concern than published reports indicate, because of widespread indiscriminate use of fertilizers, antibiotics, and pesticides, coupled with increased industrial pollution affecting the water supplies. like many other parts of the developing world, foodborne disease surveillance is limited and outbreaks are most often reported through the press but with insufficient detail to determine the etiological agents and the factors contributing to the outbreaks, leading to speculation to the cause by those interested or responsible for food prevention and control. however, there are some well investigated outbreaks in the region that have those details, and reveal where the shortcomings of both the establishments and the inspection systems have been. where the causative agents are known, the kinds of pathogens are generally similar to those found in the west, e.g., salmonella, but many outbreaks seem to have short incubation periods that point to a toxin of some kind of chemical or biological origin, but these are almost never identified. because of sectarian warfare, residents and refugees have been given food that has made them sick and solders? have been deliberately poisoned. research has been focused on microbial contamination of locally-sold foodstuffs and manager and employee knowledge of food safety and hygienic conditions in food preparation establishments. an innovative pilot project in qatar is to use seawater and sunlight for raising crops through the sahara forest project. all countries have some kind of food establishment inspection system, but they tend to be punitive if faults are found in management or employees on the premises rather than being used for their education for improving food safety. restaurants may be closed down and owners and employees fined for often unspecified infringements. however, some food control agents are moving towards employee training through seminars and courses before problems occur, which is a good disease prevention strategy. unfortunately, many of the food handlers are from asian countries with languages other than arabic and english, which makes effective food safety communication and training difficult. tourists visiting popular resorts in turkey and egypt have suffered from foodborne illnesses, usually of unknown origin but poor hygienic conditions are blamed with law suits following, and the adverse publicity affects the long-term viability of some of these resorts. food exports, important for local economies, have occasionally been contaminated resulting in recalls and sometimes illnesses and deaths, notably fenugreek seeds from egypt (e. coli o :h ), pomegranate arils from turkey (hepatitis a virus), and tahini from lebanon (salmonella). overall, in recent decades, the middle east has made strides towards improving food safety for both residents and foreign visitors or ex-pat workers. however, within the countries there are large discrepancies in the extent of effective public health oversight including food safety and food security. currently, almost all of the countries are involved to a greater or lesser extent in the civil wars in syria and yemen, or are affected through political tensions and strife in egypt, iraq, iran, israel, palestine, lebanon and turkey. in addition, the current overproduction of oil on a world-wide scale has led to a rapid decrease in revenues to most gulf states. all this points to a severe setback, and an uncertain foreseeable future for improvements in obtaining both sufficient and safe food for residents in this region. the world health organization (who) eastern mediterranean region, comprising countries in the middle east and north africa (mena), has the third highest estimated burden of foodborne diseases per population, after the african and south-east asia regions. according to the who ( a), more than million people living in this region are estimated to become ill with a foodborne disease every year and million of those affected are children under years. diarrheal diseases caused by e. coli, norovirus, campylobacter and nontyphoidal salmonella account for % of the burden of foodborne disease. an estimated people die each year from unsafe food, caused primarily by diarrheal diseases, typhoid fever, hepatitis a, and brucellosis. both typhoid fever and hepatitis a are contracted from food contaminated by the feces of an infected person and the source of brucellosis is typically unpasteurized milk or cheese from infected goats or sheep. half of the global cases of brucellosis are in people living in this region, with more than , people infected every year, causing fever, muscle pain or more severe arthritis, chronic fatigue, neurologic symptoms and depression. cholera, which after a short incubation period of - days causing severe diarrhea and dehydration, is returning to those countries with limited public health infrastructure caused by conflict, such as iraq (agence france-presse ). the list of countries covered by this chapter is similar to that of who but leaving out north african countries except egypt (which has territory in eastern asia) and adding turkey which is not always considered in the region because it is not arabic, but has interesting food safety data. therefore, the countries under review are afghanistan, bahrain, egypt, iran, iraq, israel and palestine, kuwait, lebanon, oman, pakistan, qatar, saudi arabia (ksa), syrian arab republic (syria), united arab emirates (uae) and yemen. gulf countries bahrain, kuwait, oman, qatar, ksa and the uae have similar social, political, economic, culture, religion, language and ancestry with several similarities in their food control systems and food safety programs (al-kandari and jukes ). a food and agriculture organization (fao) report covering international investments in agriculture in the near east (not identical to the countries chosen for this chapter, but many of the findings apply) states that this region is characterized by a mix of very different countries' resources and incomes (tanyeri-abur and elamin ). the wealth in the richer countries of the region is primarily dependent on oil revenues and the past economic growth has been closely linked to the oil market; about % of regional gross domestic product (gdp) is concentrated in the high income countries (qatar, kuwait, uae, saudi arabia, and bahrain) which are home to only . % of the population in the region, and many of these are expatriates working in these countries. the report indicates that food insecurity varies sharply in the region but overall the percent of the undernourished population does not exceed % in most countries of the region, except for sudan, mauritania, djibouti and yemen where the proportion of undernourished exceeds %; however, in these percentages will be totally out of date for countries like syria and iraq and in neighboring countries where refugees have reached because civil war and jihadi terrorist groups have put considerable stress on public health facilities and food availability. the countries in the region however, are largely similar when it comes to the challenges in achieving sustainable agriculture and food security. for most of these countries, the overwhelming concern is to secure adequate and stable supplies of food at the national level, making food security a concern for both rich and poor countries of the region (tanyeri-abur and elamin ). the three major problems affecting most of the countries are (i) limited water availability; (ii) population growth; and (iii) heavy dependence on food imports. water scarcity in particular, is the most critical development problem in the region and the single most important factor in limiting agricultural growth, and water availability has been declining steadily since the late s. the region as a whole has % less availability of renewable water per person in - than in - . lack of water for irrigating crops but also for potable water supplies affects many of the countries, particularly in the gulf region. it is important to note that the wealthiest countries are also those with the highest water depletion record, namely, the uae and qatar. the unprecedented growth in investment in agriculture is in large part a result of the food crisis of , which brought about a rethinking of agricultural support policies, mostly in countries of the gulf and particularly saudi arabia, which has invested heavily in the last years in large-scale agricultural production using up valuable water resources. saudi arabia announced in january that it would phase out wheat and agricultural production in the course of the next years. in july , qatar and uae took similar policy decisions (tanyeri-abur and elamin ). crops grown in the region may serve as fresh food sources for the population, but much of the food is imported with limited locally processed products, and if the policies of ksa, qatar and uae expand to other countries, more will be imported in the future (tanyeri-abur and elamin ). thus, the main foodborne disease issues are with homemade, restaurant and street food, where isolated claims of illness are followed up by inspections and possible punitive action by public health agencies responsible for food safety. those countries that rely on tourism for their main source of gdp have sometimes been damaged by adverse publicity, e.g., egypt, and to a lesser extent, turkey and lebanon. according to the food and agriculture organization, less than % of the world agricultural trade is conducted in the region. even though by tradition many of these countries relied on growing their own food, today some of these countries import almost % of their food; . % of the food in the world alone was imported to saudi arabia and united arab emirates in , and the food trade balance in food in middle east is negative, estimated at over us $ billion dollars (tajkarimi et al. ). there are specific restrictions prevalent in the arab-speaking countries related to islam and judaism with the prohibition of eating pork and blood, the drinking of alcohol, and mixing dairy foods and meat under halal and kosher food laws. therefore, parasites related to pigs, e.g., trichinella and taenia spp., are unlikely to be prevalent in these populations. however, there are many muslim and jewish feast occasions with large gatherings such as eid linked to ramadan and particularly the muslim hajj, which put a strain on food preparation, distribution and storage. good health conditions for travelers to saudi arabia for the pilgrimage to mecca (hajj) are critical and any incident that occurs has to be quickly contained to prevent extensive infectious disease outbreaks (memish and al rabeeah ) . traditional middle eastern foods are mainly related to legumes, leafy greens, fruit, dairy products and meat on special occasions; details can be found in brittin ( ) . in urban areas today, grocery stores and supermarkets can supply most of the food requirements of a family but imported foods tend to be expensive. also, some fruit and vegetable items are seasonal and are only available once or twice a year such as local plums, almonds and bananas, which tend to be cheaper than imported varieties. quality of raw produce in stores varies but they often have short shelf lives and can spoil quickly because of harvesting ripe products, bruising, and high storage temperatures. traditional rural foods include aromatic stews, stuffed vegetables, wild leaves, pulses and cracked wheat, and occasional goat or lamb meat. a typical middle eastern meal starts with a variety of cold and hot mezze (appetizers), salads and pastries, especially in greece, turkey and lebanon. many contain herbs, cheese, pickles, nuts, seeds, and parsley and lettuce are widely eaten in salads or traditional mezzes. most mezzes are vegetarian and fresh fruits and vegetables are an integral and important part of the cuisine when they are in season. tabbouleh, a salad where parsley is a major ingredient with small pieces of tomato, and some bulgur (ground wheat) in it, is often served in leaves of romaine lettuce or raw cabbage. almost as popular is fattoush, a mixed bowl of lettuce, tomatoes, cucumbers, and fried or toasted pita chips, typically seasoned with a dusting of sumac and pomegranate molasses. since leafy greens do not have a final decontamination step, they are at risk from environmental fecal contamination as reported in lebanon by faour-klingbeil et al. ( ) . hummus, a smooth chickpea paste made with tahini/tehineh, lemon juice or citric acid, garlic and salt, and often served with olive oil, is the most ubiquitous mezze. since tahini and hummus are major exported products from the region, particularly lebanon, they are prone to salmonella contamination, and are sometimes recalled from other countries, which is damaging to the local economies. dairy products are also served regularly at meals and these are locally made or imported. labneh, strained yogurt, very similar to greek yogurts, is widely used as a base for mezze which might have olive oil, pine nuts or za'atar (a mixture of thyme, sumac, and sesame seeds) added. cheeses including the popular haloumi are frequently served in restaurants. shawarma/ shwarma is frozen or refrigerated raw or marinated meat (lamb, beef or chicken) cooked on a vertical rotisserie popular throughout mena countries and now frequently seen in western nations. higher fish consumption tends to be close to where these are locally caught, either sea or river netted. one example from iraq is masquf (split large fish cooked on stakes over a fire, and eaten outdoors by a river, served with slices of tomato and onion and arab bread. crustaceans are less frequently eaten but can be obtained from imports. cosmopolitan foods are widely available in the larger cities, as are multinational fast-food chains. foodborne illnesses have been sporadically reported throughout the region over the past decades and global assessments of the kinds of problems encountered reviewed, e.g., todd ( ) and al-mazrou ( ) and more recently by tajkarimi et al. ( ) . these last authors indicate that reporting foodborne disease is functioning well in jordan, kuwait, oman, saudi arabia and uae, compared to other countries in the region. however, the foodborne outbreak surveillance systems in middle eastern developing countries are still limited with reporting of less than % of the actual outbreaks; one reason is that many foodborne illnesses occur in homes and those ill may not visit medical care facilities. in addition, available laboratory analytical support for public health agencies is often minimal or lacking, even though some research institutions may have up-to-date equipment and technical expertize. change is gradually coming and a food and drug authority has been established in both saudi arabia and jordan (al-kandari and jukes ). also, new food legislation has been initiated by egypt, lebanon and syria (tajkarimi et al. ) , but is currently stalled in last two countries. improvements in inspection service, hand held computers, customized software and improved surveillance systems are some examples of developments in food safety systems in the region. jordan, saudi arabia and bahrain have been developing unified food safety activities from farm to fork (al-kandari and jukes ). however, there is a need for substantive food safety education for all foodservice staff. increasing quality and quantity of the food safety training and human resources in governmental agencies in the region will improve the public health infrastructure. for example, the municipality of dubai has established an international annual food safety conference to improve the food safety education system of those in the region, now in its th year ( ). the following sections of the chapter focus on five aspects: gastrointestinal infections; foodborne disease outbreaks in specific countries; food safety related research and surveys; issues relating to tourism and exported food; and government oversight of the food industry, with specific examples from countries in the region. gastrointestinal diseases are frequently encountered in the middle east and many etiological agents have been identified where specific studies have been carried out to look for bacterial, viral and parasitic pathogens. the average annual incidence of culture-proven shigellosis in israel was / , from to , but each reported case was considered to represent cases indicating the high burden of the disease in the country (cohen et al. ) . orthodox jewish communities, living in highly crowded conditions and with a high number of children aged < years were the epicenter of country-wide biennial propagated epidemics of s. sonnei shigellosis. s. flexneri was the leading shigella serogroup in israeli arabs. isolates showed high rates of resistance to ampicillin and trimethoprim/sulfamethoxazole, but very low rates to quinolones and third-generation cephalosporins. there is no indication if foods or water were vehicles of these shigellosis cases. also, in israel a study of pregnancy-related listeriosis cases from to , identified cases, resulting in a yearly incidence of - cases per , births (elinav et al. ). there were fetal deaths, two neonate deaths and one maternal mortality. the incidence of israeli pregnancy-associated listeriosis has a high yearly variability and is one of the highest worldwide. the geographical distribution varied greatly between years and had a different epidemiological pattern compared with nonpregnancy-related listeriosis. the sources of the infections were not studied but all listeriosis cases have a foodborne link. this has to be further researched as to diet, and the unawareness of the israeli public of the risk for certain food products contributing to the extremely high incidence in israel, in both general and pregnancy-associated listeriosis, as occurs in other countries. a total of stool samples were collected from palestinian patients with acute diarrhea from which ( . %) yielded enteropathogenic bacteria. salmonella, campylobacter coli/ jejuni, and aeromonas hydrophilia were isolated in equal numbers from samples / ( % each), shigella boydii / ( . %), yersinia enterocolytica / ( . %) (abdelateef ) . many strains were antibiotic-resistant. children younger than years old were more susceptible to infectious diarrhea; in addition, diarrhea was more frequent in those living in crowded houses, and in houses rearing poultry, including pigeons. salmonella enterica serovar typhi continues to be an important public health problem in kuwait. analysis of the isolates from patients, collected between and , showed that the majority were from patients from the indian sub-continent, and many strains were drug resistant (dashti et al. ) . typhoid fever in kuwait is predominantly associated with those who have traveled from endemic areas to work in kuwait. the circulation of enteric viruses among the population of cairo, egypt, between march and february was studied by kamel et al. ( ) . at least one type of virus was detected in % of fecal samples, . % of which were positive for rotavirus, % for norovirus, . % for adenovirus, and . % for astrovirus. over % of infections were mixed infections. among the noroviruses, half belonged to the predominant ggii. cluster which were similar to those circulating elsewhere, but there were also new ggii. variants that were not associated with any previously known ggii. isolate. although norovirus is rarely implicated in foodborne outbreaks compared with the us and other western countries, it is clearly present in egypt. further studies are required to assess the disease burden of enteric viruses in egypt and the impact of atypical strains. the disease burden of hepatitis a and e in egypt is one of the heaviest worldwide, based on serological analysis, with hav infections occurring very early in life, with almost % seropositivity after the first years of life (kamel et al. ) . to determine the actual contamination levels in the environment, these authors conducted a survey of hav and hepatitis e virus (hev) in sewage in cairo. hav was detected by rt-pcr in of ( %) sewage samples. in addition, all the hav-positive samples were also positive for enteroviruses. that only one stool sample was hev-positive might be explained by the lower level of excretion of the virus in stools, the fragility of the virion in the environment, and technical difficulties in concentrating and amplifying the virus with standard methods. bacterial etiology was found in . % of cases of childhood diarrhea in dhahira, oman, mostly shigella sonnei and to a lesser extent salmonella (patel et al. ) . antibiotics were prescribed in . % of cases and the resistance to the common antibiotics tested was low. one reason for the low pathogen isolation rate could be that many cases had viral etiology. rotavirus was detected in stool specimens from ( %) of children, who were admitted to regional public hospitals in oman for a median of days with severe diarrhea (al awaidy et al. ) . a diverse rotavirus strain pattern in oman was identified with g ( %), g ( %), and g ( %) accounting for most of typeable strains. the authors estimated the burden for the omani government at us$ , and us $ . million annually to treat rotavirus-associated diarrhea in the outpatient and hospital settings, respectively. they recommended a rotavirus vaccination program that would substantially reduce the burden of severe diarrhea among children in the country. unlike the above countries where the health care system functions for most residents, though not always to western standards, the same cannot be said for pakistan, particularly in rural areas. poor nutrition combined with diarrheal and other foodborne diseases puts the population at risk for serious illness and death, especially among infant and children in pakistan (akhtar ) . cholera, campylobacteriosis, e. coli gastroenteritis, salmonellosis, shigellosis, typhoid, and brucellosis have been demonstrated to be the major foodborne illnesses in the country as well as infectious diseases caused by viral and parasitic agents. many fatalities have been associated with food poisoning but the actual agent has rarely been determined. many health experts believe that rapid spread of gastrointestinal diseases cannot be controlled if the public has no awareness of prevention and control measures against cholera and other forms of gastroenteritis, and that in most parts of the country, sewage is continuously contaminating streams, lakes, springs, wells, and other drinking water sources (qasim ). in may , an epidemic of diarrhea and gastroenteritis occurred in kamalia, toba tek singh, with over children and others being admitted to hospitals which had few medical supplies. apart from lack of potable drinking water, the main reason given for the rise in cases was the heat of summer when there were frequent power cuts so that food "rots" or becomes "stale" (islam ) . in remote areas of pakistan, cholera has been responsible for many outbreaks. two examples in july and august of , both in areas of conflict near afghanistan, give an idea of local but severe outbreaks. in one case authorities seemed not to want to be involved and in the other vaccinations are carried out. although water is the primary vehicle of the vibrio cholerae pathogen, it can easily contaminate prepared foods through poor hygienic practices. in july , five deaths from cholera occurred in pashtoon kot area, balochistan region of pakistan (federally administered tribal areas) along the afghan border (staff ), some km from quetta, in the absence of any emergency medical aid. the condition of an additional people suffering from the disease was said to be critical. a local tribal elder expressed the fear that outbreak of cholera might cause loss of life at large scale. he complained that the doctor and paramedics deployed at the basic health center in panjpai live in quetta and are rarely seen at the center. officials of the provincial health department appeared to be unaware about the cholera outbreak and loss of lives (or ignored these), as they sent no medical teams to the affected area. in fact, pakistani government rebuffed international media's claims, and did not respond to requests to dispatch healthcare professionals to the balochistan area. it was assumed the outbreak would continue without medical aid. in , cholera outbreaks killed hundreds of people, mostly children, in flood-hit districts of nasirabad, jaffarabad and jhal magsi where waterborne diseases were reported at a large scale because of consumption of contaminated water by local people. in august , two people died and others had fallen ill, following a cholera outbreak in kurram tribal agency near afghanistan (hussain ) . dhand and kudiad khel were the worsthit areas but vaccinations were carried out amid tight security, and tribesmen were instructed not to drink water directly from the well and boil it first instead since the wells had been contaminated from the rain water. around people were shifted to parachinar headquarters hospital, while others were discharged after medical aid. sometimes diseases kept at bay by functioning public health systems come back when these break down as is occurring in a few of the countries embroiled in internal strife and outside attacks. for instance, in iraq in october, , > cases and deaths of cholera occurred which started along the euphrates valley in september with the governorates of baghdad and babil, south of the capital, being the worst affected with more than cases each. the epidemic then spread to the northern autonomous kurdish region, which hosts hundreds of thousands of people displaced by conflict from other parts of iraq (agence france-presse ). a previous outbreak killed four people in the kurdistan region in . the united nations says the number of people displaced by conflict in iraq since the start of has topped . million which would exacerbate the spread of the disease. authorities blamed the cholera outbreak mostly on the poor quality of water caused by the low level of the euphrates. limited vaccination programs are in place in areas of conflict. in october, , two persons arriving in kuwait from iraq tested positive for cholera and both were provided proper treatment and recovered. the ministry of health recognized that further cases could be discovered among people arriving from iraq, but because kuwait has a well-structured health infrastructure with water and sewers grids, and a supply of healthy and safe food, the disease should not spread into the kuwaiti population (anonymous a) . probably there are some cases in yemen and syria, countries also with limited public health infrastructures, but have yet to be identified. in saudi arabia, a country with a well-maintained health system, the main infectious disease concern today are the infections and deaths arising from exposure to the middle east respiratory syndrome corona virus (mers-cov), which has reservoirs in camels and bats (todd and greig ) . a potential food source for this virus and other pathogens is from unpasteurized camel milk, as camel farmers drink the milk as well as being exposed through other aspects of camel contact. this brief review indicates that diarrheal diseases, caused by cholera, dysentery, hepatitis a, salmonellosis, shigellosis, typhoid fever, and other enteric diseases through water and food are major contributors to ill health in the region in agreement with the who ( b) report on global estimates of foodborne diseases. in the region, not very many outbreaks of foodborne disease tend to be investigated, or at least reported publically, and those that are tend to have fatalities or are very large. for instance, in june, , two children and one adult were brought to a hospital in dubai, uae, with suspected food poisoning (vomiting) after they ate take-away food (the father was out of town). although the mother eventually recovered, the two young children ( and years old) died, one on arrival and the other the next day. the cause was not determined (saberi and scott ) . it is not known if the family or restaurant was primarily responsible for the deadly gastrointestinal attack as bacteria can multiply quickly in the hot summer months, and the public had been recently warned to minimize eating out at this time of year, especially at smaller eateries where hygiene levels are often of lower standard. a toxin was likely involved to cause fatalities so rapidly, but it could have been an accidental contamination of the food with a chemical such as a pesticide, as much as it could have been with an enterotoxin produced by staphylococcus aureus or bacillus cereus through careless ambient temperature storage. unfortunately, this was one episode in a string of incidents, most of them with fatalities, in the county. in april, , a -year-old died of suspected food poisoning in sharjah, and in august, a -year-old girl died of food poisoning in abu dhabi. in march, , six people fell ill after eating buffet food at a restaurant in the large ibn battuta mall, dubai; in november of the same year, employees at a cement factory were hospitalized after consuming what was considered rotten food prepared at the factory kitchen in another emirate, ras al khaimah. in may, , a -year-old girl died of suspected food poisoning in sharjah. the indian family of four rushed to the hospital after series of vomiting but were too late to save the girl. dubai has been reporting foodborne outbreaks and cases through its foodborne disease investigation and surveillance system since ; in that year there were cases reported in the first nine months (saseendran ) . in , suspected cases of foodborne illnesses were reported but only cases were confirmed. no deaths were reported since the surveillance system was in place. egypt has had a particular problem with foodborne illnesses in universities and schools, mostly without a confirmed etiology, which seem to be related to poor food quality. food poisoning is not uncommon in egyptian university dormitories, where basic hygiene standards are often not observed, but the following outbreak was one of the largest. on april , hundreds of egyptian students angered by a mass outbreak of food poisoning at a cairo university stormed the offices of the country's top muslim cleric and university president, ahmed el-tayeb, because of the students who were hospitalized after a meal served at the university dormitories in the nasr city district of cairo (associated press ). the university is affiliated with al-azhar mosque, the world's foremost seat of sunni muslim learning, and awards degrees in sciences and humanities, as well as in religious studies. in the protest, thousands of al-azhar students blocked roads, broke into el-tayeb's offices by the main campus, and chanted slogans against the university's management. the causative agent was unknown, and only with the incubation period, types of symptoms and their duration would it be possible to consider the potential etiologies of this illness. because of their poor quality, campus meals were not very popular before they were being blamed for the current food poisoning outbreak. although investigators were not able to find a specific cause, the university suspended its food services director and some other staff members. within a few weeks food poisoning affected students on april , at the same university, al-azhar (masriya ) . investigations were initiated within the university and by the ministry of health, and apparently "bad tuna" had been served at the campus cafeteria; no further details were given. if tuna was the vehicle of the outbreak, scombroid poisoning was the likely cause of the illnesses. the allergic-like symptoms generally begin - minutes after ingestion and usually resolve in a few hours. scombroid fish poisoning occurs after fish, most frequently tuna, with high levels of accumulated histamine or other biogenic amines, is eaten. but "bad tuna' could equally be contaminated with bacterial or viral enteric pathogens with a longer incubation period. a month later there was another outbreak. because at least three outbreaks of food poisoning occurred at al-azhar university between april and may with over cases of food poisoning detected in the university's male dorms, the dorm's director, the university's kitchen manager and eight chefs were sentenced in november, , to years in prison with a financial bail. in a similar situation, egypt's top prosecutor ordered a swift investigation into the cases of food poisoning reported in two primary schools in october, , in suez (masriya ). an official of the ministry of education indicated that the poisoning was caused by the consumption of milk provided by the schools. the distribution of milk to all schools in the governorate was halted until the milk's validity was ensured. if milk was responsible, the etiological agent could be bacillus cereus enterotoxin if the onset time was short, or less likely an infectious disease pathogen such as salmonella or e. coli o :h . on january , , female students were diagnosed with food poisoning at al-azhar university in upper egypt's assiut/ asyut governorate, by the banks of the nile, and were briefly hospitalized in an assiut city (anonymous b) . this follows a similar incident which occurred in april when students, also in the girls' dormitories, contracted food poisoning on the university campus in luxor. this report also flags two major poisoning incidents involving at least students ill consecutively at its campuses in cairo in (probably the ones already discussed). the reason given for these repeated mass foodborne illnesses among university students is the quality of the food served them. apparently cheap, subsidized food is poorly stored, cooked and distributed to the poorer university students. in most cases the attorney general would open a criminal investigation that would be closed without knowing the microbiological cause of these outbreaks. the promed-mena editor speculated that enterotoxins of staphylococcus aureus were the most probable cause of such communal food poisoning, as a toxic dose of less than . microgram in contaminated food is sufficient to produce symptoms of staphylococcal intoxication. this toxin level is reached when s. aureus populations exceed , /g, a condition likely to be present in these university kitchens because of intense pressure on them to feed a huge number of students in a short time, taking into consideration that most of these kitchens lack basic hygienic measures with regard to safe food handling. the editor also considered shigella, with its low infective dose ( - depending on the species) as another possible agent. however, the incubation period and symptoms of s. aureus intoxication and shigellosis or dysentery are quite different. pakistan is similar to egypt in that much of the country is rural but with very large cities with high populations (total population is million in egypt and million in pakistan, the most populous of all middle eastern countries). in september, , more than of the flood victims at a relief camp in bengali boys sindhi section school in ibrahim hyderi vomited after eating cooked food and then fell unconscious; of them had to be taken to a nearby hospital (aligi ) . a local philanthropist had been providing cooked food to the flood victims but by the time the food arrived at the relief camp, the cooked rice had turned "stale". since the rice did not show any sign of spoilage, it was served to the flood victims. a similar incident had taken place days earlier at another town where more than flood affectees had fallen unconscious after consuming "stale" food and were hospitalized. none was seriously affected. during the investigation, it was noticed that the sanitary situation in and around the relief camps was very poor. even though the reason for the illness was not determined, the police took action against the donor and two caterers. in fact, based on the information of the vehicle and the symptoms, bacillus cereus enterotoxin which is known to be produced in boiled rice, was the most likely agent. in the following two outbreaks yoghurt is blamed for the serious illness and deaths though details of the symptoms are not given. rapid onset of symptoms indicates the presence of a toxin of some kind, although yoghurt is not a food known to be frequently contaminated with pathogens because of its high acidity. either the yoghurt was made under very unhygienic condition with the source of the milk perhaps being spoiled (possibly containing bacillus cereus enterotoxin), or a chemical had been added accidently such as a pesticide, or deliberately and illegally to enhance the flavor. however, it is possible other foods were involved and yoghurt was not the contaminated vehicle. in january , in lahore, a hospital employee died and two other employees became critically ill after eating contaminated yoghurt. the three employees ate rice with yoghurt at a local restaurant (ians ) . action was taken against the restaurant owner and manager. no further details are known. in early april, , a rawalpindi family of ten became seriously ill after eating a home-prepared evening meal where yoghurt was suspected to have been the contaminated food, and they were taken to a hospital, where a teenage boy and -year-old girl died (asghar ) . the surviving family members remained in critical condition for some time but eventually recovered; the cause of the illnesses was not discovered, although it was postulated by a relative who had eaten the yogurt with the meal that it was possibly poisonous or, strangely he thought a lizard might have fallen into it. in february , at least four people died and another seven were hospitalized in a critical state after eating home-cooked biryani (a dish made with spices, rice and meat or vegetables) in a suburb of karachi (mahmood ) . the owner of a grocery shop, who provided the ingredients, was arrested, and a sample taken for analysis. it is not known if any toxin was found. a month later in march, in faisalabad, more than children and women were ill after eating contaminated aalo-chanay (potatoes, chick peas, onions, tomatoes and spices) purchased from an unidentified vender (anonymous c) . as soon as the children ate the aalochaney, they felt ill and started vomiting. although they were immediately rushed to a rural health center, one boy died. a medical opinion was given that the eaters suffered from "diarrhea and cholera". however, the onset was too rapid for anything but a toxin of some kind, most likely heat-resistant since the aalo-chanay was cooked. also, in march , as many as student nurses and eight staff nurses were hospitalized with acute food poisoning at a hospital in rawalpindi after eating food at the nursing hostel, but none was critically ill (anonymous d). the nurses residing in the hostel started reporting complaints of vomiting and diarrhea along with high-grade fever at an undisclosed time after a meal. the hospital administration was criticized for failing to provide safe food and drinking water to its employees and demanded immediate inquiry into the case, but none was reported on. the illnesses are consistent with an enteric infection such as salmonella or norovirus. in april , at least constables suffered from diarrhea and were admitted to hospitals when they ate food during the sehat ka insaf program, which is a blanket method of administering the polio vaccine along with eight other vaccines, hygiene kits and vitamin a drops in order to circumvent polio-specific terrorist attacks in pakistan. local administration purchased packed food, including piece of chicken and juices from a local supporter (mayar ) . no further details are given but the chicken could have been undercooked or cross-contaminated with enteric pathogens such as salmonella and campylobacter; if the packs had been left at ambient temperatures for some time, these pathogens could have multiplied on the chicken to large numbers. over thirty children in faisalabad were hospitalized over days because of diarrhea and gastroenteritis, three seriously, and other children were expected to be ill. undetermined contaminated food was postulated as the cause, more than usual because of the extreme seasonal heat combined with frequent power outages to allow rapid bacterial growth in contaminated food. the unavailability of clean drinking water was mentioned as a contributing factor to the increasing number of gastrointestinal disease cases. hospital administrators complained that vaccines and medications were required but were not forthcoming from the health department. probably many family meals were contaminated because of the lack of potable water and any unspecified enteric bacterial pathogens present could grow rapidly in the heat. children are more vulnerable than healthy adults to infections which might explain the high proportion of sick children seeking medical help. botulism outbreaks occur periodically in iran. in a study of stool and serum specimens of patients with clinical symptoms of botulism, who were at inpatient and outpatient medical centers in tehran and other areas of iran, between april to august , specimens of patients showed the toxin and spores of c. botulinum (modarres ) . type e was the most common causative agent found in this study, being responsible for . % in all specimens; other etiologic types, in order of frequency were types a ( . %) and b ( . %). type e strains are typically associated with fish and freshwater and marine sediments. the results of this study indicate that the cases had consumed salted fish, smoked fish and canned fish, along with cans of green beans and cucumbers. a similar result over a decade later confirms that c. botulinum type e is a major pathogen in iran. in gilan province, of fish samples collected in , % of processed fish and . % of non-processed fish contained clostridium botulinum, mainly type e (tavakoli and imani fooladi ) . the processing is insufficient to kill the spores or reduce much of toxin produced because the fish tend to be partly cooked with the intestines kept intact. a total of traditional food product samples ( cheese, kashk [a type of dried yoghurt or thick cream], and salted fish) were examined using a bioassay method for detection of clostridium botulinum toxin (hosseini et al. ) . standard monovalent antitoxins were used to determine the toxin types. c. botulinum toxins were detected in . % of examined samples ( . % of cheese samples and . % of salted fish samples). none was found in kashk samples. c. botulinum types a and e were dominant in cheese and salted fish samples, respectively. consumption of these traditional foods either raw or processed may contribute to foodborne toxicity in iranian populations. in may , a quickthinking mother immediately brought her -month old boy to an israeli hospital when she saw he was suffering from vomiting, difficulty in breathing, listlessness, glassy-eyed, apathetic, and an inability to nurse or eat (bender ) . a doctor at the hospital diagnosed the child as suffering from infant botulism. he decided to treat the baby with the antitoxin stored in the emergency stocks, even before they got back the lab test results. the hospital like all israeli medical facilities keep ample supplies of biological and chemical warfare antidotes on hand in case of war or terrorist attacks, and staffers are regularly drilled in dealing with the symptoms of various chemical, neural and blister agents. the infant started recovering soon after the administration of the antidote. in the rare disease of infant botulism, spores of clostridium botulinum are ingested and the infant's flora is not mature enough to prevent germination and slow growth of the toxigenic pathogen. it is entirely possible that infant botulism occurs more frequently in the region but is not diagnosed. foodborne disease surveillance depends on an infrastructure of reporting and diagnosis in hospitals, epidemiologists, and food testing laboratories. lebanon is an example of a country where modernization in public health seems to occur at a glacial pace. however, diseases including those of foodborne and waterborne origin, are documented and published. the law of december , regarding communicable diseases in lebanon mandates all physicians, from private or public sectors, in hospitals or ambulatory services, to declare to the epidemiologic surveillance unit of the moph all diseases considered a risk to public health. the data available at the ministry of public health (moph) are compiled from different sources, and the declaration of cases remains irregular and insufficient (moph ) . in , foodborne and waterborne diseases were the most frequently reported in lebanon at a rate of . ‰ (total of cases), with the highest rate in the bekaa ( . ‰) and the lowest in the south ( . ‰). the most common infection was viral hepatitis a, which represented . % of the total food and waterborne diseases with cases. there were also cases of typhoid ( . %), cases of food poisoning (unspecified, . %), cases of dysentery ( . %), cases of brucellosis ( . %, cases of parasitic worms ( . %) and cases of hydiatic cyst ( . %). no cases of cholera and trichinosis were declared. hydiatic cyst (cystic echinococcosisis) caused by echinococcosis (typically e. granulosis) is acquired by contact with animal feces contaminated with tapeworm eggs. sources include contaminated food (meat), water, and animal fur. cysts containing tapeworm larvae may grow in the body for years before symptoms appear. when cysts become large, they may cause nausea, weakness, coughing, and belly or chest pain. occasionally, well-investigated outbreaks are published; the following two examples are from lebanon and neighboring jordan. in may , employees suffered from diarrhea, fever, and abdominal pains . - . h (mean, . h) after eating chicken noodles au gratin at a catered lunch served at a bank cafeteria (hanna et al. ). a few cases had systemic infections. salmonella enteritidis (se) was confirmed in stool and blood cultures within - h after hospital admission of the first cases, and also in leftovers of the suspect food. the same dish had been served at the bank in the past with no apparent health problems. preparation normally started in the evening prior to the day the dish is served. however, in this instance, some of the constituents had been prepared days ahead, because the dish was to be served on a monday, immediately after the week-end closure. no salmonella was found in rectal and nasal mucosal swabs taken from all kitchen workers, or in the tanker water supply (although it had high fecal coliform counts), but se was found in a frozen batch of the same raw chicken breast consignment that had been used for the chicken noodles. the batch of chicken came from a large producer of poultry and eggs in lebanon, who was advised of its potential involvement in a major foodborne outbreak. however, the investigators were refused access to the poultry-producing facility. it is highly likely that contaminated chicken carcasses had been, and would continue to be, shipped to many parts of lebanon. that the same se strain occurred in the patients, the raw chicken, and the leftover food was confirmed through random amplified polymorphic dna polymerase chain reaction (rapd-pcr). it would appear the -day delay in the chicken noodle preparation was significant in allowing the salmonella present in the ingredients not only to survive but probably to grow; undercooking, cross-contamination, inadequate storage and reheating all may have played a role in the outbreak, but no more information was available to determine which of these were the key factors in the outbreak. the bank management decided to sue the caterer and because they were aware of apparently inefficient way that public authorities were conducting the procedure, they took the initiative to call upon an independent investigative team to obtain solid evidence to win any court action. the caterers, concerned that they would be the only party blamed for the salmonella outbreak, had succeeded in concealing some raw and cooked items from destruction by the public health authorities, which was their normal practice after a complaint. these items were central to establishing contamination upstream from the caterer's kitchen. no action seems to have been taken against the poultry producer who was the source of the se, a pathogen that is invasive of flocks and difficult to eradicate. the authors complained about the obsolete lebanese laws dating back to the s that still governed what should be done following a report of "food poisoning". public health officers are mandated to stop the spread by destroying allegedly contaminated food items and closing down incriminated facilities. hanna et al. ( ) stated that this kind of action is generally lauded by the public but does not help determine the cause to develop appropriate prevention and control strategies. they also complained that because no investigation is typically done, many non-implicated foods and ingredients are wastefully discarded. the jordanian example is over two decades old, but is worth noting in detail. in september , a -case outbreak of salmonellosis occurred in a university hospital in amman after employees, patients and visitors ate in the cafeteria. the incubation period ranged from to h. symptoms included diarrhea ( %), fever ( %), abdominal pain ( %), dehydration ( %), and bloody stool ( %); were hospitalized (khuri-bulos et al. ) . cultures of eight food items were negative, but stool culture on of patients and of kitchen employees yielded salmonella enteritidis (se) group d . a cohort study revealed a foodspecific attack rate of % for the steak and potato meal and % for the rice and meat meal. stratified analysis of the steak and potato meal revealed that the potatoes were implicated most strongly. cultures were obtained from all kitchen employees, who showed no symptoms of illness, but of grew se group d . one asymptomatic, culture-positive employee had prepared the mashed potatoes on september , h before the first case presented at the hospital emergency with severe gastroenteritis symptoms. all of the food workers had negative stool cultures months earlier. the potatoes were mashed by machine, but peeled after boiling and mixed with milk by hand, using a ladle but no gloves. two different batches, the first of which was served exclusively to hospitalized patients and the second to a few remaining patients and employees, were prepared and served within to minutes of preparation. from the epidemiological data it can be assumed that the infected handler fecally contaminated only the second batch of potatoes, thus sparing most of the highly susceptible inpatients from exposure. furthermore, while potatoes clearly were implicated, individuals who ate steak only had an elevated risk of being attacked. this probably was due to surface contamination of foods being served on the same plate. kitchen employees harboring salmonella were excluded from work until they had three negative stool cultures taken week apart; it took weeks for them to return to work. stool surveillance that was routinely carried out in the hospital was ineffective in detecting infected employees to prevent this outbreak and the investigators recommended that employees adhere to proper hygienic practices including thorough washing of hands, especially when preparing food. today, salmonella is only one of many of the pathogens that can be encountered in foodborne illness. one of the newer pathogens, well established in the west is norovirus (nov), which causes more cases of foodborne disease in the u.s. than any other agent (scallan et al. ). in may , a significant increase in acute gastroenteritis (age) cases was noted in the american health clinic at incirlik air base (iab) in adana, turkey. this increased rate of age led to discussions with local turkish military public health authorities, which confirmed that the turkish military community and the residents of adana were also experiencing an anecdotal increase in age illnesses (ahmed et al. ). an epidemiologic investigation was launched to attempt to identify the cause and possible source of this age outbreak at iab from may to june with the peak incidence of cases during the week of may -june , with a total of patients seeking medical care at the clinic. of the total infected persons, patients completed the case survey, % reported diarrhea, % reported vomiting, and % reported fever. the median number of days between symptom onset and clinic visit was days. during the days prior to symptoms, % of respondents reported travelling off base, % reported eating off base, and % reported using an outdoor pool. this outbreak had a significant negative operational impact, degrading mission readiness with nearly % of the american population in a -month period affected. initiation of a clinic case-based investigation yielded stool specimens in which nov was detected in %, with % of the positive nov specimens identified without a copathogen. dna sequencing data demonstrated that several relatively rare genotypes of nov contributed to this outbreak; four different genotypes were isolated from positive specimens. two of the nov strains were previously reported in iraq and only from deployed troops, while the other two genotypes were reported in south africa and in the us. in turkey, little systematic data on circulating nov genotypes exist. however, giib/gii. strains have been frequently identified in turkish children with gastroenteritis; strains belonging to this genotype have been found in europe and mainly in children. previous reports from british troops deployed to iraq indicated that two nov strains isolated were responsible for cases of gastroenteritis there. similar mixed nov outbreaks have been previously observed and are often attributed to systematic failure of cooking/cleaning/drinking water supplies (ahmed et al. ) . one limitation of this investigation was that the survey was not used to capture data from a control group, those without recent age, preventing carrying out a risk factor analysis. another limitation was the lack of environmental samples that could be tested for nov in order to track the source of outbreak. from anecdotal information, it is likely many in the local population and the turkish military base were ill, but a formal outbreak investigation in the turkish population was never performed. from the multiple genetic types involved, one specific contaminated food or water source seems unlikely. the largest turkish nov outbreak was in keçiborlu province of isparta county between april and , , with patients seeking medical help from the healthcare centers, after suffering from nausea, vomiting and abdominal pain (more frequent than diarrhea) (s€ ozen et al. ) . because of underreporting, the number of affected people was estimated to be higher. municipal water was the suspected source but no samples tested positive. as a cautionary note, the authors suggest that nov may not be the only causative agent of gastroenteritis outbreaks, especially from an undetermined fecal source, and bacterial, viral and parasitic agents should be examined together with the nov. in saudi arabia, a national policy for reporting, notifying, and recording incidents of bacterial food poisoning was established in (al-joudy et al. ). since then salmonella food poisoning outbreaks have been reported from different regions of ksa, exhibiting seasonal and regional variations, with chicken, meat, and rice being commonly incriminated food items, and frequently reported in the saudi epidemiological bulletin. al-mazrou ( ) reviewed the history of foodborne outbreaks in ksa and saw an increase over the last few decades, especially those caused by salmonella, with the main food vehicles being chicken, meat and eggs, and s. enteritidis being the most frequent salmonella serovar responsible. according to promed editorials, restaurants and communal feasts and institutional feeding (such as in school cafeterias, hospitals, nursing homes, prisons, etc.) where large quantities of food are prepared several hours before serving are the most common settings in which foodborne illness incidents occur (http://www.promedmail.org). for instance, in , a hospital in the jizan region received suspected food poisoning cases that were ill after taking meals from a restaurant, including a woman who suffered from severe diarrhea, abdominal pain, vomiting and dizziness (fagbo ) . the restaurant was closed down and three of its workers were detained pending the results of laboratory tests. the report of an investigative committee could not find a specific cause, but noted that the restaurant had earlier been responsible for some hygienic violations. in , cases suspected of foodborne illness after eating a meal at a restaurant were admitted to various hospitals in the najran region (alhayat ) . most of the cases were not seriously ill. no report was given on the samples that were taken from the suspected restaurant, which was closed temporarily. there is an interesting observation related to variant creutzfeldt-jakob disease (vcjd); four cases have occurred in the us since the disease was first diagnosed in the united kingdom in linked to consumption of cow meat suffering from bovine spongiform encephalopathy (bse); two of these were associated with the united kingdom (where bse was first reported), but one came from saudi arabia and the most recent case in had extensive travel to the middle east and europe (cdc ) . this may indicate some source of vcjd in the middle east including saudi arabia. one of the big concerns for ksa is the annual hajj with millions of muslims from around the world converging on mecca, in saudi arabia, each year. no other mass gathering can compare with the hajj, either in scale or in regularity, and various communicable disease outbreaks of various infectious diseases have been reported repeatedly, during and following the hajj (memish ) . in , an outbreak during the hajj occurred where all the cases came from one tent occupied by soldiers located in a government camp in mina, makkah province, near mecca (al-joudi ). the camp was served by a catering company that prepared and distributed three meals daily (breakfast, lunch, and dinner). a case was defined as any individual who developed diarrhea with or without abdominal pain after eating at the camp in mina in january, . of the soldiers who were interviewed, ( %) had developed gastroenteritis, most commonly manifested by diarrhea ( %), and abdominal pains ( . %). the mean incubation period was . ae . h and the epidemic curve suggested a common point source outbreak. out of three served meals, lunch with a rice dish was found to have a statistically significant association with illness. unfortunately, no food remnants were found for sampling, and the results of stool cultures of all diarrhea patients, and rectal swabs from all food handlers were inconclusive. temperature abuse was cited as a contributory factor in this outbreak. based on the incubation period and symptomatology, bacillus cereus would be the most likely etiological agent. another example of a foodborne illnesses associated with the hajj occurred in when bangladeshi pilgrims were taken to hospitals in madina (medina) after eating a meal prepared by an unlicensed caterer (promed-mena ). they suffered from abdominal pains associated with diarrhea and vomiting. the pilgrims were all treated and discharged, except for one who remained hospitalized. samples of the food they had eaten were sent for analysis but the results are not known. considering the mass of people converging on this small part of the middle east, it is surprising there are not more foodborne disease outbreaks. this may mean excellent food control by the authorities or some illnesses are simply not recognized and reported. at least bahrainis suffered from food poisoning after eating catered sandwiches served during a wedding celebration, the biggest mass poisoning outbreak in the country's history (promed-mena ) . the wedding took place in the safala village, near the eastern island of sitra. all eventually recovered after treatment but one man who had sickle cell disease, died. teams were formed to investigate the outbreak, and blood specimens from all workers at the bakery who prepared the egg, cheese, and mayonnaise sandwiches along with leftover sandwiches and their ingredients on the caterer's premises were sent for bacteriological analysis. the bakery which supplied the sandwiches was closed by the public health directorate at the ministry pending the investigation's results. unfortunately, no final report was released to the public. the promed editor considered the etiological agent could be salmonella or staphylococcus aureus enterotoxin, depending on the length of the unstated incubation period. the region experiences some unusual type of illnesses relating to on-going hostilities. for instance, the united nations has been sending aid to reach besieged towns in syria, close to the lebanese border, but in october, , it sent hundreds of boxes of "moldy" high-energy biscuits past their 'sell-by' date in september ( of the boxes transported) to zabadani and madaya, apparently causing food poisoning (afanasieva et al. ; muhkalalati and kieke ) . officials stated these could be the only cause of an outbreak of food poisoning among almost residents who came to makeshift hospitals, mainly children who had vomiting, diarrhea and abdominal swelling almost immediately after eating the biscuits. the biscuits were described as "moldy and rotten and had been poorly stored". apparently, when the last aid order that was sent was filled, there was a shortage of food. the red crescent, who was filling the order, took some of the expired goods to complete it. however, these biscuits had only just expired and normally would not have posed any health risks to those eating them. nevertheless, the words poorly stored suggest that moisture may have encouraged microbial growth (visible mold more likely than bacteria because fungi can grow aerobically in the presence of the presumably elevated sugar content in the high energy biscuits). also, contributing to the symptoms, the residents of zabadani and madaya had been blockaded for consecutive days, and their immune systems were extremely weak. refugees are also at risk of gastrointestinal diseases from contaminated water or food. up to two million syrian migrants fleeing syria due to the civil war were living in turkey, and supplying them with safe and secure food supplies is a challenge for any host country. one incident, no doubt, one among many indicates the risk of contaminated food. in april, , five security forces were injured after syrian migrants in a tent city in turkey's southeastern province of mardin reportedly attacked guards over allegedly being poisoned from the lunch at the camp (anadolu agency ). some syrian migrants were detained after the incident; syrian migrants out of the currently residing in the temporary sheltering center in mardin's derik district applied to the center's hospital with symptoms of food poisoning, dizziness, and vomiting. after treatment they were discharged, none of them in a critical condition. although an investigation was conducted and samples from the lunch sent to the lab for analysis, no further information was available on the outbreak. promed speculated that if the lunch food was the vehicle, it would be a short incubation illness likely caused by staphylococcus aureus, bacillus cereus, clostridium perfringens, or possibly a non-biological toxin. these illnesses may cause vomiting, diarrhea, or both, and are usually short in duration (less than h), and are not associated with prominent fever. in iraq, no recent foodborne disease outbreaks have been published, but no doubt many have occurred in the last decades with so much public health infrastructure dismantled. only the most newsworthy of outbreaks are being covered by the press today. iraq and other middle eastern countries are in sectarian turmoil and on two occasions islamic state (isis/is/isil) fighters (jihadis) were likely poisoned by cooks who infiltrated their camps. in november, , a group of defected syrian soldiers (free syrian army men) who posed as cooks reportedly poisoned isis militants after they ate a contaminated lunch at the fath el-sahel camp, where of them were based (gee ). apparently about a dozen of the jihadis were killed and taken to nearby field hospitals. the 'cooks' immediately fled, along with their families, with the help of fellow revolutionaries. seven months later, in july , jihadis died after ingesting an iftar meal eaten by isis militants (akbar ; variyar ) . it remains unclear whether the jihadis, who were breaking their ramadan fast in mosul, iraq, died of accidental food poisoning or intentional poisoning, but it is likely a repeat attack of the earlier incident described above. the nature of the poison or details of the illnesses in either episode are not known. however, in both episodes, onset and severity of the attack were rapid, probably caused by a relatively tasteless chemical in lethal doses added to one or more foods. targeting the military by any means including poisoning food has always been a strategy of opposing forces. in february , a deliberate attack was foiled when afghan border police detected a significant amount of bleach in fruit and coffee stored at their main border checkpoint between afghanistan and pakistan, a likely attempt to poison the afghan security forces (tucker ) . the police decided that although none of this food had been consumed, the level of contamination was high enough to cause serious injury, and it must have been done intentionally. there had been previous incidents of intentional food poisoning aimed at afghanistan's civil defense forces, including an episode in kabul in when several people were sickened. in , in southern helmand province militants killed four afghan policemen and two civilians inside a police checkpoint by poisoning their yoghurt coordinated with an attack (anonymous a). there had been several recent poisoning incidents involving members of the afghan national police, as part of attempts by the taliban to infiltrate the security forces; three police officers were reported missing, along with their weapons and a police vehicle, following that attack in helmand province. taliban militants had first poisoned the police officers' yoghurt before launching a full scale attack on the checkpoint. similar tactics had been used by insurgents in helmand before. the same thing happened again in january when a rogue policeman collaborating with insurgents in southern province of uruzgan shot dead colleagues after first poisoning their food, but no further details are given (reuters ). turkey does have food laws that are supposed to limit food contamination and resultant foodborne illnesses. the turkish food code stipulates that all turkish food businesses have to provide food hygiene training commensurate with the work activities of their staff. to see what progress had been made in this area baş et al. ( ) evaluated knowledge, attitudes, and practices concerning food safety issues among food handlers in ankara, conducting face to face interviews and administrating questionnaires. the majority of the food handlers who responded ( . %) had not taken a basic food safety training (and probably most of non-respondents had not either). the mean food safety knowledge score was . ae . of possible points. the self-reported hygienic practices showed that only . % of those who were involved in touching or distributing unwrapped foods always used protective gloves during their working activity. of those food handlers who used gloves, only . % and . % always washed their hands before putting them on and after removing them, respectively. in addition, there was a difference handlers' scores depending on where they worked. scores were higher for food handlers in catering establishments ( . ae . ), school food services ( . ae . ) and hospital food services ( . ae . ) than restaurants ( . ae . ), hotels ( . ae . ), takeaways ( . ae . ) and kebab houses ( . ae . ). these scores may also be biased upwards since they were self-reported and not observed practices. the study demonstrated that food handlers in turkish food businesses often have lack of knowledge regarding the basic food hygiene, e.g., critical temperatures of hot or cold ready-to-eat foods, acceptable refrigerator temperature ranges, and cross-contamination. those who were trained scored better, and the authors stated there was an immediate need for education and increasing awareness among food handlers regarding safe food handling practices. in istanbul from / , thermophilic campylobacter was isolated from . %, . %, and . % of beef, mutton, and chicken samples tested, respectively (bostan et al. ). there was no significant seasonal variation in the prevalence of the pathogen. c. jejuni was the species most commonly isolated from chicken meat, while c. coli was the most common in beef ( . %) and mutton ( . %) carcasses. campylobacter isolates were most often resistant to tetracycline ( . %), followed by trimethoprim-sulfamethoxazole ( . %), nalidixic acid ( . %), erythromycin ( . %), enrofloxacin ( . %), ciprofloxacin ( . %), chloramphenicol ( . %), and gentamicin ( . %). the results of this study suggest that a high proportion of meat samples, particularly chicken carcasses, are contaminated by campylobacters, most of which are antimicrobial-resistant strains. in yemen, the prevalence of salmonella in food was determined in sana'a city from april to april by ahmed ( ) . of the different food samples collected from local markets, salmonella spp. were isolated from ( . %). the highest prevalences were in red meat ( . %), chicken ( . %), eggs ( . %), cooked foods ( . %), raw milk and milk products ( %), juices ( . %), vegetables ( . %), sandwiches ( %), and pastries ( . %). serogroups identified were b, c , c -c , d , e , and e , and some foods contained more than one isolate with different serogroups, especially red meat. because handlers in foodservice facilities play a major role in transmission of foodborne diseases (greig et al. ) , studies have been carried out to demonstrate their knowledge of practices related to food safety. in jordan, osaili et al. ( ) measured food safety knowledge of food handlers working in fast food restaurants in the cities of amman and irbid. a total of food handlers in fast food restaurants participated in this question survey study. the overall knowledge of food handlers on food safety concepts was considered to be fair ( . %). the food safety aspect with the highest percentage of correct answers was "knowledge of symptoms of foodborne illnesses" ( . %) and "personal hygiene" ( . %), while the lowest percentage of correct answers was for "safe storage, thawing, cooking and reheating of the foods" ( . %), critical practices to prevent the survival and growth of pathogens. the mean knowledge score of "personal hygiene" reported in the study was much higher than . % and . % reported by martins et al. ( ) and baş et al. ( ) , for the food handlers in portugal and turkey, respectively. also, only . % of respondents considered the duration of hand washing to be ! s. when they were asked how they check that the poultry is sufficiently cooked, only % knew "when the meat has the correct thermometer reading", although % of the respondents had thermometers in their restaurants. about % of them answered that poultry is cooked "when it has been cooked for the stated time" ( %) and "when it looks cooked" ( %). about % of them would store leftovers on the steam table ( %) and in the refrigerator ( %) while about % of the correspondents would store leftovers at room temperature in kitchen or in the oven. a low percentage of the respondents ( %) reheated leftovers to the appropriate temperature ( c). about % and % of the respondents had heard about salmonella and hepatitis a virus, respectively, but % of the respondents knew about listeria monocytogenes, staphylococcus aureus, bacillus cereus, escherichia coli o :h , clostridium perfringens, campylobacter jejuni, or shigella. food workers who had enrolled in a food safety training course had significantly higher total food safety knowledge score than those who did not take any training. there was no association between the experience or any other characteristic of food workers and total food safety knowledge score. this study suggests adopting proper food safety education training courses to food handlers, periodic evaluation of food handlers' knowledge and food safety training course materials. also, the authors considered that better pay for food handlers would improve the food safety status in foodservice institutions. similar concerns over practices that could lead to food contamination and foodborne illnesses were demonstrated in lebanon. a survey was conducted in beirut to evaluate the knowledge, attitudes and practices related to food safety issues of food handlers (n ¼ ) in foodservice establishments (n ¼ ), and to assess the influence of management type on enactment of safe practices on food premises (faour-klingbeil et al. ) . the data suggest that while respondents do have some knowledge of food safety aspects, substantial gaps in their knowledge and self-reported practices associated with critical temperature of foods and cross contamination remain, therefore posing health risks to consumer health. food handlers in corporate managed food outlets showed a significantly higher awareness on food safety practices. it is concluded that the management type is an integral element of the theory of planned behavior that influence food handlers' practices and substantiate the need for more research work on safe food handling in the context of food safety culture framework in food businesses. as in many other mena countries, there is a critical need for food safety education interventions and technical guidance fostered by synergistic participation of the private and public sector to support food handlers in smes (small and medium sized enterprises). parasites are not often looked for in middle eastern countries but they are frequent, and one of the ones of most concern for pregnant women is toxoplasma gondii which is transmitted through undercooked meat and cat feces. since stray cats are common in some localities, of fecal samples of stray cats examined in kuwait, ( . %) were found to be infected with oocysts of coccidian protozoa (abdou et al. ) . toxoplasma gondii was found in . %, and cats < months old had higher infection rate with oocyst of enteric protozoa than older cats. a serosurvey of the stray cats revealed that . % were positive to t. gondii igg. toxoplasma sero-positivity was observed in a higher number of adult cats compared to younger ones suggesting that with age the risk of exposure to t. gondii increases. thus, pregnant women handling cats and particularly kittens or cleaning out sand boxes have a chance of infecting their fetuses and eating raw meat. in pakistan, enteric pathogens are present not only in water but also foods contaminated from the environment or through human actions. mishandling of foods allows these pathogens to contaminate and multiply in them. for example, street-vended fruit salads, locally called fruit chats, offered for sale at high ambient temperatures without coverings, and khoya and burfi, two indigenous sweet dairy products, and locally produced ice cream are often heavily contaminated with enterobacter, e. coli, klebsiella, salmonella and s. aureus (akhtar ) . these contamination scenarios have led to outbreaks with cases severe enough to be hospitalized. bus and train stations where pulses (edible seeds of various crops as peas, beans, or lentils), ground meat dishes, and chickpeas are sold to passengers, and are also heavily contaminated with bacteria including clostridium perfringens. sweet dishes and home-prepared foods in small communities are commonly contaminated with s. aureus, c. perfringens, and bacillus cereus leading to rapid intoxications. one study confirmed campylobacters to be present in % of tested samples of milk and meats and . % of vegetables in three major cities of pakistan (akhtar ) . a wide array of vegetables is routinely consumed in this country and serve as a rich source of vitamins, minerals, bioactive compounds, and fiber but these can be sources of enteric infections if they are consumed contaminated. shigella spp. has been shown to develop resistance and is generally thought to be a major cause of foodborne illnesses, especially among the poor where health care facilities are minimal; shigellosis is associated with poor sanitary conditions and unsafe water for drinking and preparing foods. possible etiologies can be postulated in the following outbreaks. unfortunately, it is not only pathogens that give rise to food-associated disease. soomro et al. ( ) highlighted the indiscreet use of pesticides in agriculture and its impact on environmental pollution. despite the increased production cost associated with extensive use of pesticides, their use is common in developing countries. numerous studies have demonstrated substantial levels of pesticide residues in various foodstuffs in pakistan, and the groundwater has been observed to be considerably polluted in many parts of punjab and sindh provinces of pakistan (akhtar ) . commonly used open rural wells in the punjab were polluted with six pesticides: bifenthrin, λ-cyhalothrin, carbofuran, endosulfan, methyl parathion, and monocrotophos. in the hyderabad region % of the tested samples of eight vegetables (cauliflower, green chili, eggplant, tomato, peas, bitter gourd, spinach, and apple gourd) were found to be contaminated with pesticide residues exceeding maximum recommended limits (mrls) (tariq et al. ; anwar et al. ) . heavy metals such as cadmium (cd), copper (cu), lead (pb), and zinc (zn) arising from increased industrialization can contaminate agricultural soils and these can be found in fruits (including widely-consumed mangoes), fruit juices, vegetables directly from soil uptake or from the processing and packaging (akhtar ) . for instance, spinach, coriander, and peppermint, grown in sindh province contained . - . mg/kg of arsenic resulting in a total ingestion of arsenic . - . μg/kg body weight/day in diet (arain et al. ; khan et al. ) . aluminum concentration in branded and nonbranded biscuit samples from hyderabad were found to range . - . and . - . mg/kg, respectively (jalbani et al. ) . similarly, javed et al. ( ) detected higher concentrations of cd, cr, ni, and pb residues (mg/l) in bovine and goat milk. pakistani foods are more prone to aflatoxin contamination because of the warm and humid climate, and the situation is exacerbated by malpractices during handling and storage of edible commodities (mobeen et al. ) . samples of broken rice, wheat, maize, barley, and sorghum ranged - % with the highest aflatoxin concentration ( . μg/kg), in wheat samples (akhtar ) . chilies are widely eaten and exported, but aflatoxin levels can be eightfold higher than the eu permissible limits to pose a potential health risk to pakistani consumers; concentrations can be reduced by more appropriate care and handling of the chilies at pre-and postharvest stages. nuts and dried fruits in pakistan are cultivated and processed in the northern areas and have been shown to have aflatoxin levels above the eu limit of μg/kg in up to % of samples (ahmad et al. ; luttfullah and hussain ) . aflatoxin m in milk and milk products requires regular monitoring in pakistan since % of the total tested samples of milk were found to exceed the us tolerance limit of . μg/l (hussain and anwar ; hussain et al. ) , and buffalo milk had higher levels of aflatoxin compared with cow's milk. intentional deception of consumers by blending low cost and inferior quality ingredients to make more profit of food intended for sale is prevalent in pakistan, where families are exposed toxic dyes, sawdust, soapstone, and harmful chemicals in beverages, oil or ghee, bakery products, spices, tea, sweets, bottled water, and especially milk and milk products where more than % of samples tested have had adulterants added (akhtar ) . one of the more innovative research projects to provide more home-grown food is in qatar. the sahara forest pilot (sfp) pilot study demonstrated that there are significant comparative advantages using saltwater for the integration of food production, revegetation and renewable processes: ( ) seawater cooling system for greenhouses supports production of high-quality vegetables throughout the qatari summer, and reduces freshwater usage to less than half that of comparable greenhouses in the region; ( ) solar and desalination technologies were successfully integrated as designed into the sfp system, such as the greenhouse and evaporative hedges providing wet-cooling efficiencies without cooling towers; ( ) the external evaporative hedges provide cooling of up to c for agricultural crops and desert revegetation with vegetable and grain crops growing outdoors throughout the year; ( ) commercially interesting algae showed good tolerance to heat and high evaporation rates in the leftover salty water (miss ; clery ). the concentrated solar power plant uses mirrors in the shape of a parabolic trough to heat a fluid flowing through a pipe at its focus. the heated fluid then boils water, and the steam drives a turbine to generate power. hence, the plant has electricity to run its control systems and pumps, and can use any excess to desalinate water for irrigating the plants. in summary, sfp allows food production in all months of the year ( crops) with half the fresh water usage than in comparable greenhouses. on the basis of the pilot success, sfp is now engaged in studies aimed at building a -hectare test facility near aqaba in jordan, large enough from the -hectare operation in qatar to demonstrate a commercial enterprise. tourism is popular in several middle eastern countries, particularly beach and coastal resorts in egypt and turkey. tourism has been the major economy in egypt for many years but can be threatened not only by civil unrest and terrorism but also by foodborne illness (costa ). tourists might not stop coming to egypt due to a few reports of diarrhea; however, widespread reporting of severe cases, and lawsuits, will make tour operators much more selective, and bring pressure on the egyptian hospitality industry to improve its hygienic standards. the greater challenge is for egypt to ensure that it has the capacity to sustain a safe food supply for its own people. in doing so, it provides safe food for those who want to explore its rich history and seaside resort areas. multiple reports of illness have been reported from nile river cruises and a resort town on the coast. from september to november, , cases of hepatitis a imported from egypt were reported to the german public health authorities (bernard and frank ) . investigations pointed to a continuing common source of infection, most likely linked to nile river cruises. in addition, eight cases from france had been travelling on a nile cruise and one on a red sea diving safari (couturier et al. ). one specific cruise ship was mentioned by six of ten belgian cases (robesyn et al. ). those who took a nile cruise had typically done this in combination with a hotel stay. at least three different ships and three different hotel accommodations were mentioned in the travel histories of the french cases. the patients affected had not been vaccinated, which emphasized the need for more effective travel advice before trips to hepatitis a endemic countries (sane et al. ) . possible sources of infection might have been contaminated food obtained from a common food catering company consumed onboard, contaminated tap water supplies for the ships' bunkers, or a common exposure on shore (e.g., a restaurant where tourist groups from various ships were taken during day trips). as all of these ships continuously traveled up and down a short stretch of the river (aswan to luxor and back) with standard mustsee stops along the way, the cases possibly shared an exposure on land. both the long incubation period of hepatitis a ( - days) and long delays in collecting information on the individual cases precluded any rapid intervention on location. no specific food source was identified but it could have been juices as recognized in an earlier major outbreak. in , tourists returning from egypt included hepatitis a case-patients from european countries who were infected with a single hav strain (genotype b) (frank et al. ). the case-control study identified orange juice most likely contaminated during the manufacturing process, e.g., by an infected worker with inadequate hand hygiene or by contact of fruit or machinery with sewage-contaminated water. citrus fruit and citrus juices have occasionally been implicated as vehicles of hav and salmonella infections, with contamination typically occurring during production, or preparation just before consumption. as hav is resistant to acid, it likely can survive for prolonged periods in orange juice. it is also possible that leafy greens could contribute to foodborne illness in egypt. an international study of contamination of leafy green lettuce and spinach samples taken between and from open-field farms in belgium, brazil, egypt, norway, and spain showed that the egyptian samples were the most contaminated at . % (liu et al. ) . these authors claimed that temperature had a stronger influence than did management practices on e. coli presence and concentration. region was a variable that masked many management variables, including rainwater, surface water, manure, inorganic fertilizer, and spray irrigation. temperature, irrigation water type, fertilizer type, and irrigation method should be systematically considered in future studies of fresh produce safety. also in the spring of , a young couple was ill with vomiting and abdominal cramps after their first meal at a sharm el sheikh -star hotel in the egyptian coastal resort area, and they remained there in their bedrooms for the rest of their week (this is staffordshire ). both continued to have ongoing issues months later, with one of them suffering from reactive arthritis. other guests also complained about diarrhea. they stated that the food was disgusting; the meat was undercooked, the buffet was left out for long periods of time, with new food being piled on top of the old food, and there were flies landing on food items. in august , a family stayed at a resort hotel, also in sharm el sheikh, and all suffered severe symptoms including diarrhea, stomach cramps, and vomiting. they were put into the hotel clinic given antibiotics and intravenous drips but had not completely recovered after they returned home (galley ) . at the time other guests were also ill. they noticed that the food including chicken and beef, appeared to be undercooked a couple of times, and that one of the chefs touched raw meat and then touched cooked meat without changing gloves. the booking company confirmed that "a very small number" of guests staying at the resort in reported that they had been unwell, "with symptoms similar to a virus". the company said that guests were offered the appropriate support and advice by their overseas holiday advisors. it claimed that all of its hotels were subject to stringent monitoring and audits and this hotel achieved an extremely high score in its audit carried out in the summer of . however, high audit scores do not necessarily correlate with day-to-day safe hygienic practices (powell et al. ) . the popular beach resort of sarigerme, turkey, on the aegean sea also has had a reputation for gastroenteritis, with repeat problems of foodborne illness with british tourists on vacations organized by tour companies, although the actual hotels were different. in , an outbreak of gastric illness at this resort led to £ . m paid out in compensation, with people suffering from infections including salmonella, cryptosporidium, campylobacter and e. coli (hutchison ) . in september, , hundreds of british holidaymakers suffered from salmonellosis after returning from a hotel complex in sarigerme (disley ) . final figures may have been close to , and several were hospitalized. in october , the swannell family had booked a week's stay at the first choice holiday village resort in sarigerme, when mark swannell, , fell seriously ill a few days into the break with diarrhea, abdominal pain, nausea and lethargy (hutchison ) . he said that some of the food he was served at the hotel had been undercooked, with some chicken bloody in the middle, food was not served at the correct temperature, food was left uncovered for prolonged periods of time, and the same food had been served more than once. the family stated that cutlery, crockery and table linen used in the restaurant was not up to standard, and they saw cats in the public areas of the hotel and in the restaurant. legal action was taken. in addition to ill tourists in middle eastern countries, contaminated exported food can affect those abroad, as illustrated in the following u.s. outbreak. from march to august , of patients identified with hepatitis a in ten states, ( %) were admitted to hospital, two developed fulminant hepatitis, and one needed a liver transplant, but none died (collier et al. ) . almost all cases reported consuming pomegranate arils (seeds) from one retail chain. hepatitis a virus genotype ib, uncommon in the americas, was recovered from specimens from people with hepatitis a virus illness. pomegranate frozen arils imported from turkey were identified as the vehicle early in the investigation by combining epidemiology, genetic analysis of patient samples, and product tracing. the product was then removed from store shelves, the public warned not to eat the seeds, recalls took place, and post-exposure prophylaxis with both hepatitis a virus vaccine and immunoglobulin was provided. this investigation showed that modern public health actions can help rapidly detect and control hepatitis a virus illness caused by imported food. egyptian trade has also been adversely affected by exports. in , there were three outbreaks of hepatitis a sickening persons in -european countries. in the first report in april, persons in four scandinavian countries were infected with hepatitis a (andrews ) . epidemiological investigations traced those cases to frozen strawberries grown in egypt and morocco, though no strawberries were found to be positive for hav. the second outbreak in april was larger in extent with ill in countries, all having recently visited egypt, and the outbreak strain of the virus had the same subgenotype as the first outbreak associated with strawberries. an epidemiological investigation into the second outbreak suggested the likely source was strawberries or another fruit distributed to hotels in egypt. the third outbreak was reported in germany in may, after nine germans were infected with hepatitis a after traveling to italy. this third outbreak infected about italian residents, as well as nine germans, one dutch traveler and five polish travelers; irish residents with no travel history to italy were infected by the same strain of the virus. separate investigations in italy and ireland both implicated imported frozen mixed berries as the source, with most of those berries coming from eastern europe. it is not known if these berries came from other regions, such as egypt, or were local to eastern europe. contributing factors to the larger number ill was lack of vaccination. because hav infections were declining in europe over the last few decades, fewer people had developed antibodies to repel the virus. couple that with the fact that hepatitis a was not on the vaccination schedule for citizens of many of the countries affected, and the result was a highly susceptible population. also, most of the european travelers to egypt were not advised to get hepatitis a vaccinations when staying in all-inclusive resorts, which were attracting an increasing number of europeans traveling to egypt. further, the investigators believe contamination of the berries occurred early in the food production chain. investigators suspect that irrigation water contaminated with sewage water likely contaminated the strawberries in the two outbreaks connected to egypt. but the contamination might have also been caused by infected workers in the field or the processing facility, or by contaminated water sprayed on the berries sometime before distribution. the outbreaks indicate that fresh and frozen berries are efficient vehicles of hav infection, as previously demonstrated in the us and elsewhere (palumbo et al. ) . european authorities agreed that "the experience demonstrated the absolute necessity for extensive collaboration between countries and between the public health and food sectors to identify as quickly as possible the vehicle of infection and, ideally, to control the outbreak in a timely fashion." a more serious outbreak damaged egypt's food export trade. in july , the european union (eu) banned the import of certain egyptian seeds and beans till at least october following an official report that a single batch of egyptian fenugreek seeds probably caused two european outbreaks of e. coli infections responsible for ill persons and at least deaths. a task force of health officials set up by the european food safety authority (efsa) reported that one lot of fenugreek seeds imported from egypt was the most likely common link between the two outbreaks in northern germany and in bordeaux, france (anderson ) . both were traced back a year and a half to a shipment of , pounds ( , kg) of fenugreek seeds, that was loaded onto a ship at the egyptian port of damietta on november , . on the ship's arrival at antwerp, belgium, the seeds were barged to rotterdam to clear customs. the sealed container was trucked into germany to an unidentified importer, who resold most of the lot. an unidentified german company then resold about pounds of the seeds to the german sprouter, which is believed to be the source of the sprouts that caused the extensive german outbreak. the german importer also sold about pounds of sprout seed to the english company thompson & morgan, which repackaged the seeds into . -ounce ( grams) packages. those packages were shipped to a french distributor, who resold the seeds to about garden centers around france. investigators believe that one of those packets was the source of the second european outbreak with cases in the bordeaux area. because the seeds were likely contaminated with e. coli o :h at some point before leaving the importer, and more contaminated seeds could be in circulation, it was deemed appropriate to consider all lots of fenugreek from the egyptian exporter as suspect. soil contact or animal or human fecal contamination of the seeds likely occurred during their production or distribution in egypt. even a negative laboratory test of those seeds could not be interpreted as proof that a batch was not contaminated. trace-forward findings indicate the german importer sold seeds from the suspected lot to companies, and the shelf life of the seed can be up to years. by mid-october, , the european commission (ec) lifted import restrictions on fresh and chilled podded peas and green beans and other fresh produce from egypt, but the ban on egyptian seeds and sprouts, scheduled to expire on october , was to be extended until the end of march, , following an "unsatisfactory audit" of seed producers in egypt (news desk ). the extended ban involved arugula sprouts, leguminous vegetable sprouts (fresh or chilled), soy bean sprouts, dried (shelled) leguminous vegetables, fenugreek seeds, soy beans and mustard seeds. the ec audit showed that measures taken by the egyptian authorities to address shortcomings in the production of seeds that may be sprouted for human consumption were not sufficient "to tackle the identified risks." those shortcomings were not seen in the growing and processing sites for fresh peas and beans, and therefore those vegetables were no longer considered a food safety risk. there is no need for actual illnesses to occur to affect trade. recalls, seizures, and bans can be employed by importing countries if standards are not met, and force exporting countries like egypt to take action. for instance, in the ec suspended the import of peanuts from egypt due to the presence of aflatoxin in concentrations in excess of maximum levels specified in eu regulations (technical cooperation department ) . egypt is a major peanut exporting country and the european markets then accounted for % of its peanut exports. this decision was repealed on december and was replaced by another decision, which imposed a requirement for certification to accompany every consignment and required systematic analysis of consignments and documentation by the importing member state. under this system only egyptian exporters were allowed to ship to the eu. in august , the decision was replaced by another decision that required the competent authorities in eu member states to undertake random sampling and analysis of % only of peanut consignments from egypt for aflatoxin b and total aflatoxins. this improvement came as a result of the efforts that the egyptian government put in complying with the requirements of the eu. to this end, the egyptian ministries of agriculture and land reclamation (malr) and ministry of foreign trade (moft) issued ministerial decree no. / , which covered all stages of production, processing, sampling and exporting of peanuts. the main provisions of the decree were: exported peanuts must be produced, inspected and prepared according to set scientific procedures; and exporters who violate the rules would be suspended for year; the decree also established the legal limit for aflatoxin in peanuts in both the domestic and eu export markets. in the egyptian domestic market, the legal limit was mg/kg aflatoxin b and mg/kg total aflatoxin content. for the eu market, the legal limits were mg/kg aflatoxin b and mg/kg total aflatoxin content. in addition, the decree specified the sampling procedures that must be followed for export certification. in september of the food and veterinary office sent a mission to egypt to assess egypt's compliance with its certification system requirements. a number of recommendations on steps egypt should take to improve the control system of foodstuffs intended for export to the eu were made. in response, the egyptian authorities declared that they were taking actions to address the mission's recommendation. but to achieve that there was a need to coordinate among a number of egyptian agencies involved in the production and export of peanuts and aflatoxin control: malr, the central administration for plant quarantine (capq), the agricultural research center (arc), the ministry of foreign trade (moft), and the customs service. also a laboratory capable of testing for mycotoxins was necessary. alongside this; egypt had technical assistance from international organizations in order to build human and physical capacities necessary for achieving compliance. the action by the eu forces egypt to improve the safety of its peanut production which would be beneficial both to europeans and to all who eat products made from egyptian peanuts, including the domestic consumers. lebanon used to be a tourist haven but is less today because of a seemingly dysfunctional government following a civil war. the country produces food for both the domestic and overseas markets. unfortunately, some exported food has caused illnesses and recalls. twenty-three cases of salmonella bovismorbificans in eight states and in the district of columbia (washington, d. c.) from august to november, were linked epidemiologically to hummus eaten at three mediterranean-style restaurants in the d. c. area, all owned by the same individual (goetz ) . although samples collected from all ingredients used to make the hummus tested negative for any salmonella, the hummus was recalled and the outbreak ceased. during its investigation of the restaurants, the d.c. department of health discovered multiple food safety violations at the establishments, including inadequate food temperature control, insufficient hand washing, and the presence of pests and insects, which had to be corrected. it is not clear if any abusive temperature conditions could have allowed growth of the salmonella in the hummus. the public was not notified because by the time the hummus had been withdrawn from the market, there were no further cases. however, the contaminated ingredient in the hummus was not discovered until may, , when a traceback by the u.s. food and drug administration (fda) revealed that the tahini used to make the hummus in one of the restaurants had recently been associated with recalls in canada for contamination with s. cubana (september ) and s. senftenberg (february ). all tahini linked to these outbreaks had been imported from the same company in lebanon. the fda then mandated that all tahini products coming from this lebanese company be tested for salmonella before entering the u.s. and has recommended that u.s. and canadian officials partner to inspect the tahini manufacturing plant. this was the first time s. bovismorbificans had been implicated in a tahini outbreak in the u.s. as a result of this outbreak, the author stated it is important for public health officials and consumers to be informed that products made with imported sesame paste have been shown to be associated with salmonella outbreaks and that they should be considered as possible sources for foodborne illness in the future. in fact, contaminated sesame seed paste was in the news a few days before a cdc report on the outbreak was made public, after a supply of contaminated tahini was stolen from a california importer's warehouse, where it was being stored because a sample had tested positive for salmonella. the tahini, which had also been imported from lebanon but from a different manufacturer, was awaiting destruction, and the fda warned the public that the stolen, potentially contaminated tahini may be on the market. lebanese tahini has been implicated in several outbreaks in the past and subject to recalls (harris et al. ) . government oversight of the food industry is variable across the region with many regulations stemming back to colonial days, but modernization changes are gradually being considered or implemented. unfortunately, where some middle eastern countries are slowly moving forward to improve food safety, others are slipping back in their oversight because of conflict and lower public health priorities. there are relatively few large food processing operations except those managed by multinational companies, and most of the government oversight is on smes particularly small foodservice outlets. the states in the gulf cooperation council (gcc), each have an aggressive food safety policy but do not always follow identical approaches, some of which are well-established and some of which are innovative. the ksa has had a food inspection system in place for many years with reports of outbreaks published regularly, though no doubt it could be improved with more cooperation between the ministry of health, the municipalities and the saudi food and drug authority (sfda). the sfda was established under the council of ministers resolution no ( ) dated january , , as an independent body that directly reports to the prime minister (el sheikha ). the sfda is responsible to regulate, oversee, and control food, drug, medical devices, as well as set mandatory standard specifications thereof, whether they are imported or locally manufactured. the control and/or testing activities can be conducted at the sfda or any other agency's laboratories. moreover, the sfda is in charge of consumers' awareness on all matters related to food, drug and medical devices and associated other products and supplies. the sfda has to negotiate with the moh their mutual responsibilities following specific foodborne disease instances or consumer complaints. bahrain claims to have one of the more advanced food control systems in the region. in july , as ambient temperatures heated up, the ministry of heath urged people to make sure the food they consume is properly stored during the summer months to avoid microbial growth and risk of food poisoning, e.g., keeping meat and fish at c and to cook food thoroughly (haider ) . the ministry was aware that both visitors and locals want to eat safe food, especially as bahrain is moving towards more tourism with people are eating out more often. the ministry ordered shops to provide appropriate storage facilities, e.g., coolers and refrigerators, for food as part of its efforts to protect the public's health. inspectors were checking food stalls, ice-cream parlors and vegetable shops to ensure that customers were not being sold contaminated or rotten products. the ministry claimed to thoroughly investigate any complaints it receives, and to facilitate this a new hotline number was launched by the ministry for general public to report food contamination complaints against supermarkets, restaurants, coffee shops and hotels. specific advice for consumers included: being careful when buying salads; fruits and vegetables should be washed thoroughly before they are consumed; and dairy products such as milk, cheese and eggs, should always be refrigerated, since microorganisms grow faster in these products. the ministry claimed that bahrain has one of the best food control methods and food safety records in the region, and could even act in the future as a consultant in this field for other countries, including other gcc states. by , government oversight had stepped up. in april, the ministry of health warned people against buying food advertised on social media or sold on the street by unlicensed retailers in bahrain, either made in people's homes or by street hawkers (anonymous c) . the ministry stated that control of these home operations is difficult if someone suffers from food poisoning since inspectors are not allowed to go into homes. many homes sell food without a license and some would-be entrepreneurs even have barns where they slaughter livestock and market the meat illegally. there were , inspection visits conducted in by inspectors from the food safety and licenses group, which closed of around registered outlets. inspections cover imported food from ports right up to where it reaches restaurants and food outlets; , visits revealed around , tonnes of imported food were permitted for consumption, but tonnes were considered as non-consumable (rejected), during the same period. one of the more recent important programs is the smart inspection project launched in april . inspectors, many with masters and phd degrees, visit restaurants and coffee shops to take food samples, as well as explain to staff how to store food and ensure its safety (anonymous c) . it includes awarding food outlets that achieve a % food safety standard a blue sticker, while those meeting % of standards get a green sticker. outlets that fail to achieve basic standards are warned with a red sticker. the total number of outlets assessed between august and february was ; were presented with blue stickers, with green stickers and with red stickers. this project features daily inspections and is focused on small food outlets, some of which have caused food poisoning in the past. inspection visits depend on the hygiene of each outlet and the complaints received about them; some require two or more visits annually. high-level restaurants already have certified inspectors for evaluation and most of them require only one visit per year. the ministry's ultimate goal through this project is to decrease cases of foodborne disease, particularly important as bahrain is increasing its tourism efforts and, thus, ensuring food safety is essential. to support the ministry's initiatives, live demonstrations on food safety practices were promoted in kitchens in hypermarkets. however, if red sticker facilities fail to take advantage of educational material, they may be punished for neglecting food safety standards and guidelines though public prosecution. in a bid to improve standards of hygiene in restaurants, qatar's supreme council of health (sch) increased the number of spot checks on food outlets and has launched a hotline for residents to report food poisoning (walker ). the council is responsible for monitoring food establishments and implementing qatar's food laws along with the ministry of municipality and urban planning (mmup/baladiya). the sch embarked on an intensive inspection campaign, collecting food samples from all restaurants and food outlets in the country including suppliers. the inspection teams, which include specialized doctors from the sch's communicable diseases department and the environmental health inspection department, also medically check workers responsible for preparing food to ensure they are not carrying infections. those found to be handling food in an unhygienic way would be immediately dismissed. following a hotline complaint call, a report is filed, a team from the sch visits the affected people, then inspects the related food outlet and collects samples for laboratory examination. the latest crackdown was in response to the illness of a family of four which suffered food poisoning after eating chicken, rice and salad at a popular turkish restaurant which was closed down because a medical report prepared by the sch's environmental health section confirmed that the outlet served contaminated food and violated health regulations. tests conducted in the central food laboratory at sch found three types of bacteria causing diseases in food served by the restaurant. medical tests on the victims also showed that they were infected by the same bacteria, as well as one of the restaurant workers. another popular turkish restaurant was closed for months after it was found that several customers were treated in the hospital for food poisoning symptoms including intense nausea, vomiting and diarrhea. as part of the sch's new campaign, experts would undertake community awareness drives, and organize seminars and training sessions about food contamination to improve understanding among owners and workers in food establishments. other closures occurred because of serving food with moldy ingredients, rotten vegetables in the kitchen, insects in pasta, and generally violating the provisions of the food law. the mmup increased the number of spot-checks and naming and shaming erring establishments on its website in arabic. the amendments to the food law gave greater powers to authorities to fine and close down venues that break the law including temporarily closing down establishments if it has violated food safety and hygiene regulations, and also has the power to recommend severe penalties. a follow up to one of these closed doha turkish restaurants was after a trial when five staff were each been handed fines, jail sentences and deportation orders after they were found guilty of causing food poisoning to approximately customers ill with vomiting, nausea and diarrhea (santacruz ) . the restaurant was accused of serving spoiled and unsafe food on october, . an affected pregnant woman gave birth to her baby months prematurely. the manager of the restaurant was fined approximately $ and sentenced to spend months in jail while three other staff members were each fined approximately $ and sentenced to month in jail. during an inspection it was found that another staff member did not hold the necessary health certificate and was subsequently fined approximately $ and also sentenced to month in jail. as well as the staff members being sentenced to jail and fined, the court of environmental misdemeanours also found that the restaurant itself was guilty of causing the food poisoning outbreak, and issued the restaurant with approximately $ in fines and ordered it closed for a further months. in other parts of the world these penalties would seem unduly harsh, as it would be difficult for this restaurant ever to recover financially. coupled with education, there has been recent enforcement blitzes on food establishments such as hotels, restaurants and bakeries by oman municipalities, and a leading bakery in muscat was closed down because of rats in the premises in late december, (staff . this led food safety experts and the public to call for stricter rules and heftier fines to be imposed after surprise checks conducted by the muscat municipality, especially when it was disclosed that nearly half the restaurants in the bausher area were not following food safety standards. surprise inspections by the muscat municipality at restaurants in bausher found that around restaurants did not meet food safety standards and were violating rules formulated by the municipality. also, in the same time frame, ibri municipality officials were forced to shut down commercial shops and they destroyed more than km of outdated food in . according to the municipality's officials, health violation letters were issued throughout the year, as well as warnings were issued to different institutions operating in the wilayat of ibri. there are no easily-accessible reports on government oversight in pakistan and inspection actions are more likely to be released to the public through the press. in , the islamabad capital territory (ict), administration conducted a drive against adulterated food items with unannounced inspections of food outlets in different markets and imposed fines amounting to rs , (about us$ ) on owners for unhygienic conditions at their premises including restaurants, cafes, bakers, candy (sweet) stores, and a hotel was sealed (app ) . cleanliness conditions at the outlets' kitchens were found unsatisfactory and unhygienic while workers had not been vaccinated against viral diseases. some business owners were also paying less to their workers in contravention of the minimum wages act. business owners were directed to improve cleanliness conditions and ensure food safety standards failing which strict action would be taken against them. a cattle market was also ordered to "beef up" its security. punjab, pakistan's most populous province, has a population that is more than double that of california, and lahore, the provincial capital, has a vast array of food outlets. from the available press reports, the punjab food authority (pfa) has a mixed record of oversight of food operations. a pfa team visited the polo ground restaurant at the race ground park and found expired food, blocked sinks and unhygienic conditions in the kitchen and food storage area in contrast to the claimed high quality standards by the management of the supposedly high-class restaurant (raza ) . the team faced resistance from the management but it managed to enter the kitchen for inspection. pfa officials said the kitchen condition was similar to that of an ordinary road-side eatery, dispelling general perception that restaurants serving the elite follow higher standards of hygiene and food safety. however, the pfa in lahore had received a complaint that an assistant food safety officer had received rs , (about us$ ) bribe from the restaurant owner so he could keep his restaurant open (anonymous d) . another restaurant on peco road sealed by the pfa for poor hygiene and unsanitary conditions of its workers in the second week of march, was opened for business the very next day. typically, according to the pfa's standard operating procedure (sop), a restaurant sealed for the first time may resume business after a week. at the end of the week, the proprietor has to submit an affidavit assuring the authority that all problems pointed out by the food safety officer had been taken care of prior to reopening it for business. the pfa director general (dg) had constituted a three-member committee to probe the complaint of bribery but it was later shelved. similar situations occurred when restaurants that had reopened before the stipulated period for closure had expired. in the first week of , a restaurant was fined rs , (about us$ ) for unhygienic conditions and lack of soaps in the workers' washrooms, instead of following the pfa sops of sealing the premises. the sops regarding duration of closure and required permission from the pfa dg were stated to be flouted openly. however, a pfa spokesperson denied any wrongdoing, and the sop was being observed to the letter. she said a written permission from the dg used to be mandatory in order to de-seal restaurants, but now an operations deputy director can also issue permission for it. she also stated that the restaurant on peco road had not reopened on orders of the pfa; its owner had de-sealed it illegally. these reports indicate that there may be some illegal activities including bribery by inspectors but miscommunication on how much leeway inspection staff have on prevention and control practices may be more of the issue. in mid- ayesha mumtaz became the new operations director of the pfa, tasked with ensuring food in punjab is unadulterated and safe (reeves ) . her self-declared war on unhygienic food generated so much publicity in the last months that she became a household name in pakistan. mumtaz says many food producers know nothing about hygiene but are willing to learn. there's also a hardened mafia who are only interested in profit, she says. everyone in the street seems to know about mumtaz. storekeepers begin shooing away customers, hauling down the shutters, and heading into the shadows in the hope that mumtaz's scrutinizing eye will not fall on them. these traders would sooner lose business than risk a visit from a woman whose campaign to clean up the kitchens and food factories of pakistan has made her a national celebrity. she declared that the pfa cannot allow them to get away with their "perverse" activities and to "play havoc" with the lives of the people. consumers are unaware that the cakes and sweets that they buy over the counter are produced amid unhygienic conditions. she has found spoons encrusted with filth, fly-blown cans of gooey liquid lying around haphazardly, dirty containers, grimy rags and rusty tin cans, moldy scraps of cake, all involved in making cakes and sweets to be sold to the public. civil servants in pakistan are often accused of being lazy and corrupt. mumtaz is being feted as a rare example of a government official who actually champions the public's rights. she and her inspectors have so far raided more than , businesses, and pakistanis seem to approve. her fans call mumtaz the fearless one. hundreds of thousands have clicked like on the pfa's facebook page in appreciation of her work. there was a very famous hotel in the heart of lahore that she inspected and found the chiller where they keep all the foods together (vegetables with chicken, meat), but also a big rat; this became big news for the public. however, there are complaints that she does her raids with police and cameras to be broadcast nationally even before the owners are convicted, according to the lahore restaurant association. in , the abu dhabi food control authority (adfca) planned to check all food handlers by . the authority's emirate food safety training (efst) program, started in , provides basic training in food hygiene and safety to those who work in food outlets (olarte ) . according to the adfca, small catering businesses in most countries have the lowest standards of food safety, and most workers in abu dhabi's small restaurants are illiterate and do not speak fluent arabic or english, making it a challenge for them to understand and follow safety guidelines and regulations; % of managers and % food handlers in the capital speak south asian languages such as urdu, hindi and malayalam (pennington ) . the training is now offered in four languages -english, arabic, urdu and malayalam -which the majority of food service personnel speak, and covers basic food hygiene issues including staff hygiene, food temperature, cross-contamination, cleaning and sterilization. to help them understand and follow food-safety rules, the adfca is using photographs to teach employees how to handle food safely according to international standards. the scheme is an extension of a pilot involving small restaurants carried out in - . as part of the efforts to ensure retention of their learning, the adfca conducted spot checks at food outlets in marina and khalidiya malls, and gave guidance and advice to staff for those with violations, rather than just penalizing them, the normal practice in most middle eastern countries. the field operations manager at the adfca noted that the differing cultures, education and languages are the barriers that sometimes hinder food handlers from carrying out what they are trained to do. he recommends that supervisors should quiz them on hygienic and safety issues so that they know how to properly prepare and serve food. those who have learning difficulty or are illiterate are given assistance through illustrations, in order to make it through the lessons and pass the examination. one of the critical elements of food safety that the adfca has to monitor and ensure, is that food handlers are aware of cold ready-to-eat food being kept at c, while hot food should be kept and served very hot > c. the adfca categorizes the food premises and carries out inspections based on their risk factors -high, medium and low. restaurants and hypermarkets belong to the high-risk group; warehouses to the medium risk; while groceries, honey shops and vegetable and fruit outlets are considered low risk. recently, the establishment of the egyptian food safety authority was initiated by the minister of trade and industry, with the support of the ministry of health and the ministry of agriculture. it would be responsible for food safety and consumer protection through the provision of sound data and guidance to deal with processed or genetically modified food in accordance with food safety standards (anonymous b) . the strategic plan for the new draft law includes a revision of all egyptian laws and legislation that deal with food safety since , including around other legislations. the authority would need to apply food safety standards on imported food the same way it does for locally produced foodstuffs. adopting the draft law would in effect cancel all existing laws and create one food safety law for the country. the food safety authority plans to monitor the foods consumed by egyptians of different age groups as a basis for where to put resources. another issue to be faced is that studies in egypt based on us statistics have revealed that the cost of food spoilage costs the country million egyptian pounds annually. the chamber of food industries indicated that a unified body for food safety to apply international quality specifications and unite regulators was lacking. this reduced the competitiveness of local products, especially since most foreign countries do not recognize egyptian regulations. it was hoped that investors in food industries would bring in new investments to the sector in the upcoming period if a food safety authority were to be established, as per a ministerial decision issued in . the food safety authority has received several approvals from governments that ruled during the -year period following the revolution, but apparently nothing has been yet finalized until recently (mefreh and saeed ) . in a similar way to egypt, the lebanese government has been debating a new law on food safety for many years but unlike egypt, it has yet to make much progress. lack of agreement at the parliamentary level has resulted in different ministries (health, agriculture, industry, environment, tourism) taking action as they see fit. the latest was in november , when the minister of health conducted an extensive campaign of inspections in lebanese establishments and naming of facilities that did not meet the ministry's expectations (naylor ) . the minister personally revealed that numerous supermarkets, bakeries, butchers and restaurants had been violating food safety and sanitation standards. they shut down slaughterhouses, restaurants, supermarkets and other retailers selling contaminated food. for instance, changes needed to be made for the slaughterhouse to conform to health standards; the report said livestock must be hanged during slaughter and not laid on the ground and that the abattoir should also be equipped with refrigerators and storage units for separate types of meat and their cuts. however, discord among ministries is apparent with the tourism minister trying play down the publicity of the health minister's food safety blitzes by saying "we are in favor of full transparency, but we feel like we were 'deceived' because the food safety situation in lebanon is good and better than other countries. we apologize to tourists, but more importantly, any of the ministry of health staff is ready to apologize to the lebanese citizens for the public sector's failures throughout the years?" (yaliban ) . foodborne disease surveillance is limited in lebanon and cannot be used to indicate the actual level of foodborne illnesses in the country. lebanese food exports are also being required to conform to international standards. tahini made from sesame seed paste is a major food export to the west, but recalls of tahini manufactured in lebanon because of salmonella contamination are more frequent than they should be; one recent example was a health hazard alert for certain clic, al nakhil and al koura brand tahina products that may have contained salmonella, recall/advisory dated august , posted from canadian food inspection agency [also see tahini/hummus linked illnesses under foodborne disease in specific countries]. under the new us food and drug administration food safety modernization act, foreign companies importing foods to the us must demonstrate that they have the operational plans and facilities sufficient to produce safe food before they can ship any product to the us (fda ), which is causing some concern among lebanese tahini manufacturers and government agencies. thus, although there is knowledge about foodborne disease and other food safety issues within government, industry and academia, the political inertia means that many foodborne illnesses will continue to occur but not be properly reported or know what factors were present to cause the outbreaks. industry currently is taking the lead; apart from companies promoting food safety like boecker and gwr food safety, mena food safety associates (mefosa) (http://www.mefosa.com/), based in beirut, assists mena companies hone their competitive edge by establishing and verifying procedures and practices that ensure quality, wholesome and safe products through consulting, auditing and training services in haccp, gmps, and hygienic practices. however, lebanon's lack of a coordinated system of government oversight of the food industry pales into insignificance compared to that in syria. prior to the war, syria's healthcare system had hospital and doctor levels equivalent to other middle-income countries such as brazil, turkey and china, with life expectancy of years, and most of the disease burden being similar to that in the west with non-communicable diseases, but four years of violence have changed all of that. child vaccination levels dropped from % pre-conflict to % in march (templeton ) . as a result, outbreaks of diseases that had long been under control have spread across the land and into neighboring countries: hepatitis, measles, leishmaniasis, multi-drug-resistant tuberculosis, typhoid and even polio, which had not been seen in the middle east for years. life expectancy has dropped by two decades. medical personnel are clearly targeted because they are seen as potential enemies helping the opposite side. the majority of syria's doctors have been killed or fled the country (> medical workers have been killed since ). the situation has been called the worst humanitarian catastrophe this century, and the worst concerted attack on healthcare in living memory. at least , syrians have been killed and more than million others have been forced from their homes since the conflict began on march , , with over four million people in areas that are hard to reach for humanitarian aid, and Á million have fled mostly to neighboring turkey, lebanon, jordan, and northern iraq, while others have sought safety in europe, provoking a political crisis in the -member bloc (devi ) . another middle eastern country under stress but with less publicity is yemen. currently there is little government oversight into food as there is little to be had. the situation in yemen is characterized by large-scale displacement, civil conflict, food insecurity, high food prices, endemic poverty, diminishing resources, and movement of refugees and migrants (wfp ). the un world food programme (wfp) has been in yemen since . in , wfp conducted a comprehensive food security survey which found that % of the people ( . million) were food insecure, of which some five million were severely food insecure, meaning they were unable to buy or produce the food they need to survive. the organization's protracted relief and recovery operation (prro), aims to reach six million people between mid- and mid- with , metric tons of food and us$ . million in cash and vouchers at an overall cost of us$ million. if the conflict continues, this goal is unlikely to be met in time since both the airport and shipping port are areas being fought over. the wfp has been attempting to bring in relief supplies but cannot do so under fire, which means that only small amounts are occasionally delivered to the country (mukhashaf and miles ) . one example of this occurred in aden on july , when a ship docked after waiting a month to unload enough u.n. food aid to feed , people for a month. previous repeated attempts to send ships to aden were been blocked due to severe fighting in the port area. the prro is aligning wfp's activities with moves to increase the government's capacity to respond to the crisis and will promote recovery and resilience to enable food insecure households and communities to better withstand and recover from the effects of conflict and shocks. there are many similarities as well as substantial differences in the descriptions of issues concerning food safety and foodborne disease of each country in the region. gastrointestinal diseases are frequent throughout the middle east with some countries identifying their etiologies, such as egypt, kuwait, israel, pakistan, turkey, yemen. these include bacteria and parasites, e.g., salmonella, shigella, campylobacter, enterotoxigenic e. coli (etec), giardia, entamoeba, and occasionally enteric viruses such as hav and norovirus. however, none of the countries has a well-functioning foodborne disease surveillance system, but a few report on a regular basis like ksa, and starting recently, lebanon with pulsenet. mostly it seems that only large outbreaks or ones with fatalities that are reported on, and mainly through the press. these outbreaks are often related to point sources which are in most cases communal foods prepared for a large number of individuals as in feasts, student hostels, schools, campuses, or military camps. however, the actual etiological agents and the factors contributing to outbreaks are only rarely determined. one example is a very large outbreak in bahrain in with at least people suffering from foodborne illness after eating contaminated egg-andmayonnaise sandwiches served at a wedding party, but the etiology was not determined, even though clinical specimens and food samples were analyzed, at least in a publically-released report (promed-mena ) . based on the type of preparation including the length of time taken for preparation of the implicated food and the time from consumption to the appearance of symptoms of foodborne illness, the types of symptoms, and what has already occurred historically in foodborne disease outbreaks, possible agents can be surmised, such as bacillus cereus and staphylococcal enterotoxins, and salmonella, shigella, or norovirus infections, but promed is continually asking for more information once an outbreak is announced, and hardly ever receiving it (promed-mena ). all this indicates that even if clinical specimens or food samples are taken and analyzed, laboratories are only rarely able to determine an etiologic agent, or at least report on their results. most agents described with the little information available seem similar in all the mena countries and to those encountered in the west. however, a few pathogens are more likely to be restricted to a few nations, such polio in pakistan, cholera in iraq, mers-cov in ksa, and botulism in egypt and iran where river fish are often eaten (one case of infant botulism was diagnosed in israel but it is a rare disease anywhere); the first two are more likely transmitted though water or poor hygienic conditions, the third by camels, and only botulism exclusively through food. brucellosis is widespread in the middle east but only a few country studies indicate its link to meat or dairy products. much of the middle east is in the throes of conflict which results in unique situations in specific countries to exacerbate foodborne disease or food poisonings; these include relief agencies supplying "stale" food to those trapped and starving by the syrian civil war, almost lack of food at all in yemen, deliberate poisonings of enemies in afghanistan, syria and iraq, accidental pesticide poisonings in iran, preventing unsafe food being sold to those on the hajj in ksa, improperly prepared catered food for foreign troops in bases in afghanistan, iraq, kuwait, ksa, and turkey. countries where tourism is a major source of income can be adversely affected by bad publicity over complaints over food served in resorts, such as in egypt and turkey. also, gulf countries tend to employ workers from india and other surrounding territories, and these are typically housed in camps or separate communities from citizens and visitors, and are transported to work sites and back; conditions are not always conducive to safe food, and outbreaks are occasionally reported either from their work sites or their overnight residences where meals are prepared or catered. most food to many of these countries is imported, especially those with limited agricultural land and adequate water supplies; fruits and fresh vegetables, tend to be grown in rural or peri-urban settings for local consumption and these can be contaminated at source through polluted river or well water, such as in the bekaa valley of lebanon and mountain communities in pakistan, and the nile, tigris and euphrates fluvial plains. on one occasion, iranian watermelons were recalled and future sales banned in ksa, qatar, and uae because they were suspected of being poisoned or were injected with pesticides (nobody claimed to be ill after eating the melons), because holes were found in a few of them. however, the rationale of iranian farmers deliberately losing money seems to counter this argument, and it is more likely a sectarian economic barrier (abdullah ) . in fact, with the temporary ban the price of watermelons went up in the countries that had banned them. random tests carried out on the fruit confirmed they were free from any chemical substances, insecticides or other pollutants. the holes were most likely caused by emerging insect pupae. countries outside the gulf region reported no problems with the imported iranian melons. where some processed foods are exported, there is a risk of the importing countries recalling these if they cause foodborne illnesses or contaminants are found in them. this has happened in egypt with hepatitis a virus in strawberries and e. coli o :h in fenugreek seeds causing serious illnesses in europe and restricting further trade for an extended period. the same issue affected turkish pomegranate arils and lebanese tahini (made from imported ground sesame seeds), both containing salmonella, exported to the us. large to medium operations for broiler chickens and egg layers in ksa, kuwait, lebanon and other countries try and meet national standards or international guidelines for salmonella but are not always achieved, resulting in recalls and fines. governments are also aware of increasing concern over campylobacter in chickens, as widely-eaten poultry is a major source of this pathogen, but campylobacteriosis is not often cited as causing foodborne disease. raw milk (cow, sheep and camel) and raw milk cheese are still widely consumed in the middle east at the local level, though not usually obtained through supermarkets, and the risk of infections is high, as it is in other parts of the world, but with the added concern of brucella spp. and mers cov (the latter in the gulf countries where camels are bred and milked), both serious pathogens. yoghurt, surprisingly since it is acidic and is a source of gut beneficial lactobacilli, apparently was the foodborne vehicle to cause illnesses and deaths in afghanistan, israel, and pakistan. no agent was found in any of the samples. in the afghani example, the yoghurt was claimed to be deliberately poisoned; in the israeli one, it was apparently "stale" given to palestinian prisoners; there were two episodes in pakistan, one was from a home-prepared meal and the other from a restaurant which served rice and yoghurt. for prevention and controls strategies, most countries seem to rely on local authorities (municipalities) to do inspection of food facilities, more typically restaurants than processing plants as there are far more of them. illegal sales for unapproved products by local entrepreneurs are sometimes an issue, e.g., homeslaughtered meat in bahrain, and palestinians shipping food to israel. these illegal operations probably occur more often in porous borders within the region, and are only recognized when authorities decide to become vigilant in this area. some countries have conducted research and surveys much more than others based on the publication record, e.g., egypt, israel, palestine, ksa, turkey, and to a lesser extent, iran, lebanon, pakistan, uae, and yemen, but some research may occur without formal publication in recognized journals, making it difficult to have a true picture of how food safety problems are recognized and controlled. a few surveys have shown that home makers and food employees have limited knowledge of food safety, as in other regions. thus, some agencies or industry associations, sometimes in collaboration with outside organizations like fao or who, have attempted to train food employees in basic haccp principles, including best hand hygiene practices, and speakers give the latest food safety issues at the annual dubai international food safety conference, now in its th year. a few governments have established food safety agencies that have broad powers to inspect and control without overlapping responsibilities; these include jordan and ksa with food and drug administrations, uae with abu dhabi and dubai food control authorities, oman with its national food quality and safety centre, and pakistan with a punjab food authority. egypt and lebanon are initiating food safety authorities. israel, palestine and jordan have a cross-border agreement to collaborate on food safety issues. typical of many food control agencies in developing countries, periodic campaigns are launched to "crack down" on foodservice operations and sometimes processing plants. these are usually stimulated by complaints of the public, or the need for the responsible ministry to be seen doing something to justify its existence in compliance with regulations (if they exist). this has occurred recently in lebanon, qatar and pakistan. one issue is that poorly constructed or out-of-date regulations may be interpreted in different ways by the owners and the agencies (kullab ) . if a violation is found, the facility may be fined and/or temporarily closed down until it has satisfied the inspectors at the next visit. in one extreme instance in qatar, the owners and employees, were fined, imprisoned and deported. unfortunately, although the names of those at fault are often publicized by the media, their specific violations and how they relate to the regulations are not usually documented or at least publically released. another issue is that whether illnesses are suspected or not following a complaint, inspectors often insist that all food be discarded as soon as a sufficient violation, which may be unrelated to the complaint, has been determined; this prevents any samples being taken for outbreak investigations (hanna et al. ), as well as using the outbreak for a teaching tool for the owner and other similar operations. in conclusion, some progress has been made in the surveillance of foodborne disease in the middle east, but the disease's health and economic burden is barely being considered in many countries for future decision-making policies, an issue that is being tackled at the global level (who b). food control agencies seem to be trying to stop apparent abuses but have limited resources to do much more. this region, in particular, is severely strained because of sectarian distrust, on-going civil wars, and terrorist attacks, with refugees from iraq seeking shelter toward europe but stalled in turkey and lebanon for long periods of time. the crisis in syria is considered the greatest humanitarian disaster of the twenty first century, or even since world war ii, and it looks like the on-going fighting including outside armed forces will make food insecurity in the affected countries even worse in the foreseeable future. less public attention has been directed to yemen where food insecurity is a major concern. this coupled with gulf countries losing their wealth over low oil prices and a resultant stagnant global economy means a focus on food safety will likely become lower in priority for many of these countries. since secure food has to be safe, as illustrated by "stale" food being issued to besieged syrian residents and prisoners, it is important that relief agencies and countries themselves be aware of the risk of foodborne diseases associated with immunocompromised persons, particularly children. however, even in countries where the food supply is acceptable, inadequate hygienic practices put the local and tourist population at risk of illness and exported foods jeopardize industry profits and a poor reputation for future trade. as demonstrated by ksa, jordan and uae, single agencies or multiple agencies with clear-cut roles responsible for food safety, should be pursued by governments in consultation with industry and academia. duplication creates ambiguities for enforcement and education strategies as well as being unnecessarily costly. water supplies are also critical and some governments are weaning away farmers from depleted groundwater aquifers, and making irrigation more efficient where there are sustainable supplies. water for irrigation and processing has to be both free of pathogens and unacceptable levels of chemicals, and effectively treated waste water can substitute for groundwater. the sahara forest project in qatar is one example of a very dry country using seawater resources effectively; an even larger project is being considered from the -hectare in qatar to a -hectare test facility in jordan (clery ) . all these issues are being compounded by climate change and expected higher temperatures in already arid lands, which will make the region all the more dependent on more expensive imported foods. gulf counties have enough petro-dollars to afford these, but other countries are struggling to be self-sufficient for the near future even if the fighting ceases. the repair to destroyed infrastructure will be 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waterborne disease in developing countries -africa and the middle east. dairy food and environmental sanitation viruses of foodborne origin: a review. virus adaptation and treatment afghan cops; food poisoning at border post isis fighters die in 'iftar poisoning'; more ill after eating ramadan meals in mosul. international business times, india edition amid growing complaints, sch launches food poisoning hotline in qatar yemen: current issues and what the world food programme is doing who's first ever global estimates of foodborne diseases find children under account for almost one third of deaths. world health organization who estimates of the global burden of foodborne diseases. foodborne diseases burden epidemiology reference group - . world health organization food scandal: food poisoning rate in lebanon lowest, says tourism minister key: cord- - nc uep authors: vahora, jennifer; arwady, m. allison title: evaluation of redcap as a tool for outbreak data management, illinois, - date: - - journal: online j public health inform doi: . /ojphi.v i . sha: doc_id: cord_uid: nc uep nan the research electronic data capture (redcap) application has been used to build and manage online surveys and databases in academic research settings. public health agencies have begun to use redcap to manage disease outbreak data. in addition to survey and database development, and data management and analysis, redcap allows users to track data manipulation and user activity, automate export procedures for data downloads, and use ad hoc reporting tools and advanced features, such as branching logic, file uploading, and calculated fields. redcap supports hipaa compliance through userbased permissions and audit trails. these additional capabilities may provide an advantage over commonly used outbreak management tools such as epi info and microsoft access. the illinois department of public health (idph) has not used redcap to date. prior to adopting this web-based application, an evaluation was conducted to assess how redcap may facilitate outbreak data management. we conducted a retrospective review of four different types of outbreaks that recently occurred in illinois: a restaurant-associated foodborne illness outbreak; the introduction of middle east respiratory syndrome (mers cov) to the united states; a large rash outbreak; and a healthcare-associated cluster of new delhi metallobeta-lactamase (ndm). using these four case studies, we evaluated how redcap may have impacted the response to each outbreak using six criteria: ) magnitude of cases and contacts across jurisdictions; ) self-reporting of symptoms and exposures; ) storage and multisite access to lab reports; ) reuse of templates for future outbreaks; ) repeated measurements; and ) ability to perform long-term case follow-up. redcap would have improved data management capabilities for all four types of outbreaks. for the mers cov and rash outbreaks, redcap would have assisted with the management of large-scale outbreaks with hundreds of contacts and multi-jurisdiction response. for all four types of outbreaks, redcap would have facilitated self-reporting of symptoms and exposures through the design and administration of online surveys to cases and contacts. redcap's document upload functionality would have facilitated storage and access of lab reports for foodborne illness, mers cov, and ndm outbreaks. redcap also would allow public health responders to perform long-term monitoring of symptoms and disease incidence in ndm outbreaks. in illinois, public health agencies currently lack a secure, hipaa-compliant outbreak management system that facilitates survey development, online data entry, data management tools such as automated exports, contact tracing, and coordination across jurisdictions. the evaluation of recent outbreaks shows that redcap provides these desired capabilities. role of social media in investigating rash in mud race obstacle course participants -illinois centers for disease control and prevention. notes from the field: new delhi metallo--lactamase-producing escherichia coli associated with endoscopic retrograde cholangiopancreatography -illinois, . mmwr first confirmed cases of middle east respiratory syndrome coronavirus (mers-cov) infection in the united states, updated information on the epidemiology of mers-cov infection, and guidance for the public, clinicians, and public health authorities key: cord- - j fl authors: afolabi, michael olusegun title: pandemic influenza: a comparative ethical approach date: - - journal: public health disasters: a global ethical framework doi: . / - - - - _ sha: doc_id: cord_uid: j fl community-networks such as families and schools may foster and propagate some types of public health disasters. for such disasters, a communitarian-oriented ethical lens offers useful perspectives into the underlying relational nexus that favors the spread of infection. this chapter compares two traditional bioethical lenses—the communitarian and care ethics framework—vis-à-vis their capacities to engage the moral quandaries elicited by pandemic influenza. it argues that these quandaries preclude the analytical lens of ethical prisms that are individual-oriented but warrant a people-oriented approach. adopting this dual approach offers both a contrastive and a complementary way of rethinking the underlying socioethical tensions elicited by pandemic influenza in particular and other public health disasters generally. contemporary healthcare constitutes an instinctual and institutional response to the multifaceted cycles of health, illness, and disease. hence, the problems of diseases including infectious ones affect all and sundry irrespective of current "sick status". pandemic influenza is one such incident that afflicts all sectors of the society. it also raises questions and issues related to utility and equity, ensuring the protection of vulnerable individuals and groups in society, the need to exercise public health powers with respect for human rights as well as the just allocation of human and material resources. attending to these issues, however, juggles many kinds of personal, social, political, and professional interests against one another; thus, reflecting the traditional public health dilemma of fine-tuning individual against collective good. since the restrictive approach of individualism-driven moral lenses is unsuitable for people-centered quandaries, it seems pertinent to employ a people-centric moral lens to engage them. in this vein, the ethical prism of communitarianism and ethics of care seem apt. by examining and contrasting the core fabric of the communitarian and care ethics frameworks vis-à-vis the attendant dilemmas of pandemic influenza; this chapter attempts to tease out a broader ethical path towards engaging the challenges of pandemic influenza. to properly set the conceptual foreground essential to articulating the ethical features of pandemic influenza, however, it is important to elaborate the associated biological, social, and global dynamics. these parameters, as macphail recently argues, are exigent in the explication and engagement of pandemic or infectious disease outbreaks. there have been some speculations as to the origins of the influenza virus. it has been hypothesized that the virus originated from wild waterfowls and has only slowly evolved through multiple animal species including humans. but what is known about the disease caused by the virus-influenza-is that it is a febrile illness of the upper and lower respiratory tract, characterized by a sudden onset of fever, cough, myalgia, and malaise. pneumonia is a principal serious complication and local symptoms include sniffles, nasal discharge, dry cough, and sore throat. pandemic influenza outbreaks describe the rapid spread of influenza infection. whereas there is some conceptual controversy about the description and definition of pandemics, they generally refer to the dissemination of new infective diseases to which immunity has not been developed in a widespread manner across a significant part of the world. they could break out in nations with a large geographical size (such as china, india, and the united states) or when the number of affected nations are many. the pandemic nature of influenza is historically underscored by the - incident that killed an estimated million to million people. pandemic influenza is generally characterized by an alteration in the viral subtype (due to antigenic shift), higher mortality rates among younger groups, several waves of the particular pandemic, increased capacity of spread, and geographic variation in the impact of the outbreak. specifically, influenza pandemics occur when an influenza virus mutates or when multiple strains combine, or re-assort to produce strains to which there is no current immunity. novel outbreaks of the influenza virus occur either in large nations or across selected nations in close proximity. contemporary society experiences an increased development of new serotypes of several kinds of respiratory viruses because of the evolutionary potential afforded by the human population explosion and the great global increase in human mobility. in a manner of speaking, it seems that phds such as pandemic influenza outbreaks have evolved to become recurring features of the human experience. some insights into the biological features and processes that create pandemic outbreaks support this idea. influenza viruses belong to the orthomyxoviruses family. this comprises seven genera including influenza virus a, b, c, and d. although both the genus influenzavirus a and b affect humans and cause pandemics, influenza a has been the principal culprit in known outbreaks to the extent that four major pandemics have resulted from it ( - , , , and ) . however, genetic reassortment and exchange of influenza viruses between humans and animals generate antigenic shift, which periodically introduces new viruses to the human population. this, in addition to mutation and selection, produces antigenic drift that accounts for the year-to-year variations in influenza a subtypes. wild ducks, for instance, serve as the primary host for various influenza type a viruses that occasionally spread to other host species and cause outbreaks in such animals as fowl, swine, and horses. such outbreaks often lead to new human pandemics due to novel viruses infecting immunologically naïve people. a critical aspect of the emergence of novel virus strains is genetic variation and combination that occur at the hemagglutinin (ha) antigens (of which there are ) and neuraminidase (na) enzymes (of which there are nine) between and amongst human and animal influenza viruses. the subtypes of the ha and na surface proteins forms the basis for the classification of outbreaks. for example, the through virus was h n , the through virus was h n , the through outbreak was caused by h n , the virus was h n , and the outbreak was caused by h n ; while the most recent virus seen in eastern china in was h n . all of these traditional and new influenza viruses cause pandemics of differing proportions but more are projected to occur. this projection is well supported by the scientific community. however, it is not known when any will occur or whether it will be caused by the h n avian-derived influenza virus, newer subtypes like h n , or completely novel subtypes. virologists like webster and govorkova argue that given the number of cases of h n influenza that have occurred in humans (more than ) with a mortality or death rate of more than %, it would be prudent to develop robust plans for dealing with such pandemic influenza and its (expected) new variations. such plans, however, necessarily demand attention to the associated ethical dynamics. regardless of the specific subtype of human or animal-derived influenza outbreaks, the public health challenges and the moral quandaries are essentially the same. a critical biological feature of influenza lies in its mode and pattern of transmission. this revolves around its capacity to evolve and become airborne-transmissible between and amongst human beings. the influenza virus transmits from person to person primarily in droplets released by sneezing and coughing. some of the inhaled virus lands in the lower respiratory tract, the primary site of disease marion russier et al., "molecular requirements for a pandemic influenza virus: an acid-stable hemagglutinin protein," proceedings of the national academy of sciences , no. ( ) . pp. pp. - anna v cauldwell et al., "viral determinants of influenza a virus host range," journal of general virology , no. ( ). pp. - . couch. p.; shah. p. . cauldwell et al. p. . miller et al. pp. - shah. p. . rebekah h borse et al., "effects of vaccine program against pandemic influenza a (h n ) virus, united states, - ," emerging infectious diseases , no. ( . pp. - . cauldwell et al. p. . macphail. p. . robert g webster and elena a govorkova, "h n influenza-continuing evolution and spread," new england journal of medicine , no. ( ) . pp. - . russier et al. pp. - being the tracheobronchial tree, and sometimes the nasopharynx. largely because breathing is an essential biological need of human beings and partly because human-human associations are an inevitable part of reality, this biological feature of influenza viruses makes everyone vulnerable and susceptible to infection. specifically, crowds of people facilitate viral transmission by enabling sharp upticks in the rate of transmission. the virus also circulates for longer periods in infected persons. the biological features of influenza and its mode of transmission elicit some observations. one, pandemic influenza is not a single disease for which a single and specific therapeutic intervention that will be effective all the time can be developed. in other words, while there is a general approach to engaging this public health disaster, specific interventions will usually vary by each outbreak. this gives an existential and evolutionary advantage to the influenza virus over human communities. it also engenders a disaster dynamic in the sense that every outbreak becomes "sudden" and potentially associated with large human casualties. secondly, it shows the common vulnerability to which the local and global human community are subject vis-à-vis the ease of spread of the viral infection. thirdly, the biological features of pandemic influenza demonstrate how a collective response (human material, scientific etc.) is key to engaging its social and other attendant consequences. the importance of this last remark will become clearer against the backdrop of the social and global features of pandemic influenza outbreaks, a. theme addressed in the next section of this chapter. an influenza pandemic has the potential to cause more deaths and illnesses than any other public health threat. pandemic influenza a h n were reported. also, the h n outbreak recorded a death rate of %, and the recent h n outbreak caused human infections and deaths. in the united states, the estimated potential threat of pandemic influenza is . million deaths, million sick people, and nearly million hospitalizations, with almost . million requiring intensive-care units. global estimates are higher. for instance, the "spanish flu" caused an estimated - million global deaths. it has been projected that a recurrence of the influenza strain would probably result in the death of - million individuals. these data show that substantial numbers of deaths are an inevitable consequence and feature of pandemic influenza. however, death itself often brings about certain social consequence including the death of some of the most gifted members of the society. sir william osler, one of the pioneers of scientific medicine, died of complications arising from influenza in . influenza was cited by the german war general, erich von ludendorff, as a significant reason for why the initial gains of their last offensive faltered and ultimately failed during world war . from a biological perspective, influenza exploits naïve immune systems which tend to over-respond to the influenza virus. as such, young and promising adults constitute a large part of vulnerable victims. in this regard, potential contributions to societies are nipped in the bud, young widows and widowers emerge as well as a lot of orphans. for instance, , children were orphaned due to the outbreak in new york city. influenza also spread within households soon before or after the onset of symptoms in primary infected patients. another associated social feature of pandemic influenza is the closure of schools with an attendant truncation of learning and educational opportunities, depending on the length of the outbreak. while some of these social features are local and exert localized effects, human beings as social animals with the aid of the increased means of locomotion transmit some of the local features into a global experience. the pandemic of influenza which occurred during a time of much less globalization spread to the united states within - months of its detection in china while the pandemic spread to the u.s. from hong kong within - months. it is estimated that the burden of the next influenza pandemic will be overwhelmingly focused in the developing world. however, the epidemiological notion well-known to public health experts that infectious diseases can predicate outbreaks in neighboring places and nations implies that even so-called developed societies cannot be spared as long as the current interpenetration of people across the globe remains. the influenza outbreak, for instance, spread to countries and caused a total of , cases of infection. in short, in a globalized world, infectious diseases travel in nodes of human, material, and animal networks. data from sporadic studies suggest that influenza may be fairly prevalent in africa, albeit sub-clinically. it may, therefore, have a considerable impact on morbidity and mortality on the continent should a combination of factors create a virus that is viable enough to cause a pandemic. this will have far-reaching consequences for the continent due to the material and human resource constraints, lack of preparedness plans as well as the very limited bio-therapeutic capacities that are currently available to produce vaccines. it may likewise create the dispersal of a virus novel to other continents that have experienced typical outbreaks. geographical location plays a major role in public health, and disasters including health disasters are unique in that each affected region of the world has different social, economic, and health backgrounds. as such, while there is a global spread, the nature of each local context and how it responds shapes pandemic influenza in some key ways. first, the nature of the "disseminating" nation influences how infection spreads elsewhere. for example, china's slow reaction to the sars outbreak as well as its limiting of access to patients and other relevant information hhs, "hhs pandemic influenza plan." p. b . , no. ( ) . p. eric k noji, "public health issues in disasters," critical care medicine , no. ( ) . p. s . seemed to have deepened the global intensity of that crisis. in other words, how a local public health disaster is handled shapes the local severity and how it spreads elsewhere. on the other hand, well-handled local health crises positively influence the possible impacts on contiguous nations. in this vein, radest notes that canada's rapid and coordinated response to the sars outbreak significantly limited its spread and impact in the united states. the above examples echo the interconnectivity of the modern world and show how a course of action in one place, however passive, may significantly influence the course of events in another for good or bad. it supports the idea that contemporary health in the twenty-first century is now inevitably and inherently global with respect to infectious diseases. at the heart of these remarks, however, is the possibility of utilizing different networks of human interconnectivity to actively foster the global good. in other words, learning about how people connect and relate at different levels (individually, communally, institutionally et cetera) and learning about the chief actors and players in such a relationship nexus may provide a powerful tool for driving global public health agenda. yet, integral to such a process is how responses to pandemic influenza are framed and implemented locally as well as their attendant limitations. this theme is addressed in the next section. the human instinct for self-preservation has, at the social plane, always resulted in some institutional responses to diseases, whether rudimentary, barely adequate, or sophisticated. in the context of phds, responses are shaped by the nature of the specific disaster, where it is taking place, and what human, material, pecuniary and technological resources are available to deal with the given emergency situation. for instance, the united states prioritizes building a system that ensures stable and economically viable vaccines to engage influenza outbreaks. countries that lack the same kind of resource will clearly prioritize other approaches. however, the general approaches to pandemic influenza are therapeutic and non-therapeutic in nature. this section briefly examines them. pandemic influenza outbreaks, like most diseases, have elicited some biopharmaceutical responses geared towards mitigating its disastrous effects. due to the changing biological and social dynamics associated with the outbreak, social as well as scientific responses are always evolving to keep up. nevertheless, the therapeutic measures fashioned to combat pandemic influenza fall into two groups. these are preventive measures involving the use of anti-viral drugs as well as vaccination. in the past, drugs like rimantadine and amantadine were used as prophylaxis against influenza a. but drug resistance has increasingly been observed to these m -ion channel-blocking agents. today, drugs of choice are mainly tamiflu (oseltamivir) and relenza (zanamivir). black et al. noted that early anti-viral intervention during the pandemic helped reduce the doubling time in the early stages of the outbreak. the linkage between antiviral use and reduction in clinical severity and influenza infectiousness is generally supported in the extant literature. hence, treatment of clinical cases with anti-viral agents constitutes the first-line of engagement for pandemic influenza and these drugs are employed to control or contain pandemic outbreaks long enough for vaccines to be made. yet, drugs like oseltamivir and zanamivir, usually neuraminidase inhibitors, can only help reduce transmission if given within a day of the onset of symptoms. on the contrary, delay in symptoms diagnosis, as well as intervention, favors infection dissemination. nevertheless, antiviral agents for influenza offer some protection to families and households once infection has been detected. in clinical trials, antiviral treatments have been shown to be efficacious in preventing infection, hence, slowing down transmission as well as limiting the severity of the disease. but the effectiveness of neuraminidase such as oral oseltamivir and inhaled zanamivir at reducing mortality is uncertain. in addition, there is some evidence of side-effects. for instance, in adults as in children, oseltamivir increases the risk of nausea and vomiting. also, treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced. resistance to these anti-viral drugs has also been reported, even in people who have never been previously treated with them. ultimately, the success of antiviral prophylaxis critically depends on the identification of index cases in households, pre-schools, schools, and other institutional settings. this clearly highlights the importance of personal, social, and institutional cooperation in relation to dealing with the associated challenges. on the other hand, vaccination as one of the most effective and cost-saving strategies for ameliorating infectious diseases offers a protective approach to limiting and/or curtailing the social and economic consequences of pandemic influenza. two types of vaccines are generally used. trivalent inactivated vaccine and live attenuated influenza virus vaccine, both of which contain the predicted antigenic variants of influenza a(h n ), a(h n ), and b viruses. borse et al. estimated that vaccination program against influenza prevented , - , , clinical cases, - , hospitalizations, and - deaths. they also reported that the national health effects of vaccination were greatly influenced by the timing of vaccine administration and the effectiveness of the vaccine. similarly, ferguson et al. estimated that during a global outbreak, vaccination at the rate of % of the population per day would need to begin within months of the initial outbreak. but this is not feasible under current vaccine technologies. this pragmatic challenge would, however, create a biological and social climate in which infection may flourish in a logarithmic manner. the recurring antigenic variation in influenza viruses which leads to the frequent emergence of new infectious strains increases the likelihood of continuous outbreaks. this and the capacity of the influenza virus to acquire amino acid changes in its viral proteins implies that each outbreak will demand novel vaccines. this often delays the possible response time, again creating a window where infection can readily spread, locally and globally. for instance, it will take at least months from identification of a candidate vaccine strain until production of the very first vaccine during an outbreak. this biological fact makes it difficult to stockpile influenza vaccines ahead of outbreaks and, by consequence, limits the preparedness efforts geared towards confronting the public health challenges and moral quandaries. it is important to note that vaccines have some limitations. for instance, they are not entirely safe public health interventions, especially when specifics are examined. this fact has increasingly come to light in relation to vaccines against pandemic influenza. besides sore arm and redness at the injection site as well as red eyes which have been reported in earlier vaccine trials, there has been some association between increased incidence of narcolepsy in children and the use of the aso -adjuvanted vaccine for pandemic h n influenza in scandinavian countries. in addition, anecdotal reports of fetal deaths occurring shortly after vaccination emerged in and raised public health concerns about vaccine safety. another shortcoming associated with vaccination generally is vaccine failure, which often creates a false sense of protection in recipients while allowing the continued spread of infection. in relation to pandemic influenza specifically, vaccine failure was recently reported by manjusa et al. in people of years and above as well as those who have been vaccinated against seasonal influenza. this is quite troubling partly because vaccine failure vis-à-vis pandemic influenza vaccines has been little studied, and partly because there are countries like the united states where seasonal flu vaccine shots are almost the norm. another dimension to vaccine failure relates to the variation of influenza virus clades. nelson et al. recently reported that nigeria, côte d'ivoire, and cameroon exhibit more variable patterns of influenza virus seasonality, hence, there is a possibility of variants evolving locally within west africa. this, they further argue, undermines the assumption that a vaccine matched to globally dominant lineages will necessarily protect against these local lineages. this notion further raises the question of whether the immune system of populations living in tropical african hhs, "hhs pandemic influenza plan." p. b . environments would react similarly to a vaccine developed mainly for populations restricted to certain geographical areas of the world. on this note, in the possible event that someone originally from any of these nations were present in a pandemic influenza scenario outside african shore, the likelihood of their benefiting from vaccination seems slim. hence, a significant offshoot of vaccine failure in relation to pandemic influenza (especially if newer studies show more negative results) will be the reluctance of people to receive vaccines for seasonal flu and those developed for pandemic influenza outbreaks. these have unsettling public health and moral consequences. one way of engaging the limits of influenza vaccines involve creating a vaccine type that is capable of eliciting cross-protective peptides/epitopes that would be effective against different variants. but this is very difficult. besides the scientific technicalities, producing vaccines for pandemic influenza is not a cheap venture. for example, meltzer, cox, and fukuda estimated in that it would cost the united states about $ . billion to contain pandemic influenza. whereas the economic burden of influenza in lower-and middle-income countries involves direct costs to the health service and households and indirect costs due to a loss in human productivity, these countries also have limited financial capacities to pursue pandemic influenza vaccination as a public health tool. the impacts of the ensuing disease burden from such a constraint will not be locally confined, as it will ultimately seep into the trans-national and global terrains. in summary, the major and, perhaps, insurmountable constraint to vaccination as a tool for engaging pandemic influenza lies in the logistic challenge of producing a pandemic vaccine from scratch, conducting pre-clinical testing as well as generating billions of doses within a very short time for global distribution, which may, however, not work across all nations. but considering the limitations associated with antiviral drugs as well as vaccines in relation to combating pandemic influenza, some form of non-therapeutic approach is necessary, at least as some adjunct to mitigate the overall impact of pandemic influenza on the local and global human community. the next section addresses this theme. yazdanbakhsh and kremsner. p. e . the non-pharmaceutical and non-therapeutic approaches to pandemic influenza revolve around measures such as case isolation, school or workplace closure, restrictions on travel, quarantine as well as contact tracing. for instance, school closure is a non-pharmaceutical intervention often suggested for mitigating influenza pandemics. the logic behind this lies in the notion that children are important vectors of transmission, more infectious, and susceptible to most influenza strains than adults. it is also tied to the idea that high a contact rate in schools fosters transmission of infection. this approach, according to cauchemez and colleagues, may bring about an estimated % reduction in peak attack rates. however, this reduction will be hindered if children are not adequately isolated or if the policy is not well implemented. whereas school closure may only bring about a small reduction in cumulative attack rates, it can foster a substantial reduction in peak attack rates. closure of schools may, however, increase anxiety and create a crisis, as was observed in france during the outbreak. closure of workplaces is another non-pharmaceutical intervention for pandemic influenza. it may be warranted by the degree of the outbreak in which businesses shut down at their own discretion, and for their own safety, as was seen during the - outbreak. however, it may also be warranted by government policy. either way, business closure incurs huge economic costs, pecuniary, and other consequences for the different people tied to and/or dependent on the affected businesses or their services and goods. different forms of quarantine measures are also used to mitigate the spread of infection during an influenza pandemic. for instance, isolation and quarantine of infected patients allow some containment of infection which consequently slows down viral transmission. ultimately, quarantine contributes towards reducing the overall costs and impact of an outbreak. some medical experts see household quarantine as the most effective social distance measure, provided the level of compliance is good. yet, quarantine-at least on a general note-does not always work. for example, maritime quarantine was one of the measures employed in west africa to engage the influenza outbreak as well as interning the ill. however, historians like heaton and falola note that these approaches yielded meager success in relation to quelling the spread and virulence of the pandemic. measures such as cancellation of non-essential public gatherings and restrictions on long-distance travel might help to decrease influenza transmission rates as well as overall morbidity, their effectiveness has not been quantified. the nature of pandemic influenza, the therapeutic and non-therapeutic approaches, and the associated limitations generate some moral concerns. the next section discusses this. ethical issues arise during outbreaks of pandemic influenza. some of these are directly tied to the nature of the virus, some in relation to human responses, some to the social responses, and others to how different human beings respond differently to the several challenges elicited by the pandemic. bioethicists have underscored the critical need to reflect on the ethical issues raised by the specter of pandemic influenza outbreaks. however, what may and what may not be feasible to do will never be clear enough if these ethical quandaries are not clearly explicated. hence, this section seeks to clarify the moral quandaries elicited by pandemic influenza and show the core connecting strands that resonate amongst them. generally, contexts of uncertainty are tied to the evolving nature of knowledge. tannert et al. opine that uncertainty occurs because the more the human community gains insights into the mysteries of nature, the more they realize the limits of their knowledge about how things are. these limitations, they note, make it impossible to foresee all the associated future effects and implications of situations and decisions with certitude. in relation to medicine, jean daly notes that the art of medicine seeks to abolish uncertainty. regardless of the good intentions and telos of medicine, the stark reality is that this task has hardly been achieved. contexts. james marcum contends that uncertainty is largely a part of medicine because of the variability of the underlying biology. uncertainty is not new in the realm of science. however, in the context of public health disasters uncertainty has a strong pragmatic dimension which can influence courses of actions and decisions in multiple unfavorable ways. for example, it occurs during pandemic influenza outbreaks and generates many concerns. in this vein, borse et al. note that the public health community cannot accurately predict the arrival of a pandemic. indeed, a great deal of uncertainty occurs in relation to estimating the potential impact of a pandemic such as influenza. this scenario stifles preparedness efforts, especially in resource-constrained countries where there are often competing social needs to be met with limited budgets. however, the two main uncertainty issues embedded in pandemic influenza involve the nature of the virus and the types of responses available to engage outbreaks. on the one hand, the influenza virus undergoes constant variation in its antigens, creating new infectious strains. the virus also acquires amino acid changes in its proteins. these scenarios increase the likelihood of pandemic outbreaks. however, the question of when, where, and of what magnitude the outbreak will be is never clear-cut. worst-case scenario analysis based on the - pandemic provides no insight into the probability of an influenza pandemic in the next , , or years and how serious such an outbreak might be. this scientific uncertainty or paucity of precise knowledge ignites some social uncertainty and may prompt moral inertia in relation to the level of preparedness and the ability to mitigate the various possible ramifications of an outbreak, when it does occur. this backdrop of uncertainty creates at least three possibilities: over-preparedness, ample preparedness, and under-preparedness. assuming the level of risks remains constant, over-preparing for a pandemic will undoubtedly involve the committing and expenditure of more human and material resources to an outbreak. this will create a sense of waste (to decision and policy makers) after the incident and may affect the resources that will be committed to future outbreaks. the right amount of preparation will help curtail an outbreak while under-preparedness will barely help curtail an outbreak. however, if the level of risk increases, over-preparing may help curtail a pandemic whereas what was hitherto ample preparedness as well as what was hitherto not enough will enable the full range of the effects of a pandemic outbreak to be felt. " ibid. , no. ( ) . p. . kuby. p. . murray et al. pp. - . in other words, the changing nature of the virus demands a constant readjustment of the level of preparedness without a reliable frame of reference with the attendant possibility of some inevitable social harm. not surprisingly, scholars like peter doshi argue that there is a need for evidence-based ways to address hypothetical scenarios of non-zero probability such as the notion that novel influenza pathogens acquire increased virulence during successive "waves" of infection. the scientific uncertainty associated with health disasters such as pandemic influenza may, however, tempt government officials to attempt some form of a cover-up, hence, raising trust issues. for instance, during the cholera outbreak in naples, italian officials paid newspapers and reporters not to report the outbreak. chinese officials tried to keep the sars outbreak a secret. saudi officials, likewise, tried to silence the virologist who discovered the coronavirus in and ultimately forced him to resign from his position. incidents like these have the tendency to dissuade social cooperation during public health emergencies like influenza and have the potential to weaken the overall success of public health interventions. on the other hand, there is a lot of uncertainty surrounding the therapeutic and non-therapeutic approaches adopted vis-à-vis pandemic influenza. it is uncertain, for example, if neuraminidase antiviral drugs really cut down mortality when implemented as the first line of defense. this may create some sense of hesitation in relation to using them. secondly, it is uncertain who and who will not develop some of the associated side-effects. these factors, at a pragmatic level and for less rich nations, may dis-incentivize prioritization of funds for antiviral drugs. uncertainty likewise plays out in the context of influenza vaccines. for instance, only a small amount of any vaccine can be stockpiled because the scientific and public health community can hardly be sure of the efficacy of any given vaccine prior to an outbreak. this is due to possible vaccine failure which will make a new outbreak not amenable to the biological effects of hitherto effective vaccines. hence, vaccines are generally not produced until the new virus strain causing a pandemic is isolated. also, there is uncertainty over who will be at highest risk of infection and complications. this creates a dilemma of some sorts with the potential that a class of the people who need vaccines may not get enough, while another class of people who will benefit less from vaccination gets too much. another kind of uncertainty is linked with possible side-effects of vaccines. while some incidence of narcolepsy was reported in children after the use of aso -adjuvanted h n influenza vaccine in scandinavian countries, and there have been anecdotal reports of fetal deaths doshi. p. . shah. pp. - . hhs, "hhs pandemic influenza plan." p. s - . kotalik. p. . emanuel and wertheimer. p. . dauvilliers et al. pp. - occurring shortly after the vaccination ; it is not clear if these safety issues are one-off events or may recur for other pandemic vaccines. responding to influenza vaccine safety signals during a pandemic constitutes a scientific and public health policy issue since decision-makers must balance the immediate consequences of disease against uncertain risks. one of the consequences of the therapeutic uncertainties associated with pandemic influenza is the validity of administering potentially ineffective antiviral drugs with side-effects or vaccines that may cause harm to people. another is the validity of withholding such drugs and vaccines because it may not be useful for some class of people, or because some people may experience certain degrees of side-effects. these issues raise concerns about human rights and whether or not they may be violated through these courses of actions, or by any other course of action associated with handling a pandemic influenza outbreak. the universal declaration of human rights and the international covenant on economic, social and cultural rights documents enunciate the rights of "everyone to the enjoyment of the highest attainable standard of physical and mental health". hence, it is perhaps more than ever taken for granted that there are rights-related obligations that society, as well as healthcare providers, owe patients as well as those that may potentially fall sick. since everybody is theoretically a potential victim of ill-health depending on time, placek and social or physiological circumstances, individuals can appeal to a rights-based rhetoric to garner positive action from government and healthcare professionals in relation their health. the morality of such a claim stems partly from governments' moral obligation to their citizens and partly from the fiduciary obligations that health professionals have towards fostering the health of patients (and potential patients) in a fashion that preserves their rights as human beings. many moral concerns related to human rights come to the fore in the context of pandemic influenza outbreaks. the first is related to the limited number of vaccines that can be available for each outbreak (due to reasons outlined in the preceding section) and the best sharing formula to use. whatever adopted formula in a given place or situation, some people who may benefit could be excluded. for instance, pandemic influenza often generates a high number of sick people over a large geographic area who will need care at the same time. while this "need" begins at the local plane, it may evolve to be regional and/or global depending on the extent and severity of an outbreak. hence, the human and material resources of healthcare will be rapidly depleted and overwhelmed. since the needs of everyone cannot be met under such a scenario, there is usually some need to ration available resources. in fact, vaccines are hardly enough during pandemics, and rationing is generally considered as the ethical option. yet, the contemporary interconnection between health, the right to health and human rights implies that withholding vaccines from some people who might be potential victims of a pandemic outbreak may be a human rights violation. on the other hand, administering antiviral drugs to non-vaccinated at-risk people helps reduce the severity of illness. during disaster scenarios, the goal remains saving lives but a pandemic scenario in which - % of the population can fall sick within a very short time often demands some type of prioritization of resources. this is partly because keeping some sets of people alive, especially health workers will ultimately help society keep more people alive during a public health disaster. for instance, the traditional view is that prioritizing the vaccination of front-line healthcare workers can help reduce staff absenteeism as well as help prevent them from becoming vectors of viral infection. this is often justified by the logic that a phd situation such as pandemic influenza often makes health professionals work outside their normal scope of practice, put in extra hours, cover for ill workers, accept great risks as well as incur other situational unexpected responsibilities and supererogatory duties. although adults aged years or older, pregnant women, and people of any age with underlying medical conditions are at high risk of pandemic influenza and its associated complications, the notion that death is more tragic in children and young adults as opposed to elderly persons, perhaps, because younger persons have not had the chance to live and develop through all stages of life and accomplish their dreams has made some ethicists argue for the prioritization of vaccines to younger people. yet, if persons are inherently born with human rights and do not have to earn rights, such an idea tends to revamp the rights to health of some class of people at the expense of others. indeed, notions such as this echo the idea that mainstream bioethical issues tend to be far-flung from the values of ordinary people and often irrelevant to the decisions they experience in their encounter with healthcare. in other words, an empirical approach which takes into consideration what people would want when faced with this thorny dilemma rather than an armchair speculation ought to influence the criteria for rationing vaccines. one of the non-therapeutic responses to pandemic influenza is the isolation and quarantine of infected patients. whereas a visibly infected and sick person may have just a little objection to quarantine (after all, such a state mirrors the ambulatory limitations that most disease states naturally impose on people), it is often problematic for other categories of people. in this vein, isolation and quarantine raise concerns about the acceptability of confining people and preventing them from engaging in some of the social activities they otherwise would have loved. whereas restriction of movement is ethically problematic, it is equally problematic to allow person a who may be infectious to roam free, thereby potentially infecting other persons who may also (without the imposition of some restriction) further spread infection. it is clear from the foregoing that pandemic influenza challenges and raises some moral concerns regarding the rights of people, preempting the need to balance them against what is the optimal good of the society. but embedded in these reservations is the demand for autonomous living, broadly conceived. whereas this has been associated with western contexts, concerns about rights violations in relation to quarantine measures are not confined to the west. sambala and manderson recently commented about how ghanaians and malawians perceive public health interventions including quarantine as being intrusive. but this perception seems to run contrary to the cultural norm of most african people. in relation to this strand of thought, shah notes that during epidemics, the traditional attitude of the acholi people of uganda involves working together to isolate the sick, mark homes of the sick with long elephant grass, warn outsiders not to visit affected villages, and refraining from potentially infection-transmitting practices including sexual intercourse. this suggests at least two things. one, in traditional african societies there may be some fairly general consensus about the need to adopt mutual and social cooperation for the overall benefits of the society in engaging collective threats. secondly, it shows how the global village has increasingly penetrated and fragmented societies that were once non-individualized in orientation. but it seems that societies have been affected differently by the globalizing current of individualistic logic. for instance, macphail whereas europeans and americans generally view quarantine during influenza as almost worthless, asians such as hong kongers, expect it as the norm during health disasters, and demand it. this probably shows how strong an influence the communal-oriented confucian idea still exerts in that country. in the context of pandemic influenza outbreaks, over-emphasizing individualism and the attendant call for autonomy (even when such does not cohere with social interests) overlooks communal values and the relational nature of social interactions. it likewise ignores the complex nature of pandemic influenza and how it plays out in an equally complex web of this global age and how people more or less are susceptible to the harms of public health disasters regardless of their proximity. it has also contributed, as lachman argues, to a reduction in the fear of infectious diseases by increasing the emphasis on patients' rights, giving rise to a dangerous complacency that may do great damage to the goals of public health. one of the ways to address the attendant dangers inherent in this almost pervasive trend is recognizing the vulnerabilities even to far-flung harm that is fast becoming an integral aspect of contemporary life. vulnerability-in different forms and facets-plays out in pandemic influenza, as in other public health disasters. traditionally, belonging to the human community or occupying specific facets of life constitutes sources of vulnerability. but the state of being susceptible to harm by the actions and activities of other people or by parts of nature such as viral organisms is also a potential source. in addition, the state of vulnerability may ensue from a range of social, economic, and political conditions. in the context of pandemic influenza, the naturalistic, socioeconomic, epistemic, political, and biological dimensions of vulnerability arise. on the one hand, humans located in pandemic-prone cities or countries and other human beings linked to the global community by technological means of transportation (such as air travel) or non-technological ones (such as migrating birds) are generally vulnerable to influenza outbreaks. the likelihood of a novel strain of influenza outbreak occurring in a country such as china (for instance, jiangcun in guangzhou) where large numbers of people, birds, and swine mingle freely in certain markets is very high ; hence, making the local population and consequently the people of such a nation more vulnerable. macphail, the viral network: a pathography of the h n influenza pandemic. pp. - . bennett and carney. p. . peter j lachmann, "public health and bioethics," the journal of medicine and philosophy , no. ( ) . p. . henk ten have, "vulnerability as the antidote to neoliberalism in bioethics," revista redbioética/unesco , no. ( ). p. . on the other hand, the strength of health systems reflected by availability of experts, economic and technical resources will vary the extent of pandemic-related vulnerability which different societies will experience. in addition, it is widely believed within the scientific community that influenza pandemics can hardly be halted, but they can be delayed. therefore, the "ignorance gap" that occurs during pandemic influenza outbreaks creates a context in which some of the preparatory strategies will inevitably fail (due to no fault of anyone), thereby leaving some people less protected. in relation to the socioeconomic dynamics, it is estimated that most influenza pandemic-associated deaths occur in poor countries or in societies with scarce health resources which are already stretched by extant health priorities and challenges. farmer and campos underscore the need for bioethics to engage the growing problem posed by the gap between rich and poor nations, and how such a course of action reflects social justice. politically, communist nations such as china present unique dimensions to the vulnerabilities of pandemic flu as they may control critical information traffic and access to patients, thereby deepening the crisis situation, or misrepresenting it, and thereby subjecting the rest of the connected world to avoidable risks. the biological make-up of human beings both make them vulnerable to becoming infected with influenza virus as well as make them good vectors of dissemination. for instance, the virus has a surface molecule that enables it to attach firmly to cells in the mucous membranes of the respiratory tract, preventing it from being swept out by the ciliated epithelial cells. but breathing is a normal aspect of human existence, and the oxygenation of the human blood and other oxygendependent biochemical processes of the human body rely on it. yet, the combination of these factors facilitates the ready transfer and exchange of the influenza viruses amongst people, especially when they are in close proximity. the foregoing shows how susceptibility and vulnerability to infection during pandemic influenza reflect a combination of factors. how these combine in specific localities and regions will, therefore, determine the extent of an outbreak. it is also clear that some amount of control can be exerted on minimizing some of these factors. for instance, the use of face mask (to limit infection acquisition and spread), transparency (to combat political bottlenecks), and monetary aid (to help poor nations) will exert some preventive effects on infection transmission, hence, limiting the overall burdens and severity of an outbreak. since everyone may not receive the same level of healthcare for various reasons during a public health disaster (depending on time, place, and category of persons such as adults, the aged, or children), questions about justice and what is just in the context of a pandemic outbreak arise. pandemic outbreaks exacerbate extant inequalities to the extent that certain groups of people face disproportionate risks and impacts of disease. this obviously seems unfair, especially if pre-pandemic actions that would have ameliorated the situation were not done. for instance, school closure in certain districts may interrupt educational opportunities or growth of some children, and business closures will lead to financial losses. since such restrictions may not apply to every region of the nation, these measures may seem unfair to those affected, knowing that other children continue to have access to education, and other people continue to run their businesses. if this characterizes the feelings of some of the people affected by these restrictions, then it is reasonable that some form of compensation may be required to foster optimal compliance to the public health measures that are to implemented. indeed, bioethicists like michael selgelid and søren holm make explicit arguments for some form of compensation to people who suffer financial and other losses due to compliance with public health directives issued during influenza outbreaks. although compensation may not be a problem in more affluent nations where other educational stimulus and business tax breaks may help alleviate any temporary pandemic-associated losses, poorer countries will find it hard to compensate people for any such losses. rationing also raises issues about justice in terms of how vaccines (if available) will be shared during an influenza pandemic. given the limited amount of supply available globally, and locally in a developed economy like the us, distributing the limited supply will require determining priority groups. for people not to feel a sense of being left out during local vaccine administration, it is better to have debated and developed a preparedness plan with the consensus of the local populace. resolving vaccine distribution on a global scale will, however, involve very complex sets of factors. for instance, will countries who supply most of the technical and financial resources to develop such an influenza vaccine demand that the needs of her people be prioritized as opposed to the needs of nations that have contributed little or not at all? even if such a question were not explicitly raised, will it be fair to distribute vaccines equally if every country or affected region has not made significantly even contributions? these are unsettling questions that are bereft of simple answers. some ideas stand out when all the ethical issues generated by pandemic influenza are closely examined. four of these ideas demand attention. the first is the need to help people. secondly, the nexus of relationship that exists between people henk ten have, vulnerability: challenging bioethics (routledge, ). pp. - . michael j selgelid, "promoting justice, trust, compliance, and health: the case for compensation," the american journal of bioethics , no. ( emanuel and wertheimer. p. . and the influenza virus and the changing nature of what is known as well as what can be done to help people under such constraints will limit the help some people may ultimately get during an outbreak. thirdly, the threat of an outbreak presents different risks which vary by context, time, and place. lastly, regardless of the different situational dynamics that pandemic influenza presents locally, regionally, and globally; its threat will affect everyone to varying degrees. since nations theoretically care about their people, it is only reasonable that a people-centered approach offers a useful way to engage the moral quandaries elicited by pandemic influenza outbreaks. the subject matter of diseases is human populations. in fact, the preoccupation of medicine remains the amelioration of the distress of people technically referred to as patients. if a people-centric approach constitutes a viable way of engaging the ethical issues embedded in pandemic influenza scenarios, one way to glean a sufficiently nuanced angle on such an approach will involve turning to ethical lenses that are, in principle, people-oriented. two principal examples of such ethical prisms are communitarianism and ethics of care. this section briefly explains each of these moral lenses, and how each may help engage the ethical issues generated by pandemic influenza. the communitarian moral lens adopts a people or community-centric perspective to moral issues. applied to public health, it offers a population-centered approach which best reflects the philosophy of public health in terms of its commitment to doing the most for the greatest number of people in a society or within a social context. bioethicists like stephen holland regard the communitarian lens as useful since it aims at realizing collective interests. this same idea offers a strong justificatory argument for adopting it in relation to public health interventions. communitarianism pays attention to the social sphere, institutions, and interrelationships in relation to moral judgments that will inform public health policy and practice. its ethos provides an alternative to the dominant atomistic lens of individualism which operates via the logic of self-protection and the unbridled macphail, the viral network: a pathography of the h n influenza pandemic. p. . stephen holland, public health ethics (polity press, ) . pp. - . pursuance of self-interests. it holds that the social nature of life and institutional and social relationships should inform moral thinking, and by implication, the process of determining appropriate courses of actions should lie within the social space. to be sure, the communitarian notion appeals to the historical traditions of communities or people who share customs, ideals, and values ; and thus prioritizes common threads of thought and practices within specific communities as a strong moral basis for justifying decisions that pit different individual and social interests against one another. there is an important phenomenological aspect of communitarianism. for people raised within the traditional family structure-father, mother, children, and relatives-the family unit constitutes a micro-community which generally socializes the child into a community-oriented way of reasoning. while the strength of such an orientation is expressed in different measures by different individuals, it also provides the cognitive platform for balancing and pursuing personal interests in a feedback loop with the collective interests of other family members. yet, the ultimate measure of what level of community-oriented reasoning an individual retains in adult life will depend on their education, social experiences, whatever meanings they draw from these, and how these parameters are brought to bear in the context of specific decisions and choices. this reality partly explains the multiple versions and interpretations of communitarianism, which tends to mar its conceptual and theoretical coherence. it also partly explains why community values are not generally shared by all. communitarians advance three different types of claims: descriptive claims which stress the social nature of people; normative claims which celebrate the value of community and solidarity, and a meta-ethical claim which emphasizes the idea that political principles should mirror "shared understandings'. two of these dynamics-the normative as well as the metaethical-are important in relation to engaging the ethical issues elicited by pandemic influenza. the significance of the meta-ethical dimension of communitarianism is its capacity to help drive and ground public health policies. this is especially so considering the reality that community and living together in today's fragmented and individualistic world is generally seen ever less as a necessity and assumes the dimensions of a choice as the default state. hence, these two facets will be examined in relation to their possible insights and pragmatic importance vis-à-vis engaging the quandaries associated with influenza outbreaks. healthcare focuses on helping sick people regain optimal health and healthy people maintain good health. pellegrino and thomasma remark that medicine seeks to foster social flourishing as well as the medical good of society. if this is true, and if the end of the communitarian moral lens is to ensure the survival of the society by promoting the interests of people over the selfish interests of individuals, then how can this approach help engage issues of uncertainty, vulnerability, human rights and justice? this can come through appropriate educational policies and approaches carried out prior to and during influenza outbreaks. it is not known when and in whom influenza therapeutic interventions such as antiviral drugs and vaccines may cause side-effects. it is also not known when an outbreak will occur or the attendant magnitude. since public health disasters are classless in terms of who will and who may not be affected, the scenario of uncertainty affects every segment of people in the local communities and nation. hence, health workers, government officials, the rich, the poor, the educated and illiterates and other possible stratification of society are potential victims. a communitarian ethos is useful in at least two ways in relation to dealing with the uncertainties associated with pandemic influenza. generally, it can-with the right pre-disaster public education-help ensure that people understand the unavoidable scientific and knowledge-related gaps in preparedness policies and specific plans put together to engage a specific outbreak. this will help avoid or minimize blame, since scapegoating during disease outbreaks causes different shades of disruption and target important actors including health workers. in fact, the better educated the public is about the challenges of stockpiling vaccines, the more cooperative they will likely be to the vaccine-supply challenges that arise during an outbreak. a communitarian ethos may also help engage the real and possible harms that may ensue due to the therapeutic uncertainties associated with pandemic influenza. these harms arise from the uncertain nature of what is knowable about a pandemic virus before it strikes as well as the biological limits of the therapeutic arsenals often produced within a very narrow time window. this is also generally tied to the reality that new health interventions including drugs and vaccines come with the possibility of some adverse events, which may be linked to the chemical/biological/physical components of the product, to genetic susceptibilities in certain individuals, or to edmund d pellegrino; david c. thomasma, "the good of patients and the good of society: striking a moral balance," in public health policy and ethics, ed. michael boylan (springer, ) . pp. - . shah. p. . environmental triggers. keeping the public aware of this fact before and during an outbreak as well as emphasizing that accepting these risks (though uncomfortable at the individual plane) will serve to ensure the society overcome a pandemic should help garner some level of support critical to ensure proper compliance. since people are born with inherent human rights and do not have to earn them, it is hard to justify trumping the rights of some for the sake of public health. this is especially so if the people whose rights may be inhibited or violated do not consent to the process. to avert this, a discursive approach involving inclusive deliberations is essential. in this vein, the communitarian lens can help foster dialogue as well as call for the need to reward people for the sacrifices they may or will bear on behalf of the community and the society. for instance, guaranteeing that some compensation will be paid for financial losses incurred through workplace closure as well as apt public education about the nature, purposes, and conditions of quarantine facilities will help convince people that such temporary rights-related inconveniences are for the benefits of the overall society. in relation to vulnerability and justice, the communitarian lens can help clarify the different kinds of social, biological, and natural vulnerabilities that face different people in different contexts. for example, it can offer a way of making the important distinction between general vulnerability that people will experience as human beings, vulnerability based on age, and occupational vulnerability seen in health professionals. based on these distinctions, it can help underscore how context-specific cooperation will help ensure the overall success of the countermeasures adopted to engage a given pandemic. critical to this, however, is the moral currency of trust. trust shapes how the public evaluates risks and benefits. it also influences the acceptance of prescribed public measures to mitigate present or perceived risks. effective risk and crisis communication depend on public trust in the government during a pandemic. as such, a higher level of trust will influence a more positive level of social compliance. van der weerd and colleagues corroborated this in their empirical study of the pandemic in the netherlands. in addition to trust, transparency in terms of how priorities will be made in terms of the allocation of vaccines as well as antiviral agents, and decisions pertaining to school and/or workplace closures is important. even in western climes, public health experts have sometimes pointed out the paucity of transparency in ethical reasoning and the scanty explicit ethical justification for pandemic-related policies. obviously, an atmosphere of trust and transparency will be conducive to discussing and addressing issues related to local justice. this is especially relevant in relation to less wealthy nations or countries with weak institutions. for instance, it will be hard to garner cooperation in hitherto abandoned communities by appealing to communitarian ethos without addressing extant disparities in the social fabric as well as the healthcare system. if human beings are located in particular communities but are willy-nilly part of a global community, how well the vulnerability and justice-related issues are locally addressed will influence the extent of their regional and global dynamics. this echoes the notion that badly managed local issues associated with pandemic influenza will pose more challenges and burdens at the regional and global levels. since every nation lacks an equal capacity to deal with the local burdens of pandemic influenza, it is necessary for wealthier nations to rally around poorer ones. indeed, the transcontinental nature of health disasters including pandemic influenza and sars underscores the urgent need to strengthen how the global community deals with emerging infectious diseases, and how novel visions of global solidarity and cooperation will be key in such an endeavor. this constitutes a preventive stance and falls well within the traditional agenda of public health. this approach is also a reasonable economic and health security choice as it will statistically cut down the possibility of global and transnational infection dissemination. while the communitarian ethos as argued above offers some insights into how to flexibly engage the moral dilemmas generated by influenza outbreaks, its application in non-community-oriented contexts potentially raises some difficulty at the institutional and individual planes. such possible difficulties, however, call for a global but locally nuanced moral framework. that theme, however, will be addressed in chap. . for now, the rest of this chapter will explore another people-centric moral lens, care ethics, in relation to resolving the quandaries of pandemic influenza. in addition to the communitarian lens, the ethics of care perspective (eoc) constitutes a people-centric method of attempting to resolve ethical issues. whereas it sometimes arrives at the same conclusions reached by traditional bioethical approaches, employing it as a complimentary approach to the moral quandaries generated by pandemic influenza should yield additional nuances and insights visà-vis resolving the associated moral concerns. care ethics emphasizes varying degrees of care within relational contexts ranging from the personal sphere to the realm of moral strangers. hence, it is an other and people-centric moral lens. it has henk ten have, global bioethics: an introduction (routledge, ). p. . peter a singer et al., "ethics and sars: lessons from toronto," british medical journal , no. ( ) . pp. - . edwards, "is there a distinctive care ethics?" p. . been applied to diverse relational contexts including everyday lives, professional practices, social and public policies, as well as international relations. for scholars like steven edwards, ethics of care uses a distinct ontological commitment to realize its outcomes as well as justify its stance. it is an attempt to re-conceptualize and renegotiate the moral landscape in order to give room for a plurality of values. some have argued that the removal of friendship with its altruistic emotional sequelae and the subversion of virtue ethics from the sphere of morality were some key factors that warranted the moral change which birthed the ethics of care framework. while eoc is also linked with gender-based morality which undergirded campaigns for equal employment opportunities between the sexes, legal rights, reforms of family life and sexual standards, and better education ; scholars like noddings have pointed out that it is broader and deeper than feminist ethics. to be sure, one of its major impetus is the call for the expression of higher capabilities. care ethics also encapsulates a spectrum of ideas. for kittay, care constitutes an "achievement term" such that caring occurs only when specific acts of care have been carried out. in this vein, intentionality would not qualify as part of the baggage of care rhetoric. this obviously has some pragmatic appeal. most people, for instance, would only appreciate care if it helps contribute towards relieving their current distress. yet, caring may also constitute a general attitude and an orientation which may provide appropriate background conditions for shaping responses to others' needs and states of distresses. also, one may care but situational constraints may limit how a caring impulse may translate into pragmatic ends. therefore, that someone simply "lacked opportunity" to show care as apostle paul writes in his epistle to the philippians does not necessarily indicate the absence of care. hence, caring cannot be reduced only to materialistic terms. one way to distinguish the general caring orientation from specific acts of care is to refer to each as "caring about" and "caring for" respectively. care ethics locates morality within the ambiance of family, friends, and colleagues, and ultimately towards the public sphere. it rejects the independent and atomistic notion of the self and champions an inter-dependent and inter-related view. this approach grants eoc a psychological gestalt to which people brought up in caring relationships, at least in the early phases of their lives, can readily identify with. it thus partly appeals to kohlberg's theory of moral development. here, the emphasis is put on the foundational roles of trust and its place in fostering a deepened sense of reciprocity within a social context of inequality. not surprisingly, some ethicists describe caring as the primary virtue which offers a general account of right versus wrong actions as well as political justice. whereas the informal social contract idea underlies inter-personal and stateindividual relationships, the care ethical lens may be applied to the personal sphere as well as social institutions due to its multiple ways of situating relationality. indeed, eoc focuses on attentiveness and sensitivity to the needs of others and offers a moral compass for teasing out delicate boundaries between obligation-based ethics and responsibility-based ethics. as such, it seeks to transcend the depersonalized realm of asking "what obligations do i have to mr. x" to the humane realm of asking "how can i help mr. x" in scenarios of moral crises. since caring embodies an activity, a set of activities or a labor of care from one person to the other, it presupposes that the capacity for receiving care will be present in the recipient(s) of care. public health disasters including pandemic influenza with their myriad of ethical and pragmatic challenges create a spectrum of needs and contextual dependencies which some people will have to meet, directly and indirectly. it thus creates different types of carer versus cared-for relationships between and amongst victims, atrisk people, health workers, and government officials. since it is a foundational nexus like these that underlie the caring ethic, it will be insightful to examine how the ethics of care moral lens may help resolve the moral dilemmas elicited during pandemic influenza outbreaks. osuji. p. . whereas tirima recently argued that ethics of care is irrelevant to addressing the moral imperatives in disaster scenarios because it only builds off on relationships and, therefore, requires some proximity between the caring moral agent and the cared-for victim, such a stance is flawed for at least three important reasons. firstly, care ethics can, through relevant public policy, positively influence how victims of disasters are cared for. secondly, contexts of duty exist between some of the players and victims of disasters which form the basis of a relationship of caring. for instance, healthcare professionals incur fiduciary duties to at-risk people, victims of a public health disaster as well as the general populace that may potentially be infected and infect others. thirdly, if the care ethical prism emphasizes how individuals may offer help "in scenarios of moral crises, then it should be relevant in health scenarios where different kinds of conflicting moral emergencies occur. the application of care ethics to specific disaster contexts such as influenza outbreaks, however, requires elaboration. specifically, this needs some explication with reference to issues of uncertainty, vulnerability, human rights and justice. whereas the dilemma of uncertainty that arises during pandemic influenza affects everyone, it will affect different sets of people differently. for instance, the biological uncertainties associated with an influenza outbreak are not known to the same extent by public health experts, health workers, the literate, and illiterate members of the society. caring about the potential practical consequences that may result from the attendant "ignorance" gap should, therefore, involve sharing as much useful information as possible between and amongst the different rungs of people. the relational context, in this regard, may be situated and realized through professional associations, institutional contexts, public announcements through media outlets and patienthealth professional interactions. kunin et al. recently reported on how primary care physicians helped pass on important pandemic-related information to out-patients during the pandemic in israel. this, they concluded, helped enhance the success of the national pre-pandemic preparedness plans. indeed, during public health disasters, the speed at which information is needed by policymakers may be faster than is usually possible through traditional mechanisms of research dissemination. this scenario makes information sharing a norm; even possibly those provided by preliminary research findings. humans instinctively show care to other humans in need. while this caring instinct has been socially modified and conditioned in some parts of the world where individualistic tendencies run rife, some communal-oriented cultures give room for a freer expression of the instinct of care. the instinct of care may, however, be counterproductive in the context of phds. for instance, during pandemic influenza, sick and dying patients remain active carriers of infection, as such, will infect susceptible friends and relations who feel obligated to show care in relation to helping them. in other words, "unbridled" caring may increase the vulnerabilities elicited during pandemic influenza. yet, the care ethics moral lens may help modify and re-direct the caring impulse in a more socially useful way during a pandemic. the other-centric nature of the eoc lens implies that people should care not only about themselves but about others, perhaps, even moral strangers. how person a will care during a public health disaster will, however, differ from how b will choose to act in a manner that reflects care, depending on their levels of knowledge, resources available to them as well as their social and spatial location. in other words, how a healthcare worker will care professionally in the hospital context and supererogatorily in the non-hospital context will differ from how a lay member of the society can show care in a pandemic situation. however, appealing to the eoc may help facilitate the selflessness needed. if someone cares that their society survives an influenza outbreak, then they should be willing to play roles that will help bring about that goal. this will facilitate compliance with therapeutic measures such as vaccines and antiviral drugs as well as non-pharmaceutical measures such as contact tracing, quarantine, and workplace closure. collective adherence to these measures will help cut down the susceptibility and vulnerability of individuals, groups of people, and the society to the impact of influenza outbreaks. by enabling the willingness of people to subject themselves to the public health restrictions required to contain pandemic influenza and accept the potential risks and side-effects associated with vaccines and antiviral agents, the eoc approach may indirectly eliminate or downplay the human rights-related quandaries engendered by pandemic influenza. noddings has argued that attentiveness and responsiveness are exigent to rights, flowing from one person to the other. if this is true, then the eoc may help individuals adjust the emphasis they place on articulating their rights contextually during an influenza pandemic for the sake of the collective good. finally, an appeal to the care ethical lens may help address the moral quandaries associated with local justice. although some versions of care ethics hold the posi- ns crowcroft, lc rosella, and bn pakes, "the ethics of sharing preliminary research findings during public health emergencies: a case study from the influenza pandemic," eurosurveillance , no. ( ). pp. - . shah. p. . noddings. p. . tion that it is not possible to integrate and apply justice to care, such a limitation hardly applies to the context of a public health disaster such as pandemic influenza. for instance, the different conflicting priorities that arise during influenza outbreaks such as rationing of limited resources will be easier if some people are at least willing to forgo their interests for others. in non-familial carer and cared-for relationships involving at-risk government representatives and at-risk members of the society and familial relationships involving parents and children living in the same house, an appeal to a care ethical lens may help drive the moral sensitivity to the needs of others, enabling some vaccine-eligible persons (under the standard rationing criteria) to forgo their ration, preferring rather that other at-risk people (for example, ordinary people and younger family members) have them. this kind of selflessness approximates some form of humanitarian act in that person a decides to overlook their interests for others "without expecting rewards". however, because human beings naturally seek their own personal interests, there may be some difficulty in achieving this other-centric goal in as many people as possible in a public health disaster situation. this implies that the care ethical lens may have some limitations in relation to sufficiently engaging the ethical dilemmas raised by pandemic influenza in particular and other types of public health disasters, in general. that theme will, however, be addressed in chap. . during disasters, there is the utilitarian goal of doing the most good for as many people as possible with minimal harm. a people-oriented moral lens, this chapter argues, may be apt in accomplishing such an agenda. the chapter explored the strengths of the communitarian and care ethics moral lenses in relation to engaging the moral quandaries elicited during pandemic influenza outbreaks. because it is difficult to engage pandemic outbreaks with little prior preparation, these moral lenses become important since they can help people develop an other-centric orientation and sensitivity to the needs of others. to systematically drive the importance of a people-centered approach to pandemic influenza, this chapter explicated the biological make-up of the influenza virus as well as the social and global features of the associated pandemic. this helped underscore the local, regional, and global seriousness of pandemic influenza as a distinct type of public health disaster. the chapter went on to show how an barnes et al. p. . vawter, gervais, and garrett. p. . understanding of the social and biological dynamics of influenza has shaped the therapeutic and non-therapeutic approaches to engaging outbreaks. it also articulated some of the attendant limitations of pandemic influenza countermeasures including vaccines and anti-viral drugs. this chapter has also highlighted the ethical quandaries generated by influenza outbreaks. these are issues related to epistemic and social uncertainty, biological, social, geographical and political vulnerabilities, potential violations of human rights through some of the therapeutic and non-therapeutic countermeasures, as well as issues of local and global justice. against this conceptual background, the chapter pointed out how helping people is a central concern in pandemic influenza, and how the thorny ethical issues constitute difficulties encountered in accomplishing this goal. on that note, it showed how people-centered lenses such as communitarianism and ethics of care may be useful in engaging the associated practical and moral challenges. to clarify the importance of each of these approaches, the chapter elaborated each of these ethical lenses, and showed how each may help orient different players in the context of a pandemic influenza towards acquiring a sense of community and an other-centric sensitivity which will be 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lead poisoning outbreak in zamfara, nigeria: a multidisciplinary humanitarian response to an environmental public health disaster in a resource scarce setting ethical issues in pandemic planning monitoring the level of government trust, risk perception and intention of the general public to adopt protective measures during the influenza a (h n ) pandemic in the netherlands allocating pandemic influenza vaccines in minnesota: recommendations of the pandemic influenza ethics work group pathogenesis of the pandemic influenza virus h n influenza-continuing evolution and spread influenza in africa public health ethics: an update on an emerging field biological features of novel avian influenza a (h n ) virus key: cord- - r qf o authors: radosavljevic, vladan title: a new method of differentiation between a biological attack and other epidemics date: - - journal: biopreparedness and public health doi: . / - - - - _ sha: doc_id: cord_uid: r qf o the main obstacle in identifying a biological attack (ba), while preventing false alarms, epidemics of panic and unnecessary expenditures is the insufficient data on which to rely. Тhis new method of outbreak analysis is based on our original model of bioterrorism risk assessment. the intention was to develop a model of quick and accurate evaluation of an unusual epidemiologic event (uee) that would save time, money, human and material resources and reduce confusion and panic. this uee analysis is a subtle and detailed differentiation through assessment of ba feasibility in comparison with three other types of outbreak scenarios. there are two types of differences between these four scenarios: qualitative and quantitative. qualitative and quantitative differences are defined with and indicators, respectively. both types of indicators can have three different values: n/a, or . we have carried out a feasibility analysis for subtle and detailed differentiation among four outbreak scenarios. as a tool for feasibility analysis we have introduced a “system of elimination”. system elimination is applied if one component contains all indicators scored with or as n/a – the related scenario is then eliminated from further consideration. the system was applied to four uees: ( ) an intentional attack by a deliberate use of a biological agent (amerithrax), ( ) a spontaneous outbreak of a new or re-emerging disease (“swine flu”), ( ) a spontaneous outbreak by an accidental release of a pathogen (sverdlovsk anthrax), and ( ) a spontaneous natural outbreak of a known endemic disease that may mimic bioterrorism or biowarfare (kosovo tularemia). it was found that “agent” was the most important and the most informative uee component of the new scoring system. this system might be helpful in the analysis of unusual epidemic events and a quick differentiation between biological attacks and other epidemics. most diseases caused by potential biological warfare agents have low natural incidence rates. the lack of clinician experience with these diseases can impede rapid diagnosis and reporting to public health authorities [ ] . the main obstacle in identifying a biological attack (ba), while preventing false alarms, epidemics of panic and unnecessary expenditures is the lack of data to rely on [ ] . we are trained to consider common causes for syndromes fi rst -and unless we have a high level of suspicion -we may not realize that we need to apply non-standard methods to identify an intentional use and to detect the kind of biological agents that a terrorist might use. basically, any unexpected occurrence of one or more patients or deaths in humans or animals which might have been caused by an intentional release of pathogens may be the fi rst clue of an unusual epidemic event (uee). also, the occurrence of a single case or death caused by an unknown or already eradicated disease or agent may be considered as "unusual". three systematic models of assessing differences between natural and deliberate epidemics have been published. grunow et al. [ ] put emphasis on three groups of characteristics: ( ) political, military and social analysis of the af fl icted region (two criteria), ( ) speci fi c features of the pathogen (three criteria), and ( ) characteristics of the epidemic and clinical manifestation (six criteria). dembek et al. [ ] proposed potential clues to a deliberate epidemic which are focused on epidemic characteristics. these two models are accurate, but time consuming. however, saving time is crucial in the case of an uee. radosavljevic et al. [ ] ) suggested a model for early orientation and differentiation between natural and deliberate outbreak. our new method of outbreak analysis is based on an original model of bioterrorism risk assessment [ ] . the intention was to develop a model of quick and accurate evaluation of a uee that would save time, money, human and material resources and reduce confusion and panic. this uee analysis is a subtle and detailed differentiation through assessment of ba feasibility in comparison with other outbreak scenarios, in particular: ( ) a spontaneous outbreak of a new or re-emerging disease (nr) (such as "swine fl u"), ( ) a spontaneous outbreak by an accidental release of a pathogen (ar) (such as the sverdlovsk anthrax outbreak), and ( ) a spontaneous natural outbreak of a known endemic disease that may mimic bioterrorism or biowarfare (ne) (such as the kosovo tularemia outbreak). after identi fi cation of an uee we introduced a new method for the subtle and detailed differentiation of such an event. in our previous paper [ ] a ba was de fi ned by four components, and now we propose their equivalent terms in an uee: reservoir/source of infection vs. perpetrator, pathogen vs. biological agent, transmission mechanisms and factors vs. media and means of delivery, and susceptible population vs. target. indicators of a deliberate outbreak can be conclusive and non-conclusive [ ] . conclusive indicators are direct and comparatively objective indicators for an intentional event. non-conclusive indicators estimate only the likelihood of an intentional event on the basis of circumstantial evidence. there are three conclusive indicators of deliberate outbreaks: evidence of intelligence/secrecy activities coincident or related to an outbreak, con fi rmed presence of a known bio-agent (has characteristics of traditional biological weapons or genetically modi fi ed as agent), and evidence of a means of delivery (munitions, delivery systems or dispersion systems). all other indicators are more or less non-conclusive. equivalent to the perpetrator in a biological attack is the source, or reservoir of infection in a natural epidemic. perpetrators may behave in two ways. some bioterrorists want to avoid attribution for an attack, others want to claim credit for it, or, at least want the authorities to recognize that a disease outbreak was deliberate, and not of a natural origin. people who are accidentally included in natural outbreaks (as a source or reservoir of infection) and look like perpetrators at fi rst sight, are always highly afraid and cooperative. also, a source/reservoir of infection always completely behaves according to epidemiological characteristics (incubation period, period of communicability) [ ] . if political, military, ethnic, religious or other motives can be identi fi ed, this would lend credence to the assumption that an attack using pathogens or toxins as biological agents has taken place. in natural outbreaks usually there is no motive, but if we fi nd them, motive(s) are commonplace and simple. in natural epidemics sources of infection may be discovered by usual epidemiological and microbiological routine investigations, and there are no tendencies to keep themselves unknown (no secrecy) [ ] . there are some coincident points related to an outbreak that may be an indicator of secrecy/intelligence inclusion in a biological attack. intelligence presents an ability to get true and on-time information on a global and local level related to biological attacks [ ] . if some activities related to a biological attack are kept unobserved before an attack as well as after an attack, it is a parameter of secrecy and should be considered in the context of a biological attack. it would also be conceivable that certain persons or groups may be given suf fi cient prior warning about a biological attack and could have been spared from an epidemic by preventive measures (e.g. receiving vaccinations, adhering strictly to instructions to boil drinking water). quantitative parameters. in natural outbreaks the number and distribution of sources of infection are related to the incubation period and period of disease communicability. such regularity is seldom seen in a biological attack. here we also have to consider special situations in natural outbreaks when the incubation times and communicability may be changed: for instance in the case of an exposure to massive doses of pathogens by contaminated water or food, such as may be the case with natural disasters or accidents in water treatment plants and distribution systems or hygienic failures in kitchens. then we may have epidemiological, microbiological and clinical patterns which could resemble the characteristics we would also expect in a biological attack. strategic (large-scale) biological attack. states' institutions such as military forces, intelligence services or well-funded and possibly state-supported organizations can be perpetrators in a strategic biological attack. the present threat analysis states that in the next years only a very few so called "rogue" countries with clandestine offensive biological warfare programmes would be able to launch strategic biological attacks [ ] . such attacks include politically, military and/or ideologically motivated ones. in natural, large-scale epidemics, infection is mainly unintentionally and individually disseminated and strictly related through periods of incubation and communicability of disease. the period between deployment of a bioweapon and its effects, however, is long enough to give a terrorist a chance to escape. so, it could be very dif fi cult to fi nd a perpetrator. operational (middle-scale) biological attack. this type of attack could be carried out by all three types of perpetrators (government supported institutions/organizations, terrorist groups, individuals) [ ] . if psychological effects (fear and panic) are greater than the biological losses (diseased and died) it might also be a biological attack [ , ] . tactical (small-scale) biological attack. the terrorist or criminal groups dominate as perpetrators in this type of attack. if "hard" targets are hit, perpetrators likely have to be highly skilled, or with suicidal tendencies, and politically or ideologically motivated [ ] . qualitative indicators. qualitative indicators related to ba have no equivalents (not applicable -n/a) in two cases: natural outbreak of a known endemic disease that may mimic bioterrorism (biowarfare), or outbreak of a new or re-emerging disease. in the case of an accidental release of a pathogen, motivation, ability and intelligence information are n/a. three quantitative indicators of a ba have their equivalents in the other three outbreak scenarios -ar, ne and nr. the most dif fi cult scenario of a ba for investigators is if an endemic pathogen was used. in such a case microbial forensic tools for identifying a deliberate outbreak should be given priority. type of agent. there are two types of biological agents: conventional (natural form of the pathogen) and biological warfare agent. a qualitative parameter may be if some pathogen species or strain (subspecies) is unusual, atypical or antiquated, e.g. is identi fi ed in the region concerned for the fi rst time ever or again after a long absence, or if an agent has certain characteristics like: a special genetic signature, mixed with a stabilizing agent, highly concentrated, fi lled in munitions, high toxicity, more virulent, resistant to antibiotics, and multiple modes of transmission. many potential biological warfare agents could be obtained from natural sources (infected animals, patients, or contaminated soil). many pathogens, perhaps the majority concerned, cause zoonoses, i.e. infect animals as well as humans [ ] . the sudden occurrence of a zoonotic disease, such as brucellosis, in the absence of the natural animal host or reservoir and other likely sources of transmission may be suggestive of an unnatural cause. the so-called "zoonotic" potential should be considered in this differentiating evaluation. a regionalized animal die-off may provide a clue that something is present or may have been released that might also infect humans. this phenomenon of animal illness heralding human illness was observed during the west nile virus encephalitis outbreak in new york city in , when many local crows, along with exotic birds at the bronx zoo, died [ , ] . in the case of a so-called "reverse spread", where human disease precedes animal disease, or human and animal disease occur simultaneously, one should consider an unnatural spread. this is often also the case in plague or tularemia outbreaks and has led to speculations like in surat (india) in or kosovo. many strains isolated from nature have low virulence. therefore, a terrorist must isolate many different strains before fi nding one suf fi ciently potent as a warfare agent. considering the technical dif fi culties to obtain virulent microorganisms from nature, terrorists may fi nd it easier to steal well-characterized strains from a research laboratory, or to purchase the known pathogenic strains from a national culture collection or commercial supplier. between and , the iraqi government ordered virulent strains of anthrax and other pathogens from culture collections in france and the united states, presumably for public health research -a purpose that was legal at the time, and approved by the u.s. department of commerce [ , ] . it is speculated that one reason for the lack of success in causing illness following dissemination of anthrax spores by the cult aum shinrikyo was the inadvertent selection of a non-pathogenic strain of bacillus anthracis [ ] . strategic (large-scale) biological attack. respiratory agents are almost always candidates for strategic use because of the possibility for their clandestine use, their high dispersal potential, and their high contagiousness. category a agents, and the agents causing sars, avian in fl uenza, and pandemic in fl uenza (including swine fl u) might be candidates for use at the strategic level [ ] . operational (middle-scale) biological attack. for this type of attack, the spectrum of suitable agents is wider than for large-scale attacks, and possibilities include (in addition to the agents mentioned above) hanta viruses, multi drug resistant mycobacterium tuberculosis , hepatitis a virus, noroviruses, cryptosporidium spp. , and toxins [ ] . consequently, measures of detection and identi fi cation are more dif fi cult. also, the accessibility of these agents for terrorists is easier, and the amounts of the available agent are larger. tactical (small-scale) biological attack. the agents from all three categories and emerging biological agents are potential candidates for this purpose. biological agents are still the preferred materials of hoax perpetrators at the tactical level, probably because perpetrators could easily produce and safely handle these simulants of potential biological warfare agents. if there is a non-proportional, large amount of biological agent present in sources/reservoirs or environmental sampling, or an epidemiologically unexplainable transmission or distribution of an agent, there is a high probability of a biological attack. all four outbreak scenarios could have the same values for indicators related to agent. if we fi nd some kind of munition, delivery system or dispersion system (means of delivery) at the outbreak focus it should be the proof of a deliberate epidemic. if food, water, or fomites are the media of delivery it should be possible to trace it and fi nd out the source of infection and type (natural or arti fi cial) of epidemic. but, air as a medium of delivery remains the most complicated for investigation. looking for people who came in contact with the agent through this method of exposure may be very dif fi cult. however, several other parameters may help (type, strain and approximate amount of released agent, period of incubation, and period of communicability). also, natural epidemics will feature paths of transmission that are typical for the pathogen and its natural hosts. such deviations from natural paths of infection could indicate that biological agents have been deliberately disseminated. many diseases exhibit vastly different clinical presentations, periods of incubation, and mortality rates depending upon the route of transmission. therefore, outbreaks due to an atypical route of transmission, particularly aerosol transmission, such as in the inhalation anthrax example above, are more suggestive of an intentional use. weather factors, especially wind direction, temperature, and humidity, are important determinants of pathogen dissemination and disease occurrence and must be taken into account in an outbreak investigation. a disease outbreak occurring downwind (or downriver) of a suspected biological warfare agent production facility, such as in the sverdlovsk anthrax disaster, provides compelling evidence for an accidental or intentional release [ ] . it is useful to plot locations where cases occur on a geographic map. if affected cases are clustered in a downwind pattern, an aerosol release should be considered like in the anthrax outbreak in sverdlovsk [ ] . many people are becoming increasingly mobile and interactive with indigenous populations. as a result, they have a correspondingly greater potential for translocating diseases to previously non-endemic areas through unknown transportation of infected vectors or people during incubation or clinical symptom stages. therefore, knowledge of the at-risk population's travel and contact histories may be essential in determining the etiology and likely source of an outbreak. tourists, military personnel, traders, settlers and immigrants, and travel adventurers may carry new pathogens to unsuspecting and susceptible populations. people, storms, and fl oods can transport arthropods, rodents, snails, birds, and other creatures that can also bring new infections to previously unaffected areas. changes in human behaviour, technologic devices, the environment, institutional living, and poor nutrition or vitamin de fi cits can spark new epidemics. the speed at which an epidemic spreads is determined by the virulence, resistance and concentration of the pathogen, the contagiousness of the disease and the intensity of the transmission process, on the one hand, and on the susceptibility and disposition of the exposed population, on the other. it is unclear how changes in household sizes, working patterns, and mobility would affect transmission patterns today. incorporating detailed data on demographics and human mobility into spatially explicit models offers one method by which such extrapolation can be made more reliable, but the scale of changes mean that much uncertainty will inevitably remain. qualitative indicators: air, water, food and fomites could be the media or means of delivery for all four outbreak scenarios. quantitative indicators: three quantitative indicators of ba -munitions, delivery systems, and dispersion systems -will not exist in the other three uee scenarios -ar, ne, and nr. in natural outbreaks there is no target, but there is a susceptible (affected or endangered) population. in both natural and deliberate epidemics there can be two types of consequences: direct (death and/or illness), and indirect (political and economic). however, in a deliberate outbreak, indirect (political and economic) effects are usually intended and have great impact. in natural epidemics indirect (political and economic) effects every time are "collateral damage" or sometimes expected consequences of disasters. in addition, the use and even the threatened use of certain biological agents can have intense psychological effects on the population at large [ , ] . in naturally occurring epidemics "soft" targets are mainly affected, because "hard" targets (e.g. heads of state or other vips) are better protected than "soft" targets (e.g. the unprotected population). there are no signs or indicators of intelligence/ secret activities (e.g. repeated visits by individuals or vehicles identi fi ed as out of place, prior warning of a possible biological attack such as active or passive immunoprophylaxis or chemo-prophylaxis of a non-target population, threats, or hoaxes). there is no suspicious behaviour: unexplained contamination of a media (air, food, and water), or use of unusual fomites (of fi ce equipment, postal letters). there is also no obvious target in a natural outbreak. some parameters of an outbreak (location of the exposure/target site, importance and number of people in the site, and distribution of people from the site) may also point to a deliberate attack. large-scale attack. nowadays, one of the main objectives of a bioterrorist is to propagate fear, anxiety, uncertainty, and depression within the population, induce mistrust of the government, in fl ict economic damage, and disrupt travel and commerce [ , ] . causing signi fi cant outbreaks of disease may be a secondary objective. the ultimate goal of biological attacks is to cause political consequences. bioterrorists want to produce an epidemic of fear and panic [ , ] . this cannot be evoked in such manner if the attack is clandestine and mimics a natural outbreak. naturally occurring large-scale epidemics or pandemics are only possible by aerosol transmissible agents. all other large-scale outbreaks should raise suspicion as a potential deliberate outbreak. middle-scale and small-scale attack. in the case of "hard targets" (highly prominent and protected institutions like governmental buildings, media centres, and persons such as politicians, scientist, or high military of fi cials) being affected, the probability of a deliberate outbreak is high. consequences even in small-scale attacks can be of strategic importance. "soft targets" are considered ordinary people in public places (e.g. respiratory agents in crowded and closed places like theatres, cinemas, sports events, and political meetings). small-scale outbreaks in "soft targets" are more dif fi cult to differentiate and may be of less strategic importance. except for the most blatant violations of natural principles, bioterrorism will continue to remain dif fi cult to differentiate from naturally occurring outbreaks. certain attributes of a disease outbreak, while perhaps not pathognomonic for a biological attack when considered singly, may in combination with other attributes provide convincing evidence for intentional causation. the possibility of mixed epidemics must always be taken into consideration when assessing the outbreak of a disease, since they complicate the epidemiologic situation and can present additional dif fi culties for the investigation of unusual outbreaks. there are two types of differences between these four scenarios: qualitative and quantitative. qualitative differences are de fi ned by indicators, and quantitative by ten indicators. both types of indicators could have three different values: n/a, , or . in our previous article [ ] numerous parameters -indicators were de fi ned. by using them we have carried out feasibility analysis for subtle and detailed differentiation among four outbreak scenarios. as a tool for feasibility analysis we have introduced a "system of elimination". system elimination is necessitated if one component contains all indicators scored with or as n/a, then the related scenario is eliminated from further consideration. (table . reservoirs. reservoirs of infection are pigs [ , , ] and turkeys, and all six qualitative indicators are not applicable (ne, nr scenarios). in consideration of ba scenario there are likely no terrorists who intend to create an uncontrolled pandemic originating in a mexico rural area. later events also showed that there was no misuse or intent either for commercial purposes by pharmaceutical industries or from military experiments. therefore this scenario has been eliminated. with pigs and turkeys as the reservoir, accidental release of the pathogen is also not likely, and therefore this scenario is eliminated. agent. undoubtedly, this is a new and emerging pathogen [ , ] . this clearly eliminates a natural outbreak of a known endemic disease. air and fomites could be the media of delivery in a new or a re-emerging disease [ , , , ] . susceptible population vs. target. in the "swine fl u" pandemic, intelligence and secrecy are both scored with because of the early detection of the outbreak, and identi fi cation of the agent and reservoirs of infection. conclusion. "system elimination" clearly discriminates a spontaneous natural outbreak of a known endemic disease, a biological attack, outbreak by an accidental release of a pathogen because they do not have the components "agent" or "perpetrator". considering the fi rst component (perpetrator or reservoirs/sources) in the third scenario, the fi rst six qualitative indicators are n/a. the three quantitative indicators are each scored . taking into account the scores of for intelligence and secrecy, as well as the absolute absence of material evidence of biological attack, we should accept the scenario as a spontaneous outbreak of a new or reemerging disease. emerging diseases, both new to a region like west nile virus encephalitis, and totally "new" like sars and avian in fl uenza, have occurred in the last decade. examples include the appearance of west nile virus encephalitis in new york city in [ ] , bubonic plague cases in new york city in [ ] , or monkey pox outbreak in the usa in . the west nile virus encephalitis outbreak in new york city in constituted a true emerging infection, as the disease became established in a new location, while the plague cases were simply imported by out-of-state residents. until the epidemic in new york city in , west nile virus had never been isolated in the western hemisphere. many diseases, such as dengue fever in cuba having been imported from vietnam, or vivax malaria in korea, represent a re-establishment of endemic transmission in areas from which they were once eradicated. about new pathogens have been found in the last years [ ] . the united states was caught off-guard by the increasing aids epidemic that began in the early s. today, the aids epidemic -at the beginning of the twenty-fi rst century -is worse than the worst-case scenarios that were predicted in the early s. tuberculosis, re-emerged in the united states in the s after decades of decline, and includes newer multidrug-resistant strains. perpetrator. there were repeated and separate bas using this agent (e.g. multiple letters sent), which is not very probable in an accidental release. agent. the causative agent in this scenario is a category a agent (ames strain from the us army medical research institute for infectious diseases, fort detrick) that was misused by an experienced insider and specially prepared and released deliberately in a signi fi cant amount. because of this, a natural outbreak of a known endemic disease and a spontaneous outbreak of a new or re-emerging disease are clearly eliminated from further consideration. transmission mechanisms and devices vs. media and means of delivery. the perpetrator used postal letters (fomites) and the american postal service (delivery system) for the ba. susceptible population vs. target. three indicators -intelligence, secrecy and personal control (of employees with access to the agent) -were not successfully applied at the initial phase of the ba. intelligence is a cornerstone of prevention. information is provided using electronic surveillance methods, local intelligence systems, and observation of possible targets. repeated visits by individuals or vehicles must be identi fi ed. the impact of secrecy has been evident in some recent incidents. such an incident occurred in the aftermath of the anthrax letter attacks. although the us postal service and the cdc knew that the brentwood postal facility in washington, d.c., was contaminated, they waited for days before closing the facility and treating workers with antibiotics. by that time, one worker had died of anthrax, another was close to death, and two were gravely ill. another example is china in , when the government denied the sars epidemic for weeks, causing international alarm and spread of the disease. these examples illustrate that government secrecy is a persistent jeopardy, leaves the public in ignorance, and allows narrow-minded political agendas to undermine healthcare goals. personal control includes physical control of people (their health status) and behavioral control (cv review, control of suspect behavior, control of contacts) [ ] . conclusion. "system elimination" clearly eliminates the other three scenarios by the "agent" and "perpetrator" components. therefore, we should accept the ba scenario as the likely event. during - , biological "events" (i.e. episodes involving the deliberate use of a biological agent to harm people) were perpetrated. of these, just four post- events generated more than ten casualties [ ] . besides this, about a thousand anthrax hoaxes occurred alone between and which concerned the public, administration, and public health authorities, prompting excessive decontamination and post-exposure measures and intensive forensic and laboratory investigations in order to discriminate the events as false alarms. reservoirs/sources. in the kosovo tularemia outbreak, only an insider could be a possible perpetrator as others would not have the ability or knowledge because of the unpredictable war and after-war events. the secrecy and capacity needed would be possible only from highly sophisticated insiders. the qualitative indicators from ba and natural epidemic scenarios are not similar (rodents were reservoirs) and their differences are assessed in the rest of the indicators. quantitative indicators are also different. the number of perpetrators should be numerous but were not identi fi ed, however the number of rodents as reservoirs were numerous. comparing the accessibility to sources of the agent with the distribution sources of the agent, as well as accessibility to the target by perpetrators (humans) and rodents as reservoirs, there are signi fi cant differences. because of the timing and geographically very dispersed occurrence of cases, quantitative indicators related to a perpetrator were scored with , and those related to a natural epidemic were scored with . a spontaneous outbreak by an accidental release of a pathogen and ba were not likely scenarios because of the timing, geographic separation, and repeated occurrence of cases. agent. the implicated agent was francisella tularensis holarctica , that causes a milder form of tularemia and is endemic in the balkan region. because of this, a spontaneous outbreak of a new or re-emerging disease is clearly eliminated. transmission mechanisms and devices vs. media and means of delivery. there was no convincing and conclusive evidence for devices of delivery [ ] . it is well known tularemia could be spread by multiple natural transmission sources like water, food, or animals, as was the case in this outbreak. susceptible population vs. target. this component should provide the fi nal information to solve the conundrum between a ba and a natural epidemic scenario. there was no intelligence information (no convincing or conclusive indicator was documented regarding a possible perpetrator), no secrecy (no attempts to control information after the fi rst diagnosed cases), no control of means/media, no physical protection, chemical protection, or immunological protection (all three types of protection and ways to control transmission were absent or implemented late), and a lack of signi fi cance from a military/terrorist ba logistical standpoint in the importance and location of the target, and the number and distribution of the people affected. conclusion. "system elimination" clearly excluded a spontaneous outbreak of a new or re-emerging disease because of the agent type (not new or re-emerging). the scenario of spontaneous outbreak by an accidental release of a pathogen was also not likely because of timing, geographic dispersion, and repeated occurrence of cases without any convincing and conclusive indicator. the total score supports a scenario of a spontaneous natural outbreak of a known endemic disease that could mimic bioterrorism or bio-warfare. perpetrator. in the sverdlovsk anthrax outbreak, the large amount of agent (enough to contaminate a city with thousands of inhabitants and the surrounding area) was not likely spread from a natural source or reservoir of infection unobserved and in such a short time. these facts eliminate two scenarios: natural epidemic and a spontaneous outbreak of a new or re-emerging disease. regarding the circumstances in the s in the former soviet union with an isolated city (sverdlovsk) in siberia, for a ba scenario, capacity and secrecy are scored with . agent. there was a large amount of spores of a virulent strain of bacillus anthracis (category a agent) as the causative agent. accordingly, we scored those two indicators with . transmission mechanisms and devices vs. media and means of delivery. there were no delivery devices identi fi ed. however, the only way to spread such large quantities of anthrax spores during this short period of time was by air. susceptible population vs. target. this component should solve the doubt between a ba and accidental pathogen release scenario. in terms of intelligence, no conclusive or inconclusive perpetrator activities or other evidence related to ba were documented, but there was very conclusive evidence related to an accidental release. in terms of secrecy, there was prolonged and stringent secrecy and disinformation supported by soviet of fi cials about the event. personal control, control of means/ media, physical protection, chemical protection, immunological protection were carried out quickly. the last four indicators -importance of target, number of people in the target, distribution of people in the target, and location of target -were without signi fi cance and any military/terrorist logic in a ba scenario. an accidental release scenario was possible, especially accounting for the circumstances (military compound dealing with production of a biological warfare agent close to the city). conclusion. "system elimination" clearly eliminates a natural epidemic and a spontaneous outbreak of a new or re-emerging disease through the perpetrator/sources/reservoirs component. large amounts of the agent in the sverdlovsk anthrax outbreak were not possible from natural sources/reservoirs of infection in such a short time and would not likely have been otherwise undetected before human cases occurred. the total score supports a scenario of a spontaneous outbreak by an accidental release of a pathogen as the most likely scenario. also, if a country rejects foreign help and experts and hides the circumstances of an epidemic it could raise suspicion for an accidental release epidemic scenario. the author has developed a new scoring method of outbreak analysis: for subtle and detailed differentiation. the method was applied to four uees: ( ) an intentional attack by a deliberate use of a biological agent (amerithrax), ( ) a spontaneous outbreak of a new or re-emerging disease ("swine fl u"), ( ) a spontaneous outbreak by an accidental release of a pathogen (sverdlovsk anthrax), and ( ) a spontaneous natural outbreak of a known endemic disease that may mimic bioterrorism or biowarfare (kosovo tularemia). it was found that "agent" was the most important and the most informative uee component of the new scoring method. this method might be helpful in the analysis of unusual epidemic events and a quick way to differentiate between biological attacks and other epidemics. survival of in fl uenza viruses on environmental surfaces the occurrence of in fl uenza a virus on house hold and day care center fomites serum cross-reactive antibody response to a novel in fl uenza a (h n ) virus after vaccination with seasonal in fl uenza vaccine endemic, noti fi able bioterrorism-related diseases, united states, - emergence of a novel swine-origin in fl uenza a (h n ) virus in humans discernment between deliberate and natural infectious disease outbreaks lessons from the west nile viral encephalitis outbreak in new york city, : implications for bioterrorism preparedness pandemic potential of a strain of in fl uenza a (h n ): early fi ndings the h n in fl uenza outbreak in its historical context emerging natural threats and the deliberate use of biological agents a procedure for differentiating between the intentional release of biological warfare agents and natural outbreaks of disease: its use in analyzing the tularemia outbreak in kosovo in community transmission of in fl uenza a (h n ) virus at a rock festival in belgium the role of risk analysis in understanding bioterrorism transmission of avian in fl uenza viruses to and between humans a dictionary of epidemiology an outbreak of west nile virus in a new york city captive wildlife population environmental health and bioterrorism a new model of bioterrorism risk assessment unusual epidemiological event -new model for early orientation and differentation between natural and deliberate outbreak bioterrorism -types of epidemics, new epidemiological paradigm and levels of prevention epidemics of panic during a bioterrorist attack -a mathematical model chinese curses, anthrax, and the risk of bioterrorism pathology of fatal west nile virus infections in native and exotic birds during the outbreak biosecurity: limiting terrorist access to deadly pathogens. peaceworks no. , united states institute of peace united states dual-use exports to iraq and their impact on the health of the persian gulf war veterans. rd congress nd session, : u.s. government printing of fi ce risk factors for human anthrax among contacts of anthrax-infected livestock in kazakhstan a discussion of fi ndings and their possible implications from a workshop on bioterrorism threat assessment and risk management key: cord- -koa ao authors: stoddard, m.; johnson, k.; white, d.; nolan, r.; hochberg, n.; chakravarty, a. title: covid- isolation and containment strategies for ships: lessons from the uss theodore roosevelt outbreak date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: koa ao the control of shipborne disease outbreaks represents a vexing but entirely predictable challenge at the start of any pandemic. passenger ships, with large numbers of people confined in close quarters, can serve as incubators of disease, seeding the pandemic across the globe as infected passengers return home. short-term steps taken by local authorities can exacerbate this problem, creating humanitarian crises and worsening the scale of the outbreak. in this work, we have undertaken a model-based examination of the uss theodore roosevelt outbreak to understand the dynamics of covid- spread aboard the aircraft carrier. we have used a series of counterfactual "what-if" analyses to better understand the options available to public health authorities in such situations. the models suggest that rapid mass evacuation and widespread surveillance testing can be effective in these settings. our results lead to a set of generalizable recommendations for disease control that are broadly applicable to the current covid- crisis as well as to future pandemics. the ramifications of at-sea outbreaks have been broad, impacting the cruise industry and the military in high-profile events such as the diamond princess cruise ship and uss theodore roosevelt aircraft carrier outbreaks in early (mallapaty, ) . a precise quantitative understanding of the dynamics of transmission in such a setting can be invaluable in formulating strategies for the control of future outbreaks, both for covid- and for other pandemics. the dataset for the uss theodore roosevelt (cvn- , referred to in this paper as "the roosevelt") provides detailed insight into the kinetics of shipborne outbreaks, thanks to the navy's record-keeping and transparency. in this paper, we examined the roosevelt outbreak closely through a quantitative lens to evaluate the relative effectiveness of different disease control strategies. the roosevelt outbreak resulted in the death of one sailor, several hospitalizations, extensive negative press, significant costs for on-shore isolation facilities, and an approximately two-month departure from duty for the aircraft carrier (lagrone, jun ; peniston, ) . these negative outcomes were aggravated by the lack of fda-approved sars-cov- molecular tests at the time. notably, these outcomes occurred in spite of the high degree of compliance and top-down command of the navy, an open airbridge to shore-based facilities at all times during the outbreak based on the carrier's own air wing ("usni news fleet and marine tracker," ), and access to a mobile laboratory capable of testing for sars-cov- while at sea (peniston, ; "usni news fleet and marine tracker," ) . the navy's approach to containing the outbreak on the roosevelt involved testingbased isolation and mass evacuation to quarantine facilities on guam. the first case was detected on march , while the carrier was underway in the philippine sea ("usni news fleet and marine tracker," ), so mass evacuation was delayed until the ship reached guam (at the edge of the philippine sea, and in theory, less than two days' sail away for a carrier strike group (brain, ) ). sailors testing positive before this time were either airlifted to land or quarantined in the limited isolation facilities aboard (gilday, ) . the roosevelt docked in guam on march th , with the crew being restricted to the ship and the pier. mass evacuation started on march st, and crewmembers were evacuated until data collection stopped on may , at which point sailors remained on board and , cases ( . %) had been documented among the crew (lagrone, jun ). in a serology study performed by the cdc, a % incidence of sars-cov- -reactive antibodies was observed. the study cohort was biased in favor of crewmembers having previously tested positive, with of volunteers ( %) having previously received a positive test result by rt-pcr (payne, ) . this result is consistent with a high degree of detection accuracy by the end of the roosevelt outbreak. in the present investigation, we leverage publicly available data from the roosevelt outbreak to fit an epidemiological model and test strategies for outbreak mitigation. we evaluate the effectiveness of the navy's disease containment strategy and provide recommendations for high-contact at-sea settings with an emphasis on naval readiness. our findings also provide insight more generally into strategies for the control of covid- and other infectious diseases in shipborne settings. data regarding cumulative cases of sars-cov- infection by date among the roosevelt crew were compiled from publicly available military and civilian sources (dyer, ; lagrone, lagrone, , p. , peniston, ) . cases were detected by molecular testing and do not include serological positives. case counts include sailors who tested positive for covid- while in isolation on guam after evacuation from the ship, implying exposure while on board. when available, we also compiled data describing the number of crewmembers remaining aboard over time to reflect the navy's evacuation of the ship. this data is summarized in figure a . to determine the population-specific epidemiological parameters for sars-cov- spread in the roosevelt outbreak, we fit an ordinary differential equation (ode)-based compartmental model to the cumulative caseload data for the outbreak. the population is partitioned into four compartments representing susceptible (s), exposed (e), infectious (i), and recovered (r) individuals. we leveraged disease-specific model parameters-the latency and recovery period-from studies in the literature leveraging richer datasets describing more complete outbreak time courses, which are better suited to this purpose (rocklöv et al., ) . the population-specific parameters-the contact period and the initial exposed population-were fitted to the cumulative detected case data. equations - : odes for pre-intervention seir model initial conditions for the seir model ( ) = , ( ) = , ( ) = ( ) = the latency period a in the seir model is the duration of pre-infectious exposure. the recovery period c is the duration of infectiousness or the time to recovery. these two parameters are disease-specific and do not vary based on behavior. the contact period b describes the average time to transmission for an infected person and is dependent on the contact behaviors of the population. r , the intrinsic reproductive number in a population, is the ratio of c/b (ridenhour . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; et al., ) . the initial exposed population e is the predicted number of exposed sailors at the time of the first detected case. the model is agnostic to the source of these exposures. we used a least squares minimization to fit the model-predicted number of infections to the reported cases from the first two weeks of the outbreak. we assumed disease dynamics in this period reflect the underlying rate of disease spread before outbreak response measures such as increased testing-based isolation and mass evacuation began impacting the number of cases. these fit parameters do not represent truly unchecked spread, as basic pandemic preparedness measures such as enhanced cleaning, limited testing, and symptom-based isolation were already in place on the roosevelt when the outbreak emerged (gilday, ). we assume the contact rate did not change throughout the duration of the outbreak and we assume there are no additional introductions of disease from outside the ship. likewise, we used this fit contact rate to inform the modeling implemented in the remainder of our analysis. the navy employed two strategies to control the roosevelt outbreak: removal of sailors at random by mass evacuation and targeted removal of sailors who tested positive by isolation (either onboard or onshore) (lagrone, jun ). to evaluate and optimize these strategies in the context of shipborne outbreaks, we varied the key implementation parameters for each strategy and the combination of both strategies. the testing-based isolation strategy is defined by the percent of the initial crew tested each day, which is assumed to be constant throughout the outbreak. for the evacuation-based strategy, we explore the impact of evacuation rate, defined as the percent of the initial crew removed each day, the final crew size at which evacuation is stopped, and the timing of the start of evacuation. we assume that the underlying epidemiological parameters -the contact rate among onboard crewmembers, latency period, and recovery time -do not change over the course of simulation. to assess the applicability of these findings to outbreaks with a higher basic reproductive number (r ) or to outbreaks with a larger number of initial exposures (e ), we varied these parameters accordingly. both r and e are population-specific parameters and are expected to vary by scenario. the seir model fit to the days of the roosevelt outbreak data was consistent with a constant contact rate, with strong parameter identifiability for the fit population-specific parameters: the contact period and the initial exposed population ( figure b ). the fit parameter values and their standard errors (ses) are summarized in table . the fit contact period is consistent with an r value of . , which is much lower than the estimate of the r on the diamond princess, which was approximately (gilday, ). . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; when we predicted the impact of removal of sailors at random at the reported times, we found that the actual outbreak caseload data falls only slightly below the % confidence interval for variation introduced by random evacuation of sailors in a crew of , ( figure c ). this suggests that throughout the outbreak interval, the evacuated population was minimally enriched for infected and exposed sailors relative to the population on board the ship -that is, the evacuees were effectively selected at random from the sailors on the ship. this result is surprising given that testing on board the roosevelt increased from approximately tests per day in march to tests per day in april (peniston, ) . the apparent failure of the additional tests to result in more efficient removal of actively infected sailors may be explained by long delays in turnaround of test results (dyer, ), as well as the difficulty in identifying sars-cov- infectious individuals due to delayed symptom onset and asymptomatic infections (he et al., ; johnson et al., ) . prior analyses have demonstrated the importance of rapid test results to decrease time to isolation (johnson et al., ) . in figure , we assess the impact of a mass evacuation-based outbreak mitigation strategy, in which testing is absent and sailor removals are exposure-agnostic. our analysis suggests mass evacuation can be an effective strategy by reducing the size of the population exposed to the pathogen. a successful evacuation preserves the health of the vast majority of sailors removed from the ship, but under the simulated outbreak conditions, nearly all sailors remaining on a b c . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; board become infected. in this vein, the simulation predicts that , of the roosevelt sailors ( . %) would have eventually become infected without the navy's interventions ( figure b ). for a successful evacuation plan, the simulations indicate that above a certain threshold for the rate of evacuation, the outbreak size is only dependent on the final number of sailors remaining on the ship. for the outbreak conditions simulated in our model, this threshold falls around a % daily rate of evacuation. this result indicates that mass evacuation-based strategies can be successful with an achievable rate of deboarding. in many at-sea scenarios, immediate mass evacuation is not possible until the ship has sailed to port. in these cases, there will be a delay in evacuation after detection of the first case ( figure ) . a delay in implementation reduces the effectiveness of evacuation-based strategies. however, if the delay is not too large, it may be overcome by increasing the rate of evacuation. for example, a one-week delay may be overcome by increasing the evacuation rate from % to % of the crew daily ( figure a ). after three weeks, however, the best-case outcomes are no longer accessible, even with a % daily evacuation rate ( figure b ). in agreement with this result, figure c demonstrates that delayed implementation time erodes the effectiveness of even aggressive evacuation strategies. capt. crozier recommended rapid evacuation at a rate of sailors per day (approximately % of the initial crew) until % of the crew remained to maintain essential functions aboard the roosevelt. if this strategy had been implemented immediately at detection of the first case, the seir model predicts an outbreak size of infected sailors ( %) by may in this scenario, a significant improvement on the actual case count of , by may (moriarty, ) . the downside of this strategy is that the sailors remaining on the ship are intended to perform important and physically demanding tasks, but nearly all of them will become infected, likely impeding their work. given that data collection stops on may for the roosevelt, it is unclear what happened to the sailors remaining on board after evacuation. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; day or b) day after detection of the first case. black dots represent capt. crozier's proposed strategy, which involved evacuating % of the crew daily until % remained. c) dependence on time of implementation for retention of a % skeleton crew at a %, %, %, and % daily evacuation rate. guaranteeing a healthy crew on board a disease-burdened ship is impossible in an evacuationonly response model (figure ). implementing an effective testing-based isolation strategy significantly improves outcomes for crewmembers remaining on board the ship ( figure ). as shown in figure a , capt. crozier's target crew of % of the initial population could have been safely maintained aboard if a testing rate of % daily relative to the total crew size ( % of the final crew size) and an evacuation rate of % daily had been implemented immediately after detection of the first case. the simulation assumes testing readouts and removal of positive cases are instantaneous and that testing accuracy is perfect. abbott's binaxnow covid- rapid tests, which recently received emergency authorization from the fda, may meet these criteria (koval, ) . similar to the evacuation-only case, the rate of evacuation does not significantly impact outbreak outcomes above a certain threshold. in this case, an evacuation rate of approximately % daily is required for optimal results. for evacuation rates greater than this threshold, the impact of testing is nearly switch-like. if testing is implemented at a higher than % daily rate, the outbreak size is very small (< %). for lower rates of testing, the outbreak size is a much larger fraction of the total crew. a b c . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; more tests are needed to safely retain a larger crew. impact of testing and evacuation rates on outbreak size when a) %, b) %, or c) % of the initial crew remains after evacuation. black point on a) represents the navy's intended strategy for tests per day combined with capt. crozier's recommendation for % daily evacuation. the model also demonstrates that retaining a larger crew is feasible. a higher testing rate is required to achieve outbreak containment with a larger crew remaining on board ( figure b , c). while a less than % rate of daily testing relative to the original crew size can contain disease when % of the initial crew remains on board, a daily testing rate of at least % is required for containment when % of the crew remains on board. as expected, the epidemiological cost of insufficient testing is larger if more crewmembers remain on board. figure further demonstrates the feasibility of retaining crews of varying sizes if extensive testing is implemented. the steep relationship between testing rate and disease control is readily observed in this figure; a two-fold reduction in testing frequency results in nearcomplete abolition of testing-driven improvements in outbreak outcome. the full-crew simulations are particularly important to guide outbreak response in scenarios where onboard removal by isolation is possible but mass evacuation to land is not. crewmember evacuation occurs at a rate of % daily until the target crew size is reached. test randomly administered to the crew with isolation of detected cases. testing rate is relative to the size of the initial crew. an important caveat to testing-based strategies is that their success relies on the immediate isolation or removal of positive cases. this means that the functional size of the crew may be smaller than the target size due to removal of infected individuals upon detection ( figure s ). the simulation assumes that all detected positives can be removed. if the testing strategy is highly effective, the fraction of the crew removed due to infection is small (< %). if testing is ineffective, more than % of the target a b c . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; crew may require removal upon testing positive. if the testing regime is highly ineffective, the intended number of crew members may remain on duty due to extensive undetected cases. although recovery time and latency period are disease-specific parameters expected to hold constant across demographically comparable populations, r and e are population and outbreak-specific. to assess the applicability of our findings to other at-sea scenarios, we performed a sensitivity analysis to gauge the impact of changes in r and e on the effectiveness of a successful outbreak containment strategy. the selected strategy involves evacuation of % of crew members daily until % of the initial crew remains; testing at a rate of % of the total crew daily; and immediate implementation of both measures at the time of detection of the first case ( figure ). this strategy corresponds to capt. crozier's suggested evacuation plan and the navy's intended testing capacity (gilday, ). our analysis suggests that this strategy is robust to significant increases in r , representing scenarios with higher rates of disease-spreading contact among crewmembers, as well as significant increases in e , representing late detection of the outbreak or a super-spreader disease introduction event. sensitivity analysis: the navy's strategy is successful under a wide range of possible outbreak parameters. in this heatmap, the following strategy is simulated under a variety of disease spread scenarios: after detection of the first case, evacuation of % of sailors per day until a crew of % remains; testing is carried out at a rate of % of the total crew per day. black point represents fit parameters for the roosevelt dataset. the purple region represents combinations of r and e for which containment is successful. disease control in the early stages of a pandemic depends significantly on the ability to contain shipborne outbreaks, as these provide significant opportunities for pathogens to spread in an uncontrolled manner and propagate internationally when passengers are released before the outbreak has run its course. the challenge of managing shipborne disease outbreaks has been evident throughout history: the concept of quarantine itself dates back to restrictions placed on sailors in the era of the black death; in , troopships were instrumental in spreading the influenza pandemic (baraniuk, ); and in recent years, the cruise ship industry ("covid- pandemic on cruise ships," ; el damanhoury and cullinane, ; hines, ) and the . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; navy (aquino and brice, ; khaokham et al., ) have both struggled with a variety of infectious disease outbreaks on ships. a generalized quantitative examination of disease control strategies can thus provide valuable inputs into public health strategy. our work uses a model-based approach, rooted in the characteristics of the roosevelt outbreak and based on a counterfactual analysis, to explore the effectiveness of different strategies in shipborne disease control. shipborne outbreaks are particularly challenging to control because of the high rate of spread and the ineffectiveness of social distancing and contact tracing in the closed confines of an onboard setting. reports estimated the r on the diamond princess to be as high as (rocklöv et al., ) , with the virus spreading evenly throughout all of the ship's decks primarily as a result of close-range aerosol transmission (grasso macola, ) . according to another study, the use of social distancing and mask wearing on the roosevelt had a minimal impact on likelihood of infection (for example, the percentage of sailors infected was % vs % for mask wearing or not, and % vs % for social distancing or not (payne, ) ). faced with these constraints, passenger ships can quickly become large floating reservoirs of disease. this work outlines several practical strategies to avoid this outcome in different scenarios (table ) . first, in the case of a novel pathogen (at the start of the next pandemic), the best strategy for shipborne outbreaks is likely to be mass evacuation. we note that in the case of the roosevelt, this was likely made impossible by political constraints. there was a nine-day time lag between the detection of the first case, while the roosevelt was underway in the phillipine sea, and the start of mass evacuation in guam, which was at most two days' sail away (peniston, ) . similarly, at the outset of the diamond princess outbreak, the ship was quarantined for nearly a month in yokohama harbor, with her passengers onboard (grasso macola, ) . delays in mass evacuation at the beginning of a shipborne outbreak can create a much larger problem for local authorities, as was observed in the diamond princess outbreak, where passengers released from the ship went on to spread the disease locally (endo, ; rich and yamamitsu, ) . in this context, it is encouraging that a number of cruise lines have proposed agreements with local authorities that expedite rapid evacuation to shore at the start of an outbreak (sebastian, ) . recently, the cdc published new guidance to facilitate a return to cruising, stipulating antigen testing of all passengers and social distancing and symptom-based screening of passengers while underway. however, a recent outbreak at the rose garden of the white house demonstrated the limitations of antigen tests (facher, ), for which the cdc itself regards negative results as "presumptive" (cdc, ). previous studies on the roosevelt demonstrated the limitations of social distancing in an onboard setting (payne, ) , and our prior work has demonstrated the limited utility of symptom-based testing for the containment of sars-cov- outbreaks (johnson et al., ) . as an alternative, we suggest requiring negative pcr tests for all passengers after a -day quarantine, as the cdc requires for crewmembers (hhs, ) . arguably, if testing on the roosevelt had been operating at full capacity, isolating the infected sailors by airlifting them to land using the organically embedded air wing of the roosevelt (two c- greyhounds and six mh- sea king helicopters) could have had a significant impact on the growth and spread of the outbreak ("uss theodore roosevelt (cvn- )," ). although testing was slow to ramp up in the specific case of the roosevelt, mass . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november , . ; testing and targeted removal can be decisive in enabling continued safe operations. the relationship between testing frequency and strategy effectiveness is steep: low levels of testing are ineffectual, while high levels of testing can be highly effective. for a ship with similar disease spread dynamics as the roosevelt, a crew of any size can be maintained aboard while containing disease if testing is sufficient. thus, the availability of widespread and rapid testing is a crucial prerequisite for naval readiness in pandemic settings. a scenario-specific and modelbased assessment of the required testing frequency is desirable, as small changes in the effective rate of testing (by reduced test sensitivity, slower turnaround times) may render testing ineffective. it is encouraging that the navy quickly learned from the roosevelt outbreak to implement rapid control of a second outbreak on the destroyer uss kidd using proactive testing-and-isolation strategies, even as the roosevelt outbreak was still being managed (olson, ) . finally, when isolation and evacuation are not possible, such as in a submarine, quarantine and testing of the full crew before entry are the only feasible strategies for disease control. we note that lowering the r will also facilitate disease control on ships. a number of authors have pointed out the risk posed by unfiltered forced-air ventilation systems (baraniuk, ; malone, ) , and installing higher-quality filters on heating, ventilation and airconditioning systems is an easy step to take in reducing the rate of transmission of an airborne pathogen. our work contains a number of simplifying assumptions that are worth exploring in further work. we assumed that testing was perfectly accurate and instantaneous, resulting in an optimistic assessment of the efficacy of testing-based strategies. further study is required to assess the impact of testing limitations on these strategies and to identify the time to outbreak detection for a given testing frequency. additionally, our results are dependent on the . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november , . ; https://doi.org/ . timeline: how covid- spread aboard the diamond princess cruise ship temporal dynamics in viral shedding and transmissibility of covid- framework for conditional sailing and initial phase covid- testing requirements for protection of crew [www document cruise ship norovrius outbreak sickens ; coronavirus plagues others [www document this time is different: model-based evaluation of the implications of sars-cov- infection kinetics for disease control seroepidemiologic investigation of an outbreak of pandemic influenza a h n aboard a us navy vessel--san diego abbott's fast, $ , -minute, easy-to-use covid- antigen test receives fda emergency use authorization; mobile app displays test results to help our return to daily life almost sailors on carrier roosevelt have tested positive for covid- timeline: theodore roosevelt covid- outbreak investigation [www document the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application what the cruise-ship outbreaks reveal about covid- uss theodore roosevelt, covid- , and ships: lessons learned public health responses to covid- outbreaks on cruise ships -worldwide destroyer uss kidd returns to sea after six weeks in port dealing with coronavirus outbreak -navy -stripes sars-cov- infections and serologic responses from a sample of the battle of uss theodore roosevelt: a timeline hundreds released from diamond princess cruise ship in japan unraveling r : considerations for public health applications covid- outbreak on the diamond princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures cruise lines propose covid- safety measures to cdc -wsj [www document out of control': when schools opened in a virus hot spot wikipedia. van beusekom, m., . covid- spread freely aboard uss theodore roosevelt preparation for quarantine on the cruise ship diamond princess in japan due to covid- key: cord- -x re authors: bdeir, fadl; hossain, liaquat; crawford, john title: emerging coordination and knowledge transfer process during disease outbreak date: - - journal: nan doi: . /kmrp. . sha: doc_id: cord_uid: x re when multiple agencies respond to a disease outbreak (i.e., h n and sars), the coordination of actions is complex and evolves over time. there has not been any systematic empirical study of the dynamics of emerging coordination behaviour and knowledge transfer process during a disease outbreak. in this paper, we first introduce our approach for the analysis of multi-agency intervention during a disease outbreak using the study of social networks. using social networks and its analytic framework, we explore questions such as: how does the multi-agency coordination emerge for supporting the complex knowledge transfer process during different phases of disease outbreak? how effective are these formal and informal coordination mechanisms in achieving a robust outcome in response coordination through effective knowledge transfer process during the outbreak? what are the key lessons learned by studying the emerging coordination and knowledge transfer process during past disease outbreak in improving the multi-agency preparedness for dealing with future outbreaks? the discussion is supported by a qualitative study of the implementation of the results of the analysis. we reveal that profound understanding of social network behaviour and emerging coordination concepts are pivotal to the optimisation of knowledge transfer process which is a prerequisite for successful outbreak intervention. we look qualitatively at how hunter new england area health services applied these concepts to lead a successful coordination plan during an h n endemic. disaster management is inherently complex due to the interdependent nature of the responses from multiple organisations that have responsibility for dealing with the situation collectively (comfort et al, ) . it has long been advocated that standard hierarchical management structures may not necessarily be the most efficient ones in such situations (neal & phillips, ) . this is due to the demanding requirement for extensive inter-organizational interactions, communication, and collaboration with interwoven dependencies (chen et al, ) . disease outbreak can be considered as a particular example of a disaster where the dynamics of the situation is particularly important. it is distinct from earthquakes, bushfire, or floods that can only affect a particular geographical area (that might be large but nevertheless bounded area). table is a comparison chart highlighting some differences between disease outbreak and bushfire or flood disasters. one of the intriguing facts is that outbreaks have different transmission and infection rates not only between countries but also between different states in a single country and within each state of similar demographics and geographic characteristics. an example is the following reported cases of infection in australia for the h n outbreak (eastwood et al, ) . table shows that within the same country the infection rate can differ by up to fivefold from one state to another (e.g., compare new south wales (nsw) rates with those of victoria and australian capital territory). table disaggregates information about outbreak within the same state (eastwood et al, ) . we can see that hunter new england (hne) had the lowest transmission rate ( . per , population), whereas an adjacent health area (north coast) had a transmission rate more than twice as large ( per , ). also, hne had the lowest number of confirmed cases in nsw state ( only). table indicates that within the same state there is about an eightfold variation in table differences between disease outbreak and bushfire/flood disasters disease outbreak bushfire/flood wave pattern behaviour determined by the pathogen infectivity; might re-infect the same affected area/population after burning a certain area, does not return to it can arise out of another disaster (flood or earthquake) due to environmental and population behavioural changes rarely preceded by other disasters outbreaks can cross geographic boundaries to be a global phenomenon (h n , sars) bounded by geographical characteristics (bush/ rivers locations) population discriminative; usually some population segments (elderly, children) are more vulnerable than others population is targeted based on geographical location vulnerability alone mutative and adaptive (influenza is the best example). this antigenic-drift adds to the complexity of the spread patterns n/a the spread patterns are influenced by different factors including pathogen contagion, demography, and behaviour spread is based on simple factor(s) mainly geographical characteristics might have a deterministic effect on health workforce (health workers will have families to protect; more infection in health work force as result of contact with pathogens more than others in population) relief effort worker can relocate family to safe location creates hotspots that 'move', 'die', or 'fragment' to hundreds of other locations depending on population movements hotspots are population independent. can be predicted based on geography and meteorology can be nature made or man-made (bio-terrorism) can be nature made or man-made (arsonists) the australian total includes all territories. knowledge transfer process during disease outbreak fadl bdeir et al infection rates. taking into consideration that demographics are similar and pathogen is the same, then management and coordination of the response to the outbreak is one factor affecting the infection rate. this effort is led by the corresponding agencies in each individual state and area health services within the states. usually, outbreak detection and intervention plans standardise each type of outbreak according to disease type. hence, researchers and epidemiologists prepare tuberculosis plans, influenza plans and so on. by contrast, coordination of the multi-agency response is left to public health officials with very little academic research to support their decisions (comfort et al, ; dawes & government, ; shen & shaw, ; chen et al, ) . as a result, there are discrepancies in the application of resources, which will impact on infection rates and may partially explain the variation in the rates shown in tables and . successful intervention is a direct consequence of successful coordination. it is the coordination effort that brings together different types of resources such as information, expertise, and supplies (chandler, ) for the most efficient intervention plan. coordination is also based on building a common understanding about the task in hand. in this paper, we use measures from social network theory to better understand the dynamics of inter-organisational coordination during disease outbreaks and how this leads to collective decentralised knowledge sharing. we collect disease outbreak coordination data from hunter new england area health services (hneahs) in nsw, australia for demonstrating the effectiveness of these network-based measures to accomplish an effective coordination and communication plan that will contribute to the reduction of infected cases and transmission rates. then we use the theoretical concept of social-based knowledge management sharing to suggest the fundamental principles for modelling knowledge sharing during disease outbreaks. a considerable amount of research has been undertaken into disease outbreaks from an epidemiological perspective including the role of pathogen transformation, mutation, and infection, and the modelling of disease spread. some of these approaches represent epidemics of communicable diseases as markovian or non-markovian processes and apply stochastic epidemic threshold theory to guide public health measures aimed at preventing major outbreaks. other approaches identify general properties of emerging infectious agents to determine the success of different public health measures such as isolating symptomatic individuals or tracing and quarantining their contacts. there has also been a promising attempt to develop a disease outbreak event corpus. however, in contrast to the models of disease outbreak, there has been relatively little work been done on modelling the response of the multiple agencies responsible for dealing with the outbreak (chen et al, ) . since there are not many studies that deal with organisational dynamics at play in the disease outbreak context, we use an investigative approach with a qualitative case study to capture rich information from senior health disaster management practitioners in the field. this provides a better insight into the complexity of the problem, a better understanding of the context, and a much needed holistic view of the entire coordination system. our the discripancy with the nsw total in table is due to differences in population projections. in this case study, we explore the multi-agency coordination and communication that took place in hneahs during the endemic. hneahs is located in northern nsw within a geographical area of over , km , spans local council areas, and has a population of about , . hneahs is unique in that it is the only health service in nsw with a major metropolitan centre (newcastle/lake macquarie), as well as a mix of several large regional centres and many smaller rural centres, as well as remote communities within its borders. hneahs activates the health service functional area coordination (hsfac) centre during major health crises. hsfac is responsible for activating the emergency operations centre (eoc) located in the john hunters hospital, leading management response, providing intelligence and guidance, and monitoring the cases reported by the 'front line' (i.e., emergency department (ed), general practitioners (gps), and other relevant health professionals). hsfac objectives are as follows: send a unified message to the community. have standardised information distributed to the front line (i.e., eds, gps). apply robust case definition communication policy to reduce the time between receiving it from the state level until deployed in the front line, as well as getting a confirmation about its deployment. providing intelligence and relevant information to the front line in as short as one page, rather than long irrelevant policies. pre-empting any industrial dispute due to changing work conditions like long work hours. keep the different sectors of the industry informed about the outbreak development. table , the hneahs has achieved the lowest transmission rate in nsw. this can be at least partially credited to their successful management and coordination effort. using network theory to investigate their organisational coordination and communication model presents a unique opportunity to discover the characteristics of this model. the interview data used here were collected in october . in order to capture a holistic view of the complexity and dynamics of the coordination process, we conducted semi-structured interviews with the senior hsfac leaders in hne. the interviews focused on recalling the communication and coordination processes that took place during the h n endemic. these exploratory interviews were structured in to five sections where each section focused on one aspect of the coordination process. these sections were designed to be used for a follow-up using qualitative data capturing techniques. they were also designed to build a meta-data network structure for the coordination that will be used for further analysis. the sections and their relative primary questions are presented in table and the complete questionnaire is given in the appendix. in this paper, we discuss sections b and c (actors and processes) compiled in the form of inbound and outbound communication protocols. in this section, we introduce the necessary theoretical background relating to coordination, coordination complexity in disasters, and social network analysis. coordination is increasingly seen to be important as organisations become more reliant on interdisciplinary teams of specialties and distributed operations for addressing complicated situations demanding a multi organisational response. the oxford english dictionary defines coordination as a 'harmonious combination of agents or functions toward the production of a result'. malone & crowston ( ) defined coordination as 'the act of managing interdependencies between activities performed to achieve a goal'. in its simplest conceptualisation, coordination brings the activities of many disciplines or organisations together to achieve desired goals. it describes both processes and the goals (chisholm, ) and is particularly challenging where the chains of interaction are complex and long. research in coordination is therefore an interdisciplinary study that assists in building useful cooperative work tools for supporting activities, actor relations, and their interdependencies for achieving goals collectively. complexity of coordination in multi-agency dynamic environments during disasters has been studied by kapucu ( ) and hossain & kuti ( ) using a framework primarily drawn from dynamic network theory and complex adaptive systems theory. kapucu observed that coordination in extreme events is guided by a group of interconnected actors who necessarily rely on each other to achieve the goals collectively. he further highlighted the difficulty of building effective networks of action, which is particularly difficult in dynamic environments. a major facet of coordination is communication, which has been studied by feczak and hossain ( ) within the context of temporal team dynamics for bug fixing behaviour during open source software lifecycle management. a study by miller & moser ( ) suggests that 'communication can play a key role in the ability of agents to reach, and maintain, superior coordination'. the two concepts are linked because communication can be regarded as a necessary and sufficient precedent associated with coordination. disease outbreak represents a dynamic environment in which coordination mechanisms must be dynamic in order to adapt to the consequences of disease spread. therefore, the coordination structure for disease outbreaks cannot be modelled or analysed using current standard and static coordination methods that focus on market theory proposed by malone & crowston. the concept of dynamic emerging coordination (comfort et al, ) is seen to be better suited to model the inter-organisational communication where agencies have a tendency to establish, drop, and enhance communication links over time in order to achieve the optimal coordination scheme. we propose that emerging coordination can be best modelled as a complex adaptive system where the components are interacting dynamically with each other within the environment. some of the characteristics of such coordination are: information sharing can be regarded as the backbone of any successful coordination (iannella & henricksen, ) . information flow can be unidirectional or bidirectional. therefore, rapid information flow is essential for dynamic coordination because it provides the essential situational data necessary for quick adaptation. the coordination context is a direct result of the environment motivating the coordination. besides dictating the resources sought after, the environment also influences the nature of the organisations that coordinate with each other. self-organising behaviour self-organisation is a dynamic and adaptive process where systems acquire and maintain structure without external control (de wolf & holvoet, ) . under these circumstances, operations will autonomously organise themselves within the whole coordination structure. this can further suggest that the system is adaptive to any external perturbations and change, in which case it will always be attracted to the self-organised state rather than to chaos. this is the main reason for referring to such coordination systems as 'dynamic' since self-organising is inherited from adaptability, resilience, and flexibility. visualising inter-organisational coordination as a network structure is not uncommon. hossain ( ) has shown the viability of using network modelling for interorganisational coordination and collaboration. using this modelling approach, a node represents an entity (organisation, agent), and the links represent communication channels. these channels can be unidirectional (oneway communication -push or feed communication) or bidirectional (two-way communication). modelling emergent coordination as a network structure can be beneficial as it can incorporate the dynamism of the process of emergence. this is represented by re-configuring the nodes based on their new contexts, which are determined by updated communication links. hence, it is possible to add new agencies to the structure, move the important ones to the action centre of the network structure and the unimportant ones to the periphery. also, this structure can be analysed across time. below are some of the measures that can be applied in such a coordination structure. centrality is the number of links to and from an organisation measured within the locality of the specific node (freeman, ) . in a directed, asymmetric network, there can be in-degree centrality, number of ties received, and out-degree as the numbers of ties sent. indegree is an indication of the importance of the node for its connected neighbours. it can be one that requires resources or a decision-making authority. out-degree will be an organisation actively establishing links to acquire resources. betweenness is a measure of the nodes that lie on the shortest path that connects everyone else in the network, hence it measures the degree to which a node occupies a strategic position within the network (freeman, ) . this means that these nodes have quick access to new information and share this information with others. these nodes act as information relays since they will be used to pass information quickly to others. weak ties are efficient in knowledge sharing (granovetter, ) . they provide access to new information since they bridge otherwise disconnected nodes or groups (or what are known as structural holes) (hansen, ) . a bridge is a link in a network that provides the only path between structural holes. linking nodes across the structural hole bridges two networks together (harary et al, ) . these weak ties, or bridges, are instrumental for learning new information because they provide access to novel information which would otherwise be absent within the standard contacts' reach (valente, ) . one other facet of coordination and networks is the informal coordination. it can be defined as when individuals or organisations establish communication networks (cns) outside the standard coordination structure to 'get things done' (baker, ; han, ) . informal networks can fill the lines that formal channels ignore, or capitalise existing ones to circumvent their complications, inefficiencies, or even their inaccuracies. informal networks are an integral part of any coordination process. indeed cross et al ( ) even stated that, 'work increasingly occurs through informal networks of relationships rather through channels tightly prescribed by formal reporting structure of detailed work processes' (cross et al, ) . devons supports that 'informal relationships are deliberately and consciously established and developed with the intent of exploiting them for the purpose of coordination ' (cited in chisholm, ) . in a multi-organisational coordination, it is expected that organisations will efficiently utilise their existing links to maximise their fit and access to required resources. otherwise, if their existing links do not provide access to the needed resource, they will actively branch new ones. the challenge remains in not falling into the temptation of burdening themselves with too many links, which will generate information redundancy and communication overhead. we discuss outbound and inbound communication related to the h n coordination dynamics separately. inbound communication represents a node receiving communication, and outbound represents a node establishing the communication channel. such a link indicates the presence of a coordination relationship between both organisations. this coordination might be in the form of information sharing or resources exchange. outbound communication is discussed in two parts: formal and informal outbound communication. formal outbound communication started with the contain phase when hsfac activated the eoc that should function as the main coordinator during such situations. in order to achieve the objectives discussed previously, hsfac team elicited the existing communication channels rather than trying to establish new ones from scratch. it examined them, strengthened those that needs further support, and worked to bridge any structural holes. the communication plan displayed in figure is named the pheromone communication, and followed oneto-many, short, rapid, and two-way communication approaches. it represents the communication links starting from the state public health and ending at the eds in all the hne hospitals. these links are primarily used to distribute quick and intelligent information rather than standard operating manuals and polices which in turn were posted on the hne website for further reference. the case definition is a one-page communication that is essential for having unified cases admitted to the patients tracking system. also, the same structure is used to receive feedback acknowledgment of case definition deployment into the system. the health service functional area coordinator (hsfac) has strategically positioned itself on the path of communication that bridges the state public health and the director of clinical operations (dco). by covering this structural hole, they are able to control and filter the information flow between the two nodes to the benefit of the ed nodes that are linked to the dco. hence, the dissemination of the case definition is reduced from h to min including the acknowledgment from the eds that the new case definition has been imported into the system. it can be noticed that hsfac is not positioned in a high degree centrality so that it is not overburdened with a communication overhead. they actually elicited the dco's high degree centrality and its existing communication channels to pass the intended communication. furthermore, the hsfac team consciously used informal cns when it was essential to do so. this form of communication was found effective especially when they had to communicate with other bodies (medical and non-medical) outside their own jurisdiction. so, they extended to establish informal communication with the following parties: (a) gps: hne has five divisions of gps divided into five executive divisions that work under different jurisdiction and have a direct link to state health services. being the first point of contact for many potential cases and being geographically dispersed, the gps represent an excellent network of information collection nodes and an effective medium for message dissemination. hence, the importance of establishing coordination bridges with them. once this informal link was established, the gps network became so efficient that it was possible to set up an urgent meeting with the executive managers of the five divisions within min notice. this relationship was also used to train the gps to build up their surge capacity to receive more patients rather than directing them to the hospitals and risking over-stretching of the respective eds. (b) industrial response grid: hsfac wanted to avoid industrial disputes that might arise from changing working conditions, and so updated the local business network about the outbreak and disseminated information on how to protect their workforce. in order not be overwhelmed by the need for thousands of messages, the hsfac communicated with the main bodies representing the different industries who then passed the communication to their members. (c) consultancy grid: in order to get advice from the required disciplines, the hsfac co-opted expertise personnel from different domains: respiratory, clinical care, infection control, pharmacy, and secondary workforce liaison officer. (d) ambulance grid: during the outbreak, it was discovered that the area ambulance services new south wales (asnsw) was not being updated with the latest outbreak information. hence, an informal link was established to them to provide the latest outbreak and case definition information. figure shows these four informal communication lines between the hsfac and the four networks discussed above. one can deduce from the above information that some of the important features of the emerging coordination were successfully implemented by the hsfac team: active discovery of the structural holes and bridge building. the hsfac acted as the information broker and passed essential information, while at the same time not overloading themselves with high figure outbound communication. fadl bdeir et al information demands. one successful method was to sustain a one-way (outbound) informal information feed such as in the example with the industrial response grid and asnsw. active development of the informal networks when needed in two-way relationships (e.g., gps) and use their surge capacity to protect valuable resources, such as eds, from high demand since these have limited surge capacity. from the discussion above, the hsfac has utilised network measures efficiently in deciding their relative position in the network and in bridging structural holes when needed. results relating to inbound communication will be presented in two parts: the global and federal inbound case definition communication figure shows inbound communication starting from the who to the hne hsfac that passes the latest information about h n , most importantly the revised and updated 'case definitions' that define which individuals fall under the pandemic follow-up, and management criteria based on symptoms and medical tests. such communication was through the standard hierarchical communication channels that ensured standardised case definitions nationwide. an important part of disaster management is the collation of data relating to damage impact. in dynamic environments such as a disease outbreak, the need for continual live and accurate data cannot be overstated. this is not only required for effective management, but rather for the whole coordination process and successful resource distribution. however, it is practically impossible for a single agency to collect all the data. there will be many agencies gathering information, each following its own protocols under its own jurisdiction. the coordination of the information collection effort and the assessment and optimal investment of this information complete the data collection circle. disease monitoring systems must be adaptive according to different criteria: intensive care units (icus) for example usually have a limited number of beds and nurses, as well as a strict nurse to bed ratio. also the icus' surge capacity is limited and can only add a small number of beds or personnel. resources such as these need a 'lead monitor' that will quickly flag the number of cases that are using, or will use, this resource. this will enable the organisation to operate within their capacity or coordinate with other organisations to receive overflow cases. the monitoring system needs to be distributed geographically and functionally in order to capture cases at early signs of development. this has to be achieved without over-extending resources but rather by using existing ones, such as gps, whose network extends over a wide area of communities and in many scenarios are the first referral point for patients. on the basis of these criteria, hne hsfac established an inbound monitoring system to capture case details as they are identified with lead indicators on specifically critical resources. figure shows the network positions and functionality of each monitor. again, the hsfac did not position itself as the central node in the network. they aggregated the lag monitors, which require less attention than the lead ones, to the public health emergency operation centre. on the other hand lead monitors, which have high urgency, were directly connected to the hsfac in order to communicate their existence to relevant parties quickly and to predict resource requirements, as well as planning their required surge capacities. in this scenario, the hsfac sacrificed the higher degree of centrality and betweenness, which would have meant a connection to every single node (star network). this would have meant maintaining a link to every single organisation along with the burden of processing all inbound information. analysing the cn is a necessary prerequisite to build a knowledge sharing system since the latter uses these channels to transfer the knowledge among individuals, organisations, communities, or groups (argyris, ). not only knowledge building and sharing is an essential ingredient in productivity, competitiveness, and maintaining institutional memory (leonard- barton, ; laycock, ) , but also a key component for coordinating disaster management and relief efforts (zhang et al, ) . sharing knowledge during disasters needs to be further researched by academics. there are two broad categories of knowledge (polanyi, ; nonaka & takeuchi, ) : . explicit knowledge: this knowledge is usually created by systematic methods through structured and managed methods and is usually the product of formal approaches. it is usually stored in the form of (brannback, ) . case definitions that were discussed previously that are created and transmitted by who and to hsfac team and then disseminated to eds, jps and front line public health sectors are a form of changing explicit knowledge that need to be quickly distributed through the network channels. . tacit knowledge: simply refers to the knowledge in 'people's heads'. they build it through experience, personal learning, and interaction (brannback, ; gourlay, ) . this form of knowledge is hard to transfer and requires certain procedures like transferring people through different departments in the organisation or creating an interaction medium through which they can share the knowledge with others (nonaka & toyama, ) . in our case, an example of tacit knowledge is the disease-specific knowledge such as respiratory and infection control knowledge deeply known to subject matter experts. the 'shared knowledge base' (skb) is fundamental in reaching common perception during disease outbreaks. it is the building block for the common understanding of the situational information, events development, and agreement on the approach to the situation in hand. building this skb will require a medium that will diffuse domain-specific knowledge from those who know to those who need. in disasters, this also has to happen in a timely manner. yet this does not necessarily mean that the skb should be located in a central location accessible to all parties: the reason being that during the outbreak coordination, a coalition of different agencies is formed (gerberding, ) . as discussed above, each one of those agencies has different knowledge requirements, ranging from specific expertise (ed, icu) to general knowledge (gps) and to others with no domain knowledge at all (industrial response grid). in analysing the skb we will use the process view that is explained by hossain et al as, 'the exchange of tacit knowledge among individuals, teams, groups, and communities is critical to the development and sustainability of a knowledge-creating organisation ' (hossain et al, ) . this process-centric approach enables the utilisation of social networks and cns to create distributed skb among the community of interest or coalition of organisations (argyris, ; watson, ) . we will look at how these networks can be used to create the skb for both tacit and explicit knowledge. . tacit to explicit knowledge skb: one example of interpreting tacit knowledge to explicit in the h n coordination discussed above is the informal communication with the industrial response grid, gp grid, and the ambulance grid. these groups did not need an in-depth knowledge of the technicalities of the disease characteristics; their knowledge requirement was more of updating their broad understanding of the symptoms, risks, and protection procedures. hence co-opting domain matter experts (respiratory, infection control y) to create the information needed and channel it through the information communication structure. as discussed in the communication section, this information was pushed to each group rather than creating a central knowledge base (kb) and relying on their willingness to access and use it. this also enabled tailoring the pushed information to these groups based on their general needs, as well as scheduling the information updates periodically according to each group requirement rather than tying them all to a one-bit-one-time scenario. using the domain matter experts to create the explicit knowledge from their tacit knowledge can be represented in figure , which is adapted from hossain et al ( ). the filled geometric shapes represent tacit knowledge and the letters are the explicit knowledge generated from the tacit. the generated transferable explicit knowledge will then be 'pushed' along the informal newly established channels to create a shared pool of knowledge within each group of this network, without the overhead of a centralised one for the whole groups. projecting this process on the communication channels represented in figure will produce figure . the letters represent the explicit knowledge created from the tacit and then pushed to each group to create the skb within each group. . explicit skb: the most vivid representation of explicit knowledge is the case definition. this is produced by who, then passed to federal level, followed by state then to local ending with departmental level. one of the important aspects about this knowledge is it is field operational and actionable information that has an impact on which patients are to be categorised as 'cases' and therefore admitted to the system and followed up accordingly. yet one of the challenges in creating a distributed operational skb is synchronising it between all parties (eds in this case); otherwise, cases will be incoherent and hence inaccurate. this requires a strong and efficient cn. theoretically this mandates analysing the network using social network techniques, and then developing the weak ties to strong ones (granovetter, ) . this distributed yet synchronised shared knowledge will create a coherent understanding across the distributed nodes of the cn. figure shows pushing the distributed explicit case definition knowledge to the departments yet without creating a single cognitive entity across the organisation. another type of tacit knowledge is the inbound casespatients confirmed to be infected with the virus. here for statistics and high-level follow-up the data are being collected from front line departments to central location. this suits the decision makers on area or state level and acts as a central feed channel for follow-up authorities. in disasters, even situational and operational knowledge is essential for local teams, however, there will always be the need to aggregate inbound data for analysis and high level resource management. ensuring a skb is up to date and correctly distributed and implemented across all parties should be the fruit of such research. information and communication technology systems (ict) are a typical medium to build efficient skb systems and spread network. below, we will highlight some characteristics of such systems for both case definition and informal outbound communication. these are mostly intended for one-way communication with no or minimal feedback. the ict system design should take into consideration that it will need to communicate with many different technology systems that are not compatible among each other and will surely contain legacy systems. one can only rightly expect to interact with different corporate systems; some are standard off the shelf and others are built bottom up as per need, while others will be developed on ad-hoc basis. the main features of such ict systems are elaborated in table . case definition outbound transfer these will need to be very reliable and robust. also, rather than feedback, we will adopt the 'acknowledgment' terminology where the eds will need to acknowledge to the distributing party (hsfac) receipt and deployment of these data into their systems. main features of such ict systems will be as per table . this tacit knowledge will be required by higher authority. hence, it has to be arranged and formatted in a way that suits their needs. some of the features of such ict systems are discussed in table . the coordination of interventions for disease outbreaks is a complex task and, at the same time, is underresearched resulting in even less understood knowledge knowledge transfer process during disease outbreak fadl bdeir et al management systems. a good coordination structure is expected to lower infection rates. in this exploratory study, we show the potential use of social network theory to analyse the communication channels implicated in the management of outbreaks. we illustrate this potential by using a particular example of the management of an outbreak of h n by the hneahs. a qualitative analysis using network methods to address the complexity of the task, suggests design elements that optimise the level of resource use. in particular, sacrificing the inbound and outbound high degree of centrality by using link aggregations might be a feasible approach for demanding information dissemination organisations. we also discuss the shared knowledge management characteristics and outline the main ict system features design considerations. it is also important to reflect on the data collection approach that we followed for this study. the investigative approach provided us with the first 'insight' into this domain. this approach is useful since no reliable academic data has been collected in this context before. multi to one: information gathered from different locations to end up in a central one table characteristics of the ict system for informal communication redistributable: informal information will be expected -and sometimes required -to be redistributed and disseminated down the other party's hierarchy or chain push: after being built, data will be 'pushed' to other parties limited feedback: the skb should be built with broad audience in mind, however, feedback from such a large audience is expected to be huge and often unnecessary. hence, limited feedback functionality is provided open ability: the ability to communicate with a wide spectrum of ict systems correctly and easily one to many: single entity sending to many knowledge transfer process during disease outbreak further insight is required into the complexity that involves players, characteristics, communication, and the dynamics that affect the processes. this includes the following aspects: . when does the initiation point of disease outbreak start and which parties are involved at this stage? . what type of agencies are involved at different stages of the outbreak phases? . how do the formal and informal relationships evolve during the coordination lifetime? . what are the dynamics that affect nodes' (organisations) and links' performance during the outbreak? therefore, more qualitative and quantitative data are needed. in a future case, we are planning to arrange follow-up interviews with the players at key positions during the outbreak management and intervention period. this would assist in capturing rich qualitative data that will then be utilised as the basis for further analysis. we also aim to collect quantitative data for statistical validation leading to generalisations of the hypotheses generated by this study. such data will provide a good foundation for structural and statistical analysis of the network. in this phase, we will capture the dynamic behaviour of the network expressed by the creation and loss of links and nodes. combining qualitative and quantitative data with network analysis techniques, will provide a more powerful understanding of the coordination in outbreaks and creates an opportunity to propose an efficient disease outbreak coordination model based on network theory. on organizational learning tapping into the power of informal groups r&d collaboration: role of ba in knowledgecreating networks coordination in emergency response management coordination in rapidly evolving disaster response systems: the role of information complex systems in crisis: anticipation and resilience in dynamic environments making invisible work visible: using social network analysis to support strategic collaboration information, technology and coordination: lessons from the world trade center response: center for technology in government emergence versus self-organisation: different concepts but promising when combined australia's pandemic 'protect' strategy: the tension between prevention and patient management measuring coordination gaps of open source groups through social networks centrality in social networks: conceptual clarification faster y but fast enough? responding to the epidemic of severe acute respiratory syndrome towards conceptual clarity for 'tacit knowledge': a review of empirical studies the strength of weak ties the informal organization you've got to live with the search-transfer problem: the role of weak ties in sharing knowledge across organization subunits structural models: an introduction to the theory of directed graphs effect of organisational position and network centrality on project coordination disaster response preparedness coordination through social networks understanding knowledge management, sharing and transfer systems in organizations managing information in the disaster coordination centre: lessons and opportunities interorganizational coordination in dynamic context: networks in emergency response management collaborating to compete: achieving effective knowledge sharing in organizations wellsprings of knowledge: building and sustaining the sources of innovation what is coordination theory and how can it help design cooperative work systems communication and coordination effective emergency management: reconsidering the bureaucratic approach the knowledge-creating company: how japanese companies create the dynamics of innovation the knowledge-creating theory revisited: knowledge creation as a synthesizing process personal knowledge: towards a post-critical philosophy managing coordination in emergency response systems with information technologies social network thresholds in the diffusion of innovations data management, databases and organizations engineering self-organising systems a knowledge management framework for the support of decision making in humanitarian assistance/disaster relief outbreak: how is the outbreak detected? what is the information route from the time an infection is detected until containment is successful? what are the criteria to categorise a disease spread as being do. (cases threshold/are there different thresholds for different disease types?) what are the criteria that a certain disease has been contained/'back to normal' situation is declared? inter-organisational: * organisations that coordinate together whenever a do is declared f name/role (intervention, communication) jurisdiction (community/local/state/federal/ private/who) f contact details f phase of mobilisation (is it called to join) f area of work * where: area/jurisdiction/service covered by each organisation (some organisations might cover geographical area/some might cover professional service/some other might cover information or communication services) * workflow: how does involvement start, progress and finish for each organisation? intra-organisational: in order to research informal networks: what are specific departments within these organisations that get involved? same questions as above. individuals: individuals playing pivotal role in intervention and outbreak management and coordination. name/contact/position/role before do/role during do/communication procedures or protocols action: an overview of how the coordination process (communication and intervention) takes place. is there communication plan/protocol/standards? * is it predefined? * does it change and how? * are historical data available? * how does involvement start, progress and finish for each organisation? key: cord- -rcv pl d authors: o’ryan, miguel l.; nataro, james p.; cleary, thomas g. title: microorganisms responsible for neonatal diarrhea date: - - journal: infectious diseases of the fetus and newborn infant doi: . /b - - - / - sha: doc_id: cord_uid: rcv pl d nan at the beginning of the st century, diari..eal disease continues to be a significant cause of morbidity and mortality worldwide. during the period of to , an estimated . billion children younger than years suffered an episode of acute diarrhea every year in developing countries; among these, . million required outpatient medical care, and million required hospitalization. approximately million diarrhea-associated deaths occurred in this age group annually, primarily in the most impoverished areas of the world.' these estimates are somewhat lower than the more than million annual deaths from diarrhea reported in the prior years? indicating progress in prevention and treatment of acute diarrhea. in the united states, approximately childhood deaths per year were reported during the late ~,~*~ although the actual number may be higher: accurate incidence rates for acute diarrhea in neonates from different populations are not readily available. the relative sparing of the newborn probably results from low exposure to enteropathogens and protection associated with brea~t-feeding.~-' after the first few months of life, increasing interaction with other individuals and the environment, including introduction of artificial feeding, increases the risk of exposure to enteropathogens. for most pathogens, the incidence of acute diarrhea peaks in children between months and years old? neonatal diarrhea is more common in underdeveloped areas, where low educational levels, crowding, and poor standards of medical care, environmental sanitation, and personal hygiene favor early contact with enteropathogens. as the incidence of neonatal gastroenteritis rises, there is a proportional increase in neonatal deaths because medical care for the poor often is inadequate.' *" for very low birth weight infants (< g), the death rate from diarrhea is -fold greater than for higher-birth-weight infants. this chapter discusses the pathogenesis, diagnosis, treatment, and prevention of gastroenteritis based on the available knowledge about pathogens that can cause neonatal diarrhea. pathogens that rarely or never cause acute diarrhea in neonates are not discussed. after an overview of host defense mechanisms and protective factors in human milk, the remainder of the chapter is devoted to specific pathogens that cause inflammatory or noninflammatory diarrhea. the neonate is a host that is uniquely susceptible to enteric infections. neonates have not had the opportunity to develop local or systemic immune responses, and in the first few days of life, they have not acquired the highly important enteric flora that protects the normal adult gastrointestinal tract.i -" still less is known about the barrier effect of the neonate's gastric acidity," intestinal mucus,z or each of which provides protection against gastrointestinal tract infections in older infants, children, and adults. the gastric acid barrier appears to be least effective during the first months of life. the average gastric ph level of the newborn is high (ph to ; mean, ). , although the ph falls to low levels by the end of the first day of life (ph to ), it subsequently rises again; by to days of life, the hydrochloric acid output of the neonatal stomach is far less than that of older infants and ~hildren.~~.'~ the buffering action of frequent milk feedings and the short gastric emptying interpose additional factors in the neonate that would be expected to permit viable ingested organisms to reach the small intestine. the intestinal epithelium serves as a nutrient absorptive machine, barrier to pathogen entry, and regulator of inflammation. intestinal epithelial cells have receptors for bacterial products and produce chemokines (e.g., interleukm [ il]- , monocyte chemotactic protein type [ mcp- , granulocyte macrophage-cell stimulating factor [ gm-csf] ) and proinflammatory cytokines (e.g., il- , tumor necrosis factor-a [tnf-a], il- ) in response to invasion by enteropathogens." the gut epithelium orchestrates the immune response. however, in the newborn, phagocytic, chemotactic, and complement functions are immature. b and t lymphocyte functions are impaired, resulting in a preferential igm production in response to antigenic stimulation. igg is actively transferred from mother to infant across the placenta at about weeks' gestation and peaks by about weeks; premature neonates, especially those born before weeks' gestation, are deficient in these maternally derived serum antib~dies.~' h e - the importance of breast-feeding infants for the prevention of diarrheal disease has long been e m p h a s i~e d .~~~~* -~~ published studies reporting the association between breastfeeding and diarrhea are extensive and suggest that infants who are breast-fed suffer fewer episodes of diarrhea than those who are not. this protection is greatest during a child's first months of life and declines with increasing age, during the period of weaning, partial breast-feeding confers protection that is intermediate between that gained by infants who are exclusively breast-fed and that by those who are exclusively bottle-fed. a striking demonstration of the protection afforded by breast-feeding of newborns has been provided by mata and urrutiai in their studies of a population of infants born in a rural guatemalan village. despite extremely poor sanitation and the demonstration of fecal organisms in the colostrum and milk of almost one third of diarrheal disease did not occur in any newborns. the incidence of diarrhea rose significantly only after these infants reached to months old, at which time solids and other fluids were used to supplement the human milk feedings. at that time, escherichia coli and gram-negative anaerobes (e.g., bacteroides) were found to colonize the intestinal tract.i in contrast, urban infants of a similar ethnic background who were partly or totally artificially fed frequently acquired diarrheal disease caused by enteropathogenic e. coli (epec) . multiple mechanisms by which breast-feeding protects against diarrhea have been postulated. breast-feeding confers protection by active components in milk and by decreased exposure to organisms present on or in contaminated bottles, food, or water. many protective components have been identified in human milk and generally are classified as belonging to the major categories of cells, antibody, antiinflammatory factors, and glycoconjugates and other nonantibody f a~t o r s .~~-~' examples of milk antibodies are summarized in table - . for any given pathogen, multiple milk factors may help protect the infant. human milk typically targets a major pathogenic mechanism using multiple, redundant strategies. redundancy of milk protective factors and targeting of complex virulence machinery have created a formidable barrier to enteropathogens. despite the fact that pathogens can rapidly divide and mutate, milk continues to protect infants. for example, human milk has secretory antibodies to shigellu virulence antigens and lipopoly-saccharide^,^^.^^ neutral glycolipid gb to bind shiga and lactoferrin to disrupt and degrade the surface-expressed virulence antigen^.^^-^^ in a similar way, milk contains antibodies directed toward the surface expressed virulence antigens of epec, ' oligosaccharides that block cell attachment? and lactoferrin that disrupts and degrades the surface expressed epec antigens ' human milk can initiate and maintain the growth of bifidobacterium and low ph in the feces of newborn infants, creating an environment antagonistic to the growth of e. ~o l i . ' the protective effect of human milk antibodies against enteropathogen-specific disease has been described for vibrio cholerae, campylobacter j e j~n i , ~~ epec, enterotoxigenic e. coli (etec), shigella, ' and giardia lamblia , and for bovine milk concentrate against etec, rota~irus,~' and shigella. in , the nonlactose carbohydrate fraction of human milk was found to consist mainly of oligosa~charides.~~ in , montreuil and mullet determined that up to . % of colostrum and up to . % of mature milk are oligosaccharides. human milk contains a larger quantity of the oligosaccharides than does milk from other mammals, and its composition is singularly complex. the metabolic fate of the oligosaccharides is of interest. only water, lactose, and lipids are present in greater amounts than the oligosaccharides. despite the fact that substantial energy must be expended by the mother to synthesize the many hundreds of different milk oligosaccharides, the infant does not use them as food. most of the oligosaccharides pass through the gut undigested. it is thought that they are present primarily to serve as receptor analogues that misdirect enteropathogen attachment factors away from gut epithelial carbohydrate receptors. likewise, enteropathogens use the oligosaccharide portion of glycolipids and glycoproteins as targets for attachment of whole bacteria and toxins. evidence is emerging that these glycoconjugates may have an important role in protection of the breast-fed infant from disease. human milk protects suckling mice from the heat-stable enterotoxin (st) of e. coli; on the basis of its chemical stability and physical properties, the protective factor has been deduced to be a neutral fucosyloligosaccharide. ~ experiments have shown that epec attachment to hep- cells can be inhibited by purified oligosaccharide fractions from human milk. oligosaccharides also may be relevant to protection from norwalk virus and other caliciviruses, because these viruses attach to human abo, lewis, and secretor blood group antigens. ' human milk contains large amounts of these carbohydrates. the ganglioside fraction in human milk has been shown to inhibit the action of heat-labile toxin (lt) and cholera toxin on ileal loops more effectively than secretory iga. s lactadherin in human milk has been shown to bind rotavirus and to inhibit viral replication in vitro and in v~v o . ~~ a study of infants in mexico showed that lactadherin in human milk protected infants from symptoms of rotavirus infection. e. coli organisms promptly colonize the lower intestinal tracts of healthy infants in their first few days of life - and constitute the predominant aerobic coliform fecal flora throughout life in humans and in many animals. the concept that this species might cause enteric disease was first suggested in the late th and early th centuries, when several veterinary workers described the association of diarrhea (i.e., in , m r '~ observed that bacterium (now escherichia) coli was found more often in the small intestines of children with diarrhea than in children without diarrhea. adam * confirmed these findings and noted the similarity with asiatic cholera and calf scours. he further extended these observations by suggesting that e. coli strains from patients with diarrhea could be distinguished from normal coliform flora by certain sugar fermentation patterns. although he called these disease-producing organisms dyspepsicoli and introduced the important concept that e. coli could cause enteric disease, biochemical reactions have not proved to be a reliable means of distinguishing nonpathogenic from pathogenic e. coli strains. there are now at least six recognized enteric pathotypes of e. ~oli.'~ the pathotypes can be distinguished clinically, epidemiologically, and pathogenetically (table - ) . - etec organisms are defined by their ability to secrete the lt or the st enterotoxin, or both. lt is closely related to cholera toxin and similarly acts by means of intestinal adenylate c y c l a~e , '~~~'~~ prostaglandin s y n t h e~i s , '~~~'~~ and possibly platelet activating f a c t~r . '~~' '~~ st (particularly the variant sta) causes secretion by specifically activating intestinal mucosal guanylate cyclase.' "-' l the stb toxin causes noncyclic, nucleotide-mediated bicarbonate secretion and appears to be important only in animals. ' -" enteroinvasive e. coli (eiec) has the capacity to invade the intestinal mucosa, thereby causing an inflammatory enteritis much like shigellosi~.'~~~''~ epec elicits diarrhea by a signal transduction m e~h a n i s m~~~'~~~~~'~'~~ which is accompanied by a characteristic attaching-and-effacing histopathologic lesion in the small intestine. ' enterohemorrhagic e. coli (ehec) also induces an attaching-and-effacing lesion, but in the colon?' ehec also secretes shiga toxin, which gives rise to the sequela of hemolytic-uremic syndrome (hus). diffusely adherent e. coli executes a signal transduction effect, which is accompanied by the induction of long cellular processes. enteroaggregative e. coli (eaec) adheres to the intestinal mucosa and elaborates enterotoxins and a major problem in the recognition of etec, eiec, epec, and ehec strains of e. coli is that they are indistinguishable from normal coliform flora of the intestinal tract by the usual bacteriologic methods. serotyping is of value in recognizing epec serotypes' and eiec, because these organisms tend to fall into a limited number of specific serogroups (see table - ).' ' eiec invasiveness is confirmed by inoculating fresh isolates into guinea pig conjunctivae, as described by sereny. ' the ability of organisms to produce enterotoxins (lt or st) is encoded by a transmissible plasmid that can be lost by one strain of e. coli or transferred to a previously unrecognized although the enterotoxin plasmids appear to prefer certain serogroups (different from epec or invasive serogro~ps),'~~ etec is not expected to be strictly limited to a particular set of serogroups. instead, these strains can be recognized only by examining for the enterotoxin. this is done in ligated animal or by enzyme-linked immunosorbent assay (elisa)' for lt or in suckling mice for st. , specific dna probes also are available for lt and st. whether there are other mechanisms involved in the ability of the versatile e. coli species to cause enteric disease, such as by producing other types of enterotoxins"' or by fimbriate adherence traits a l~n e , '~~. '~' remains to be elucidated. cytoto~ns. ~ , in tissue although early work on the recognition of e. coli as a potential enteric pathogen focused on biochemical or serologic distinctions, there followed a shift in emphasis to the enterotoxins produced by previously recognized and entirely "new" strains of e. coli. beginning in the mid- s with work by de and colleague^'^^^'^^ in calcutta, e. coli strains from patients with diarrhea were found to cause a fluid secretory response in ligated rabbit ileal loops analogous to that seen with v; cholerue. work by taylor and associate^'^"^^ showed that the viable e. coli strains were not required to produce this secretory response and that this enterotoxin production correlated poorly with classically recognized epec serotypes. in sho paulo, trabulsi'& made similar observations with e. coli isolated from children with diarrhea, and several veterinary workers demonstrated that etec was associated with diarrhea in piglets and cal~es.'~~-'~o a similar pattern was described in with acute undifferentiated diarrhea in adults in bengal from whom e. coli could be isolated from the upper small bowel only during acute i l l n e~s . '~' "~~ these strains of e. coli produced a nondialyzable, lt, ammonium sulfate-precipitable enterotoxin.' analogous to the usually short-lived diarrheal illnesses of e. coli reported by several workers, a short-lived course of the secretory response to e. coli culture filtrates compared with the secretory response of cholera toxin was de~cribed."~ however, like responses to cholera toxin, secretory responses to e. coli were associated with activation of intestinal mucosal adenylate cyclase that paralleled the fluid secretory r e~p o n s e . '~~. '~~ the two types of enterotoxins produced by e. have been found to be plasmid-encoded traits that are potentially separable from each other and from the equally important plasmid-encoded adherence traits for patho-st causes an immediate and reversible secretory whereas the effects of lt (e.g., cholera toxin) follow a lag period necessitated by its intracellular site of a~t i o n . '~~' '~' '~~ only lt appears to cause fluid secretion by activating adenylate cyclase, which is accomplished by toxininduced adp-ribosylation of the gsa signaling p r~t e i n .~' "~~ the activation of adenylate cyclase by lt and by cholera toxin is highly promiscuous, occurring in many cell types and resulting in development of nonintestinal tissue culture assay systems such as the chinese hamster ovary (cho) cell assay' and y adrenal cell assay.' the antigenic similarity of lt and cholera toxin and their apparent binding to the monosialoganglioside gm, have enabled development of elisas for detection of lt and cholera t~x i n . '~~, '~' -'~~ st is a much smaller molecule and is distinct antigenically from lt and cholera t~x i n . '~~, '~'~'~' al though it fails to alter camp levels, st increases intracellular intestinal mucosal cyclic guanosine monophosphate (cgmp) concentrations and specifically activates plasma membrane-associated intestinal guanylate cy~lase."'-"~ like camp analogues, cgmp analogues cause intestinal secretion that mimics the response to st."' the receptor for sta responds to an endogenous ligand called guunylin, of which sta is a structural homologue.'" because the capacity to produce an enterotoxin may be transmissible between different organisms by a plasmid or even a bacteri~phage,''~-'~' interstrain gene transfer genesis. [ ] [ ] [ ] may be expected to be responsible for occasional toxigenic non-e. coli. enterotoxigenic klebsiella and citrobacter strains have been associated with diarrhea in a few reports, often in the same patients with etec.' ,' likewise, certain strains of salmonella appear to produce an lt, cho cellpositive toxin that may play a similar role in the pathogenesis of the watery, noninflammatory diarrhea sometimes seen with salmonella enteritidis i n f e c t i~n . '~~"~ at least equally important as enterotoxigenicity for e. coli to cause disease is the ability of these organisms to colonize the upper small bowel, where the enterotoxin produced has its greatest effect. a separable, plasmid-encoded colonization trait was first recognized in porcine e. coli. veterinary workers demonstrated that the fimbriate k- surface antigen was necessary for etec to cause disease in piglets. ' an autosomal dominant allele appears to be responsible for the specific intestinal receptor in piglets. in elegant studies by gibbons and c o -~o r k e r s , '~~ the homozygous recessive piglets lacked the receptor for k- and were resistant to scours caused by etec. at least analogous colonization factors have been described for human e. coli isolate^^^"^'"^^ against which local iga antibody may be produced. these antigens potentially may be useful in vaccine development. data on the epidemiology and transmission of etec remain scanty for the neonatal period. in the past decades, these strains have been recognized among adults with endemic, cholera-like diarrhea in calcutta, india, and in dacca, banglade~h,''~*'~' and among travelers to areas such as mexico and central a f r i~a . '~~-'~~ the isolation of etec is uncommon in sporadic diarrheal illnesses in temperate climates where sanitation facilities are good and where winter viral patterns of diarrhea predominate. etec is commonly isolated from infants and children with acute watery summer diarrhea in areas where sanitary facilities are less than optimal. - *' -' these include areas such as afria, ~~~il, , , , , gentir~a,'~~ bengal,' '' mexico,' o and native american reservations in the southwestern united state^."^"'^ in a multicenter study of acute diarrhea in infants and children in china, india, mexico, myanmar, and pakistan, % of cases (versus % of controls) had etec.le a case-control study from northwestern spain showed a highly significant association of etec with . % of neonatal diarrhea, often acquired in the ho~pital.''~ although all types of etec (lt and/or st producers) are associated with cholera-like, non inflammatory, watery diarrhea in adults in these areas, they probably constitute the major cause (along with rotaviruses) of dehydrating diarrhea in infants and young children in these areas. in this setting, peaks of illnesses tend to occur in the summer or rainy season, and dehydrating illnesses may be life threatening, especially in infants and young ~h i l d r e n . ~~'~'~'~ humans are probably the major reservoirs for the human strains of etec, and contaminated food and water probably constitute the principal vector^.''^"^^ although antitoxic immunity to lt and asymptomatic infection with ltproducing e. coli tends to increase with age, st is poorly immunogenic, and st-producing e. coli continues to be associated with symptomatic illnesses into adulthood in endemic area~.l'~>l'~ the association of etec with outbreaks of diarrhea in newborn nurseries is well documented. ryder and colleagues'g isolated an st-producing e. coli from % of infants with diarrhea, from the environment, and in one instance, from an infant's formula during a -month period in a prolonged outbreak in .a special care nursery in texas. another st-producing e. coli outbreak was reported in by gross and a~sociates'~~ from a maternity hospital in scotland. etec and epec were significantly associated with diarrhea among infants younger than year in bang ade~h.l~ ' an outbreak of diarrhea in a newborn special care nursery that was associated with enterotoxigenic organisms that were not limited to the same serotype or even the same species has been reported.lg the short-lived etec, klebsiella, and citrobacter species in this outbreak raised the possibility that each infant's indigenous bowel flora might become transiently toxigenic, possibly by receiving the lt genome from a plasmid or even a bacteriophage. the clinical manifestations of etec diarrhea tend to be mild and self-limited, except in small or undernourished infants, in whom dehydration may constitute a major threat to life. in many parts of the developing world, acute diarrheal illnesses are the leading recognized causes of death. there is some suggestion that the diarrheal illnesses associated with st-producing etec may be particularly severe.' most probably the best definition of the clinical manifestations of etec infection comes from volunteer studies with adults. ingestion of ' to '' human etec isolates that produce lt and st or st alone resulted in a % to % attack rate of mild to moderate diarrheal illnesses within to hours that lasted to days.' these illnesses, typical for traveler's diarrhea, were manifested by malaise, anorexia, abdominal cramps, and sometimes explosive diarrhea. nausea and vomiting occur relatively infrequently, and up to one third of patients may have a low-grade fever. although illnesses usually resolve spontaneously within to days, they occasionally may persist for week or longer. the diarrhea is noninflammatory, without fecal leukocytes or blood. in outbreaks in infants and neonates, the duration has been in the same range ( to days), with a mean of approximately days. as in cholera, the pathologic changes associated with etec infection are minimal. from animal experiments in which thiry-vella loops were infected with these organisms and at a time when the secretory and adenylate cyclase responses were present, there was only a mild discharge of mucus from goblet cells and otherwise no significant pathologic change in the intestinal tract.lo unless terminal complications of severe hypotension ensue, etec organisms rarely disseminate beyond the intestinal tract. like cholera, etec diarrhea is typically limited to being an intraluminal infection. the preliminary diagnosis of etec diarrhea can be suspected by the epidemiologic setting and the noninflammatory nature of stool specimens, which reveal few or no leukocytes. although the ability of e. coli to produce enterotoxins may be lost or transmitted to other strains, there is a tendency for the enterotoxin plasmids to occur among certain predominant serotypes, as shown in table - ."' these serotypes differ from epec or invasive serotypes, but their demonstration does not prove that they are enterotoxigenic. the only definitive way to identify etec is to demonstrate the enterotoxin itself by a specific gene probe for the toxin codon, by a bioassay such as tissue culture or ileal loop assays for lt or the suckling mouse assay for st, or in the case of lt, by immunoassay such as elisa. however, even these sensitive bioassays are limited by the unavailability of any selective media for detecting etec by culture. even though substantial improvements have been made in enterotoxin assay (particularly for lt), the necessary random selection of e. coli from a relatively nonselective stool culture plate resulted in a sensitivity of only % of epidemiologically incriminated cases in an outbreak when to isolates were randomly picked and tested for enter~toxigenicity."~ by also examining paired serum samples for antibody against lt, only % demonstrated significant serum antibody titer rises, for a total sensitivity of etec isolation or serum antibody titer rises of only %. some have suggested that isolates may be pooled for lt or st assay. the capacity to prove with radiolabeled or enzyme-tagged oligonucleotide gene sequences for the enterotoxins (lt or st) further facilitates the identification of enterotoxigenic organisms.' s a novel method of combining immunomagnetic separation (using antibodycoated magnetic beads) followed by dna or polymerase chain reaction (pcr) probing may enhance the sensitivity of screenin fecal or food specimens for etec or other the mainstay of treatment of any diarrheal illness is rehydration."' this principle especially pertains to etec diarrhea, which is an intraluminal infection. the glucose absorptive mechanism remains intact in e. coli enterotoxininduced secretion, much as it does in cholera, a concept that has resulted in the major advance of oral glucose-electrolyte therapy. this regimen can usually provide fully adequate rehydration in infants and children able to tolerate oral fluids, replacing the need for parented rehydration in most cases . , its use is particularly critical in rural areas and developing nations, where early application before dehydration becomes severe may be lifesaving. the standard world health organization solution contains . g nacl, . g nahco,, . g kcl, and g glucose per liter of clean or boiled drinking water.i ' this corresponds to the following concentrations: mmoyl of sodium, mmovl of potassium, mmoyl of bicarbonate, mmol/l of chloride, and mmol/l of glucose. a variety of recipes for homemade preparations have been described?" but unless the cost is prohibitive, the premade standard solution is preferred. each ounces of this solution should be followed by ounces of plain water. if there is concern about hypertonicity, especially in small infants in whom a high intake and constant direct supervision of feeding cannot be ensured, the concentration of salt can be reduced.' a reduced osmolality solution with mmol/l of sodium and mmoyl of glucose and a total osmolality of (instead of ) mosm/kg has been found to reduce stool output by % and illness duration by % in a multicenter trial involving children in four countries. commercially available rehydration solutions are increasingly available ~orldwide.'~' pathogens. lf , the role of antimicrobial agents in the treatment or prevention of etec is controversial. this infection usually resolves within to days in the absence of antibacterial therapy. moreover, there is concern about the potential for coexistence of enterotoxigenicity and antibiotic resistance on the same plasmid, and co-transfer of multiple antibiotic resistance and enterotoxigenicity has been well d~cumented."~ widespread use of prophylactic antibiotics in areas where antimicrobial resistance is common has the potential for selecting for rather than against enterotoxigenic organisms. the prevention and control of etec infections would be similar to those discussed under epec serotypes. the use of breast-feeding should be encouraged. eiec causes diarrhea by means of shigella-like intestinal epithelial invasion (discussed later). s ' the somatic antigens of these invasive strains have been identified and seem to fall into of recognized groups (see table - ). most, if not all, of these bacteria share cell wall antigens with one or another of the various shigelza serotypes and produce positive reactions with antisera against the cross-reacting antigen."* however, not all strains of e. coli belonging to the serogroups associated with dysentery-lke illness are pathogenic, because a large ( mda) invasive plasmid is also required. additional biologic tests, including the guinea pig conjunctivitis (sereny) test or a gene probe for the plasmid, are used to confirm the property of inva~iveness."~ although an outbreak of foodborne eiec diarrhea has been well documented among adults who ate an imported cheese,"' little is known about the epidemiology and transmission of this organism, especially in newborns and infants. whether the infectious dose may be as low as it is for shigella is unknown; however, studies of adult volunteers suggest that attack rates may be somewhat lower after ingestion of even large numbers of eiec than would be expected with shigella. the outbreak of eiec diarrhea resulted in a dysentery-like syndrome with an inflammatory exudate in stool and invasion and disruption of colonic mucosa."' descriptions of extensive and severe ileocolitis in infants dying with e. coli diarrhea indicate that neonatal disease also can be caused by invasive strains capable of mimicking the pathologic features of shigellosis. the immunofluorescent demonstration of e. coli together with an acute inflammatory infiltrate " in the intestinal tissue of infants tends to support this impression, although it has been suggested that the organisms may have invaded the bowel wall in the postmortem ~e r i d . l '~ there is still little direct evidence concerning the role of invasive strains of e. coli in the cause of neonatal diarrhea. the infrequency with which newborns manifest a dysentery-like syndrome makes it unlikely that this pathogen is responsible for a very large proportion of the diarrheal disease that occurs during the first month of life. the diagnosis should be suspected in infants who have an inflammatory diarrhea as evidenced by fecal polymorphonuclear neutrophils or even bloody dysenteric syndromes from whom no other invasive pathogens, such as campylobacter, shigella, salmonella, vibrio, or yersinia, can be isolated. in this instance, it may be appropriate to have the fecal e. coli isolated and serotyped or tested for invasiveness in the sereny test. plasmid pattern analysis and chromosomal restriction endonuclease digestion pattern analysis by pulsed-field gel electrophoresis have been used to evaluate strains involved in outbreaks. the management and prevention of eiec diarrhea should be similar to those for acute shigella or other e. coli enteric infections. the serologic distinction of e. coli strains associated with epidemic and sporadic infantile diarrhea was first suggested by goldschmidt in and confirmed by dulaney and michelson in . these researchers found that certain strains of e. coli associated with institutional outbreaks of diarrhea would agglutinate with antisera on slides. in , bra?" isolated a serologically homogeneous strain of e. coli (subsequently identified as serogroup ) from % of infants with summer diarrhea in england. he subsequently summarized a larger experience with this organism isolated from only % of asymptomatic controls but from % of infants with diarrhea, one half of which was hospital this strain (initially called e. coli-gomez by varela in ) also was associated with infantile diarrhea in a second type of e. coli (called beta by giles in and subsequently identified as ) was associated with an outbreak of infantile diarrhea in aberdeen, s~o t l a n d .~'~*~'~ from this early work primarily with epidemic diarrhea in infants has developed an elaborate serotyping system for certain e. coli strains that were clearly associated with infantile these strains first were called enteropathogenic e. coli by neter and colleagues in , and the association with particular serotypes can still be observed. as shown in table - , these organisms are distinct from the enterotoxigenic or enteroinvasive organisms or those that inhabit the normal gastrointestinal tract. they exhibit localized adherence to hep- cells, a phenotype that has been suggested to be useful for diagnosis and pathogenesis research. 'i epec is an important cause of diarrhea in infants in developing or transitional c~u n t r i e s .~"~~' -~~~ outbreaks have become rare in the united states and other industrialized countries, but they still ccur. ~~ some have attributed the rarity of this recognition of illness in part to the declining severity of diarrheal disease caused by epec within the past years, resulting in fewer cultures being obtained from infants with relatively mild symptom^.^^^^^^ however, several other variables influence the apparent incidence of this disease in the community. a problem arises with false-positive epec on the basis of the nonspecific cross-reactions seen with improper shortening of the serotyping p r o c e d~r e .~~~,~~~ because of their complexity and relatively low yield, neither slide agglutination nor hep- cell adherence or dna probe tests are provided as part of the routine identification of enteric pathogens by most clinical bacteriology laboratories. failure to recognize the presence of epec in fecal specimens is the inevitable consequence. the apparent incidence of epec gastroenteritis also varies with the epidemiologic circumstances under which stool cultures are obtained. the prevalence of enteropathogenic strains is higher among infants from whom cultures are obtained during a community epidemic compared with those obtained during sporadic diarrheal disease. neither reflects the incidence of epec infection among infants involved in a nursery outbreak or hospital epidemic. epec gastroenteritis is a worldwide problem, and socioeconomic conditions play a significant role in determining the incidence of this disease in different populations. s for instance, it is unusual for newborn infants born in a rural environment to manifest diarrheal disease caused by epec; most infections of the gastrointestinal tract in these infants occur after the first months of conversely, among infants born in large cities, the attack rate of epec is high during the first months of life. this age distribution reflects in large part the frequency with which epec causes crossinfection outbreaks among nursery populations' '~ ~ ; however, a predominance of epec in infants in the first months of life also has been described in community epidemic^^^'-^^^ and among sporadic cases of diarrhea acquired outside the h~s p i t a l . '~' -~~~ the disparity in the incidence of neonatal epec infection between rural and urban populations has been ascribed to two factors: the trend away from breast-feeding among mothers in industrialized societies and the crowding together of susceptible newborns in nurseries in countries in which hospital deliveries predominate over home d e l i~e r i e s . '~~~'~~ although the predominant serogroup can vary from year to year, , , ,z . ~ the same strains have been prevalent during the past years in great britain? puerto r~c o ?~~ guatemala: panama, newfoundland, indonesia, thailand, and south when living conditions are poor and overcrowding of susceptible infants exists, there is a rise in the incidence of neonatal diarrhea in general and epec gastroenteritis in p a r t i c~l a r .~'~~~~~~~~~ a h igher incidence of asymptomatic family carriers is found in such situations. b newborn infants can acquire epec during the first days of life by one of several routes: ( ) organisms from the mother ingested at the time of birth; ( ) bacteria from other infants or toddlers with diarrheal disease or from asymptomatic adults colonized with the organism, commonly transmitted on the hands of nursery personnel or parents; ( ) airborne or droplet infection; ( ) fomites; or ( ) organisms present in formulas or solid food supplements. only the first two routes have been shown conclusively to be of any real significance in the transmission of disease or the propagation of epidemics. most neonates acquire epec at the time of delivery through ingestion of organisms residing in the maternal birth canal or rectum. stool cultures taken from women before, during, or shortly after delivery have shown that % to % carry epec at some time during this period. ~s ~ ~ ~ ' use of fluorescent antibody techniquesz ' or cultures during a community outbreak of epec gastroenteritis" revealed twice this number of persons excreting the organism. virtually none of the women carrying pathogenic strains of e. coli had symptoms referable to the gastrointestinal tract. many of the mothers whose stools contain epec transmit these organisms to their infant~, ~*~' resulting in an asymptomatic infection rate of % to % among newborns cultured at random in nursery surveys. ~ ~ '~ these results must be considered conservative and are probably an artifact of the sampling technique. one study using antisera to identify as many e. coli as possible in fecal cultures showed a correlation between the coliform flora in % of motherinfant pairs? of particular interest was the observation that the groups of e. coli isolated from the infants' mucus immediately after delivery correlated with those subsequently recovered from their stools, supporting the contention that these organisms were acquired orally at the time of birth. in mothers whose stools contained the same group as their offspring, the mean time from rupture of membranes to delivery was about hours longer than in those whose infants did not acquire the same serogroups, suggesting that ascending colonization before birth also can play a role in determining the newborn's fecal flora. the contours of the epidemiologic curves in nurse$ - and communi@ - outbreaks are in keeping with a contact mode of spread. transmission of organisms from infant to infant takes place by way of the fecal-oral route in almost all cases, most likely on the hands of persons attending to their care. * , , ill infants represent the greatest risk to those around them because of the large numbers of organisms found in their stools - and crossinfection also has been initiated by infants who were healthy at the time of their admission to the nursery. , - a newborn exposed to epec is likely to acquire enteric infection if contact with a person excreting the organism is intimate and prolonged, as in a hospital or family setting. stool culture surveys taken during outbreaks have shown that between % and % of term neonates residing in the nursery carry epec in their intestinal tracts.' , , 'm despite descriptions of nursery outbreaks in which virtually every neonate or low-birth-weight infant became infected, there is ample evidence that exposure to pathogenic strains of e. coli does not necessarily result in greater likelihood of illness for premature infants than for term infants. , * , any increased prevalence of cross-infections that may exist among premature infants can be explained more readily by the prolonged hospital stays, their increased handling, and the clustering of infants born in different institutions than by a particular susceptibility to epec based on immature defense mechanisms. the most extensive studies on the epidemiology of gastroenteritis related to e. coli have dealt with events that took place during outbreaks in newborn nurseries. unfortunately, investigations of this sort frequently regard the epidemic as an isolated phenomenon and ignore the strong interdependence that exists between community-and hospital-acquired ~~~~~~ , , n ot surprisingly, the direction of spread is most often from the reservoir of disease within the community to the hospital. when the original source of a nursery outbreak can be established, frequently it is an infant born of a carrier mother who recently acquired her epec infection from a toddler living in the home. cross-infection epidemics also can be initiated by infected newborns who have been admitted directly into a clean nursery unit from the surrounding d i s t r i~t~~~~~~~*~~~ or have been transferred from a nearby hospital. after a nursery epidemic has begun, it generally follows one of two major patterns. some are explosive, with rapid involvement of all susceptible infants and a duration that seldom exceeds or months. * , * the case-fatality rate in these epidemics may be very high. other nursery outbreaks have an insidious onset with a few mild, unrecognized cases; the patients may not even develop illness until after discharge from the hospital. during the next few days to weeks, neonates with an increased number of loose stools are reported by the nurses; shortly thereafter, the appearance of the first severely ill infants makes it apparent that an epidemic has begun. unless oral antimicrobial therapy is instituted (see "therapy"), nursery outbreaks like these may continue for months - or with cycles of illness followed by periods of relative quiescence. this pattern can be caused by multiple strains (of different phage or antibiogram types) sequentially introduced into the nursery? * . the nursery can be a source of infection for the community. the release of infants who are in the incubation stages of their illness or are convalescent carriers about to relapse may lead to secondary cases of diarrheal disease among young siblings living in widely scattered areas. , , these children further disseminate infection to neighboring households, involving playmates of their own age, young infants, and mothers. as the sickest of these contact cases are admitted to different hospitals, they contaminate new susceptible persons, completing the cycle and compounding the outbreak. this feedback mechanism has proved to be a means of spreading infantile gastroenteritis through entire ~o~n t i e s , ~~~~~~,~~~ and even provinces. one major epidemic of diarrhea related to epec :b that occurred in the metropolitan chicago and northwestern indiana region during the winter of involved more than children and community hospitals during a period of months. , almost all of the patients were younger than years old, and % were younger than month, producing an age-specific attack rate of nearly % of neonates in the community. the importance of the hospital as a source of cross-infection in this epidemic was demonstrated through interviews with patients' families, indicating that a minimum of % of infants had direct or indirect contact with a hospital shortly before the onset of their illness. it has been suggested, but not proved, that asymptomatic carriers of epec in close contact with a newborn infant, such as nursery personnel or family members, might play an important role in its t r a n s m i~s i o n .~~~'~"~~~ stool culture surveys have shown that at any one time about % of and % to % of young who are free of illness harbor epec strains. higher percentages have been recorded during community epidemics? * s be cause this intestinal carriage is transitory: the number of individuals who excrete epec at one time or another during the year is far higher than the % figure recorded for single specimens. nursery personnel feed, bathe, and diaper a constantly changing population of newborns, about % to % of whom excrete epec. * despite this constant exposure, intestinal carriage among nursery workers is surprisingly low. even during outbreaks of diarrheal illness, when dissemination of organisms is most intense, less than % of the hospital personnel in direct contact with infected neonates are themselves excreting pathogenic strains of e. coli. ', , although adult asymptomatic carriers generally excrete fewer organisms than patients with acute illness large numbers of pathogenic bacteria may nevertheless exist in their stools? s however, no nursery outbreak and few family cases o have been traced to a symptomless carrier. instead, passive transfer of bacteria from infant to infant by the hands of personnel appears to be of primary importance in these outbreaks. cities, . , epec can be recovered from the throat or nose of % to % of infants with diarrheal illness p and from about % of asymptomatic the throat and nasal mucosa may represent a portal of entry or a source of transmission for epec. environmental studies have shown that epec is distributed readily and widely in the vicinity of an infant with active diarrheal disease, often within day of admission to the ~a r d . '~' , '~~ massive numbers of organisms are shed in the diarrheal stool or vomitus of infected e. coli organisms may survive to weeks in dust . and can be found in the nursery air when the bedding or diapers of infected infants are disturbed during routine nursing procedure^^^^^^^ or on floors, walls, cupboards, and nursery equipment such as scales, hand towels, bassinets, incubators, and oxygen tents of other infant^?^,'^^,'^^ documentation of the presence of epec in nursery air and dust does not establish the importance of this route as a source of cross-infection. one study presented evidence of the respiratory transmission of epec; however, even in the cases described, the investigators pointed out that fecal-oral transmission could not be completely ruled additional clinical and experimental data are required to clarify the significance of droplet and environmental infection. coliform organisms have also been isolated in significant numbers from human mi k, ~ ~ prebottled infant f rmulas, ~~ and formulas prepared in the home. epec in particular has been found in stool cultures obtained from donors of human milk and workers in a nursery formula room. o in one instance, epec :b was isolated from a donor, and subsequently, the same serogroup was recovered in massive amounts in almost pure culture from her milk. pathogenic strains of e. coli have also been isolated from raw cow's milk '' and from drinking ~a t e r .~" likewise, epec has been isolated from flies during an epidemic, but this fact has not been shown to be of epidemiologic significance. ' infection of the newborn infant with epec takes place exclusively by the oral route. attempts to induce disease in adult volunteers by rectal instillation of infected material have been unsuc~essful.~~ there are no reports of disease occurring after transplacental invasion of the fetal bloodstream by enteropathogenic or nonenteropathogenic strains of e. coli. ascending intrauterine infection after prolonged rupture of the membranes has been reported only once; the neonate in this case suffered only from mild diarrhea. bacterial cultures of the meconium and feces of newborns indicate that enteropathogenic strains of e. coli can colonize effectively the intestinal tract in the first days of although e. coli may disappear completely from stools of breast-fed children during the ensuing weeks, this disappearance is believed to be related to factors present in the human milk rather than the gastric secretions. ~ ~ the use of breast-feeding or expressed human milk has even been effective in terminating nursery epidemics caused by epec :b , probably by reducing the incidence of crossinfections among infants. although dose-effect studies have not been performed among newborns, severe diarrhea has occurred after ingestion of ' epec organisms by very young the high incidence of cross-infection outbreaks in newborn nurseries suggests that a far lower inoculum can often effect spread in this setting. the role of circulating immunity in the prevention of gastrointestinal tract disease related to epec has not been clearly established. virtually % of maternal sera have been found to contain hemaggl~tinating, '~~~''~~'~ or bacteriostatic ' ~ ' antibodies against epec. the passive transfer of these antibodies across the placenta is extremely inefficient. titers in blood of newborn infants are, on average, to times lower than those in the corresponding maternal sera. group-specific hemagglutinating antibodies against the antigen of epec are present in % to % of cord blood samp es, ~ ~ whereas b a~t e r i c i d a l~'~~~~~ or bacterio-static " activity against these organisms can be found much more frequently. tests for bacterial agglutination, which are relatively insensitive, are positive in only a small percentage of neonate^.'^^'^" the importance of circulating antibodies in the susceptibility of infants to epec infection is unknown. experiments with suckling mice have failed to demonstrate any effect of humoral immunity on the establishment or course of duration of intestinal colonization with e. coli in mothers or their infants. similar observations have been made in epidemiologic studies among premature human infants using enteropathogenic ( :b ) and nonenteropathogenic ( :h ) strains of e. coli as the indicator organisms. in a cohort of mothers and their infants followed from birth to months old, cooper and associate^'^ were able to show a far higher incidence of clinical epec disease in infants of epec-negative mothers than in infants born of mothers with epec isolated from stool cultures. this finding suggested to the investigators the possibility that mothers harboring epec in their gastrointestinal tracts transfer specific antibodies to their infants that confer some protection during the first weeks of life. protection against enteric infections in humans often correlates more closely with levels of local secretory than serum antibodies. although it is known that colonization of newborns with e. coli leads to the production of coproantibodies against the ingested the clinical significance of this intestinal immunity is uncertain. the previously mentioned experiment with mice showed no effect of active intestinal immunity on enteric col~nization.~'~ in human infants, the frequency of bacteriologic and clinical relapse related to epec of the same and the capacity of one strain of epec to superinfect a patient already harboring a different train^^^,^^^,^^^ also cast some doubt on the ability of mucosal antibodies to inhibit or alter the course of intestinal infection. studies of the protective effects of orally administered epec vaccines could help to resolve these question^.'^' the mechanism by which epec causes diarrhea involves a complex array of plasmid and chromosomally encoded traits. epec serotypes usually do not make one of the recognized enterotoxins (lt or st) as usually measured in tissue culture or animal r n~d e l s ,~'~~~'~ nor do these serotypes cause a typical invasive colitis or produce a positive sereny test only uncommonly do epec strains invade the bloodstream or disseminate. nevertheless, epec strains that test negative in these tests are capable of causing diarrhea; inocula of '' e. coli or organisms caused diarrhea in of adult volunteers. some epec strains may secrete weak enterot~xins,~~''~'~ but the consensus opinion is that the attaching and effacing lesion constitutes the critical secretory virulence pheno-clinical pathologic reports reveal the characteristic attachin and effacing lesion in the small intestine of infected infants? the lesion is manifested by intimate (about nm) apposition of the epec to the enterocytes plasma membrane, with dissolution of the normal brush border and rearrangement of the cyto~keleton.'''~~~~ in some instances, the bacteria are observed to rise up on pedestal-like structures, which are diagnostic of the infection.i ' villus blunting, crypt hypertrophy, histiocytic infiltration in the lamina propria, and a reduction in the brush border enzymes may also be ~bserved.~'~'~'~ two major epec virulence factors have been described; strains with both factors are designated as typical epec. * * ' one such factor is the locus of enterocyte effacement (lee), a type secretion system encoded by the lee chromosomal pathogenicity i~land.~'~-~'* the lee secretion apparatus injects proteins directly from the cytoplasm of the infecting bacterium into the cytoplasm of the target enter~cytes.~'~ the injected proteins constitute cytoskeletal toxins, which together elicit the close apposition of the bacterium to the cell, cause the effacement of microvilli, and most likely give rise to the net secretory one critical secreted protein, called towinterleukin- receptor (tir),"' inserts into the plasma membrane of the epithelial cell, where it serves as the receptor for a lee-encoded epec outer membrane protein called intimin.'" animals infected with attaching and effacin pathogens mount antibody responses to intimin and t i r ! and both are considered potential immunogens. the lack of protection from epec reinfection suggests that natural antibody responses to tir and intimin are not protective. the second major virulence factor of typical epec is the bundle-forming pilus (bfp), which is encoded on a partially conserved mda virulence plasmid called epec adherence factor bfp, a member of the type iv pilus family, mediates aggregation of the bacteria to each other and probably to enterocytes themselves, thereby facilitating mucosal colonization. a bfp mutant was shown to be attenuated in adult volunteers. the principal pathologic lesion with epec is the focal destructive adherence of the organism, effacing the microvillous brush border with villus blunting, crypt hypertrophy, histiocytic infiltration of the lamina propria, and reduced brush border enzymes. rothbaum and colleagues described similar findings with dissolution of the glycocalyx and flattened microvilli with the nontoxigenic epec strain :b . there has been a wide range of pathologic findings reported in infants dying of epec gastroenteritis. most newborns dying with diarrheal disease caused by epec show no morphologic changes of the gastrointestinal tract by gross or microscopic examination of tiss~es.~'~'~'' bra?" described such "meager" changes in the intestinal tract that "the impression received was that the term gastroenteritis is incorrect." at the other extreme, extensive and severe involvement of the intestinal tract, although distinctly unusual among neonates with epec diarrhea, has been discussed in several reviews of the pathologic anatomy of this disease. v , changes virtually identical to those found in infants dying with necrotizing enterocolitis have been reported. drucker and c o -~o r k e r s~'~ found that among infants who were dying of epec diarrhea, "intestinal gangrene, and/or perforation, andlor peritonitis were present in five, and intestinal pneumatosis in five." the reasons for such wide discrepancies in epec disease pathology are not clear. the severity of intestinal lesions at the time of death does not correlate with the birth weight of the patient, the age of onset of illness, the serogroup of the infecting strain, or the prior administration of oral or systemic antimicrobial agents. the suggestion that the intensity of inflammatory changes may depend on the duration of the diarrhea '' cannot be corroborated in autopsy s t~d i e s~'~*~"~~~ or small intestinal it is difficult to reconcile such a thesis with the observation that a wide range of intestinal findings can be seen at autopsy among newborns infected by a single serotype of epec during an epidemic. the nonspecific pathologic picture described by some researchers includes capillary congestion and edema of the bowel wall and an increase in the number of eosinophils, plasma cells, macrophages, and mononuclear cells in the mucosa and submucosa. , , villous patterns are generally well preserved, although some flattening and broadening of the villi are seen in the more severe cases. almost complete absence of villi and failure of regeneration of small bowel mucosa have been reported in an extreme case. edema in and around the myenteric plexuses of auerbach, a common associated finding, has been suggested as a cause of the gastrointestinal tract dilatation often seen at autopsy in infants with epec infection^.^^^'^^^'^^^ in general, the distal small intestine shows the most marked alterations; however, the reported pathologic findings may be found at all levels of the intestinal tract. several complications of epec infection have been reported. candidal esophagitis accounted for significant morbidity in two series collected before'" and the antibiotic era. oral thrush has been seen in % of epecinfected infants treated with oral or systemic antib i o t i c~. '~~,~~"~~ some degree of fatty metamorphosis of the liver has been reported by several investigators" i ' ; however, these changes are nonspecific and probably result from the poor caloric intake associated with persistent diarrhea or vomiting. some degree of bronchopneumonia, probably a terminal event in most cases, exists in a large proportion of newborns dying of epec i n f e~t i o n .~" " '~'~~~ in one reported series of infant cases, epec was demonstrated by immunofluorescent staining in the bronchi, alveoli, and interalveolar septa. mesenteric lymph nodes are often swollen and congested with reactive germinal centers in the lymphoid f o l l i~l e s . '~~~~, '~~ severe lymphoid depletion, unrelated to the duration or severity of the antecedent illness, also has been de~cribed.'~~ the kidneys frequently show tubular epithelial toxic changes. various degrees of tubular degeneration and cloudy swelling of convoluted tubules are common finding^.^'^,'^^,^^^ renal vein thrombosis or cortical necrosis may be observed in infants with disseminated intravascular coagulation in the terminal phases of the illness. the heart is grossly normal in most instances but may show minimal vacuolar changes of nonspecific toxic myocarditis on microscopic examinati n. ~~'~~' candidal abscesses of the heart and kidneys' , , have been described. with the exception of mild congestion of the pia arachnoid vessels and some edema of the meninges, examination of the central nervous system reveals few changes? despite the observation of braf l that "inflammation of the middle ear [is] exceptional," strains of epec have been isolated from a significant number of specimens of the middle ear in case series in which dissection of the temporal bone has been performed. exposure of newborns to epec may be followed by one of several possible consequences: no infection, infection without illness, illness with gastroenteritis of variable severity and duration, and rarely, septicemia with or without metastatic foci of infection accompanying gastroenteritis. when infants are exposed to epec, a significant number become colonized as temporary st , or pharyngeal carriers with no signs of clinical disease. although l a~r e l l~~' showed that the percentage of asymptomatic infections rises steadily as age increases, this observation has not been confirmed by other investigator^.^'^.^^^ similarly, the suggestion that prematurity per se is associated with a low incidence of inapparent epec infection has been documented in several clinical but refuted in others. , most neonates who acquire infection with epec eventually show some clinical evidence of gastroenteritis. the incubation period is quite variable. its duration has been calculated mostly from evidence in outbreaks in newborn nurseries, where the time of first exposure can be clearly defined in terms of birth or admission dates. in these circumstances, almost all infants show signs of illness between and days after exposure, and most cases show signs within the first days. , , in some naturally and experi-menta infections with heavy exposure, the incubation period may be as short as hours; the stated upper limit is days. the first positive stool culture and the earliest recognizable clinical signs of disease occur simultaneously in most although colonization may precede symptoms by to days. , th e gastroenteritis associated with epec infection in the newborn is notable for its marked variation in clinical pattern. clinical manifestations vary from mild illness manifest only by transient anorexia and failure to gain weight to a sudden explosive fulminating diarrhea causing death within hours of onset. prematurity, underlying disease, and congenital anomalies often are associated with the more severe forms of illness. , , , experienced clinicians have observed that the severity of epec gastroenteritis has declined markedly during the past decades. the onset of illness usually is insidious, with vague signs of reluctance to feed, lethargy, spitting up of formula, mild abdominal distention, or even weight loss that may occur for or days before the first loose stool is passed. diarrhea usually begins abruptly. it may be continuous and violent, or in milder infections, it may run an intermittent course with or more days of normal stools followed by or more days of diarrhea. emesis sometimes is a prominent and persistent early finding. stools are loose and bright yellow initially, later becoming watery, mucoid, and green. flecks or streaks of blood, which are commonly seen with enterocolitis caused by salmonella, campylobacter, or shigella, are rarely a feature of epec diarrheal disease. a characteristic seminal smell may pervade the environment of infants infected with epec :b , , , and an odor variously described as "pungent," "musty," or "fetid" often surrounds patients excreting other strains in their stool^.^^','^^ because the buttocks are repeatedly covered with liquid stools, excoriation of the perianal skin can be an early and persistent problem. fever is an inconstant feature, and when it occurs, the patient's temperature rarely rises above " c. convulsions occur infrequently; their occurrence should alert the clinician to the possible presence of electrolyte disturbances, particularly hypernatremia. prolonged hematochezia, distention, edema, and jaundice are ominous signs and suggest an unfavorable p r o g n o~i s .~'~,~~~*~*~ m ost infants receiving antimicrobial agents orally show a cessation of diarrhea, tolerate oral feedings, and resume weight gain within to days after therapy has been those with mild illness who receive no treatment can continue to have intermittent loose stools for to weeks. in one outbreak related to epec :k , more than one third of the untreated or inappropriately treated infants had diarrhea for more than days in the absence of a recognized enteric pathogen on repeated culturing. recurrence of diarrhea and vomiting after a period of initial improvement is characteristic of epec e n t e r i t i~. '~'~~~~~~~ though seen most often in newborns who have been treated inadequately or not treated at all, clinical relapses also occur after appropriate therapy. occasionally, the signs of illness during a relapse can be more severe than those accompanying the initial attack of illness. , , not all clinical relapses result from persistent infection. a significant number of relapses, particularly those that consistently follow attempts at reinstitution of formula fee ding^?^^.^^^ are caused by disaccharide intolerance rather than bacterial proliferation. intestinal superinfections, caused by another serotype of epecz or by completely different enteric pathogens, such as salmonella or shigella, also can delay the resolution of symptoms. rarely, infants suffer a "relapse" caused by an organism from the same group as the original strain but differing in its h antigen. unless complete serotyping is performed on all epec isolates, such an event easily could be dismissed as being a recurrence rather than a superinfection with a new ~r g a n i s m . '~~*~~~ antimicrobial agents to which the infecting organisms are susceptible often may not eradicate epec: , , which may persist for weeks , , or months after the acute illness has subsided. although reinfection cannot always be excluded, a significant number of infants are discharged from the hospital with positive rectal dehydration is the most common and serious complication of gastroenteritis caused by epec or a toxin-producing e. coli. virtually all deaths directly attributable to the intestinal infection are caused by disturbances in fluids and electrolytes. when stools are frequent in number, large in volume, and violent in release, as they often are in severe infections with abrupt onset, a neonate can lose up to % of body weight in a few h o~r s .~~~,~~~ rarely, fluid excretion into the lumen of the bowel proceeds so rapidly that reduction of circulating blood volume and shock may intervene before passage of even a single loose before the discovery of the etiologic agent, epidemic diarrhea of the newborn was also known by the term cholera infantum. mild disease, particularly when aggravated by poor fluid intake, can lead to a subtle but serious deterioration of an infant's metabolic status. sometimes, a week or more of illness elapses before it becomes apparent that an infant with borderline acidosis and dehydration who seemed to be responding to oral fluids alone requires parenteral therapy for impr~vement?~~ it is incumbent on the clinician caring for small infants with gastroenteritis to follow them closely, with particular attention to serial weights, until full recovery can be confirmed. there are few other complications, with the possible exception of aspiration pneumonia, directly related to epec gastroenteritis. protracted diarrhea and nutritional failure may occur as a consequence of functional damage to the small intestinal mucosa, with secondary intolerance to dietary necrotizing enterocolitis, which occasionally results in perforation of the bowel and peritonitis, has not been causally related to infection with epec. , , a review of most of the large clinical series describing epec disease in infants who ranged in age from neonates to children aged years revealed only three proven instances of ba~teremia:~~**~~ one possible urinary tract infection: and one documented case of meningitis in an infant of unspecified age. focal infections among neonates were limited to several cases of otitis and a subcutaneous abscess from which epec was isolated. additional complications include interstitial pneumonia, gastrointestinal bleeding with or without disseminated intravascular coagulatio , ~.~~~ and methemoglobinemia caused by a mutant of epec :b that was capable of generating large quantities of nitrite from proteins present in the gastrointestinal tract. the gold standard of epec diagnostics is identification in the stool of e. coli carrying genes for bfp and lee. identification of these genes can be accomplished by molecular methods (discussed later), but lack of access to these methods has led many labs to rely on surrogate markers, such as serotyping." classic epec has been recovered from the vomitus, stool, or bowel contents of infected newborns. isolation from bile and the upper respiratory t r a~t~~~~~~*~~~ ha s been described in those instances in which a specific search has been made. less commonly, epec is isolated from ascetic fluid'" or purulent exudates * * , occasionally, the organism has been recovered from blood c u l t~r e s ?~~,~~~ urine: and cerebrospinal fluid. stool cultures generally are more reliable than rectal swabs in detecting the presence of enteric pathogens, although a properly obtained swab should be adequate to demonstrate epec in most cases. ' , * specimens should be obtained as early in the course of the illness as possible because organisms are present in virtually pure culture during the acute phase of the enteritis but diminish in numbers during convalescence. because of the preponderance of epec in diarrheal stools, two cultures are adequate for isolation of these pathogens in almost all cases of active disease. studies using fluorescent antibody methods for identification of epec in stool specimens have demonstrated that during the incubation period of the illness, during convalescence, and among asymptomatic carriers of epec, organisms can be excreted in such small numbers that they escape detection by standard bacteriologic methods in a significant proportion of as many as to specimens may be required to detect epec using methods that identify individual epec isolates in the ~t . ~~~ after a stool specimen is received, it should be plated as quickly as possible onto noninhibiting media or placed in a preservative medium if it is to be held for longer periods. deep freezing of specimens preserves viable epec when a prolonged delay in isolation is necessary?" no selective media, biochemical reactions, or colonial variations permit differentiation of pathogenic and nonpathogenic strains. certain features may aid in the recognition of two important serogroups. cultures of serogroups :b and :b , unlike many other coliforms, are sticky or stringy when picked with a wire loop and are rarely hemolytic on blood whereas :b colonies emit a distinctive evanescent odor commonly described as "~e m i n a l . ' '~~~,~~~ this unusual odor first led b r a y to suspect that specific strains of e. coli might be responsible for infantile gastroenteritis. because serotyping is simpler than molecular detection and because epec have long been known to belong to certain highly characteristic serotypes, serotyping can be used to identify likely epec strains, especially in outbreaks? e. coli, like other enterobacteriaceae members, possesses cell wall somatic antigens (o), envelope or capsular antigens (k), and if motile, flagellar antigens (h). many of the groups may be further divided into two or more subgroups (a, b, c), and the k antigens are divisible into at least three varieties (b, l, a) on the basis of their physical behavior. organisms that do not possess flagellar antigens are nonmotile (designated nm). the epec b capsular surface antigen prevents agglutination by antibodies directed against the underlying antigen. heating at °c for hour inactivates the agglutinability and antigenicity of the b antigen. slide agglutination tests with polyvalent or ob antiserum may be performed on suspensions of colonies typical of e. coli that have been isolated from infants with diarrhea, especially in nursery outbreaks. however, because of numerous false-positive "cross-reactions:' the and k (or b) type must be confirmed by titration with the specific a n t i~e r a .~~~ the presence of epec does not prove that epec is the cause of diarrhea in an individual patient. mixed cultures with two or three serotypes of epec have been demonstrated in % to % of patients. * * this need not mean that two or three serotypes are causative agents. secondary infection with hospital-acquired strains can occur during convalesand some infants may have been asymptomatic carriers of one serotype at the time that another produced diarrheal disease. a similar explanation may pertain to mixed infections with epec and salmonella or shigella. * nelson reported the presence of these pathogens in combination with epec in % of infants who were cultured as part of an antibiotic therapy trial. salmonella and shigella that had not been identified on cultures obtained at admission were isolated only after institution of oral therapy with neomycin. the investigator postulated that the alteration in bowel flora brought about by the neomycin facilitated the growth of these organisms, which had previously been suppressed and obscured by coliform over- the importance of seeking all enteric pathogens in primary and follow-up cultures of infantile diarrhea is apparent, particularly when the specimen originates from a patient in a newborn nursery or infants' ward. although epec gastroenteritis was once considered to be synonymous with "summer diarrhea," community outbreaks have occurred as frequently, if not more frequently, in the colder seasons. , * it has been suggested that the increased incidence at that time of year might be related to the heightened chance of contact between infants and toddlers cence,l , , , that is bound to occur when children remain indoors in close contact.z nursery epidemics, which depend on the chance introduction and dissemination of epec within a relatively homogeneous population and stable environment, demonstrate no seasonal prevalence. average relative humidity, temperature, and hours of daylight have no significant effect in determining whether an outbreak will follow the introduction of enteropathogenic strains of e. coli into a ward of infants. there are no clinical studies of the variations in peripheral leukocyte count, urine, or cerebrospinal fluid in neonatal enteritis caused by epec. microscopic examination of stools of infants with acute diarrheal illness caused by these organisms usually has revealed an absence of fecal polymorphonuclear l e~k o c y t e s~'~~~~~~~~~*~~~ although data on fecal lactoferrin in human volunteers suggest that an inflammatory process may be important in epec diarrhea. , stool ph can be neutral, acid, or alkaline. serologic methods have not proved to be useful in attempting to establish a retrospective diagnosis of epec infection in neonates. rising or significantly elevated agglutinin titers rarely could be demonstrated in early investigation^^'^"'^^^'; hemagglutinating antibodies showed a significant response in no more than % to % of cases. , fluorescent antibody techniques have shown promise for preliminary identification of epec in acute infantile diarrhea. this method is specific, with few false-positive results, and it is more sensitive than conventional plating and isolation t e c h n i q~e s .~~~,~~' .~~~ the rapidity with which determinations can be performed makes them ideally suited for screening ill infants and possible carriers in determining the extent and progression of a n~r s e r f '~,~~~ or om mu nit$^^^^'' outbreak. because immunofluorescence does not depend on the viability of organisms and is not affected by antibiotics that suppress growth on culture plates, it can be used to advantage in following bacteriologic responses and relapses in patients receiving oral the rap^.^","^ the use of fluorescent antibody techniques offers many advantages in the surveillance and epidemiologic control of epec gastroenteritis. immunofluorescent methods should supplement but not replace standard bacteriologic and serologic methods for identification of enteric pathogens. specific gene probes and pcr primers for the bfp adhesin, the intimin-encoding gene (eue) and for a cryptic plasmid locus (eaf) are a~ailable.~~ detection of bfp or eaf are superior to detection of eue, because many non-epec, including nonpathogens, carry the eae gene. b pcr and gene probe analysis can be performed directly on the stools of suspect infants. however, confirmation of infection by the identification of the organism in pure culture should be pursued. before widespread use of molecular methods, the hep- cell adherence assay was proposed for epec diagnosis."' the presence of a focal or localized adherence (la) pattern on the surface of hep- or hela cells after -hour coincubation is a highly sensitive and specific test for detection of epec. the requirement for cell culture and expertise in reading this assay limits its utility to the research setting. an elisa for the bfp has been described but is not readily available? the capacity of la + epec to polymerize f-actin can be detected in tissue culture cells stained with rhodamine-labeled phall~idin.~~' this fluorescence-actin staining (fas) test is cumbersome and impractical for routine clinical use. the mortality rate recorded previously in epidemics of epec gastroenteritis is impressive for its variability. during the s and s, when organisms later recognized as classic enteropathogenic serotypes were infecting infants, the case-fatality ratio among neonates was about %. during the s and s, many nursery epidemics still claimed about one of every four infected infants, but several outbreaks involving the same serotypes under similar epidemiologic circumstances had fatality rates of less than h. in th e s, reports appeared in the literature of a nursery epidemic with a % neonatal mortality rate and of an extensive outbreak in a nursery for premature infants with % fatalities ; another report stated that among " consecutive infants admitted to the hospital for epec diarrheal disease, none died of diarrheal disease per se." a significant proportion of the infants who died during or shortly after an episode of gastroenteritis already were compromised by preexisting disease , , or by congenital m a l f~r m a t i o n s~'~,~~'~~~~ at the time they acquired their illness. these underlying pathologic conditions appear to exert a strongly unfavorable influence, probably by reducing the infant's ability to respond to the added stresses imposed by the gastrointestinal tract infection. although prematurity is often mentioned as a factor predisposing to a fatal outcome, the overall mortality rate among premature infants with epec gastroenteritis has not differed significantly over the years from that recorded for term the management of epec gastroenteritis should be directed primarily toward prevention or correction of problems caused by loss of fluids and electr ytes.i~~ most neonates have a relatively mild illness that can be treated with oral rehydration. infants who appear toxic, those with voluminous diarrhea and persistent vomiting, and those with increasing weight loss should be hospitalized for observation and treatment with parenteral fluids and careful maintenance of fluid and electrolyte balance and possibly with antimicrobial therapy. clinical studies suggest that slow nasogastric infusion of an elemental diet can be valuable in treating infants who have intractable diarrhea that is unresponsive to standard modes of therapy. there is no evidence that the use of proprietary formulas containing kaolin or pectin is effective in reducing the number of diarrheal stools in neonates with gastroenteritis. attempts to suppress the growth of enteric pathogens by feeding lactobacillus to the infant in the form of yogurt, powder, or granules have not been shown to be of value. a trial of cholestyramine in newborns with epec gastroenteritis had no effect on the duration or severity of the diarrhea. the use of atropine-like drugs, paregoric, or loperamide to reduce intestinal motility or cramping should be avoided. inhibition of peristalsis interferes with an efficient protective mechanism designed to rid the body of intestinal pathogens and may lead to fluid retention in the lumen of the bowel that may be sufficient to mask depletion of extracellular fluid and electrolytes. the value of antimicrobial therapy in management of neonatal epec gastroenteritis, if any, is uncertain. there are no adequately controlled studies defining the benefits of any antibiotic in eliminating epec from the gastrointestinal tract, reducing the risk of cross-infection in community or nursery outbreaks, or modifymg the severity of the illness. proponents of the use of antimicrobial agents have based their claims for efficacy on anecdotal observations or comparative studies. nonetheless, several clinical investigations have provided sufficient information to guide the physician faced with the dilemma of deciding whether to treat an individual infant or an entire nursery population suffering from epec diarrheal disease. it should be emphasized, however, that these guidelines must be considered tentative until rigidly controlled, double-blind studies have established the efficacy of antibiotics on a more rational and scientific basis. oral therapy with n e o m y~i n ,~'~'~~' ~olistin,'~~or chloram-phenic ~~~ appears to be effective in rapidly reducing the number of susceptible epec organisms in the stool of infected infants. studies comparing the responses of infants treated orally with ne~mycin?~' gentamicin: p~l p y x i n :~~ or kanamy~in'~' with the responses of infants receiving supportive therapy alone have shown that complete eradication of epec occurs more rapidly in those receiving an antimicrobial agent. in most cases, stool cultures are free of epec to days after the start of therapy. bacteriologic failure, defined as continued isolation of organisms during or after a course of an antimicrobial agent, can be expected to occur in % to % of patients? s such relapses generally are not associated with a recurrence of ~y m p t~m~.~~i *~~~*~~~ the effectiveness of oral antimicrobial therapy in reducing the duration of epec excretion serves to diminish environmental contamination and the spread of pathogenic organisms from one infant to another. breaking the chain of fecal-oral transmission by administering antimicrobial agents simultaneously to all carriers of epec and their immediate contacts in the nursery has appeared to be valuable in terminating outbreaks that have failed to respond to more conservative m e a s~r e s .~'~,~~,~~~ the apparent reduction in morbidity and mortality associated with oral administration of neomycin, . , colistin, . . p o l y m y x i r~,~~~ or gentamicin & during nursery epidemics has led to the impression that these drugs also exert a beneficial clinical effect in severely or moderately ill infants. reports describing bacteriologic: or histopathol~gic~'~ evidence of tissue invasion by epec have persuaded some investigators to suggest the use of parenteral rather than oral drug therapy in debilitated or malnourished infants. on the basis of these data, there appears to be sufficient evidence to recommend oral administration of nonabsorbable antibiotics in the treatment of severely or moderately ill newborns with epec gastroenteritis. the drug most frequently used for initial therapy is neomycin sulfate in a dosage of mg/kg/day administered orally every hours in three divided doses. s in communities in which neomycin-resistant epec has been prevalent, treatment with colistin sulfate or polymyxin b in a dosage of to mglkglday orally and divided into three equal doses may be appropriate. however, it is rarely necessary to use this approach. treatment should be continued only until stool cultures become negative for epec. because of the unavoidable delay before cultures can be reported, most infants receive therapy for to days. if fluorescent antibody testing of rectal swab specimens is available, therapy can be discontinued as soon as epec no longer is identified in smears; this takes no more than hours in more than % of cases. after diarrhea and vomiting have stopped and the infant tolerates formula feedings, shows a steady weight gain, and appears clinically well, discharge with outpatient follow-up is indicated. bacteriologic relapses do not require therapy unless they are associated with illness or high epidemiologic risks to other young infants in the household. because the infecting organisms in these recurrences generally continue to show in vitro susceptibility to the original drug, it should be reinstituted pending bacteriologic re~ults. ~~ when clinical judgment suggests that a neonate may be suffering from bacterial sepsis and epec diarrheal disease, parenteral antimicrobial therapy is indicated after appropriate cultures have been obtained. the routine use of systemic therapy in severe cases of epec enteritis is not appropriate on the basis of current clinical experience. antimicrobial susceptibility patterns of epec are an important determinant of the success of therapy in infections with these organism^.^^',^^'^^^ these patterns are unpredictable, depending on the ecologic pressures exerted by local antibiotic and on the incidence of transmissible resistance factors in the enteric flora of the particular population served by an i n s t i t~t i o n .~~~"~~ for these reasons, variations in susceptibility patterns are apparent in different n~r s e r i e s~~~, '~~ and even from time to time within the same institution. , , sudden changes in clinical response may even occur during the course of a single epidemic as drugsusceptible strains of epec are replaced by strains with multidrug r e~i s t a n c e .~~~'~~' ,~~' because differences can exist in the susceptibilities of different epec serogroups to various antimicrobial agents, regional susceptibility patterns should be reported on the basis of ob group or serotype rather than for epec as a whole. knowledge of the resistance pattern in one's area may help in the initial choice of antimicrobial therapy. the prevention of hospital outbreaks of epec gastroenteritis is best accomplished by careful attention to infection control policies for a nursery. all infants hospitalized with diarrhea should have a bacteriologic evaluation. if the laboratory is equipped and staffed to perform fluorescent antibody testing, infants transferred from another institution to a newborn, premature, or intensive care nursery and all infants with gastroenteritis on admission during an outbreak of epec diarrhea or in a highly endemic area can be held in an observation area for or hours until the results of the fluorescent antibody test or pcr are received. because of the difficulty in diagnosing epec infection, reference laboratories, such as those at the centers for disease control and prevention (cdc), should be notified when an outbreak is suspected. infants suspected to be excreting epec, even if healthy in appearance, then can be separated from others and given oral therapy until the test results are negative. some experts have suggested that when the rapid results obtainable with fluorescent antibody procedures are not available, all infants admitted with diarrhea in a setting where epec is common may be treated as if they were excreting epec or some other enteric pathogen until contrary proof is obtained. stool cultures should be obtained at admission, and contact precautions should be enforced among all who come into contact with the infant. additional epidemiologic studies are needed to establish the advantages of careful isolation and nursing techniques, particularly in smaller community hospitals in which the number of infants in a "gastroenteritis ward may be small. the use of prophylactic antibiotics has been shown to be of no value and can select for increased r e~i s t a n c e .~~~"~~ unfortunately, it can be difficult to keep a nursery continuously free of epec. specific procedures have been suggested for handling a suspected outbreak of bacterial enteritis in a newborn nursery or infant care ~n i t .~~~l~~~*~~~ evidence indicating that a significant proportion of e. coli enteritis may be caused by nontypeable strains has required some modification of these earlier recommendations. the following infection control measures may be appropriate: . the unit is closed, when possible, to all new admissions. . cultures for enteric pathogens are obtained from nursing personnel assigned to the unit at the time of the outbreak. . stool specimens obtained from all infants in the nursery can be screened by the fluorescent antibody or another technique and cultured. identification of a classic enteropathogenic serotype provides a useful epidemiologic marker; however, failure to isolate one of these strains does not eliminate the possibility of illness caused by a nontypeable epec. . antimicrobial therapy with oral neomycin or colistin can be considered for all infants with a positive fluorescent antibody test or culture result. the initial drug of choice depends on local patterns of susceptibility. depending on the results of susceptibility tests, subsequent therapy may require modification. . if an identifiable epec strain is isolated, second and third stool specimens from all infants in the unit are reexamined by the fluorescent antibody technique or culture at -hour intervals. if this is not practical, exposed infants should be carefully followed. . early discharge for healthy, mature, uninfected infants is advocated. . an epidemiologic investigation should be performed to seek the factor or factors responsible for the outbreak. a surveillance system may be established for all those in contact with the nursery, including physicians and other health care personnel, housekeeping personnel, and postpartum mothers with evidence of enteric disease. a telephone, mail, or home survey may be conducted on all infants who were residing in the involved unit during the weeks before the outbreak. . when all patients and contacts are discharged and control of the outbreak is achieved, a thorough terminal disinfection of the involved nursery is mandatory. above all, personnel and parents should pay scrupulous attention to hand hygiene when handling infants. ' since a multistate outbreak of enterohemorrhagic colitis was associated with e. coli :h , shiga toxin-producing e. coli (stec) have been recognized as emerging gastrointestinal pathogens in most of the industrialized world. a particularly virulent subset of stec, ehec, causes frequent and severe outbreaks of gastrointestinal the most virulent ehec belong to serotype :h . ehec has a bovine reservoir and is transmitted by undercooked meat, unpasteurized milk, and contaminated vegetables such as lettuce, alfalfa sprouts, and radish sprouts (as occurred in more than schoolchildren in japan). it also spreads directly from person to the clinical syndrome is that of bloody, noninflammatory (sometimes voluminous) diarrhea that is distinct from febrile dysentery with fecal leukocytes seen in shigellosis or eiec infection^.^^ most cases of ehec infections have been recognized in outbreaks of bloody diarrhea or hus in daycare centers, schools, nursing homes, and c o m m~n i t i e s .~~~-~~~ although ehec infections often involve infants and young children, the frequency of this infection in neonates remains unclear; animal studies suggest that receptors for the shiga toxin may be developmentally regulated and that susceptibility to disease may be age related. the capacity of ehec to cause disease is related to the phage-encoded capacity of the organism to produce a vero cell cytotoxin, subsequently shown to be one of the shiga toxins. - shiga toxin is neutralized by antiserum against shiga toxin, whereas shiga toxin , although biologically similar, is not neutralized by anti-shiga toxin. , like shiga toxin made by shigella dysenteriae, both e. coli shiga toxins act by inhibiting protein synthesis by cleaving an adenosine residue from position in the s ribosomal rna (rrna) to prevent elongation factor- -dependent aminoacyl transfer rna (trna) from binding to the s rrna. the virulence of ehec also may be determined in part by a -mda plasmid that encodes for a fimbrial adhesin in and . , this phenotype is mediated by the lee pathogenicity island, which is highly homologous to the island present in epec strains. ehec and other stec infections should be suspected in neonates who have bloody diarrhea or who may have been exposed in the course of an outbreak among older individuals. because most cases are caused by ingestion of contaminated food, neonates have a degree of epidemiologic protection from the illness. diagnosis of stec diarrhea is made by isolation and identification of the pathogen in the feces. e. coli :h does not ferment sorbitol, and this biochemical trait is commonly used in the detection of this s e r~t y p e .~~. '~~ because some nonpathogenic e. coli share this characteristic, confirmation of the serotype by slide agglutination is required. these techniques can be performed in most clinical laboratories. however, detection of non- serotypes is problematic and relies on detection of the shiga toxin; available methods include shiga toxin elisa, latex agglutination, and molecular method^.^^,^^^ these should be performed by a reference laboratory. hus in infants is not necessarily caused by stec infection. even in older patients, however, the stool is typically negative for stec at the time the that hus develops. ' serum and fecal detection of cytotoxin has been performed in such patients, but no diagnostic modality is definitive once hus has s~pervened!~~,~~~ antimicrobial therapy should not be administered to patients who may have stec infection, although their role in inducing hus remains c o n t r o~e r s i a l .~~~'~~~ management of the diarrhea and possible sequelae is supportive, with proper emphasis on fluid and electrolyte replacement. aggressive rehydration is helpful in minimizing the frequency of serious sequelae. the hep- adherence assay is useful for the detection of epec, which exhibit a classic la pattern."' two other adherence patterns can be discerned in this assay: aggregative (aa) and diffuse (da). these two patterns have been suggested to define additional pathotypes of diarrheogenic e. coli." strains exhibiting the aa pattern (i.e., eaec) are common pathogens of infants.lz eaec cause diarrhea by colonization of the intestinal mucosa and elaboration of enterotoxins and c y t o t o~i n s .~~~~~ many strains can be shown to elicit secretion of inflammatory cytokines in vitro, which may contribute to growth retardation associated with prolonged otherwise asymptomatic colonization.io several virulence factors in eaec are under the control of the virulence gene activator aggr. presence of the aggr regulator or its effector genes has been proposed as a means of detecting truly virulent eaec strains (called typical eaec), , and an empirical gene probe long used for eaec detection has been shown to correspond to one gene under aggr the mode of transmission of eaec has not been well established. in adult volunteer studies, the infectious dose is high (> lo colony-forming units [ cfu] ), suggesting that in adults at least, person-to-person transmission is unlikely. .m several outbreaks have been linked to consumption of contaminated f~o d . "~~,~'~ the largest of these outbreaks involved almost schoolchildren in japan "; a contaminated school lunch was the implicated source of the outbreak. some studies have demonstrated contamination of condiments or milk, which could represent vehicles of foodborne transmission. several nursery outbreaks of eaec have been bserved, ~'~~'~ although in no case has the mechanism of transmission been established. the fist reported nursery outbreak involved infants in nis, serbia, in . because these infants did not ingest milk from a common source, it is presumed that horizontal transmission by environmental contamination or hands of health care personnel was possible. most of the infants were full term and previously well, and they were housed in two separate nursery rooms. the earliest epidemiologic studies of eaec implicated this organism as a cause of endemic diarrhea in developing c o~n t r i e s .~'~-~'~ in this setting, eaec as defined by the m pattern of adherence to hep- cells can be found in upward of % of the population at any one time>l newer molecular diagnostic modalities have revised this figure downward, although the organism remains highly prevalent in many areas. several studies from the indian subcontinent implicated eaec among the most frequent enteric pathogen^.^'^.^'^.^^^ other sites reproducibly reporting high incidence rates include and bra~il."~'*~~' there is evidence that eaec may be emerging in incidence. a study from spo paulo, brazil, implicated eaec as the prevalent e. coli pathotypes in infants i ; epec had previously been shown to be the most common pathogen in this community. many other sites in developing countries of africa:" asia, ° ~ and south america " have described high endemic rates. several studies have suggested that eaec is also a common cause of infant diarrhea in industrialized c~u n t r i e s . "~~~~~~ using molecular diagnostic methods, a large prospective study in the united kingdom implicated eaec as the second most common enteric bacterial pathogen after cumpylob~cter.~~~ a similar study from switzerland found eaec to be the most common bacterial enter~pathogen.~'~ studies from the united states also have demonstrated a high rate of eaec diarrhea in infants; using molecular diagnostic methods, eaec was implicated in % and % of outpatient and inpatient diarrhea cohorts, respectively, compared with less than % of asymptomatic control infants (p < . ). although epidemiologic studies have shown that eaec can cause diarrhea in all age groups, several studies suggest that the infection is particularly common in infants younger than months d. * descriptions from outbreaks and volunteer studies suggest that eaec diarrhea is watery in character with mucus but without blood or frank pus. o o patients typically are afebrile. several epidemiologic studies have suggested that many infants may have bloody diarrhea, i but fecal leukocytes are uncommon. the earliest reports of eaec infection suggested that this pathogen may be particularly associated with persistent diarrhea (> days). - however, later studies suggest that persistent diarrhea may occur in only a subset of infected infants!" in the serbian outbreak of infected infants, the mean duration of diarrhea was . days ''; diarrhea persisted more than days in only three patients. infants in this outbreak had frequent, green, odorless stools. in three cases, the stools had mucus, but none had visible blood. eleven babies developed temperatures in excess of oc; only one had vomiting. despite a lack of clinical evidence suggesting inflammatory enteritis, several clinical studies have suggested that eaec is associated with subclinical inflammation, including the shedding of fecal cytokines and la~toferrin.'~~.~'~ studies in fortaleza, brazil, suggest that children asymptomatically excreting eaec may exhibit growth shortfalls compared with uninfected peers.lo a study from germany reported an association between eaec isolation and infant colic in infants without diarrhea. z this observation has not been repeated. eaec should be considered in the differential diagnosis of persistent diarrhea and failure to thrive in infants. diagnosis of eaec requires identification of the organism in the patient's feces. the hep- adherence assay can be used for this purpose"'; some reports suggest that the adherence phenotype can be observed using formalin-fixed cell^^^'^^^' thereby obviating the need to cultivate eukaryotic cells for each assay. pcr and gene probe for typical eaec are available. successful antibiotic therapy has been reported using fluoroquinolones in adult although preliminary studies suggest that a~ithrornycin~~~ or r i f a~i m i n~~~ also may be effective. therapy in infected infants should be guided by the results of susceptibility testing, as eaec frequently is antibiotic re~istant.~" additional e. coli pathotypes have been described, including diffusely adherent e. coli (daec), and cytodetaching e. c i .~~~ daec has been specifically associated with diarrhea outside of infancy, as infants may have some degree of inherent resistance to infection. cytodetaching e. coli represent organisms that secrete the e. coli hem~lysin.~~' it is not clear whether these latter organisms are true enteric pathogens. there are differences in invasiveness of salmonella strains related to serotype. s. typhi, s. choleraesuis, salmonella heidelberg, p and salmonella dub inm are particularly invasive, with bacteremia and extraintestinal focal infections occurring frequently. salmonella species possess genes closely related to those for the shigella invasion plasmid anti ensthese genes are probably essential to intestinal infection. virulence plasmids, which increase invasiveness in some serotypes, have been recognized, although the precise mechanisms of virulence remain to be elucidated; resistance to complement-mediated bacteriolysis by inhibition of insertion of the terminal c b- membrane attack complex into the outer membrane may be laboratory studies have demonstrated dramatic strain-related difference in the ability of s. typhimurium t o evoke fluid secretion, to invade intestinal mucosa, and to disseminate beyond the production of an enterotoxin immunologically related to cholera toxin by about two thirds of salmonella strains may be related to the watery diarrhea often seen. part because of the properties of their lipopolysaccharide~~~~~~~~ persistence of the organism within phagolysosomes of phagocytic cells may occur with any species of salmonella. it is not completely clear how the organisms have adapted to survive in the harsh intracellular environment, but their survival has major clinical significance. it accounts for relapses after therapy. it explains the inadequacy of some antimicrobial agents that do not penetrate phagolysosomes. it perhaps is the reason for prolonged febrile courses that occur even in the face of appropriate therapy. although humoral immunity and cell-mediated immunity are stimulated during salmonella infections, it is believed that cell-mediated immunity plays a greater role in eradication of the ba~teria. '~ t cell activation of macrophages appears to be important in killing intracellular salmonella. defective interferon-y production by monocytes of newborns in response to s. typhimurium lipopolysaccharide may explain in part the unusual susceptibility of infants to salmonella infection. studies in mice suggest that helper t cell (th ) responses in peyer's patches and mesenteric lymph nodes may be central to protection of the intestinal m~c o s a .~~~ humans who lack the il- receptor and therefore have impaired th responses and interferon-y production are at increased risk for salmonella infe~tion.~~' in typhoid fever, presence of an envelope antigen, vi, is known to enhance virulence. patients who develop classic enteric fever have positive stool cultures in the first few days after ingestion of the organism and again late in the course after a period of bacteremia. this course reflects early colonization of the gut, penetration of gut epithelium with infection of mesenteric lymph nodes, and reseeding of the gut during a subsequent bacteremic pha~e. ~' studies of s. typhimurium in monkeys suggest similar initial steps in pathogenesis (e.g., colonization of gut, penetration of gut epithelium, infection of mesenteric lymph nodes) but failure of the organism to cause a detectable level of ba~teremia. ~~ although both salmonella and shigella invade intestinal mucosa, the resultant pathologic changes are different. shigella multiplies within and kills enterocytes with production of ulcerations and a brisk inflammatory response, whereas salmonella passes through the mucosa and multiplies within the lamina propria, where the organisms are ingested by phagocytes; consequently, ulcer formation is less striking, although villus tip cells are sometimes sloughed. acute crypt abscesses can be seen in the stomach and small intestine, but the most dramatic changes occur in the colon, where acute diffuse inflammation with mucosal edema and crypt abscesses are the most consistent findings. v with s. typhi there also is hyperplasia of peyer's patches in the ileum, with ulceration of overlying tissues. salmonella strains, with the exception of s. typhi, are well adapted to a variety of animal hosts; human infection often can be traced to infected meat, contaminated milk, or contact with a specific animal. half of commercial poultry samples are contaminated with salmonella. definition of the serotype causing infection can sometimes suggest the likely source. for example, s. dublin is closely associated with cattle; human cases occur with a higher-than-predicted frequency in people who drink raw milk.@' for s. typhimurium, which is the most common serotype and accounts for more than one third of all reported human cases, a single source has not been established, although there is an association with cattle. despite the ban by the u.s. food and drug administration (fda) on interstate commercial distribution of small turtles, these animals continue to be associated with infection, as illustrated by a series of cases in puerto ~i~~.~~~ various pet reptiles are an important source of a variety of unusual salmonella serotypes such as salmonella marina, salmonella chameleon, salmonella arizonae, salmonella java, salmonella stanley, salmonella poona, salmonella jangwain, salmonella tilene, salmonella pomona, salmonella miami, salmonella manhattan, salmonella litchfield, salmonella rubislaw, and salmonella w a~s e n a a r .~~-~~ salmonella organisms are hardy and capable of prolonged survival; organisms have been documented to survive in flour for nearly a year? salmonella tennessee has been shown to remain viable for many hours on non-nutritive surfaces (i.e., glass, hours; stainless steel, hours; enameled surface, hours; rubber mattress, hours; linen, hours; and rubber tabletop, infection with salmonella is, like most enteric infections, more common in young children than in adults. the frequency of infection is far greater in the first years of life; roughly equal numbers of cases are reported during each decade beyond years of age. although the peak incidence occurs in the second through sixth months of life, infection in the neonate is relatively common. researchers at the cdc have estimated the incidence of salmonella infection in the first month of life at nearly cases per , infants? adult volunteer studies suggest that large numbers of salmonella ( lo to lo ) need to be ingested to cause di~ease. ~' however, it is likely that lower doses cause illness in infants. the occurrence of nursery ~u t b r e a k s~"~~~~~ and intrafamilial spread suggests that organisms are easily spread from person to person; this pattern is typical of low-inoculum diseases transmitted by the fecal-oral route. the neonate with salmonella infection infrequently acquires the organism from his or her mother during delivery. although the index case in an outbreak can often be traced to a mother, - , subsequent cases result from contaminated objects in the nursery e n~i r o n m e n t~~"~~~ serving as a reservoir coming in contact with hands of attending p e r~o n n e l .~~.~'~ the mother of an index case may be symptomatic ~ i ~ or asymptomatic with preclinical infecti n, '~ convalescent infedon, , , or chronic carriage. the risk of the newborn becoming infected once salmonella is introduced into a nursery has been reported to be as high as % to %, , but the frequency of infection may be lower because isolated cases without a subsequent epidemic are unlikely to be reported. gastric acidity is an important barrier to salmonella infection. patients with anatomic or functional achlorhydria are at increased risk of developing salmonellosis. ~ the hyp~chlorhydria'~ and rapid gastric emptying typical of early lifez may in part explain the susceptibility of infants to salmonella. premature and low-birth-weight infants appear to be at higher risk of acquiring salmonella infection than term whether this reflects increased exposure because of prolonged hospital stays or increased susceptibility on the basis of intestinal or immune function is unclear. contaminated food or water is often the source of salmonella infection in older patients; the limited diet of the infant makes contaminated food a less likely source of infection. although human milk? - raw milk? powdered milk, - formula: and cereal i have been implicated in transmission to infants, more often fomites, such as delivery room resu~citators, ~' rectal thermometer~, '~>~'~ oropharyngeal suction device^,^^^'^^' water baths for heating formula? soap dispenser^,^" " clean" medicine airconditioning mattresses, radiant and serve as reservoirs. one unusual outbreak involving premature and term infants was traced to faulty plumbing, which caused massive contamination of environment and personnel. after salmonella enters a nursery, it is difficult to eradicate. epidemics lasting to week^,'@^,^^' weeks,& months, b year:' " and to months b have been reported. spread to nearby pediatric wards has the incubation period in nursery outbreaks has varied widely in several studies where careful attention has been paid to this variable. in one outbreak of salmonella oranienburg involving newborns, % of cases occurred within days of in an outbreak of s. typhimurium, each of the ill infants presented within days of birth. these incubation periods are similar to those reported for salmonella newport in older children and adults, % of whom have been reported to be ill within days of e~p o s u r e .~'~'~~' conversely, one outbreak of salmonella nienstedten involving newborns was characterized by incubation periods of to days. the usual incubation period associated with fecal-oral nursery transmission is not found with congenital typhoid. during pregnancy, typhoid fever is associated with bacteremic infection of the fetus. the congenitally infected infants are symptomatic at birth. they are usually born during the second to fourth week of untreated maternal illness. usually, the mother is a carrier; fecal-oral transmission of s. typhi can occur with delayed illness in the newborn. several major clinical syndromes occur with nontyphoidal salmonella infection in young infants. colonization without illness may be the most common outcome of ingestion of salmonella by the neonate. such colonization usually is detected when an outbreak is under investigation. most infected infants who become ill have abrupt onset of loose, green, mucus-containing stools, or they have bloody diarrhea; an elevated temperature is also a common finding in salmonella gastroenteritis in the first months of life. o grossly bloody stools are found in the minority of patients, although grossly bloody stools can occur in the first hours of life. hematochezia is more typically associated with noninfectious causes (e.g., swallowed maternal blood, intestinal ischemia, hemorrhagic diseases, anorectal fissures) at this early age. there appear to be major differences in presentation related to the serotype of s. enteritidis causing infection. for example, in one epidemic of s. oranienb~rg~'~ involving newborns, % had grossly bloody stools, % were febrile, % had mucus in their stools, and only % were healthy. in a series of s. newport infections involving premature infants; % of infants with gastroenteritis had blood in their stools, % had fever, % had mucus in their stools, and % were asymptomatic. in an outbreak of s. typhim~rium~~' involving ill and healthy infants, none had bloody stools; all of the symptomatic infants were febrile and usually had loose, green stools. of infants infected by salmonella virchow, % were asymptomatic; the rest had mild diarrhea! seals and colleagues described infants with s. nienstedten, all of whom had watery diarrhea and low-grade fever; none had bloody stools. in a large outbreak in zimbabwe of s. heidelberg infection reported by bannerman, % of infants were asymptomatic, % had diarrhea, % had fever, % had pneumonia, and % developed meningitis. an outbreak of salmonella worthington was characterized primarily by diarrhea, fever, and jaundice, although of infants developed meningitis and % died. in dramatic contrast to these series, none of infants with positive stool cultures for s. tennessee had an illness in a nursery found to be contaminated with that organism. a few infants with salmonella gastroenteritis have developed necrotizing e n t e r o c o l i t i~, ~~~~~~ but it is not clear whether salmonella was the cause. although gastroenteritis is usually self-limited, chronic diarrhea has sometimes been attributed to s a l r n~n e l l a .~~~~~~~ whether chronic diarrhea is caused by salmonella is uncertain. although some infants develop carbohydrate intolerance after a bout of salmonella and salmonella is typically listed as one of the causes of postinfectious protracted diarrhea, it is difficult to be sure that the relationship is causal. the prolonged excretion of salmonella after a bout of gastroenteritis may sometimes cause non-specific chronic diarrhea to be erroneously attributed to salmonella. major extraintestinal complications of salmonella infection may develop in the neonate who becomes bacteremic. extraintestinal spread may develop in infants who initially present with diarrhea and in some who have no gastrointestinal tract signs. bacteremia appears to be more common in the neonate than in the older a study of more than children with salmonella infection showed that extraintestinal infection occurred significantly more often ( . % versus . %) in the first months of life. several retrospective studies suggest that infants in the first month of life may have a risk of bacteremia as high as % to %. one retrospective suggests that the risk is not increased in infancy and estimates that the risk of bacteremia in childhood salmonella gastroenteritis is between . % and . %. prospective studies of infants in the first year of life suggest that the risk of bacteremia is . % to . %. * although selection biases in these studies limit the reliability of these estimates, the risk is substantial. the salmonella species isolated from infants include some serotypes that appear to be more invasive in the first months of life than in older children or healthy adults (s. newport, s. agona, s. blockley, s. derby, s. enteritidis, s. heidelberg, s. infantis, s. javiana, s. saint-paul, and s. typhimurium) and serotypes that are aggressive in every age group (s. choleraesuis and s. dublin). other serotypes appear more likely to cause bacteremia in adults (s. typhi, s. paratyphi a, and s. paratyphi b). virtually any salmonella serotype can cause bacteremic disease in neonates. a few infants with salmonella gastroenteritis have died with e. coli or pseudomonas aeruginosa sepsis; but the role of salmonella in these cases is unclear. unlike the situation in older children in whom bacteremic salmonellosis often is associated with underlying medical conditions, bacteremia may occur in infants who have no immunocompromising conditions. salmonella bacteremia is often not suspected clinically because the syndrome is not usually d i s t i n~t i v e . ~~~~~ even afebrile, well-appearing children with salmonella gastroenteritis have been documented to have bacteremia that persists for several days. although infants with bacteremia may have spontaneous resolution without therapy: a sufficient number develop complications to warrant empirical antimicrobial therapy when bacteremia is suspected. the frequency of complications is highest in the first month of life. meningitis is the most feared complication of bacteremic salmonella disease. between % and % of all cases of nontyphoidal salmonella meningitis occur in the first months of life. the serotypes associated with neonatal meningitis (s. typhimurium, s. heidelberg, s. enteritidis, s. saint-paul, s. newport, and s. panama) are serotypes frequently associated with bacteremia. meningitis has a high mortality rate, in part because of the high relapse rates. relapse has been reported in up to % of ca~es. ~' in some studies, more than % of patients with meningitis have died, although more typically, % to % of infants die. * the survivors suffer the expected complications of gram-negative neonatal meningitis, including hydrocephalus, seizures, ventriculitis, abscess formation, subdural empyema, and permanent neurologic impairment. neurologic sequelae have included retardation, hemiparesis, epilepsy, visual impairment, and a t h e t o~i s .~~~ in large nursery outbreaks, it is common to find infants whose course is complicated by pneum~nia?'~ osteo-myeliti~, ">~~~ or septic arthriti~. '~,~'~ othe r rare complications of salmonellosis include p e r i~a r d i t i s ,~~ p y e l i t i~,~~ peritonitis: otitis media: mas ti ti^,^^^ chole~ystitis,~~' endophthalmiti~,~~~ cutaneous abscesses, and infected cephal~hematoma?~' other focal infections seen in older children and adults, such as endocarditis and infected aortic aneurysms, rarely or never have been reported in neonates. , altho ugh the mortality rate in two reviews of nursery outbreaks was . % to . %," in some series, it reached %. enteric fever, most often related to s. typhi but also occurring with s. paratyphi a, s. paratyphi b, s. paratyphi c, and other salmonella species, is reported much less commonly in infants than in older patients. infected infants develop typical findings of neonatal sepsis and meningitis. current data suggest that mortality is about y .~~' in utero infection with s. typhi has been described. typhoid f e~e r~" *~~' and nontyphoidal salmonella infections during pregnancy put women at risk of aborting the fetus. premature labor usually occurs during the second to the fourth week of maternal typhoid if the woman is untreated. in a survey of typhoid fever in pregnancy during the preantibiotic era, of women with well-documented cases delivered prematurely, with resultant fetal death; the rest delivered at term, although only infants survived. the outlook for carrying the pregnancy to term and delivering a healthy infant appears to have improved dramatically during the antibiotic era. however, one of seven women with typhoid in a series still delivered a dead fetus with extensive liver necrosis. in the preantibiotic era, about % of pregnant women with typhoid fever died. with appropriate antimicrobial therapy, pregnancy does not appear to put the woman at increased risk of death. despite these welldescribed cases, typhoid fever is rare early in life. of cases of typhoid fever that osler and m~c r a e~~~ reported, only were in the first year of life. in areas where typhoid fever is still endemic, systematic search for infants with enteric fever has failed to find many cases. the few infections with s. typhi documented in children in the first year of life often present as a brief nondescript "viral syndrome" or as p n e~r n o n i t i s ?~~*~~' fever, diarrhea, cough, vomiting, rash, and splenomegaly may occur; the fever may be high, and the duration of illness may be many weeks. the current practice of early discharge of newborn infants, although potentially decreasing the risk of exposure, can make recognition of a nursery outbreak difficult. diagnosis of neonatal salmonellosis should trigger an investigation for other cases. other than diarrhea, signs of neonatal salmonella infection are similar to the nonspecific findings seen in most neonatal infections. lethargy, poor feeding, pallor, jaundice, apnea, respiratory distress, weight loss, and fever are common. enlarged liver and spleen are common in those neonates with positive blood cultures. laboratory studies are required to establish the diagnosis because the clinical picture is not distinct. the fecal leukocyte examination reveals polymorphonuclear leukocytes in % to % . of persons with salmonella infection, but it has not been evaluated in neonates. obviously, the presence of fecal leukocytes is consistent with colitis of any cause and therefore is a nonspecific finding. routine stool cultures usually detect salmonella if two or three different enteric media (i.e., macconkey's, eosin-methylene blue, salmonella-shigella, tergitol , xylose-lysine-deoxycholate, brilliant green, or bismuth sulfite agar) are used. stool, rather than rectal swab material, is preferable for culture, particularly if the aim of culture is to detect carriers. on the infrequent occasions when proctoscopy is performed, mucosal edema, hyperemia, friability, and hemorrhages may be seen.*' infants who are bacteremic often do not appear sufficiently toxic to raise the suspicion of b a~t e r e m i a .~~~ blood cultures should be obtained as a routine part of evaluation of neonates with suspected or documented salmonella infection. ill neonates with salmonella infection should have a cerebrospinal fluid examination performed. bone marrow cultures also may be indicated when enteric fever is suspected. there are no consistent abnormalities in the white blood cell count. serologic studies are not helpful in establishing the diagnosis, although antibodies to and flagellar antigens develop in many infected newborns. if an outbreak of salmonellosis is suspected, further characterization of the organism is imperative? determination of somatic and flagellar antigens to characterize the specific serotype may be critical to investigation of an outbreak. when the serotype found during investigation of an outbreak is a common one (e.g., s. typhimurium), antimicrobial resistance testing , and use of molecular techniques such as plasmid chara~terization~~~ can be helpful in determining whether a single-strain, common-source outbreak is in progress. and ampicillin or amoxicillin versus placebo. in contrast to these studies, data suggest that there may be a role for quinolone antibiotics in adults and ~h i l d r e n ,~~~,~~~ but these drugs are not approved for use in neonates, and resistance has been en~ountered.~'~ because these studies have few data as to the risk-benefit ratio of therapy in the neonate, it is uncertain whether they should influence treatment decisions in neonates. studies that have included a small number of neonates suggest little benefit from antimicrobial therapy. * * however, because bacteremia is common in neonates, antimicrobial therapy for infants younger than months who have salmonella gastroenteritis often is recommended, v v especially if the infant appears toxic. premature infants and those who have other significant debilitating conditions also should probably be treated. the duration of therapy is debatable but should probably be no more than to days if the infant is not seriously ill and if blood cultures are sterile. if toxicity, clinical deterioration, or documented bacteremia complicates gastroenteritis, prolonged treatment is indicated. even with antimicrobial therapy, some infants develop complications. the relatively low risk of extraintestinal dissemination must be balanced against the well-documented risk of prolonging the carrier state. for infants who develop chronic diarrhea and malnutrition, hyperalimentation may be required; the role of antimicrobial agents in this setting is unclear. the infant with typhoid fever should be treated with an antimicrobial agent; relapses sometimes occur after therapy. colonized healthy infants discovered by stool cultures during evaluation of an outbreak ought to be isolated but probably should not receive antimicrobial therapy. such infants should be discharged from the nursery as early as possible and followed carefully as outpatients. antimicrobial treatment of neonates who have documented extraintestinal dissemination must be prolonged. bacteremia without localization is generally treated with at least a -day course of therapy. therapy for salmonella meningitis must be given for at least weeks to lessen the risk of relapse. about three fourths of patients who have relapses have been treated for three weeks or less? similar to meningitis, treatment for osteomyelitis must be prolonged to be adequate. although cures have been reported with weeks of therapy, to weeks of therapy is recommended. in vitro susceptibility data for salmonella isolates must be interpreted with caution. the aminoglycosides show good in vitro activity but poor clinical efficacy, perhaps because of the low ph of the phagolysosome. aminoglycosides have poor activity in an acid environment. the stability of some drugs in this acid environment also may explain in vitro and in vivo disparities. the intracellular localization and survival of salmonella within phagocytic cells also presumably explains the relapses encountered with virtually every regimen. resistance to antibiotics has long been a problem with salmonella i n f e c t i~n .~~,~~~,~~' there has been a steady increase in resistance to salmonella in the united states over the last years. with the emergence of typhimurium type dt , resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline has increased from . % in and to % in . resistance plasmids have been selected and transmitted, partly because therapy has been given for mild illness that should not have been treated and partly because of use of antibiotics in animal feeds. resistance to chloramphenicol and ampicillin has made trimethoprim-sulfamethoxazole increasingly important for the treatment of salmonella infection in those patients who require therapy. however, with increasing resistance to all three of these agents in asia? the middle e~r o p e ,~~~,~'~ ar gentina, and north america, , the third-generation cephalosporins and quinolones represent drugs of choice for invasive salmonellosis. the quinolones currently are not approved for persons younger than years. cefotaxime, ceftriaxone, and cefoperazone represent acceptable alternative drugs for typhoidal and nontyphoidal salmonellosis when resistance is e n c o~n t e r e d .~~"~~~ because the second-generation cephalosporins, such as cefuroxime, are less active in vitro than the third-generation cephalosporins and are not consistently clinically effective, they should not be data suggest that cefoperazone may sterilize blood and cause patients with typhoid fever to become afebrile more rapidly than with chl~ramphenicol,~~~ perhaps because cefoperazone is excreted into bile in high concent r a t i o n~.~~~ the third-generation cephalosporins may have higher cure and lower relapse rates than ampicillin or chloramphenicol in children with salmonella meningitis. the doses of ampicillin, chloramphenicol, or cefotaxime used in infants with gastroenteritis pending results of blood cultures are the same as those used in treatment of sepsis. because of the risk of gray baby syndrome, chloramphenicol should not be used in neonates unless other effective agents are not available. trimethoprim-sulfamethoxazole, although useful in older children and adults, is not used in neonates because of the risk of kernicterus. nosocomial infection with strains of salmonella resistant to multiple antibiotics, including third-generation cephalosporins, has emerged as a problem in south america. nonantibiotic interventions are important in the control of salmonella infections. limited data suggest that intravenous immune globulin (igiv) ( mg/kg on days , , , and of therapy) along with antibiotic therapy may decrease the risk of bacteremia and death in preterm infants with salmonella ga~troenteritis.~~~ early recognition and intervention in nursery outbreaks of salmonella are crucial to control. when a neonate develops salmonellosis, a search for other infants who have been in the same nursery should be undertaken. when two or more cases are recognized, environmental cultures, cultures of all infants, cohorting and contact isolation of infected infants, rigorous enforcement of hand hygiene, early discharge of infected infants, and thorough cleaning of all possible fomites in the nursery and delivery rooms are important elements of control. if cases continue to occur, the nursery should be closed to further admissions. cultures of nursery personnel are likely to be helpful in the unusual situation of an s. typhi outbreak in which a chronic carrier may be among the caretakers. culture of health care personnel during outbreaks of salmonellosis caused by other salmonella species is debatable, although often recommended. data suggest that nurses infected with salmonella rarely infect patients in the hospital setting. the fact that nursing personnel are sometimes found to be colonized during nursery outmay be a result rather than a cause of those epidemics. the potential role of vaccines in control of neonatal disease is minimal. for the vast number of non-s. ryphi serotypes, there is no prospect for an immunization strategy. multiple doses of the commercially available oral live attenuated vaccine (ty la; vivotif, berna), has been shown in chilean schoolchildren to reduce typhoid fever cases by more than %. , however, the vaccine is not recommended for persons younger than years, in part because immunogenicity of ty la is age dependent; children younger than months fail to respond with development of immunity!" vi capsular polysaccharide vaccine is available for children older than years and is effective in a single dose. whether some degree of protection of infants could the virulence of shigellae has been studied extensively since their recognition as major pathogens at the beginning of the th century. the major determinants of virulence are encoded by a -to -mda p l a~m i d .~~~.~~~ this plasmid, which is found in all virulent shigellae, encodes the synthesis of proteins that are required for invasion of mammalian cells and for the vigorous inflammatory response that is characteristic of the d i s e a~e .~~*~~ shigellae that have lost this plasmid, have deletions of genetic material from the region involved in synthesis of these proteins, or have the plasmid inserted into the chromosome lose the ability to invade eukaryotic cells and become aviru ent o ; maintenance of the plasmid can be detected in the clinical microbiology lab by ability to bind congo red. the ability to invade cells is the basic pathogenic property shared by all ~h i g e l l a e~~'~~~~ and by the shigella-like invasive e. coli, which also possesses the shigella virulence plasmid. ~ ~ ~ ~ in the laboratory, shigella invasiveness is studied in tissue culture (hela cell invasion), in animal intestine, or in rabbit or guinea pig eye, where instillation of the organism causes keratoconjunctivitis (sereny test)."' animal model studies have shown that bacteria penetrate and kill colonic mucosal cells and then elicit a brisk inflammatory response. in addition to the virulence plasmid, several chromosomal loci enhance virulence. v this has been best studied in s. flexneri in which multiple virulence-enhancing regions of the chromosome have been defined. s - the specific gene products of some of the chromosomal loci are not known; one chromosomal virulence segment encodes for synthesis of the repeat units of lipopolysaccharide. intact lipopolysaccharide is necessary but not sufficient to cause virulence. at least two cell-damaging cytotoxins that also are chromosomally encoded are produced by shigellae. one of these toxins (shiga toxin) is made in large quantities by s. dysenteriae serotype (the shiga bacillus) and is made infrequently by other shigellae. shiga toxin is a major virulence factor in s. dysenteriae, enhancing virulence at the colonic mucosa and also giving rise to sequelae similar to those caused by stec (discussed earlier). this toxin kills cells by interfering with peptide elongation during protein ~y n t h e s i s .~'~-~'~ additional toxins may also be secreted by shigellae, although their roles in virulence are not established. although much of the epidemiology of shigellosis is predictable based on its infectious dose, certain elements are unexplained. shigellae, like other organisms transmitted by the fecal-oral route, are commonly spread by food and water, but the low infecting inoculum allows person-to-person spread. because of this low inoculum, shigella is one of the few enteric pathogens that can infect swimmers. the dose required to cause illness in adult volunteers is as low as organisms for s. dysenteriae serotype , " about organisms for s. f l e~n e r i ,~~~ and organisms for s. ~o n n e i .~'~ personto-person transmission of infection probably explains the continuing occurrence of shigella in the developed world. enteropathogens that require large inocula and hence are best spread by food or drinking water are less common in industrialized societies because of sewage disposal facilities, water treatment, and food-handling practices. in the united states, daycare centers currently serve as a major focus for acquisition of shigell~sis.~'~ numerous outbreaks of shigellosis related to crowding, poor sanitation, and the low dose required for diseases have occurred in this setting. given the ease of transmission, it is not surprising that the peak incidence of disease is in the first years of life. it is, however, paradoxical that symptomatic infection is uncommon in the first year of life. - the best data on the age-related incidence of shigellosis come from mata'~~'~ prospective studies of guatemalan infants. in these studies, stool cultures were performed weekly on a group of children followed from birth to years old. the rate of infection was more than -fold lower in the first months of life than (fig. - ) . the same age-related incidence has been described in the united states and in a rural egyptian village. this anomaly has been explained by the salutary effects of brea~t-feeding.~~'-~~' however, it is likely that breast-feeding alone does not explain the resistance of infants to shigellosis. a review of three large case series - suggests that about . % ( of ) of shigellosis cases occur in infants in the neonatal period. the largest series of neonatal ~higellosis~~~ suggests that the course, complications, and etiologic serogroups are different in neonates than in older children. although newborns are routinely contaminated by maternal feces, neonatal shigellosis is rare. other aspects of the epidemiology of shigellosis elude simple explanation. the seasonality (summer-fall peak in the united states, rainy season peak in the tropics) is not well explained. the geographic variation in species causing infection likewise is not well understood. in the united states, most shigella infections are caused by s. sonnei or, less commonly, s. flexneri. in most of the developing world, the relative importance of these two species is reversed, and other shigella serotypes, especially s. dysenteriae serotype , are identified more frequently. as hygiene improves, the proportion of s. sonnei increases and that of s. flexneri decreases. data from bangladesh suggest that s. dysenteriae is less common in neonates, but s. sonnei and s. boydii are more c mmon. ~~ there appear to be some important differences in the relative frequencies of various complications of shigella infection related to age. some of these differences and estimates are based on data that are undoubtedly compromised by reporting biases. s. dysenteriae serotype characteristically causes a more severe illness than other shigellae with more complications, including pseudomembranous colitis, hemolysis, and hus. however, illnesses caused by various shigella serotypes usually are indistinguishable from each other and conventionally are discussed together. the incubation period of shigellosis is related to the number of organisms ingested, but in general, it is between and hours. volunteer studies have shown that after ingestion, illness may be delayed for a week or more. neonatal shigellosis seems to have a similar incubation period. more than one half of the neonatal cases occur within days of birth, consistent with fecal-oral transmission during parturition. mothers of infected neonates are sometimes carriers, although more typically they are symptomatic during the perinatal period. intrauterine infection is rare. in the older child, the initial signs are usually high fever, abdominal pain, vomiting, toxicity, and large-volume watery stools; diarrhea may be bloody or may become bloody. painful defecation and severe, crampy abdominal pain associated with frequent passage of small-volume stools with gross blood and mucus are characteristic findings in older children or adults who develop severe colitis. many children, however, never develop bloody diarrhea. adult volunteer studies have demonstrated that variations in presentation and course are not related to the dose ingested because some patients develop colitis with dysentery but others develop only watery diarrhea after ingestion of the same i n o c u l~m .~~~ the neonate with shigellosis may have a mild diarrheal syndrome or a severe ~o l i t i s .~~~~~~~-~~ fever in neonates is usually low grade (< " f) if the course is uncomplicated. the neonate has less bloody diarrhea, more dehydration, more bacteremia, and a greater likelihood of death than the older ~h i l d . ~~ physical examination of the neonate may show signs of toxicity and dehydration, although fever, abdominal tenderness, and rectal findings are less striking than in the older complications of shigellosis are common. although the illness is self-limited in the normal host, resolution may be delayed for a week or more. in neonates and malnourished children, chronic diarrhea may follow a bout of shigello~is. ~',~~ between % and % of hospitalized children with shigella have convulsions before or during the course of usually, the seizures are brief, generalized, and associated with high fever. seizures are uncommon in the first months of life, although neonates have been described with seizures. the cerebrospinal fluid generally reveals normal values in these children, but a few have mild cerebrospinal fluid pleocytosis. the neurologic outcome generally is good even with focal or prolonged seizures, but fatalities do occasionally occur, often associated with toxic encephalpa thy.^^' although the seizures had been postulated to result from the neurotoxicity of shiga toxin, this explanation was proved to be incorrect because most shigellae make little or no shiga toxin and the strains isolated from children with neurologic symptoms do not produce shiga t~x i n .~'~,~~' hemolysis with or without development of uremia is a complication primarily of s. dysenteriae serotype infection. sepsis during the course of shigellosis may be caused by the shigella itself or by other gut flora that gain access to the bloodstream through damaged mucosa. ' * the risk of sepsis is higher in the first year of life, particularly in neo-nates, . - , , in malnourished children, and in those with s. dysenteriae serotype infection. sepsis occurs in up to % of neonates with given the infrequency of neonatal shigellosis, it is striking that % of reported cases of shigella sepsis have involved infants in the first month of life. one of the infants with ba~teremia~~' reportedly had no discernible illness. disseminated intravascular coagulation may develop in those patients whose course is complicated by sepsis. meningitis has been described in a septic neonate. colonic perforation has occurred in n e o n a t e~, ~"~~~ older children,@' and adults. although this complication of toxic megacolon is rare, it appears to be more common in neonates than in older individuals. bronchopneumonia may complicate the course of shigellosis, but shigellae are rarely isolated from lungs or tracheal secretions." the syndrome of sudden death in the setting of extreme toxicity with hyperpyrexia and convulsions but without dehydration or sepsis (i.e., ekiri ~yndrome)~~'"~ is rare in neonates. in the nonbacteremic child, other extraintestinal foci of infection, including ~a g i n a~~~. "~ and eye,"' rarely occur. reiter's syndrome, which rarely complicates the illness in children, has not been reported in neonates. although infection is less common in infants than in toddlers, case fatality rates are highest in infant^.^^'^^' the mortality rate in newborns appears to be about twice that of older children. in industrialized societies, less than % of children with shigellosis die, whereas in developing countries, up to % die. these differences in mortality rates are related to n~t r i t i o n . ~~ availability of medical care, antibiotic resistance of many shigellae, the frequency of sepsis, and the higher frequency of s examination of stool for leukocytes as an indication of colitis is useful in support of the clinical suspicion of shigellosis. the white blood cell count and differential count also are used as supporting evidence for the diagnosis. leukemoid reactions (white blood cells > , /mm ) occur in almost % of children with s. dysenteriae serotype but in less than % of children with other ~h i g e l l a e .~~~ leukemoid reactions are more frequent in infants than in older ~hildren. ~' even when the total white blood cell count is not dramatically elevated, there may be a striking left shift. almost % of children with shigellosis have greater than % bands on the differential cell few reports address the white blood cell count in newborns, but those that do suggest that normal or low rather than elevated counts are more common. although serum and fecal antibodies develop to lipopolysaccharides and the virulence plasmid-associated polypeptide~, ~~ serologic studies are not useful in the diagnosis of shigellosis. pcr can identify shigella and eiec in feces. colonoscopy typically shows inflammatory changes that are most severe in the distal segments of therapy because dehydration is particularly common in neonatal shigellosis, attention to correction of fluid and electrolyte disturbances is always the first concern when the illness is suspected. although debate continues over the indications for antimicrobial therapy in the patient with shigellosis, the benefits of therapy generally appear to outweigh the risks. the chief disadvantages of antimicrobial therapy include cost, drug toxicity, and emergence of antibiotic-resistant shigellae. because of the self-limited nature of shigellosis, it has been argued that less severe illness should not be treated. however, children can feel quite ill during the typical bout of shigellosis, and appropriate antimicrobial therapy shortens the duration of illness and eliminates shigellae from stool, decreasing secondary spread. complications are probably decreased by antibiotics. given the high mortality rates of neonatal shigellosis, therapy should not be withheld. the empirical choice of an antimicrobial agent is dictated by susceptibility data for strains circulating in the community at the time the patient's infection occurs. multiresistant shigellae complicate the choice of empirical therapy before availability of susceptibility data for the patient's isolate. plasmid-encoded resistance (r factors) for multiple antibiotics has been observed frequently in s. dysenteriae serotype outbreaks and with other ~higellae.~'~.~'~ antimicrobial resistance patterns fluctuate from year to year in a given locale. however, despite the guesswork involved, early preemptive therapy is indicated when an illness is strongly suggestive of shigellosis. in vitro susceptibility does not always adequately predict therapeutic responses. cefa~lor, ~~ furazolidone, ~ephalexin, '~ amo~icillin, ~' kanam~cin, ~' and ~e f a m a n d o l e~~~ all are relatively ineffective agents. the optimal duration of therapy is debatable. studies in children older than years and in adults suggest that singledose regimens may be as effective in relieving symptoms as courses given for days. the single-dose regimens generally are not as effective in eliminating shigellae from the feces as are the longer courses. a third-generation cephalosporin, such as ceftriaxone, may be the best empirical choice. optimal doses for newborns with shigellosis have not been established. trimethoprim at a dose of lomg/kg/day (maximum, mg/day) and sulfamethoxazole at a dose of mg/kg/day (maximum, mg/day) in two divided doses for a total of days are recommended for the older child if the organism is s~s c e p t i b l e . ~~-~~~ if the condition of the infant does not permit orally administration, the drug usually is divided into three doses given intravenously over ampicillin at a dose of mg/kg/day in four divided doses taken orally for days may be used if the strain is susceptible. for the rare newborn who acquires shigellosis, appropriate therapy often is delayed until susceptibility data are available. this occurs because shigellosis is so rare in newborns that it is almost never the presumptive diagnosis of the child with watery or bloody diarrhea. although a sulfonamide is as efficacious as ampicillin when the infecting strain is sus~eptible, ~~ sulfonamides are avoided in neonates because of concern about the potential risk of kernicterus. the risk of empirical ampicillin therapy is that shigellae are frequently resistant to the drug; % of shigellae currently circulating in the united states are ampicillin resistant. for the neonate infected with ampicillin-resistant shigella, there are few data on which to base a recommendation. ceftriaxone is generally active against shigellae, but in the neonate, this drug can displace bilirubin-binding sites and elicit clinically significant cholestasis. data on children and adults suggest that clinical improvement occurs with c e f t r i a x~n e .~~~*~~~ quinolones, such as ciprofloxacin and ofloxacin, have been shown to be effective agents for treating s h i g e l l o s i~~~~~~~~ in adults, but they are not approved for use in children younger than years. other drugs sometimes used to treat diarrhea pose special risks to the infant with shigellosis. the antimotility agents, in addition to their intoxication risk, may pose a special danger in dysentery. in adults, diphenoxylate hydrochloride with atropine has been shown to prolong fever and excretion of the ~rganism.~" the response to appropriate antibiotic therapy is generally gratifying. improvement is often obvious in less than hours. complete resolution of diarrhea may not occur until a week or more after the start of treatment. in those who have severe colitis or those infected by s. dysenteriae serotype , the response to treatment is somewhat delayed. for most of the developing world, the best strategy for prevention of shigellosis during infancy is prolonged breastfeeding. specific antibodies in milk appear to prevent symptomatic shigellosis ' ; nonspecific modification of gut flora and the lack of bacterial contamination of human milk also may be important. breast-feeding, even when other foods are consumed, decreases the risk of shigellosis; children who continue to consume human milk into the third year of life are still partially protected from in the united states, the best means of preventing infection in the infant is good hand hygiene when an older sibling or parent develops diarrhea. even in unsanitary environments, secondary spread of shigellae can be dramatically decreased by hand hygiene after defecation and before meals. spread of shigellae in the hospital nursery can presumably be prevented by the use of contact isolation for infants with diarrhea and attention to thorough hand hygiene. although nursery personnel have acquired shigellosis from infected newborns, further transmission to other infants in the nursery, although is rare. in contrast to salmonella, large outbreaks of nosocomial shigellosis in neonates are rare. unfortunately, good hygiene is a particularly difficult problem in daycare centers. the gathering of susceptible children, breakdown in hand hygiene, failure to use different personnel for food preparation and diaper changing, and difficulty controlling the behavior of toddlers all contribute to daycare-focused outbreaks of shigellosis. immunization strategies have been studied since the turn of the th century, but no satisfactory immunization has been developed. even if immunizations are improved, a role in managing neonates seems unlikely. campylobacter was first recognized in an aborted sheep fetus in the early o s o and was named vibrio fetus by smith and taylor in . this organism subsequently was identified as a major venereally transmitted cause of abortion and sterility and as a cause of scours in cattle, sheep, and goats. s it was not until , when it was isolated from the blood culture of a pregnant woman who subsequently aborted at months' gestation, that the significance of campylobacter as a relatively rare cause of bacteremia and perinatal infections in humans was a~preciated.~l'-~'~ during the s, campylobacter was recognized to be an opportunistic pathogen in debilitated in , v fetus and related organisms were separated from the vibrios (such as v cholerae and v parahaemolyticus) and placed in a new genus, campylobacter (greek word for "curved rod"). since , several campylobacter species have been recognized as a common cause of e n t e r i t i~~l~.~~~ and, in some cases, extraintestinal infections. the genus campylobacter contains species, most of which are recognized as animal and human pathogens. the most commonly considered causes of human disease are campylobacter fetus, campylobacter jejuni, campylobacter coli, campylobacter lari, and campylobacter upsaliensis (table - ),' - although campylobacter mucosalis has been isolated from stool of children with diarrhea. dna hybridization studies have shown that these species are distinct, sharing less than % dna homology under stringent hybridization ~o n d i t i o n s .~~~,~~~ helicobacter pylori was originally named campylobacter pylori, but because of differences in dna, it was reclassified and is no longer considered in the campylobacter genus. strains of c. fetus are divided into two subspecies: c. fetus subsp. fetus and c. fetus subsp. venerealis. the first subspecies causes sporadic abortion in cattle and sheep ; in by far the most common syndrome caused by a campylobacter species is enteritis. c. jejuni and c. coli cause gastroenteritis and generally are referred to collectively as c. jejuni, although dna hybridization studies show them to be different. in the laboratory, c. jejuni can be differentiated from c. coli because it is capable of hydrolyzing hippurate, whereas c. coli is not. most isolates that are associated with diarrhea ( % to %) are identified as c. jejuni, - and in some cases, individuals have been shown to be simultaneously infected with c. jejuni and c. ~o l i . ~~~ because of the fastidious nature of c. jejuni, which is difficult to isolate from fecal flora, its widespread occurrence was not recognized until . - previously called related vibrios by this organism had been associated with bloody diarrhea and colitis in infants and adults only when it had been associated with a recognized b a~t e r e m i a .~~~-~~~ in the late s, development of selective fecal culture methods for c. jejuni enabled its recognition worldwide as one of the most common causes of enteritis in persons of all ages. it is an uncommon infection in neonates who generally develop gastroenteritis when i n f e~t e d .~'~-~~~-~~' bacteremia with c. jejuni enteritis also is uncommon. ~ , l* * - maternal symptoms considered to be related to c. jejuni infection generally are mild and include fever ( %) and diarrhea ( %). in contrast to the serious disease in newborns that is caused by c. fetus, neonatal infections with although meningitis occurs in rare third trimester infection related to c. fetus or c. jejuni may results in abortion or stillbirth. pathogenesis c. fetus does not produce recognized enterotoxins or cytotoxins and does not appear to be locally invasive by the sereny instead, these infections may be associated with penetration of the organism through a relatively intact intestinal mucosa to the reticuloendothelial system and blo~dstream.~'~ whether this reflects a capacity to resist serum factors or to multiply intracellularly remains to be determined. c. jejuni is capable of producing illness by several mechanisms. these organisms have been shown to produce an lt enterotoxin and a c y t o t o x i r~.~~~~~~~ this enterotoxin is known to be a heat-labile protein with a molecular mass of to mda. it shares functional and immunologic properties with cholera toxin and e. coli lt. c. jejuni and c. coli also elaborate a cytotoxin that is toxic for a number of mammalian cells. - the toxin is heat labile, trypsin sensitive, and not neutralized by immune sera to shiga toxin or the cytotoxin of clostridium dificile. the role of these toxins as virulence factors in diarrheal disease remains unpr~ved.'~~,~~ several animal models have been tested for use in the study of this pathogen. potential models for the study of c. jejuni enteritis include dogs, which may acquire symptomatic infection ; -to -day old ~h i c k s~~' -~~; chicken embryo cells, which are readily invaded by c. jejuni "; rhesus monkeys ; and rabbits by means of the removable intestinal tie adult rabbit technique. an established small mammal model that mimics human disease in the absence of previous treatment or surgical procedure has not been successful in adult mice. an infant mouse mode , and a hamster of diarrhea appear promising. c. jejuni is negative in the sereny test for invasivenes~,~~~ and most investigators report no fluid accumulation in ligated rabbit ileal loops. the pathologic findings of c. fetus infection in the perinatal period include placental necrosis '' and, in the neonate, widespread endothelial proliferation, intravascular fibrin deposition, perivascular inflammation, and hemorrhagic necrosis in the brain. the tendency for intravascular location and hepatosplenomegaly in adults infcctcd with c. fetus has been the pathologic findings in infants and children infected with c. fetus can include an acute inflammatory process in the colon or rectum, as evidenced by the tendency for patients to have bloody diarrhea with numerous fecal leukocytes. there also can be crypt abscess formation and an ulcerative colitis or pseudomembranous colitis-like or a hemorrhagic jejunitis or ileitis. b , , mesenteric lymphadenitis, ileocolitis and acute appendicitis also have been described. infection with campylobacter species occurs after ingestion of contaminated food, including unpasteurized milk, poultry, and contaminated water.' , - m any farm animals and pets, such as chickens, dogs, s and cats (especially young animals), are potential sources. the intrafamilial spread of infection in h o~s e h o l d s ,~~~,~~~ the occurrence of outbreaks in and the apparent laboratory acquisition of c. jejuni all suggest that c. jejuni infection may occur after person-to-person transmission of the organism. outbreaks of c. jejuni in the child daycare setting are not common. volunteer studies i have shown a variable range in the infecting dose, with many volunteers developing no illness. the report of illness after ingestion of lo organisms in a glass of milk and production of illness in a single volunteer by organisms i substantiate the variation in individual susceptibility. the potential for low-inoculum disease has significant implications for the importance of strict enteric precautions when infected persons are hospitalized, particularly in maternity and nursery areas. when diarrhea in neonates caused by c. jejuni has been r e p~r t e d ,~~~-~~' maternal-infant transmission during labor has generally been documented. ~ * ~ p ~ the lior serotyping system, restriction length polymorphism, and pulse-field gel electrophoresis have been used to confirm the identity of the infant and maternal isolates. most mothers gave no history of diarrhea during pregnancy. * , outbreaks have occurred in neonatal intensive care units because of person-to-person spread. z the frequency of asymptomatic carriage of c. jejuni ranges from % to . % ' , to as high as % to %. , , , - in a cohort study in mexico, % of all infections related to c. jejuni were asymptomatic. infected children, if untreated, can be expected to excrete the organisms for or weeks; however, more than % are culture negative after ~e e k s .~~~,~~~a~ ymptomatic excreters pose a significant risk in the neonatal period, in which acquisition from an infected mother can be clinically important. , s , c. jejuni has increasingly been recognized as a cause of watery and inflammatory diarrhea in temperate and tropical climates throughout the world. it has been isolated from % to % of all fecal cultures from patients with diarrheal illnesses in various parts of the world. - , * - there is a tendency for c. jejuni enteritis to occur in the summer in countries with temperate climates. the reservoir of campylobacter is the gastrointestinal tract of domestic and wild birds and animals. it infects sheep, cattle, goats, antelope, swine, chickens, domestic turkeys, and pet dogs. c. fetus often is carried asymptomatically in the intestinal or biliary tracts of sheep and cattle. during the course of a bacteremic illness in pregnant animals, c. fetus organisms, which have a high affinity for placental tissue, invade the uterus and multiply in the immunologically immature fetus. the infected fetuses generally are aborted. whether this organism is acquired by humans from animals or is carried asymptomatically for long periods in humans, who may then transmit the organism through sexual contact as appears to occur in animals, is unclear. it is believed that this subspecies rarely is found in the human intestine and that it is not a cause of human enteriti~?'~ c. fetus infections predominantly occur in older men with a history of farm or animal exposure and in pregnant women in their third trimester. ~ , , symptomatically or asymptomatically infected women may have recurrent abortions or premature deliveries and are the source of organisms associated with life-threatening perinatal infections of the fetus or newborn infant. , - in several instances of neonatal sepsis and meningitis, c. fetus was isolated from culture of maternal cervix or vagina. , s a n osocomial nursery outbreak has been associated with carriage in some healthy infants. ' other outbreaks have been associated with meningitis , cervical cultures have remained positive in women who have had recurrent abortions and whose husbands have antibody titer elevations. the most commonly incriminated reservoir of c. jejuni is poultry. ,s , , m ost chickens in several different geographic locations had a large number (mean, x /g) of c. jejuni in the lower intestinal tract or feces. this occurred in some instances despite the use of tetracycline, to which the campylobacter was susceptible in vitro, in the chicken feed. the internal cavities of chickens remain positive for carnpylobacter even after they have been cleaned, packaged, and fr zen. ~~ however, unlike salmonella, c. jejuni organisms that survive usually do not multiply to high concen-tration~?~' domestic puppies or kittens w i t h c. jejuni diarrhea also can provide a source for spread, especially to infants or c. jejuni enteritis also has been associated in a number of outbreaks with consumption of unpasteurized in retrospect, the first reported human cases of c. jejuni enteritis were probably in a milk-borne outbreak reported in . because campylobacter infections of the udder are not seen, milk is probably contaminated from fecal shedding of the organism. these organisms are killed by adequate heating. fecally contaminated water is a potential vehicle for c. jejuni infections. several phenotypic and genotypic methods have been used for distinguishing c. jejuni strains from animals and humans involved in epidemics. clinical manifestations of infection caused by campylobacter depend on the species involved (see table - ). human infections with c. fetus are rare and generally are limited to bacteremia in patients with predisposing condition^^^^.^^^ or to bacteremia or uterine infections with prolonged fever and pneumonitis that lasts for several weeks in women during the third trimester of pregnancy. unless appropriately treated, symptoms usually resolve only after abortion or delivery of an infected infant? j , - * these infected neonates, who are often premature, develop signs suggesting sepsis, including fever, cough, respiratory distress, vomiting, diarrhea, cyanosis, convulsions, and jaundice. the condition typically progresses to meningitis, which may be rapidly fatal or may result in serious neurologic ~equelae.~" additional systemic manifestations include pericarditis, pneumonia, peritonitis, salpingitis, septic arthritis, and abscesses. c. jejuni infection typically involves the gastrointestinal tract, producing watery diarrhea or a dysentery-like illness with fever and abdominal pain and stools that contain blood and ~u c u s .~~~~~~'~~' " ' older infants and children generally are affected, but neonates with diarrhea have been reported. infection in neonates generally is not clinically apparent or is mild. stools can contain blood, mucus, and pus p * * ; fever often is ab~ent. ~~"~' the illness usually responds to appropriate antimicrobial which shortens the period of fecal shedding. extraintestinal infections related to c. jejuni other than bacteremia are rare but include cholecystitis, urinary tract and meningitis. bacteremia is a complication of gastrointestinal infe~tion, ~' especially in malnourished children. meningitis that appears to occur secondary to intestinal infection also has been reported in premature infants who have had intraventricular needle aspirations for neonatal hydrocephalus.'i complications in older children and adults that have been associated with c. jejuni enteritis include reiter's syndrome, guillain-barre ~y n d r o m e , ~~~~~* and reactive persistent c. jejuni infections have been described in patients infected with human immunodeficiency extraintestinal manifestations generally occur in patients who are immunosuppressed or at the extremes of age.' campybbacter zari has caused chronic diarrhea and bacteremia in a neonate!% most important in the diagnosis of campylobacter infection is a high index of suspicion based on clinical grounds. c. fetus and c. jejuni are fastidious and may be overlooked on routine fecal cultures. isolation of campylobacter from blood or other sterile body sites does not represent the same problem as isolation from stool. growth occurs with standard blood culture media, but it may be slow. in the case of c. fetus infecting the bloodstream or central nervous system, blood culture flasks should be blindly subcultured and held for at least days or the organism may not be detected because of slow or inapparent the diagnosis of c. fetus infection should be considered when there is an unexplained febrile illness in the third trimester of pregnancy or in the event of recurrent abortion, prematurity, or neonatal sepsis with or without meningitis. a high index of suspicion and prompt, appropriate antimicrobial therapy may prevent the potentially serious neonatal complications that may follow maternal c. fetus infection. campylobacter is distinguished from the vibrio organisms by its characteristics of carbohydrate nonfermentation and by its different nucleotide base omp position.^^^^^^^-^^^*^^^ campylobacter is . to . fm wide and . to . long. it is a fastidious, microaerophilic, curved, motile gram-negative bacillus that has a single polar flagellum and is oxidase and catalase positive, except for c. upsaliensis, which is generally catalase negative or weakly positive. c. jejuni and c. fetus are separated by growth temperature (c. fetus grows best at ' c but can be cultured at ' c; c. jejuni grows best at ' c) and by nalidixic acid and cephalosporin susceptibilities, because c. jejuni is susceptible to nalidixic acid and resistant to cephalosporins. c. jejuni grows best in a microaerobic environment of % oxygen and % carbon dioxide at ' c. it grows on a variety of media, including brucella and mueller-hinton agars, but optimal isolation requires the addition of selective and nutritional supplements. growth at ' c in the presence of cephalosporins is used to culture selectively for c. jejuni from fecal specimens. in a study of six media, charcoal-based selective media and a modified charcoal cefoperazone deoxycholate agar were the most selective for identification of campylobacter species. extending the incubation time from to hours led to an increase in the isolation rate regardless of the medium its typical darting motility may provide a clue to identification, even in fresh fecal specimens, when viewed by phase-contrast microscopy. when the organism has been cultured, it is presumptively identified by motility and by its curved, sometimes sea gulllike appearance on carbolfuchsin stain. polymorphonuclear leukocytes are usually found in stools when bloody diarrhea occurs and indicate the occurrence of ~o l i t i s .~~~*~~* to avoid potentially serious c. jejuni infection in the newborn infant, careful histories of any diarrheal illnesses in the family should be obtained, and pregnant women with any enteric illness should have cultures for this and other enteric pathogens. detection of c. jejuni and c. coli by pcr has been reported and in the future may be useful for the rapid and reliable identification of this organism. the differential diagnosis of c, fetus infections include the numerous agents that cause neonatal sepsis or meningitis, especially gram-negative bacilli. diagnostic considerations for inflammatory or bloody enteritis include necrotizing enterocolitis, allergic proctitis, and salmonella; rarely shigellu, and other infectious agents occur. agglutination, complement fixation, bactericidal, immunofluorescence, and elisa tests have been used for serologic diagnosis of c. jejuni infection and to study the immune response, but these assays are of limited value in establishing the diagnosis during an acute infection. the prognosis is grave in newborn infants with sepsis or meningitis caused by c. fetus. in infants with c. jejuni gastroenteritis, limited data suggest that appropriate, early antimicrobial therapy results in improvement and rapid clearance of the organism from stool. campylobacter species are often resistant to p-lactams, including ampicillin and cephalosporins. v mo st strains are susceptible to erythromycin, gentamicin, tetracycline, chloramphenicol, and the newer quinolones, although resistance to these agents has been r e p~r t e d .~~' ,~~~ it appears that a parenteral aminoglycoside is the drug of choice for c. fetus infections, pending in vitro susceptibility studies. in the case of central nervous system involvement, cefotaxime and chloramphenicol are potential alternative drugs. depending on in vitro susceptibilities, which vary somewhat with locale, erythromycin is the drug of choice for treating c. jejuni e n t e r i t i~.~~~~~"~~' ' if erythromycin therapy is initiated within the first days of illness, a reduction in excretion of the organism and resolution of symptoms occur. although data regarding treatment of asymptomatic or convalescent carriers are not available, it seems appropriate to treat colonized pregnant women in the third trimester of pregnancy when there is a risk of perinatal or neonatal infection. the failure of prophylactic parenteral gentamicin in a premature infant has been documented, followed by successful resolution of symptoms and fecal shedding with erythromycin. because there appears to be an increased risk of toxicity with erythromycin estolate during pregnancy and other forms of erythromycin should probably be used in these settings. azithromycin appears to be effective if the organism is susceptible. strains that are erythromycin resistant often are resistant to azithromycin. cumpylobucter tends to have higher minimal inhibitory concentrations for clarithromycin than for a~ithromycin.~~~ furazolidone has been used in children and ciprofloxacin in nonpregnant patients older than years. contact precautions should be employed during any acute diarrheal illness and until the diarrhea has subsided. hand hygiene after handling raw poultry and washing cutting boards and utensils with soap and water after contact with raw poultry may decrease risk of infection. pasteurization of milk and chlorination of water are critically important. infected food handlers and hospital employees who are asymptomatic pose no known hazard for disease transmission if proper personal hygiene measures are maintained. ingestion of human milk that contains anti<. jejuni antibodies has been shown to protect infants from diarrhea due to c. j e j~n i .~~,~~~ c. dificile is a spore-forming, gram-positive, anaerobic bacillus that produces two toxins. in the presence of antibiotic pressure, c. dificile colonic overgrowth and toxin production occur. the virulence properties of c. dificile are related to production of an enterotoxin that causes fluid secretion (toxin a) and a cytotoxin detectable by its cytopathic effects in tissue culture (toxin b). * both the usual manifestations of c. dificile disease in older children and adults include watery d&rhea, abdominal pain and tenderness, nausea, vomiting, and low-grade fever. grossly bloody diarrhea is unusual, although occult fecal blood is common. leukocytosis is present during severe illness. diarrhea usually begins to days into a course of antimicrobial therapy but may be delayed until several weeks after completion of the therapeutic course. usually, the illness is mild and self-limited if the offending drug is discontinued. severe colitis with pseudomembranes is less common now than in previous years because the risk of diarrhea developing during antimicrobial therapy is recognized and the antimicrobial agent typically is stopped. it is unclear whether this organism causes disease in newborns. one study from a newborn intensive care unit suggests that toxin a in stools is associated with an increased frequency of abnormal stools. endoscopic findings of pseudomembranes and hyperemic, friable rectal mucosa suggest the diagnosis of pseudomembranous colitis. pseudomembranes are not always present in c. dificile colitis; mild cases are often described as nonspecific colitis. several noninvasive techniques are used to establish the diagnosis, including enzyme immunoassay (eia) for toxin detection and pcr. - isolation of c. dificile from stool does not distinguish between toxigenic and nontoxigenic isolates. if c. dificile is isolated, testing for toxin by cell culture or eia should be performed to confirm the presence of a toxigenic strain. there are multiple commercially available eias that detect either toxin a or both toxins a and b. - these assays are sensitive and easy to perform. other assays are available for epidemiologic investigation of outbreaks of disease due to c. d i f i~i l e .~~~ in older children and adults, the diagnosis is confirmed by culture of c. dificile and demonstration of toxin in feces. in neonates, these data are inadequate to prove that an illness is related to c. dificile. when the clinical picture is consistent, the stool studies are positive for c. dificile and no other cause for illness is found, a diagnosis of "possible" c. dificile is made. a favorable response to eradication of c. dificile is supportive evidence that the diagnosis is c rrect. ~~ because of the uncertainty implicit in the ambiguity of neonatal diagnostic criteria, other diagnoses must be considered. when the decision is made that a neonate's illness might be related to c. difjcile, the initial approach should include fluid and electrolyte therapy and discontinuation of the offending antimicrobial agent. if the illness persists or worsens or if the patient has severe diarrhea, specific therapy with r n e t r o n i d a z~l e~~~*~~~ should be instituted. metronidazole is considered to be the treatment of choice for most patients with c. difjcile ~olitis. ~' rarely is there a need to consider orally administered vancomycin or bacitracin in after initiation of therapy, signs of illness generally resolve within several days, titers decrease, and fecal toxins disappear eventually. recurrence of colitis after discontinuation of metronidazole or vancomycin has been documented in % to % of adults.g relapses are treated with a second course of metronidazole or vancomycin. drugs that decrease intestinal motility should not be administered. neutralizing antibody against c. dificile otoxin has been demonstrated in human colostrum.' secretory component of siga binds to toxin a to inhibit its binding to receptors data show that there are nonantibody factors present in milk that interfere with the action of toxin b in addition to secretory iga directed at toxin a. breast-feeding appears to decrease the frequency of colonization by c. d i f j~i l e .~'~ in addition to standard precautions, contact precautions are recommended for the duration of illness. meticulous hand hygiene techniques, proper handling of contaminated waste and fomites, and limiting the use of antimicrobial agents are the best available methods for control of c. dificile infection. b! cholerue is a gram-negative, curved bacillus with a polar flagellum. of the many serotypes, only enterotoxin-producing organisms of serotype and cause epidemics. b! cholerue is divided into two serotypes, inaba and ogawa, and two biotypes, classic and el tor; the latter is the predominant biotype. nontoxigenic strains and non- strains of v cholerae can cause diarrhea and sepsis but do not cause outbreaks? ~ a pathogenesis b! cholerue group is the classic example of an enteropathogen whose virulence is caused by enterotoxin production. cholera toxin is an -mda protein whose five b subunits cause toxin binding to the enterocyte membrane ganglioside gm, and whose a subunit causes adenosine diphosphate ribosylation of a guanosine triphosphate-binding regulatory subunit of adenylate cy~lase."~~~'~ the elevated camp levels that result from stimulation of enterocytes by cholera toxin cause secretion of salt and water with concomitant inhibition of absorption. two other toxins are also encoded within the virulence cassette that encodes cholera toxin. these toxins, zona occludens toxin (zot) and accessory cholera toxin (ace), are consistently found in illness-causing strains of and but not usually in v; cholerae organisms that are less virulent. since , v cholerae , biotype el tor, has spread from india and southeast asia to africa, the middle east, southern europe, and the southern, western, and central pacific islands in the aquatic environment. the usual reported vehicles of transmission have included contaminated water or ice; contaminated food, particularly raw or undercooked shellfish; moist grains held at ambient temperature; and raw or partially dried fish. the usual mode of infection is ingestion of contaminated food or water. boiling water or treating it with chlorine or iodine and adequate cooking of food kill the organism. asymptomatic infection of family contacts is common but direct person-to-person transmission of disease has not been documented. persons with low gastric acidity are at increased risk for cholera infection. cholera acquired during pregnancy, particularly in the third trimester, is associated with a high incidence of fetal miscarriage can be attributed to a fetal acidosis and hypoxemia resulting from the marked metabolic and circulatory changes that this disease induces in the mother. it is not surprising that the likelihood of delivering a stillborn child is closely correlated with the severity of the maternal illness. the inability to culture v; cholerue from stillborn infants of infected mothers, together with the usual absence of bacteremia in cholera, suggests that transplacental fetal infection is not a cause of intrauterine death. neonatal cholera is a rare disease. this generalization also applies to the new strains, although mild '* and severe forms of illness have rarely been described in newborns. among neonates admitted to a cholera research hospital in dacca, bangladesh, there were infants ill with ~holera.~" even infants born to mothers with active diarrheal disease may escape infection, despite evidence that rice-water stools, almost certain to be ingested during the birth process, may contain as many as lo organism~/ml.~~~ the reason for this apparently low attack rate among newborns is not certain; however, it probably can be attributed in large part to the protection conferred by breast-feedingg ' human milk contains antibodies and receptor-like glycoprotein that inhibit adherence of v choleraeu and gangliosides that bind cholera toxin. the role of transplacentally acquired vibriocidal maternal antibodies has not been determined. because v cholerae causes neither bacteremia nor intestinal invasion, protection against illness is more likely to be a function of mucosal rather than serum additional factors that may reduce the incidence of neonatal cholera include the large inoculum required for infection and the limited exposure of the newborn to the contaminated food and water. clinicians should request that appropriate cultures be performed for stool specimens from persons suspected of having cholera. the specimen is plated on thiosulfate citrate bile salts sucrose agar directly or after enrichment in alkaline peptone water. isolates of v cholerae should be confirmed at a state health department and then sent to the cdc for testing for production of cholera toxin. a fourfold rise in vibriocidal antibody titers between acute and convalescent serum samples or a fourfold decline in titers between early and late (> months) convalescent serum specimens can confirm the diagnosis. probes have been developed to test for cholera toxin. * the most important modality of therapy is administration of oral or parented rehydration therapy to correct dehydration and electrolyte imbalance and maintain h y d r a t i~n .~~ antimicrobial therapy can eradicate vibrios, reduce the duration of diarrhea, and reduce requirements for fluid replacement. one cholera vaccine, which is administered parenterally, is licensed in the united states but is of very limited value. several experimental oral vaccines are being t e~t e d ? *~-~~' i.: enterocolitica is a major cause of enteritis in much of the industrialized enteritis due to this organism primarily occurs in infants and young children, and infections in the united states are reported to be more common in the north than in the s o~t h .~~~-~~~ h i m als, especially swine, have been shown to serve as the reservoir for y. enterocolitica. a history of recent exposure to chitterlings (i.e., pig intestine) is common. transmission has also occurred after ingestion of contaminated milk and infusion of contaminated blood p r o d~c t s .~~~,~~~ virulence of y. enterocolitica is related primarily to a virulence plasmid, which is closely related to the virulence plasmids of yersinia pseudotuberculosis and yersinia p e s t i~.~~'~~~~ an st enterotoxin, which is closely related to the st of etec, may also be important. infection with y. enterocolitica is recognized as one of the causes of bacterial gastroenteritis in young children, but knowledge of neonatal infection with this organism is fragmentary. even in large series, isolation of yersinia from newborns is rare? , the youngest infants whose clinical course has been described in detail were days to several months old at the onset of their illness. , - there were no features of the gastroenteritis to distinguish it from that caused by other invasive enteric pathogens such as shigella or salmonella. infants presented with watery diarrhea or with stools containing mucus with streaks of blood. sepsis was common in these infants particularly in the first months of life when % of enteritis was complicated by sepsis. , , , fever is not a consistent finding in children with bacteremia, and meningitis is rare. in older children, fever and right lower quadrant pain mimicking appendicitis are often found. diagnosis y enterocolitica can be recovered from throat swabs, mesenteric lymph nodes, peritoneal fluid, blood, and stool. because laboratory identification of organisms from stool requires special techniques, laboratory personnel should be notified when yersinia is suspected. because avirulent environmental isolates occur, biotyping and serotyping are useful in assessing the clinical relevance of isolates. pcr has been used to detect pathogenic strain^.^^^'^^^ the effect of antimicrobial therapy on the outcome of gastrointestinal infection is uncertain. it has been recommended that antibiotics be reserved for sepsis or prolonged and severe gastroenteritisg '; however, there are no prospective studies comparing the efficacy of various antimicrobial agents with each other or with supportive therapy alone. most strains of y. enterocolitica are susceptible to trimethoprimsulfamethoxazole, the aminoglycosides, piperacillin, imipenem, third-generation cephalosporins, amoxicillin-clavulanate potassium, and chloramphenicol, and resistant to amoxicillin, ampicillin, carbenicillin, ticarcillin, and m a c r o l i d e~.~~~-~~~ therapy in individual cases should be guided by in vitro susceptibility testing, although cefotaxime has been successfully used in bacteremic infants? aerornonas hydrophila is widely distributed in animals and the environment. although wound infection, pneumonia, and sepsis (especially in immunocompromised hosts) represent typical aeromonas infections, gastroenteritis increasingly is being recognized. the organism is a gramnegative, oxidase-positive, facultatively anaerobic bacillus belonging to the family vibrionaceae. like other members of this family, it produces an enter~toxin~~' that causes fluid secretion in rabbit ileal loops.%' some strains cause fluid accumulation in the suckling mouse model,"' whereas other strains are i n~a s i v e~~~ or cytotoxic. the enterotoxin is not immunologically related to cholera toxin or the heat lt of although volunteer studies and studies with monkeys have failed to provide supportive evidence for enteropathog e n i~i t y ?~~,~~ there is good reason to believe that a. hydrophila does cause diarrhea in children. the earliest description of aeromonas causing diarrhea was an outbreak that occurred in a neonatal unit. although several studies have failed to show an association with diarrhea,% - most studies have found more aeromonas isolates among children with gastroenteritis than among ~o n t r o l s ?~~-~~~ part of the controversy may be caused by strain differences; some strains possess virulence traits related to production of gastroenteritis, whereas others do not. , the diarrhea described in children is a disease of summer, primarily affecting children in the first years of life. in one study, ( %) of cases of aeromonas detected during a -month period occurred in infants younger than month. typically, watery diarrhea with no fever has been described; although there are descriptions of watery diarrhea with fever? however, in %, a dysentery-like illness occurred. dysentery-like illness has been described in the neonate. in one third of children, diarrhea has been reported to last for more than ~eeks. ~' there may be species-related differences in clinical features of aeromonas-associated gastroenteritis in children. organisms that were formerly classified as a. hydrophila are now sometimes labeled as aeromonas sobria or aeromonas ~a v i a e .~~'~~~' fever and abdominal pain appear to be particularly common with a. sobria. one series of a. hydrophila isolates from newborns in dallas showed more blood cultures than stool cultures positive for a e r o m o n a~.~~~ diagnosis of enteric infection associated with aeromonas often is not made because this organism is not routinely sought in stool cultures. when the organism is suspected, the laboratory should be notified so that oxidase testing can be performed. the organism is usually susceptible to aztreonam, imipenem, meropenem, third-generation cephalosporins, trimethoprim-sulfamethoxazole, and chloramphenicol.q ~ plesiomonas shigelloides is a gram-negative, facultative anaerobic bacillus that, like aeromonas, is a member of the vibrionaceae family. it is widely disseminated in the environment; outbreaks of disease are usually related to ingestion of contaminated water or seafood. although it has been associated with outbreaks of diarrheal disease and has been found more commonly in ill than well controls, the role of i? shigelloides in diarrheal disease has remained contro~ersial.~~~ if it is a true enteropathogen, the mechanism by which it causes disease is ~n c l e a r . ~~'~~' the role of this organism in neonatal diarrhea has not been extensively investigated. infections of neonates have been r e p~r t e d ?~' .~~~ but most cases of enteric disease currently reported in the united states are in adults. typical illness consists of watery diarrhea and cramps; sometimes, fever, bloody stools, and emesis occur and last for to days. diagnosis is not usually made by clinical microbiology laboratory testing because, as with aeromonas, coliforms can be confused with l ? shigelloides unless an oxidase test is performed. the true frequency of infection is unknown. the organism has antibiotic susceptibilities similar to those of a e r~m o n a s .~~~'~~~ proving that an organism causes diarrhea is difficult, particularly when it may be present in large numbers in stools of healthy persons. bacteria that have been associated with acute gastroenteritis may be considered causative when the following criteria are met: . a single specific strain of the organism should be found as the predominant organism in most affected infants by different investigators in outbreaks of enteric disease in different communities. . this strain should be isolated in a significantly lower percentage and in smaller numbers from stool specimens of healthy infants. . available methods must be used to exclude other recognized enteropathogens, including viruses and parasites, enterotoxigenic agents, and fastidious organisms such as ca mpylobacter. . demonstration of effective specific antimicrobial therapy and specific antibody responses and, ultimately, production of experimental disease in volunteers are helpful in establishing the identity of a microorganism as a pathogen. optimally, the putative pathogen should have virulence traits that can be demonstrated in model systems. most bacteria that have been suggested as occasional causes of gastroenteritis in neonates fail to fulfill one or more of these criteria. their role in the cause of diarrheal disease is questionable. this is particularly true of microorganisms described in early reports in which the possibility of infection with more recently recognized agents could not be excluded. much of the clinical, bacteriologic, and epidemiologic data collected earlier linking unusual enteropathogens to infantile diarrhea must be reevaluated in light of current knowledge and methodology. several reports of acute gastroenteritis believed to have been caused by klebsiella suggest that, rather than playing an etiologic role, these organisms had probably proliferated within an already inflamed b~w e l .~~~-' '~' the recovery of klebsiella-enterobacter in pure culture from diarrheal stools has led several investigators to suggest that these bacteria may occasionally play a causative role in infantile gastroenteritis and enterocoliti~.'~~~~'"~ ingestion of infant formula contaminated with enterobacter sakazakii has been associated with development of bloody diarrhea and sepsis.'oo however, klebsiella species also may be isolated in pure culture from stools of newborns with no enteric s y m p t o m~. '~~~~'~' ' in one study, certain capsular types of klebsiella were more often isolated from infants with diarrheal disease than from normal infants.ioo later work has shown that klebsiella pneumoniae, enterobacter cloacae, and citrobacter species are capable of isolation of citrobacter species, such as those of klebsiella species, describe associations with enteric illnesses in up to % of cases. - there is inadequate evidence to define the roles of klebsiella, enterobacter, and citrobacter species as etiologic agents of enteric illnesses. listeria monocytogenes, one of the classic causes of neonatal sepsis and meningitis (see chapter ), has been linked to outbreaks of febrile diarrheal disease in immunocompetent adults and ~h i l d r e n . '~'~~'~~' seventy-two percent of ill individuals have had fever.ioz outbreaks have been related to ingestion of contaminated foods. listeria has rarely been described as a cause of neonatal gastroenteriti~.'~~~-~~~~ infection with enterotoxin-producing bacteroides fragilis has been associated with mild watery diarrhea.' these infections have a peak incidence in -to -year-old infants. these toxin-producing organisms cannot be detected in routine hospital laboratories. a variety of organisms has been isolated from infant stools during episodes of diarrhea. most of these reports have failed to associate illness with specific organisms in a way that has stood the test of time. for example, i? aeruginosa - and have been associated with diarrhea, but proteus , [ ] [ ] [ ] [ ] [ ] [ ] [ ] there are few convincing data suggesting that either is a true enteropathogen. these organisms generally are recovered as frequently from healthy infants as from infants with diarrheal disease, suggesting that their presence in stool cultures is significant. , - an association between providencia and neonatal enteritis has been substantiated largely by anecdotal reports of nursery outbreaks. . ~ @' these bacteria are rarely isolated from infants with sporadic or community-acquired diarrheal disease.' ~' m" b~ candida albicans usually is acquired during passage through the birth canal and is considered a normal, although minor, component of the fecal flora of the neonate (see chapter ).' ' intestinal overgrowth of these organisms frequently accompanies infantile gastroenteriti~, "~~~~~'~~~*'~~~ particularly after antimicrobial therapy. , ,' - the upper small gut may become colonized with candida in malnourished children with diarrhea ; whether the presence of the organism is cause or effect is unclear. stool cultures obtained from infants with diarrheal disease are therefore inconclusive, and although candida enteritis has been reported in adults,' the importance of this organism as a primary cause of neonatal gastroenteritis has been difficult to prove. clinical descriptions of nursery epidemics of candidal enteritis are poorly documented, generally preceding the recognition of epec and rotaviruses as a cause of neonatal diarrhea. even well studied cases of intestinal involvement add little in the way of substantive proof because secondary invasion of candida has been shown to be a complication of coliform enteritis. , producing e n~e r o~o~n s~ ~~~~ ~ ~ ' " ~ reports of although diarrhea has sometimes been described as a finding in neonatal disseminated candidiasis, more typically, gastrointestinal tract involvement with disseminated candida is associated with abdominal distention and bloody stools mimicking necrotizing enterocoliti~.~~~"~~~-~~~~ typically, affected infants are premature and have courses complicated by antibiotic administration, intravascular catheter use, and surgical procedures during the first several weeks of life. a trial of oral anticandidal therapy may be helpful in neonates suffering from diarrhea in the presence of oral or cutaneous candidiasis. if the therapy is appropriate, a response should be forthcoming within to days. diarrhea sometimes occurs as a manifestation of systemic infection. patients with staphylococcal toxic shock syndrome, for example, often have diarrhea. loose stools sometimes occur in sepsis, but it is unclear whether the diarrhea is a cause or an effect. the organisms isolated from blood cultures in a group of bangladeshi infants and children with diarrhea included staphylococcus aureus, haemophilus inpuenzae, streptococcus pneumoniae, r aeruginosa, and various gramnegative enteric bacilli.' it is unknown whether the bacteriology of sepsis associated with diarrhea is similar in the well-nourished infants seen in industrialized countries. acute diarrhea associated with intestinal parasites is infrequent during the neonatal period. in areas with high endemicity, infection of the newborn is likely to be associated with inadequate maternal and delivery care, insufficient environmental sanitation, and poor personal hygiene standards. the occurrence of symptomatic intestinal parasitic infection during the first month of life requires acquisition of the parasite during the first days or weeks; the incubation period for e. histolytica and g. larnblia is to weeks, and for cryptosporidium parvum, it is to days. the newborn can be infected during delivery by contact with maternal feces, o in the hospital through contact with the mother or personnel, or in the household through contact with infected individuals in close contact with the child. contaminated water can be an important source of infection for g. lamblia and c. parvum. organisms formerly identified as e. histolytica have been reclassified into two species that are morphologically identical but genetically distinct: e. histolytica and e. dispar. the former can cause acute nonbloody and bloody diarrhea, necrotizing enterocolitis, ameboma, and liver abscess, and the latter is a noninvasive parasite that does not cause disease. early acquisition of disease tends to be more severe in young infants; rarely, amebic liver abscess and rapidly fatal colitis have been reported in infant^."^^-'^^^ for example, a -dayold child from india who presented with to episodes of watery and mucous diarrhea, lethargy, jaundice, and mildly elevated liver enzymes has been described; the child recovered completely after days of intravenous o m i d a~o l e . '~~~ however, asymptomatic colonization of neonates with various species of ameba is common in areas of high endemi~ity."~~ diagnosis can be established by stool examination for cysts and trophozoites and by serologic studies.' through the use of pcr, isoenzyme analysis, and antigen detection assays, e. histolytica and e. dispar can be differentiated. ' serum antibody assays may be helpful in establishing the diagnosis of amebic dysentery and extraintestinal amebiasis with liver involvement. the efficacy of treatment with metronidazole for colitis or liver abscess has not been established for the newborn period, although this therapy has been used with success. o patients with colitis or liver abscess caused by e. histolytica are treated also with iodoquinol, as are asymptomatic carriers. g. lamblia is a binucleate, flagellated protozoan parasite with trophozoite and cyst stages. it is spread by the fecal-oral route through ingestion of cysts. child-care center outbreaks reflecting person-to-person spread have demonstrated high i n f e~t i v i t y . "~~~'~~~ foodborne transmission and waterborne transmission also occur. infection is often asymptomatic or mildly symptomatic; cases of severe symptomatic infection during the immediate newborn period have not been reported. symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive typical in the youngest children. seroprevalence studies have demonstrated evidence of past or current infection in % of peruvian children by the age of months.io ' in a study of lactating bangladeshi mothers and their infants, % of women and % of infants excreted giardia once during the study; in some infants, this occurred before they were months old.'o of these infected infants, % had diarrhea, suggesting that the early exposure to the parasite resulted in disease. in a prospective study of diarrhea conducted in mexico, infants frequently were infected with giardia from birth to months, with a crude incidence rate of first giardia infection of . infections per child-year in this age group. the symptom status of these children was not reported but this study strongly suggests that g. lamblia may be more common than currently recognized among newborns living in developing areas. the diagnosis of giardiasis can be made on the basis of demonstration of antigen by eia or by microscopy of feces, duodenal fluid or, less frequently, duodenal b i~p~y . ' '~~~' '~' breast-feeding is believed to protect against symptomatic g i a r d i a~i s .~-~~* '~~~ this protection may be mediated by cellular and humoral i nrnunity ~~"~~*"~~ and nonspecifically by the antigiardial effects of unsaturated fatty acids.iob giardia infections causing severe diarrhea may respond to metronidazole or furazolidone.' c. parvum is a coccidian protozoon related to toxoplasma gondii, lsospora belli, and plasmodium species. s' the life cycle involves ingestion of thick-walled oocysts; release of sporozoites, which penetrate intestinal epithelium; and development of merozoites. there is asexual and sexual reproduction, with the latter resulting in formation of new oocysts that can be passed in stools. cryptosporidium species are ubiquitous. infection often occurs in persons traveling to endemic areas.'o because cryptosporidium infects a wide variety of animal species, there is often a history of animal contact among infected individ~als."~' person-to-person spread, particularly in household c~n t a c t s '~~'~' '~~ and daycare center^,"^^"'^^ is well documented and suggests that the organism is highly infectious. waterborne outbreaks of cryptosporidiosis occur and can be of massive proportion^."^^ the clinical manifestations of illness in immunocompetent persons resemble those of giardia infection but are somewhat shorter in d~ration'"~; asymptomatic carriage is rare. symptoms and signs include watery diarrhea, abdominal pain, myalgia, fever, and weight loss. * ~ ~' " ~' infection in the first month of life has been described.""~"" because symptoms resolve before excretion of oocysts ceases, a newborn whose mother has been ill with cryptosporidiosis in the month before delivery might be at risk even if the mother is asymptomatic at the time of the child's birth."'* with the increasing frequency of human immunodeficiency virus infection, it is likely that women with symptomatic cryptosporidiosis occasionally will deliver an infant who will become infected. infants infected early in life may develop chronic diarrhea and maln~trition."'~ the diagnosis of cryptosporidiosis is most typically made by examination of fecal smears using the giemsa stain, ziehl-neelsen stain, auramine-rhodamine stain, sheather's sugar flotation, an immunofluorescence procedure, a modified concentration-sugar flotation method, or an eia.' io , lo nitazoxanide is effective therapy of immunocompetent adults and children ill with cryptosporidiosis.'io because illness is usually self-limited in the normal host, attention to fluid, electrolyte, and nutritional status usually suffices. enteric isolation of hospitalized infants with this illness is appropriate because of the high infectivity. several studies suggest that the risk of infection early in life may be decreased by breast-feeding. ' '"j viruses that infect the intestinal mucosa and cause primarily gastroenteritis are referred to as enteric viruses; they should not be confused with enteroviruses, members of picornaviridae family that are associated primarily with systemic illnesses. enteric viruses include rotaviruses, enteric adenoviruses, human caliciviruses, and astroviruses. other viruses such as coronaviruses, breda viruses, pestiviruses, parvoviruses, toroviruses, and picobirnaviruses have been sporadically associated with acute diarrhea but are currently considered of uncertain relevance. extensive reviews on the role of enteric viruses in childhood diarrhea can be found elsewhere." -"" all four enteric viruses could conceivably infect the newborn, but the extent of exposure and clinical manifestations are largely unknown for astrovirus, enteric adenovirus, and human caliciviruses. rotavirus is the most extensively studied enteric virus. neonatal rotavirus infections have similar virologic and clinical characteristics to infection in older children, although some differences exist. rotavirus is a -nm, nonenveloped virus composed of three concentric protein shells: a segmented genome ( segments), an rna-dependent polymerase, and enzymes required for messenger rna synthesis are located within the inner core. each segment codes for at least one viral protein (vp). the vp can be part of the structure of the virus, or it may be a nonstructural protein (nsp) required for replication, viral assembly, budding, determination of host range, or viral pathogenesis."" six distinct rotavirus groups (a through f) have been identified serologically based on common group of which three (a, b, and c) have been identified in humans.'io because group a rotaviruses represent more than % of isolated strains in humans worldwide, further discussion focuses on this group. group a rotaviruses are subclassified into serotypes based on neutralization epitopes located on the outer capsid. both rotavirus surface proteins, vp and vp , can induce production of neutralizing antibodies. at least vp types (g serotypes: gi to g , g to g , and g ) and nine vp types (p serotypes: pia, plb, p a, p , p b, p , p , p , and p ) have been detected among human r o t a v i r u~e s .~~~~-~~~~ by sequencing the vp -coding gene, eight genomic p types (genotypes) have been identified that correspond to one or more of the described p antigenic types (genotype to antigenic type pla, to plb, to p a, to p , to p b, to p , to p , and to p )."" combining g antigenic with p antigenic and genetic typing, a specific rotavirus strain can be identified p antigenic type (p genetic type), g type. as an example, the human neonatal m strain is described as p a[ ], gi. from newborn nurseries, some of which seem to be endemic to the newborn units with high rates of asymptomatic infe~tion,"~~-"~' and less commonly, outbreaks of symptomatic infection.iiz these findings suggest that specific conditions of the newborn environment (e.g., child, nursery, personnel) may increase the possibility of reassortments between human strains; such strains may persist in these settings possibly through constant transmission involving asymptomatic newborns, adults, and contaminated surfaces. rotavirus primarily infects mature enterocytes located in the mid and upper villous e p i t h e l i~m .~~~~-"~~ lactase, which is present only on the brush border of the differentiated epithelial cells at these sites, may act as a combined receptor and uncoating enzyme for the virus, permitting transfer of the particles into the cell. perhaps for this reason, infection is limited to the mature columnar enterocytes; crypt cells and crypt-derived cuboidal cells, which lack a brush border, appear to be resistant to rotaviral i n f e~t i o n . "~~' "~~ this concept also may explain why rotavirus infection is less common in infants younger than weeks' gestational age than in more mature infants ; between and weeks' gestational age, lactase activity is approximately % of that found in term infants. the upper small intestine is most commonly involved, although lesions may extend to the distal ileum and rarely to the ~ l n .~~~~ ~~~~ interaction between intestinal cell and rotavirus structural and nonstructural proteins occurs, resulting in death of infected villous enter~cytes."~~ once infected, the villous enterocyte is sloughed, resulting in an altered mucosal architecture that becomes stunted and flattened. the gross appearance of the bowel is usually normal; however, under the dissecting microscope, scattered focal lesions of the mucosal surface are apparent in most cases. light microscopy also shows patchy changes in villous morphology, compatible with a process of infection, inflammation, and accelerated mucosal renewal. the villi take on a shortened and blunt appearance as tall columnar cells are shed and replaced by less mature cuboidal entero-ischemia may also play a role in the loss and stunting of villi" and activation of the enteric nervous system; active secretion of fluid and electrolytes may be another pathogenic mechanism. during the recovery phase, the enteroblastic cells mature and reconstruct the villous structure. because of the loss of mature enterocytes on the tips of the villi, the surface area of the intestine is reduced. diarrhea that occurs may be a result of this decrease in surface area, disruption in epithelial integrity, transient disaccharidase deficiency, or altered countercurrent mechanisms and net secretion of water and electrolytes. ' ~ ~ ~ ~ ~ nsp has been found to induce age-dependent diarrhea in cd mice by triggering calcium-dependent chloride and water secretion. the potential role of this "viral enterotoxin" in human disease is not yet clear. , infants with asymptomatic rotavirus infections in the nursery are less likely than uninfected nursery mates to experience severe rotavirus infection later in life - ; this finding suggested protective immunity and supported vaccine development. most studies have indicated that serum and intestinal antirotavirus antibody levels are correlated with protection against i n f e~t i o n "~~-"~~ although this correlation has not been ~n i v e r s a l .~~~~-~~~~ breast-feeding protects against rotavirus disease during the first year of life, probably including newborns. the high prevalence of antirotaviral antibodies in colostrum and human milk has been demonstrated by numerous investigators in widely diverse geographic areas. maternal rotavirus infection or immunization is accompanied by the appearance of specific antibodies in milk, probably through stimulation of the enteromammary immune between % and % of women examined in london, bangladesh, guatemala, costa rica, and the united states had antirotaviral iga antibodies in their milk for up to years of rotavirus-specific igg antibodies have been found during the first few postpartum days in about one third of human milk samples a~s a y e d ,~~@~"~~ whereas i@ antibodies were detectable in about one half. glycoproteins in human milk have been shown to prevent rotavirus infection in vitro and in an animal model." the concentration of one milk glycoprotein, lactadherin, was found to be significantly higher in human milk ingested by cytes.l , , infants who developed asymptomatic rotavirus infection than in milk ingested by infants who developed symptomatic infe~tion. ~ rotaviruses probably infect neonates more commonly than previously recognized, although most infections seem to be asymptomatic or mildly symptomatic. " ~ - in a prospective study, the prevalence of rotavirus infection among neonatal intensive care unit patients was . %. rotavirus has a mean incubation period of days, with a range of to days in children and in experimentally infected adults. fecal excretion of virus often begins a day or so before illness and maximal excretion usually occurs during the third and fourth days, and generally diminishes by the end of the first week, although low concentrations of virus have been detected in neonates for up to weeks. , [ ] [ ] [ ] [ ] rotavirus infections are markedly seasonal (autumn and winter) in many areas of the world, although in some countries seasonality is less striking; the reason for this is u n~l e a r .~~~" '~~ in nurseries in which persisting endemic infection has permitted long-term surveillance of large numbers of neonates, rotavirus excretion can follow the seasonal pattern of the community but can also show no seasonal it is not clear how units in which infection remains endemic for months or years differ from those with a low incidence of rotavirus. some nurseries are free of rotavirus infection' or minimally a f f e~t e d~~"~" whereas others have rotavirus diarrheal disease throughout the year or in outbreaks that involve % to % of low birth weight does not seem to be an important factor in determining the attack rate among infants at risk but may be important in rn rta ity.i~~~ infants in premature or special-care nurseries, despite their prolonged stays and the increased handling necessary for their care, do not demonstrate a higher susceptibility to infection; data regarding shedding of the virus are inconsi~tent!~*~~~~ after infection is introduced into a nursery, rotavirus probably will spread steadily and remain endemic until the nursery is closed to new admissions or nursing practices permit interruption of the cycle. exactly how the virus is introduced and transmitted is uncertain, although limited observations and experience with other types of enteric disease in maternity units suggest several possibilities. the early appearance of virus in stools of some neonates indicates that infection probably was acquired at delivery. virus particles can be detected on the first v s or second" day of life in a significant number of infected infants. by day or , most infected infants who will shed virus, with or without signs of illness, are doing so. , the large numbers of virus particles e x~r e t e d "~~,~~~~ suggest a fairly large and early oral inoculum. it is unlikely that contamination from any source other than maternal feces could provide an inoculum large enough to cause infection by the second day. transfer of particles from infant to infant on the hands of nursing and medical staff is probably the most important means of viral spread. with ' to " viral particles usually present in g of stool, the hands of personnel easily could become contaminated after infection is introduced into a nursery. there are numerous reports of nosocomial and daycare center rotavirus gastroenteritis outbreaks that attest to the ease with which this agent spreads through a hospital or institutional setting.'io admission of a symptomatic child usually is the initiating event, although transfer of a neonate with inapparent infection from one ward to another also has been incriminated. the most important factors influencing the incidence of rotavirus diarrhea in a nursery are the proximity to other newborns and the frequency of handling. during a -month study, infants cared for by nursing staff and kept in communal nurseries experienced three epidemics of diarrhea with attack rates between % and %. during the same period, only % of infants rooming in with their mothers became ill, even though they had frequent contact with adult relatives and siblings. there is no clear evidence of airborne or droplet infection originating in the upper respiratory tract or spread by aerosolization of diarrheal fluid while diapers are changed. indirect evidence of airborne transmission includes the high infection rate in closed settings, the isolation of the virus from respiratory secretions,izo and the experimental observation of transmission by aerosol droplets in mice.' however, the respiratory isolation achieved by placin an evidence indicates that transplacental or ascending intrauterine infection occurs. transmission of virus through contaminated fomites, formula, or food is possible but has not been documented in newborns. rotavirus particles have not been found in human milk or c o l o~t r u m .~~~~~~~~ exposure of a newborn to rotavirus can result in asymptomatic infection or cause mild or severe gastro-outbreaks with high attack rates as measured by rotavirus excretion have been described but the extent of symptomatic infection severe rotavirus infection is seldom reported during the newborn period but the extent of underreporting of severe disease, especially in the less developed areas of the world, has not been evaluated. it has been hypothesized that asymptomatic infections during the newborn period are the result of naturally attenuated strains circulating in this environment. rna electrophoretic patterns of rotaviruses found in certain nurseries have shown uniform and it has been suggested that these strains may be attenuated. the presence of unusual antigenic types such as the p a[ ] type within nurseries also suggests "less virulent strains." at least rotavirus strains were documented to co-circulate in a tertiary care center during a -month period " and in a different setting the same rotavirus strains by electropherotype produced asymptomatic infection in neonates and symptomatic infection in older infants. newborns within a nursery exposed to a given rotavirus strain can develop symptomatic or asymptomatic infection. ~ ~ i because newborns routinely have frequent relatively loose stools, it is possible that mild diarrhea episodes caused by rotavirus are being wrongly labeled as asymptomatic episodes. no clinical feature is pathognomonic of rotaviral gastroenteritis. early signs of illness, such as lethargy, irritability, vomiting, and poor feeding, usually are followed in a few hours by the passage of watery yellow or green stools free of blood but sometimes containing mucus. , - diarrhea usually decreases by the second day of illness and is much infant in a closed incubator is not fully protective. s no enteritisel . . . , ,l , , varies. . . . , improved by the third or fourth day. occasionally, intestinal fluid loss and poor weight gain may continue for or weeks, particularly in low-birth-weight infants. although reducing substances frequently are present in early fecal ~a m p l e s "~~~'~~~' ~ this finding is not necessarily abnormal in neonates, particularly those who are breast-fed. nevertheless, infants with prolonged diarrhea should be investigated for monosaccharide or disaccharide malabsorption or intolerance to cow's milk protein or in a prospective % of newborns with gastrointestinal symptoms in a neonatal intensive care unit had rotavirus detected in their stools. frequent stooling (present in %), bloody mucoid stool ( %), and watery stools ( %) were risk factors for a rotavirus infection. bloody mucoid stools, intestinal dilatation, and abdominal distention were significantly more common in preterm infants, but severe outcomes such as necrotizing enterocolitis and death did not differ among infected term and preterm infants. longitudinal studies in newborn nurseries and investigations of outbreaks among neonates rarely describe a severe adverse outcome or death. , , because these infants are under constant observation, early detection of excessive fluid losses and the availability of immediate medical care are probably major factors in determining outcome. rotavirus gastroenteritis causes almost , deaths of infants every year,i i concentrated largely in the poorest regions of the world. it is likely that in places where hospital-based care is uncommon, rotavirus causes neonatal deaths secondary to dehydration. group a rotavirus has been associated with a wide array of diseases in infants and children; reye syndromes, encephalitis-aseptic meningitis, sudden infant death syndrome, inflammatory bowel disease, and kawasaki syndrome have been described but not systematically studied. case reports and small case series have associated neonatal rotavirus infection with necrotizing e n t e r o c~l i t i s .~~'~"~~~ rotavirus infection may play a role in a small proportion of cases of necrotizing enterocolitis, although it probably represents one of many potential triggering factors. a significant association between neonatal rotavirus infection and bradycardia-apnea episodes was detected in one prospective study. the possible association between natural rotavirus infection and i n t u s s u~c e p t i o n~~~~~~~~~ gained support after the association was made between the human-simian reassortant vaccine and intussusception in infants older than months (attributable risk = : , ). intussusception is extremely uncommon in the newborn; it is highly unlikely that rotavirus triggers this disease in neonates. there are many methods used for detection of rotavirus in stool specimens, including electron microscopy, immune electron microscopy, elisa, latex agglutination, gel electrophoresis, culture of the virus, and reverse transcriptasepolymerase chain reaction. elisa and latex agglutination currently are the most widely used diagnostic techniques for detection of rotavirus in clinical samples. many commercial kits are available that differ in specificity and ~e n s i t i v i t y . '~~~-'~~~ in general, latex agglutination assays are more rapid than elisas but are less sensitive. the sensitivity and specificity of the commercially available elisas surpass %. checking of the elisa by another method such as gel electrophoresis or pcr amplification may be desirable if there is concern about false-positive results. fecal material for detection of rotavirus infection should be obtained during the acute phase of illness. whole-stool samples are preferred, although suspensions of rectal swab specimens have been adequate for detection of rotavirus by rotavirus are relatively resistant to environmental temperatures, even tropical temperatures, although °c is desirable for short-term storage and - °c for prolonged storage.'io excretion of viral particles may precede signs of illness by several days' ; maximal excretion by older infants and children usually occurs to days after onset of symptoms. neonates can shed virus for to weeks after onset of symptoms. the primary goal of therapy is restoration and maintenance of fluid and electrolyte balance. despite the documented defect in carbohydrate digestion with rotavirus diarrhea, rehydration often can be accomplished with glucoseelectrolyte or sucrose-electrolyte solutions given orally . , - intravenous fluids may be needed in neonates who are severely dehydrated, who have ileus, or who refuse to feed. persistent or recurrent diarrhea after introduction of milkbased formulas or human milk warrants investigation for secondary carbohydrate or milk protein i n t~l e r a n c e . '~~~~~~" disaccharidase levels and xylose absorption return to normal within a few days to weeks after infe~tion."~~ intractable diarrhea related to severe morphologic and enzymatic changes of the bowel mucosa is possible although rare in the newborn; it may require an elemental diet or parenteral nutrition. efficacy of anti-rotavirus antibodies (e.g., hyperimmune colostrum, antibody-supplemented formula, human serum immunoglobulin) and of probiotics has been p~s t u l a t e d , '~~~~'~~' although not convincingly shown ; the widespread clinical use of these measures seems remote. one study suggests that use of lactobacillus during the diarrheal episode may decrease the duration of rotavirus-associated hospital stays, especially when used early in the course of the disease, although more studies are needed before recommending widespread use. hand hygiene before and after contact with each infant remains the single most important means of preventing the spread of infection. because rotavirus is often excreted several days before illness is recognized, isolation of an infant with diarrhea may be too late to prevent cross-infection unless all nursing personnel and medical staff have adhered to this fundamental precaution. infants who develop gastroenteritis should be moved out of the nursery area if adequate facilities are available and the infant's condition permits transfer. the use of an incubator is of value in reducing transmission of disease only by serving as a reminder that proper hand-hygiene and glove techniques are required, but is of little value as a physical barrier to the spread of encouraging rooming-in of infants with their mothers has been shown to be helpful in preventing or containing nursery epidemics.' temporary closure of the nursery may be required for clinically significant outbreaks that cannot be controlled with other measures. development of rotavirus vaccines began in the early s. candidate vaccines included bovine and rhesus monkey elisa. , attenuated strains, human attenuated strains, and bovinehuman and rhesus-human reassortant strains."" in august , the first licensed rotavirus vaccine, rotashield, an oral formulation of a simian-human quadrivalent reassortant vaccine, was recommended for use in children when they were , , and months old. after approximately , children were vaccinated with more than million doses, a significantly increased risk of intussusception was observed among vaccinated children, with an overall odds ratio of . .iz use of this vaccine was terminated. two new vaccine candidates are undergoing phase i clinical trials: a "pentavalent" bovine-human reassortant vaccine including g types gl-g and p type pla[ ] and a monovalent human attenuated pla[ ]g vaccine. the epidemiology of rotavirus infection will change significantly if one or both candidates become widely available in the future. the impact on neonatal infection will depend on the effect of herd immunity in decreasing circulation of rotavirus strains. stools from breast-fed neonates are typically watery and yellow, green, or brown. the frequency of stooling can vary from one every other day to eight evacuations per day. in an active, healthy infant who is feeding well, has no vomiting, and has a soft abdomen, these varied patterns of stooling are not a cause for concern. physicians need to consider the child's previous frequency and consistency of stools and establish a diagnosis of acute diarrhea on an individual basis. close follow-up of weight increase in infants with nonformed stools can help confirm the clinical impression. a normal weight gain should direct medical action away from stool exams or treatment. diarrhea during the neonatal period is a clinical manifestation of a wide variety of disorders (table - ). the most common initiating factor is a primary infection of the gastrointestinal tract that is mild to moderate in severity, chapter self-limited, and responsive to supportive measures. acute diarrhea can also be an initial manifestation of a systemic infection, including bacterial and viral neonatal sepsis. infants with moderate to severe diarrhea require close monitoring until the etiologic diagnosis and the clinical evolution are clarified. there are noninfectious diseases leading to chronic intractable diarrhea that may result in severe nutritional disturbances or even death unless the specific underlying condition is identified and treated appropriately. the differential diagnosis of a diarrheal illness requires a careful clinical examination to determine whether the child has a localized or a systemic process. lethargy, abnormalities in body temperature, hypothermia or hyperthermia, decreased feeding, abdominal distention, vomiting, pallor, respiratory distress, apnea, cyanosis, hernodynamic instability, hypotension, hepatomegaly or splenomegaly, coagulation or bleeding disorders, petechiae, and exanthemas should lead to an intense laboratory investigation directed at systemic viral or bacterial infection. if the process is deemed a localized intestinal infection, initial evaluation can be focused on differentiating an inflammatory-invasive pathogen from those that cause a noninflammatory process. for this, stool examination for fecal leukocytes, red blood cells, and lactoferrin can be a helpful indicator of the former. inflammatory diarrhea can be caused by shigella, salmonella, carnpylobacter, v parahaemolyticus, k: enterocolitica, eiec, eaec, c. difjcile, necrotizing enterocolitis, antibioticassociated colitis, and allergic colitis (i.e., milk or soy intolerance). noninflammatory causes of diarrhea include etec, epec, rotaviruses, enteric adenoviruses, calicivirus, astrovirus, g. larnblia and cryptosporidium. although supportive fluid therapy is mandatory for all types of diarrhea, the brief examination for fecal leukocytes and red blood cells can direct the diagnostic and therapeutic approach. pathogens such as shigella, salmonella, and ehec can 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infection-associated persistent diarrhea key: cord- -tfp idq authors: hale, alison c.; sánchez-vizcaíno, fernando; rowlingson, barry; radford, alan d.; giorgi, emanuele; o’brien, sarah j.; diggle, peter j. title: a real-time spatio-temporal syndromic surveillance system with application to small companion animals date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: tfp idq lack of disease surveillance in small companion animals worldwide has contributed to a deficit in our ability to detect and respond to outbreaks. in this paper we describe the first real-time syndromic surveillance system that conducts integrated spatio-temporal analysis of data from a national network of veterinary premises for the early detection of disease outbreaks in small animals. we illustrate the system’s performance using data relating to gastrointestinal disease in dogs and cats. the data consist of approximately one million electronic health records for dogs and cats, collected from uk veterinary premises between march and . for this illustration, the system predicts the relative reporting rate of gastrointestinal disease amongst all presentations, and updates its predictions as new data accrue. the system was able to detect simulated outbreaks of varying spatial geometry, extent and severity. the system is flexible: it generates outcomes that are easily interpretable; the user can set their own outbreak detection thresholds. the system provides the foundation for prompt detection and control of health threats in companion animals. in the uk through surveillance schemes such as the small animal veterinary surveillance network (savsnet) . savsnet harnesses the growing volume of patient electronic health records (ehrs) available from small animal practices and complementary data from diagnostic laboratories to improve animal and human health through rapid and actionable research and surveillance. here we propose a real-time syndromic surveillance system that uses a spatio-temporal model in conjunction with bayesian inference for the early detection of health-event outbreaks. specifically, we use a markov chain monte carlo (mcmc) algorithm to generate samples from the bayesian predictive distribution of the underlying spatio-temporal surface. these samples are then used to compute predictive probabilities at given thresholds; a high predictive probability at a particular location and time gives an early warning of a possible disease outbreak. the system provides end-users (i.e. practising veterinary surgeons) decision-support tools for immediate analysis and easy interpretation of their data. as an example, we apply our model to small companion animal ehrs collected over two years by savsnet from a large network of uk veterinary premises. we illustrate the feasibility of our proposed surveillance system using gastrointestinal (gi) disease in dogs and cats as an example. gastrointestinal (gi) disease is one of the four syndromes for which savsnet currently gathers information for every consultation it receives. gi disease affects animal welfare, can be expensive to manage and may be transmissible to other pets or, more rarely, to people . current approaches to preventing and controlling gi disease in companion animals have focussed on individuals or small groups of animals. this seems to have had little impact on gi disease, which remains one of the commonest reasons for presenting for veterinary care in the uk , , - , although precise data to confirm this has been lacking. a more coordinated population-scale approach to gi disease surveillance in companion animals is needed. this paper focuses on the early detection of a gi disease outbreak, which we define as an unexplained, spatially and temporally localised increase in the fraction of gi consultations amongst all consultations. we illustrate the performance of our proposed surveillance system on simulated gi disease outbreaks of varying spatial extent and severity. this is, to our knowledge, the first surveillance system that conducts integrated spatio-temporal analysis of data from a national network of veterinary practices so as to enable real-time detection of spatially and temporally localised changes in reporting patterns across the network. the paper is structured as follows. first, we give details of the savsnet and socioeconomic data used in this paper. we then give the rationale for our methodological approach, describe the spatio-temporal stochastic model that is the foundation of our surveillance system, and report the results of fitting our model to our savsnet-acquired data. we then simulate spatio-temporal gi outbreaks by perturbing the actual savsnet data in various ways to demonstrate the ability of the surveillance system to achieve timely outbreak-detection. finally, we discuss the similarities and differences between our proposed system and other approaches in the literature, and also extensions for joint human and veterinary surveillance. savsnet. data collection. data were collected electronically in near-real-time from volunteer veterinary premises or sites using a compatible version of the practice management system (pms) namely robovet (vetsolutions, edinburgh) and teleos systems ltd (birmingham). this study used data for dogs and cats collected over the period between st march and th february . in our analysis we included data from an increasing number of premises as they enrolled in the robovet and teleos systems. by th february we had data from practices (amounting to a total of distinct premises) located in england, wales and scotland. the data were extracted from consultations where a booked appointment was made to see a veterinary surgeon or nurse, including out-of-hours consultations. through the savsnet system a compulsory, single-question questionnaire is appended at the end of each consultation allowing the attending veterinary surgeon or nurse to categorise the main reason for the animal's presentation into syndromes (currently gi disease, respiratory disease, pruritus and renal disease) or other routine veterinary interventions (i.e., trauma, neoplasia, 'other sick' , vaccination, 'other healthy' or post-operative check-up). specifically, the definition provided to participating veterinary surgeons to categorise the animal presentation as gi disease is that the main reason for the animal's presentation are signs including but not limited to diarrhoea, vomiting, weight loss and poor appetite. a full description of the savsnet data collection protocol has been described by sánchez-vizcaíno et al. . the data for this study were gathered on a consultation-by-consultation basis, and include the date the animal was seen, unique identifiers for practice, premise and animal, the animal description (including species, breed, sex and date of birth), the syndromic level classification and the full postcode of each veterinary premise and pet owner. data were only gathered if the owner had not opted out of study participation. the collection and use of these data were approved by the university of liverpool's research ethics committee (reth ); as such all collection and use of these data were performed in accordance with the relevant guidelines and regulations. data management. text-based data for species and breed were cleaned to deal with misspellings or the use of non-standard terms by mapping to standard terms. a full description of this cleaning procedure has been described elsewhere . many breeds were present in the data set, some represented by only a few individuals, limiting the scope for analysis by breed. thus, for the purposes of this study, only the animal's classification as purebred or crossbred was used. to identify localised outbreaks we needed to geocode all postcodes. the text-based data for each owner's full postcode were automatically cleaned by applying mapping rules of typical misspellings (e.g. letter 'o' instead of zero). any remaining records containing erroneous postcodes were discarded from our outbreak prediction as they could not be geocoded. similarly, if the age of the animal was recorded outside the range to years then the record was excluded. savsnet records with missing data were removed before the analysis. if an animal attended a veterinary premise on more than one occasion during the study period we included all attendances outbreak detection modelling rationale. as noted earlier, we define an outbreak as an unexplained spatially and temporally localised increase in the fraction of gi consultations amongst all consultations. the term "unexplained" refers to the fact that, for reasons that are well understood, some areas or times of year will experience higher fractions of gi consultations than others because of spatial variation in the local population susceptibility or temporal variation in the region-wide susceptibility to gi. we adjust for these known effects using measured explanatory variables, as described below in the section on explanatory variable selection. we then equate "unexplained" to "stochastic" and include this in our model as a latent, spatially and temporally correlated process s i,t , where i denotes premise and t denotes time, in days. by definition, the expected value of each s i,t is zero, and our goal is to determine where and when its actual value is materially greater than zero. note that the natural pattern of gi consultations will always be subject to fluctuations in time and space that cannot be explained fully by measured variables. it follows that outbreak detection is not a statistical hypothesis-testing problem. our approach acknowledges this by the fact that the actual value of s i,t will never be exactly zero. our formal solution is therefore to calculate, for each premise i and day t, the predictive probability q (i.e. the probability conditional on all available data up to and including day t) that s i,t > l, where l is a user-specified threshold representing an effect large enough to be of practical concern. we then declare an outbreak affecting premise i if this probability exceeds q , the required positive predictive value per premise, say q = . or . . as with any prediction problem using observational data, it is not possible simultaneously to control both the positive and negative predictive probabilities. prediction model. to accommodate the spatial and temporal correlations that would characterise an outbreak of gi disease, we use a spatio-temporal mixed effects regression model, and fit the model using bayesian inference. we define our binary response variable y j,it to take the value if the j th consultation at the i th premise on day t is a gi disease presentation and otherwise. conditionally on an unobserved, spatio-temporally structured random effect s i,t , the y j,i,t are distributed as mutually independent bernoulli variables with probabilities p j,i,t defined by is the quantile function of the standard normal distribution. the vector d j,i,t denotes the set of explanatory variables and θ their associated regression parameters. we discuss selection of explanatory variables, d j,i,t , below. the spatio-temporally structured collection of random effects for all premises and days is written as , and we denote by τ and n, respectively, the total numbers of days and premises contained in the data-set. the complete vector s follows a multivariate normal distribution with mean zero and covariance matrix that incorporates the spatio-temporal context of the data. specifically, we assume that, conditionally on its past, s (t) follows a multivariate gaussian distribution with mean vector ϕ − s t ( ) and spatial covariance matrix Ω, which we construct as follows. firstly, we associate with premise i a polygon consisting of all points closer to premise i than to any other premise; the resulting polygons, v i are called voronoi polygons. secondly, we define the neighbours of i to be the set n(i) of premises whose voronoi polygons are contiguous with v i . finally, we define distance-decay weights where u ik is the distance between premises i and k, and δ is a scaling parameter with units of distance. we then specify the conditional distribution of each s i,t given all other s k,t to be normal with mean ρm it where . together, these modelling assumptions imply that the so-called full conditional distributions of the s i,t that together determine the joint distribution of s are of the form using these full conditional distributions, we can simulate from the bayesian predictive distribution of the random effects s i,t using an mcmc algorithm based on auxiliary variable techniques as described in section . of rue & held . our system is intended to be run in near-real-time, but the mcmc computations eventually become prohibitive as the time-span of the data, τ, grows. to counteract this, we run the mcmc algorithm on a moving nine-day window, which is long enough to capture the temporal correlation in our data; the magnitude of the within-premise autocorrelation of s i,t for a time lag of eight days is typically around . . over a time-window of this size, the effects of any systematic time-trend or seasonal effect on the fraction of gi consultations are negligible, which removes the need to include these as explicit terms in the model; see also section below on selection of explanatory variables. we adopt the following set of mutually independent priors for the model parameters: θ ~ mvn ( , i); log σ ~ n (− , ); ρ ~ uniform ( , ); ϕ ~ uniform ( , ); δ ~ uniform { , , …, } these were chosen to be vague, in the sense that they have little influence on the predictive inferences for the random effects s i,t that constitute the primary goal of the analysis. however, if inferences about the model parameters are required, samples from their bayesian joint posterior distribution are produced automatically as a by-product of the mcmc algorithm. outbreak detection. let e i,t denote the exceedence probability for premise i on day t, i.e. the probability that s i,t > l conditional on all available data up to and including day t, where l is the user-specified threshold value. to calculate the e i,t , we generate m posterior samples s s , , from the joint predictive distribution of the random effects s i,t using an mcmc algorithm, and calculate and otherwise. for this calculation to be accurate, we need the mcmc algorithm first to run for a sufficiently long time, called the burn-in period, to have reached convergence and then for a further m iterations to feed eq. ( ), where m is sufficiently large that the sampling error on the right-hand-side of ( ) is negligible. we used a burn-in period of , iterations, followed by m = , iterations. the spatio-temporal model was fitted using the r package 'caramellar' www.nature.com/scientificreports www.nature.com/scientificreports/ hence, they do not take account of spatial and/or temporal correlation. nevertheless, we can use a standard probit regression model to establish whether there is a prima-facie case for including each explanatory variable in our outbreak prediction model, eq. ( ), using the following rule. we retained an explanatory variable if its effect was nominally significant at the conventional % level. this inclusion rule is conservative in the sense that in the presence of spatial or temporal correlation the standard probit regression analysis is likely to over-state the significance of individual regression effects. for both species, this led us to discard the explanatory variables pet insurance, micro-chipping and neutering status and to retain the following: • the three-level factor 'country' for the pet owner's home address (i.e. england, scotland or wales); • the two-level factor 'weekday' with values and indicating if the consultation date is a weekend day (saturday, sunday or public holiday) or a working weekday (monday to friday), respectively -we considered using day of the week as a factor on levels, but this did not improve the fit significantly using a likelihood ratio (deviance difference) test; • the two-level factor 'gender' with values and corresponding to 'female' and 'male' , respectively; • the two-level factor 'purebred' with values and corresponding to crossbred or purebred, respectively; • the continuous variable ' age' denoting the animal's age, in years and age = age × age, both included because the quadratic term improves the model fit; • the continuous variable 'imd' , is the rescaled deprivation measure relating to the pet owner's home address (as described above in our section on data sources). as noted earlier, fitting the model to moving nine-day windows of data removes any long-term trend or seasonal effects. the resulting provisional glm is where p denotes the probability that a presentation of a dog or cat (depending on the species evaluated) to a savsnet veterinary premise is recorded as a gi disease consultation. the first two terms on the right-hand side of eq. ( ) capture the interaction between country and imd, so as to account for the fact that the three countries use different imd measures, whilst θ θ θ … , , , are regression parameters for the remaining explanatory variables in the model. the glm outputs for dogs and cats can be found as supplementary tables s and s , respectively. all computation was carried out using r version . . . our model's ability to identify an outbreak, i.e. its sensitivity, is influenced by factors including the outbreak's duration, spatial extent and the number of infected animals presenting at premises in the locality. in each of our simulations, we construct an outbreak by adding varying numbers of aberrant gi disease to the actual (baseline) savsnet-recorded cases in a specified set of premises over a specified number of consecutive days. simulation model. we use the actual savsnet total consultations for dogs during february , together with their associated explanatory variables, to simulate a step increase in the proportion of gi disease cases affecting one or more premises from a given day t , corresponding to february , by augmenting eq. ( ) with an extra term as follows ( ) where the indicator function i i for premise i has value for premise i and all days ≥ t t if premise i is affected by the outbreak, and has value otherwise. by varying the value of γ we can control the probability of a gi case at an affected premise. for each simulation, we proceed as follows: ( ) use the actual savsnet consultations during february to fit the no-outbreak model using eq. ( ) and to generate simulated realisations of s i,t ; ( ) for t t ≥ , use the actual explanatory variables and the simulated s i,t to compute p j,i,t using eq. ( ) with γ > ; ( ) use the computed values of p j,i,t to simulate case and control flags ( or respectively) and use these to reassign each actual savsnet data consultation as either a case or control. see supplementary material for detailed r-code. simulation scenarios. we applied our simulation model to three sets of premises, which we selected based on their numbers of neighbours, defined to be other premises within an km radius, with the additional constraint that none of the sets of premises were within each other's km radius. the selected sets of premises, which we designated as dense, medium and sparse, had , and neighbours, respectively. the savsnet data gave no indication that these selected premises are atypical or that they experienced a genuine outbreak during the top row of timeseries plots is the 'baseline' , that is the actual savsnet data without any simulated outbreak i.e. γ = . the subsequent rows from top to bottom depict increasing severities of simulated outbreak labelled according the probability of a case at premise i e.g. p = and so on. the columns, from left to right, relate to the density of the region; 'sparse' , 'medium' and 'dense' respectively. for each simulation we plot the timeseries of the predicted distribution of s i,t for premise i. in each time timeseries the solid black line is the predicted value of s i,t , shaded areas are pointwise %, % and % predictive intervals. as an aid to rapid interpretation, we use a traffic-light system: if the predictive probability, q, is above . (defined as 'very high') the light shows red, if above . ('high') orange, if above . (medium) yellow, otherwise ('low') green (no outbreak). the outbreak commences on th february. the more intense the outbreak is the more the traffic light system tends towards red. www.nature.com/scientificreports www.nature.com/scientificreports/ during february ( , and for dense, medium and sparse, respectively) and similar proportions of gi consultations ( . , . and . for dense, medium and sparse, respectively). using these three sets of premises, we simulated under different scenarios as follows. performance evaluation. we use each scenario to generate a simulated set of consultations for february , to which we fit our model using eq. ( ). to assess the capability of our model to detect outbreaks we then use the predictive distribution s i,t from which we compute summary statistics, including exceedence probabilities and times to detection. we set the positive predictive value of the system at q = . . we set values of the reporting threshold at l = , . and . . note that l = corresponds to an observed pattern exactly equal to expectation and is analogous to, although formally different from, using statistical rather than clinical significance in hypothesis testing. we do not recommend using l = in practice, but use it here only as a benchmark to compare the system's performance under different scenarios. in a genuine application, the threshold value l would be chosen to represent a clinically significant increase in reporting rate, and the positive predictive value q to balance sensitivity against specificity. note, in this context, that because s i,t is measured on the probit scale, the increase in the fraction of gi cases corresponding to a fixed increase in s i,t necessarily depends on the baseline fraction. for example, if the expected fraction is . , which corresponds to setting θ = d and s i,t = in eq. ( ), then a log( ) threshold for s i,t represents a fraction log( ) = . i.e. an increase of . . in contrast, for a baseline fraction . , a log( ) threshold now represents a fraction . , i.e. an increase of . . simulation results. for each of the three regions (sparse, medium, dense) we ran our model a hundred times on the baseline data, where each run had a different random seed; we did not detect any false-positives with l = . given the february baseline data, in table we report the credible intervals of the regression parameters estimated from the outbreak detection model's mcmc samples. our model detected a simulated outbreak in out of the outbreak scenarios when the reporting threshold was set at l = ( table ) . the model detected an outbreak on the first day of its actual onset in six scenarios, one day after onset in a further seven scenarios and two days after onset in a further one scenario (table ) . alerting timeliness was inversely related to outbreak severity (table ) . figures and give a more detailed illustration of the performance of our outbreak detection methodology in response to a step change in the proportion of cases, for schemes and respectively and with the threshold value l = . these figures also illustrate the use of a traffic-light system whereby, rather than fixing a single value for the positive predictive probability, q, we report a categorised value of the exceedence probabilities at each premise on each day to indicate the strength of the evidence for an outbreak. we focus on the sparse and dense sets of premises since the central premises of these two sets had almost identical numbers of consultations. recall that under scheme the outbreak affects only the central premise of each set. also, the prediction algorithm exploits the estimated spatial correlation amongst the fractions of gi cases at different premises. as a consequence, the system is better able to detect an outbreak at a single premise when this premise does not have close 'outbreak-free' neighbours whose fractions of gi cases are as expected. in effect, the model smooths its predictions over a range corresponding to its estimated correlation range; fig. shows an example of this phenomenon. this explains why, under scheme (fig. ) , the system delivers a stronger detection signal for the sparse than for the dense set. under scheme (fig. ) , the results for the sparse and dense sets are more similar. also, because the outbreak affects more premises in the medium, and dense sets, their results show generally stronger detection signals than in scheme , as indicated by the increased number of traffic-lights tending towards red in fig. compared with fig. . results of our model's performance using the reporting thresholds l = . and l = . are available in the supplementary files; see table s and figs s and s , and table s and figs s and s , respectively. for example, given scheme (density sparse and p = . ) then: with l = we detect an outbreak over the period to february (see fig. ); with l = . we also detect an outbreak, albeit less strongly, over the period to february (see fig. s in supplementary material); with l = . we do not detect the outbreak (see fig. s ). an increase in the reporting threshold value l necessarily reduces the probability that an outbreak will be declared and increases its time to detection (tables s and s , figs s -s ). this emphasises that the choice of l must be made in context and is unrelated to the inherent quality of the outbreak detection algorithm. setting the probability of a case to . and with l = , the model's performance was compared with similar models in the sparse, medium and dense regions: , . all the variation is accounted for by the latent term s i,t so in a real-world application this model would be more prone to false-positives; in the context of scheme our www.nature.com/scientificreports www.nature.com/scientificreports/ simulations showed this model to be more sensitive. comparing this model with the full model (eq. ) we find they are identical in terms of timeliness but the model without covariates shows more strength of the evidence for the outbreak in that the exceedence probabilities are higher overall. (b) model without spatial correlation -scheme . in the presence of the outbreak only occurring at the central premise we found this model to be more sensitive at detecting outbreaks since the surrounding premises will not influence, and hence reduce, the inferred effects of the outbreak at the single central premise. compared with the full model (with spatial correlation) we find this model to be identical in terms of timeliness for the sparse and dense regions, but the outbreak is now detected in the medium region with a one-day lag. overall, the exceedence probabilities are higher in all regions. (c) model without spatial correlation -scheme . with the outbreak spread over the neighbouring premises, this model was less sensitive as the neighbours did not influence, and therefore support, the detection of the outbreak. in particular we did not detect the outbreak in the medium and dense regions. syndromic surveillance systems offer the opportunity to enhance the public and animal health community's ability to detect, and respond quickly to, disease outbreaks . the last decade has seen a growth in the field of disease surveillance in companion animals, notably in the uk , and in the usa , . however, to the best of our knowledge, this is the first surveillance system that conducts integrated spatio-temporal analysis of data from a national network of veterinary practices so as to enable real-time detection of spatially and temporally localised changes in reporting rate patterns across the network. we have illustrated the applicability of our proposed surveillance system using gastrointestinal disease syndrome in dogs and cats as an example. the system is fed with electronic health records (ehrs) collected in real-time through savsnet from volunteer veterinary premises across the uk. we applied our system to simulated gi disease outbreaks of varying spatial extent and severity, amongst which the system was able to detect of the . had these been real outbreaks, the proposed surveillance system would have triggered timely investigations, which ultimately would have aided control strategies. the system requires the user to specify a reporting threshold corresponding to an increase in case incidence (reporting rate) that would be considered large enough to be of practical importance. given this reporting threshold, the system delivers the predictive probability, q, at each location (here, veterinary premise), that the threshold is currently exceeded. declaring an outbreak when this probability is greater than a specified value q is equivalent to fixing the positive predictive value of the system (per location, per day) at q . alternatively, reporting the actual value of q gives an indication of the strength of evidence for an outbreak. increasing the value of the reporting threshold, l, necessarily reduces the value of q and consequently increases the average time to detection of an outbreak at a fixed value of q . a critical component of a syndromic surveillance system is the application of optimal disease aberration detection methods. most of the methods used in veterinary and public health surveillance systems are concerned with detecting disease-outbreaks and health-related threats in time rather than in space [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, disease incidences vary naturally in both space and time. thus, for example, these techniques may be late at detecting outbreaks that start locally when the surveillance region is large . in contrast, our proposed method has the advantage of being able to directly incorporate data for each individual animal's consultation, including the date of the visit and the location of the pet's owner. in temporal aberration detection algorithms, explanatory variables such as seasonality and day-of-the-week effects would generally be incorporated, but most of these methods cannot easily include individual-level explanatory variables. www.nature.com/scientificreports www.nature.com/scientificreports/ earlier spatio-temporal aberration detection methods have been introduced by rogerson , . however, these approaches lack measures of uncertainty associated with the identified clusters and are unable to account for covariate information. also, they are based on an assessment of global pattern change throughout the fig. . and . the top and bottom rows relate to the density of the region, 'sparse' and 'dense' , respectively, and the left and right columns relate to simulation schemes and respectively. the simulated probability of a case at the premise in the centre of each region is p = . . to aid interpretation, we use the traffic-light system described in fig. caption, as such each coloured circle on the map is derived from the predicted distribution of s i,t at each corresponding premise. panels (a,c) show when the central premise has neighbours who are not experiencing an outbreak it is less able to detect the outbreak, panel (c), when compared to a premise without neighbours, panel (a). if the neighbours also experience an outbreak the system is then better able to detect this outbreak at central premise, panel (d), compared with when the neighbours did not experience an outbreak, panel (c). www.nature.com/scientificreports www.nature.com/scientificreports/ geographical area under study, as opposed to our method, which is used to detect the specific geographical location of an outbreak. prospective space-time scan statistics have also been used in syndromic surveillance systems for the early detection of disease outbreaks , . the space-time permutation scan statistic uses only case numbers, with no need for population-at-risk data and, in contrast to rogerson's methods, does operate locally in both space and time. this method may therefore be suitable for setting up surveillance systems in the small animal sector where only case numbers are available. however, it does not acknowledge the uncertainty associated with any identified clusters, cannot easily incorporate continuous covariates, and can only detect outbreaks characterised by excess cases within a specified, regular shaped affected area, for example a circle or ellipse. also, in our context the number of veterinary premises participating in savsnet can change over time due to the ongoing process of recruiting new premises and/or as a result of premises that could potentially stop being part of the project. this can lead to biased results if a space-time permutation model is used, as the method cannot distinguish an increase in cases due to a local population increase versus an increase in disease risk. our spatio-temporal model, in conjunction with a bayesian inferential framework, takes account of all sources of uncertainty in both parameter estimation and prediction, and is able to accommodate spatial, temporal and individual-level covariate information. other examples of bayesian approaches include markov models , bayesian information fusion networks and bayesian hierarchical models [ ] [ ] [ ] . an earlier near-real-time syndromic surveillance system in small animals has been developed in the usa utilising ehrs from a similar network of primary care veterinary hospitals . briefly, in this approach the daily proportion of patients with a given clinical or laboratory finding was contrasted with an equivalent average proportion from a historical comparison period allowing construction of the proportionate diagnostic outcome ratio (pdor) . our surveillance system builds upon a similar epidemiological metric by modelling the spatio-temporal reporting rate of gi disease in dogs and cats as a proportion of all presentations. the two approaches use different inferential methods: the us study uses confidence intervals for recognising aberrant health events, whilst our approach uses predictive probabilities of exceeding policy-relevant thresholds. a more important difference is that we use a bespoke model that incorporates spatio-temporal covariance structure, with the aim of detecting outbreaks that are spatially and temporally localised without imposing any artificial assumptions on the geometrical shape of an outbreak or the extent of spatial correlation in disease incidence. our inferential paradigm of predictive inference within a generalized linear mixed model could equally be applied in purely temporal surveillance settings where the aim is the timely detection of area-wide increases in reporting rate, but in that context we cannot claim the same level of novelty. another usa study explored the feasibility of using veterinary laboratory test orders as one of the data sources for syndromic surveillance in companion animals . the inherent biases associated with the use of laboratory data in veterinary medicine have been described elsewhere , [ ] [ ] [ ] . however, the results derived from shaffer et al. demonstrated the stability and timely availability of test order data for companion animals and the potential of using these data as a basis for outbreak detection. in addition to ehrs from veterinary practices, savsnet also receives routine downloads of diagnostic test results from commercial diagnostic laboratories throughout the uk . although laboratory test results are less timely than test orders, future research is warranted to explore whether the former data could be used to enhance the real-time syndromic surveillance system described here, which is based on real-time data from consultations in small animal premises. raising the reporting threshold, l, and/or the required positive predictive probability, q , increases the specificity of the system at the cost of reducing its sensitivity, and conversely. in our analysis of the simulated outbreaks, we chose different reporting thresholds to illustrate the performance of our system. however, in any substantive application, the specified reporting threshold can and should be adjusted so as best to reflect end-users' (i.e. veterinary surgeons in practice) preferred balance between sensitivity and specificity. a pragmatic choice would be to set the threshold to some proportion above the historic average at each premise. end-users (hereafter "analysts") of a real-time surveillance system will be responsible for receiving system outputs, interpreting them, and if necessary following up on alarms. therefore, in addition to flexibility, another important attribute of a surveillance system should be that it reports outcomes in an easily interpretable manner. our system generates outputs in the form of practice-specific time-series and maps that display the spatio-temporal evolution of gi disease risk over an area of interest in a user-friendly manner; see fig. . additionally, we have illustrated the use of a traffic-light device as a visual aid for analysts to quickly identify potential gi disease outbreaks on a given day at their own premises. the traffic-light device is based on predictive probabilities for exceedence of reporting thresholds that can be tailored to the analysts' needs. we intend to integrate our daily model-based predictions into the savsnet system so as to make them available to each participating premise through their savsnet web interface. this implementation will include the other two syndromes with outbreak potential that are currently recorded by savsnet (respiratory disease and pruritus). this syndromic surveillance system should be a step towards facilitating the prompt detection and control of health threats in companion animals throughout the uk. in addition, the identified temporal and geographical trends in specific syndromes can be a valuable contribution to the evidence-base when veterinarians are deciding how to treat individual animals in their practice. one of the challenges of conducting epidemiological studies in the small animal sector is that information about the population-at-risk (in our study defined as the overall population of small animals across the uk or target population) is generally lacking. this makes it impossible to measure parameters typically used in human health surveillance systems, such as the average incidence in a day or period of days. other methods must therefore be employed to approximate, for instance, an incidence rate ratio. evidence suggests that in countries with developed pet industries, a high proportion of owned pet animals (pets who may approximate the target population) attend a veterinary surgeon , . therefore, although no single data source can detect all outbreaks that may occur in companion animal populations, ehrs of the kind that are extensively collected from veterinary practices ( ) : | https://doi.org/ . /s - - - www.nature.com/scientificreports www.nature.com/scientificreports/ in many developed countries may be the best available source to include in surveillance activities for increasing our capabilities to detect those outbreaks that result from both endemic and potential emerging pathogens. one limitation of this study is that the veterinary practices contributing data to our system were selected by convenience, based on their use of a compatible version of pms, and recruited on the basis of their willingness to take part in the savsnet project. hence, the data used in our system might not be representative of the source population (in our study defined as the overall veterinary-visiting population across the uk). for this reason, we aimed to develop a syndromic surveillance system to detect changes in the relative, rather than absolute, incidence of gi disease presentations in the small animal veterinary premises participating in savsnet. nevertheless, the practices included in the current study were widely distributed around the uk and represented . % of those practices that constituted the source population in . thus, the number and geographical extent of savsnet-participating practices is such that changes in the relative risk of gi disease in this large network of premises can act as a proxy for changes in the level of gi disease in the wider source population. a further limitation relates to missing data. over the spatial domain and time-period of the simulation we found that % of consultations do not record location and % do not record breed. as a result, in total about % of the data are discarded due to incomplete data, our methodology assumes that these data are missing completely at random so that there is no inherent bias in the spatial distribution of the available data. another limitation is that each animal was classified only by its breed-status (purebred or crossbred). as such, we were unable to adjust for breed-specific phenotypes that could have an impact on the incidence of gi disease presentations. however, overall the breed distribution in our study population is consistent with previous studies. labrador retriever was the most common dog breed in our population as it is in earlier studies , , . also, nineteen out of the top twenty-six dog breeds in our study population were also in the top twenty breeds listed by the kennel club . in future work we aim to identify additional means by which breeds can be effectively summarised according to both shared genotype and phenotype. we are aware that the detection of a high relative risk for gi disease could trigger a false alarm if it is due to a localised decrease in the incidence of diagnosing other syndrome/s and routine veterinary interventions, leading to a higher than expected fraction of gi disease consultations. conversely, a localised increase in the incidence of diagnosing other syndromes could conceal a genuine gi disease outbreak. if the goal is to detect anomalous patterns of absolute incidence rather than relative risk, then provided that data are available to calculate any changes in the population base of each premise our approach can be modified accordingly, for example by using a poisson log-linear version of our spatio-temporal mixed model rather than the current binomial probit-linear version. in order to understand and mitigate shared gi disease aetiologies between humans and animals it would be necessary to develop a 'one health' surveillance system that integrates human and veterinary healthcare databases. in future work, we intend to adapt the approach described in this paper to human gi disease surveillance by re-calibrating the model against data relating to human gi disease presentations at general practitioner surgeries. a further extension of the approach would then be to a bivariate model for the joint surveillance of veterinary and human gi disease risk. a suitable starting point for this would be to replace the single eq. ( ) by a pair of equations, j k t jk t t k t , , , , , where eqs. ( ) and ( ) describe the relative risk of gi at veterinary premise i and gp surgery k, respectively. a bivariate model would allow non-zero correlations between the s i,t and ′ s k t , corresponding to closely located pairs of veterinary premises and gp surgeries. we have demonstrated the feasibility of a real-time spatio-temporal syndromic surveillance system using as an example small animal veterinary premises in the uk. our detection algorithm uses bayesian predictive inference within a spatio-temporal model. the method demonstrated promising performance in detecting simulated outbreaks signals of varying spatial extent and severity at different reporting thresholds. the system is flexible: the reporting threshold of elevated risk and the positive predictive probability per premise and day may be set to whatever levels best meet the needs of a particular application; the system estimates the parameters of the model from historical data rather than imposing specific values for these, and can therefore be re-calibrated to detect outbreaks of any syndrome of interest. a traffic-light system based on exceedence probabilities offers a visual aid to rapid identification of potential outbreaks on a given day at each premise. we intend to implement the system on savsnet servers for the early detection of outbreaks in gi and in other syndromes that have outbreak potential and are routinely recorded in savsnet. the datasets generated and/or analysed during the current study are not publicly available due to issues of companion animal owner confidentiality, but are available on request from the savsnet data access and publication panel (savsnet@liverpool.ac.uk) for researchers who meet the criteria for access to confidential data. the r scripts used for pre-processing and analysing the data supporting this article can be found as supplementary material online. the r package 'precara' developed for pre-processing the data supporting this article is publicly available from the 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surveillance in canada epidemiology & animal health management, and industry branches of the nzva, proceedings of the epidemiology & animal health management branch of the nzva detecting emerging diseases in farm animals through clinical observations estimation of the number and demographics of companion dogs in the uk health status and population characteristics of dogs and cats examined at private veterinary practices in the united states breed registration statistics processes spatially referenced data (precara) we wish to thank data providers both in practice (vetsolutions, teleos, cvs and non-corporate practitioners) and in diagnostic laboratories, without whose support and participation, this research would not be possible. the study was conceived and designed by a. the authors declare no competing interests. supplementary information is available for this paper at https://doi.org/ . /s - - - .correspondence and requests for materials should be addressed to a.c.h. or f.s.-v. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- -y ji k authors: connell, anna r.; connell, jeff; leahy, t. ronan; hassan, jaythoon title: mumps outbreaks in vaccinated populations—is it time to re-assess the clinical efficacy of vaccines? date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: y ji k history illustrates the remarkable public health impact of mass vaccination, by dramatically improving life expectancy and reducing the burden of infectious diseases and co-morbidities worldwide. it has been perceived that if an individual adhered to the mmr vaccine schedule that immunity to mumps virus (muv) would be lifelong. recent mumps outbreaks in individuals who had received two doses of the measles mumps rubella (mmr) vaccine has challenged the efficacy of the mmr vaccine. however, clinical symptoms, complications, viral shedding and transmission associated with mumps infection has been shown to be reduced in vaccinated individuals, demonstrating a benefit of this vaccine. therefore, the question of what constitutes a good mumps vaccine and how its impact is assessed in this modern era remains to be addressed. epidemiology of the individuals most affected by the outbreaks (predominantly young adults) and variance in the circulating muv genotype have been well-described alluding to a collection of influences such as vaccine hesitancy, heterogeneous vaccine uptake, primary, and/or secondary vaccine failures. this review aims to discuss in detail the interplay of factors thought to be contributing to the current mumps outbreaks seen in highly vaccinated populations. in addition, how mumps diagnoses has progressed and impacted the understanding of mumps infection since a mumps vaccine was first developed, the limitations of current laboratory tests in confirming protection in vaccinated individuals and how vaccine effectiveness is quantified are also considered. by highlighting knowledge gaps within this area, this state-of-the-art review proposes a change of perspective regarding the impact of a vaccine in a highly vaccinated population from a clinical, diagnostic and public perspective, highlighting a need for a paradigm shift on what is considered vaccine immunity. muv is an enveloped, non-segmented, negative-sense, single stranded rna virus that varies between a spherical and pleiomorphic shape of ∼ nm ( - nm) ( , ) . muv is responsible for an acute viral infection, spread by respiratory droplets (via coughs, sneezes) and urine ( , ) . with an incubation period of - days, muv replicates in the nasopharynx and regional lymph nodes, with a secondary viremia occurring late in the incubation period ( , ) . muv can be detected from saliva up to days prior, and as late as days after clinical onset of parotitis ( ) . the muv genome of seven genes consists of , nucleotides, and encodes six structural proteins and at least two non-structural proteins; the nucleocapsid protein (np), v protein (v), phosphoprotein (p), matrix (m) protein, fusion (f) protein, small hydrophobic (sh) protein, hemagglutininneuraminidase (hn) protein, and large (l) protein. the role of the i protein is not known ( , , ) . the sh gene is the most variable region of the muv genome; a - % intravariation and - % inter-variation has been documented ( ) . this gene is used in molecular phylogeny for genotyping and to identify transmission patterns in populations ( ) . despite being serologically monotypic, muv genotypes (a to l) have been described to date (muv genotypes e and m are omitted, as the muv previously assigned to these groups were later re-assigned) ( , , ) . the geographic distributions of the muv genotypes varies worldwide but can co-circulate and thus drive temporal shifts in their distribution. genotype a was frequently isolated in europe until the 's. currently genotypes c, d, e, g, and h are prevalent in europe and the united states of america (usa) whereas genotypes b, f and i are more common in asian countries ( table ) ( , , , ) . since numerous mumps vaccines have been developed worldwide, varying in efficacy and safety profiles but primarily consisting of an attenuated live muv without an adjuvant ( , ( ) ( ) ( ) . currently in europe and for the majority of the g countries who have a mumps vaccine in their immunization schedule (table ) , the mumps vaccine is included as part of the trivalent measles, mumps rubella (mmr) vaccine, and is primarily administered in two doses ( , ) . the jeryl lynn (jl) vaccine, derived from the genotype a muv strain was first developed in the usa and has been used extensively in the united kingdom (uk), ireland and usa since it was licensed in ( ) . derived from a single clinical sample, and propagated in a chick embryo cell culture, two viral isolates (jl and jl ) are present, differing by ∼ nucleotides and amino acid changes ( ) ( ) ( ) . the rit mumps vaccine, developed from the dominant viral component (jl ) in the jl vaccine strain appears to have comparative safety and efficacy (seroconversion) profiles to the jl vaccine strain ( , ( ) ( ) ( ) . however, since no controlled clinical trials of efficacy have been published to compare the two doses of the two vaccines, the clinical significance of this observation is not known. despite the integration of the mmr vaccine into childhood immunization programs, cyclical outbreaks [defined as two or more cases linked by place and time ( ) ] of muv have been documented in several highly vaccinated populations such as ireland and the united kingdom ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) . between august -and january , , mumps cases were notified in ireland, primarily affecting individuals between the ages of - years. of the % of cases that stated vaccination status, % had received two doses of the mmr vaccine ( ) . an upsurge of mumps cases has also occurred in states of the united states over the last decades, primarily affecting people between and years in close contact/shared settings ( ) . in indiana, . % of mumps cases ( . % of university affiliated and % of community cases) had documented evidence of mmr vaccination ( ) . this results in a significant resource burden for public health departments to control. several reviews, both observational and systematic have demonstrated the clinical benefit of a mumps vaccine ( , ) , the pathogenesis and genomic diversity of the muv ( , , ) and the epidemiology surrounding the outbreak ( , , ) . it is not clear why these mumps outbreaks occur, although it has been alluded to be due to a number of interrelated factors, such as sub-optimal vaccine uptake ( , , ) , primary or secondary vaccine failure or failure of the mumps vaccine to protect individuals from infection (vaccine efficacy) ( ) (figure ). history depicts the remarkable public health impact of mass vaccination. previously inevitable childhood diseases with potentially debilitating or deadly outcomes have seen their rates plummet worldwide or become successfully eradicated. immunizations of vaccine preventable diseases are estimated to prevent ∼ - million deaths per annum and increase life expectancy by ∼ years ( ) . more recently there has been a shift in the public and media perception of vaccines to their safety, which has facilitated outbreaks such as mumps ( ) . organized opposition to vaccinations has a long history; public outcry and resistance following the introduction of the smallpox vaccine in the nineteenth century led to the introduction in england of the vaccination act of ( ) . with one in eight children in the usa under the age of currently thought to be unvaccinated due to parental choice, the who now considers vaccine hesitancy as one of the ten threats to global health in ( ) . vaccine hesitancy, defined as a "delay in acceptance or refusal of vaccines despite availability of vaccination services" involves a multitude of social, political, cultural and emotional factors in highly vaccinated, western populations ( , ) . one of the main issues is the parental concerns regarding the perceived risk of a vaccine to their child (such as timing/schedules of vaccines, associated pain of administration, and potential adverse effects) vs. the disease morbidity and mortality associated with the vaccine preventable disease ( , ) . the retracted paper published in the lancet in ( ) and "anti-vaccination" opinions on social media have also contributed to the persistent and insistent misinformation ( ) , despite vast follow-up epidemiological studies showing no relationship between the mmr vaccine and autism, or differing cognitive development/intelligence ( ) ( ) ( ) . however, the resultant reaction of the public led to the uptake of the first mmr vaccine falling sharply from , with uptake falling to below % in ( , ) . the age demographic that are experiencing the most cases of mumps in ireland during the current ongoing outbreak would have been scheduled to have received the first mmr vaccine between and . nevertheless, no deductions can be made, due to the lack of vaccination status information provided with reported cases ( ) . frontiers in immunology | www.frontiersin.org heterogeneity of immunization coverage in specific populations or geographic locations of susceptibility is also becoming an important epidemiological issue in maintaining proficient population immunity for mumps ( , , ) . the who recommends a > % mmr vaccine coverage for herd immunity. maintenance of such coverage is well-demonstrated in finland, where a country-wide -dose mmr vaccination program initiated in the 's eliminated measles, mumps and rubella within years ( , ) . recent publications from around the world indicate that the level of mmr vaccine uptake is far lower than what is recommended [reviewed in ramanathan et al. ( ) ] ( , ( ) ( ) ( ) ( ) . of the g nations that implement a mumps vaccine within their vaccination schedule, only countries have maintained vaccine coverage levels of > % (table ) . however, poor uptake/incomplete vaccination alone may not be the only issue relating to mumps outbreaks. in the netherlands, mumps outbreaks still occurred with an overall herd immunity threshold of - %, and where and % received the first and second mmr at months and years, respectively ( , ) . the clinical presentation of mumps is pathognomic (bi-lateral parotitis); therefore supporting laboratory diagnosis was rarely employed in the past. as the classical symptoms of mumps are not always typical, there may have been a significant number of individuals in the past who may have been infected but were not identified as such. when mumps vaccination was introduced in , the criteria the vaccine had to meet was the proof that it was clinically effective, i.e., that it reduced the risk of disease in vaccinated individuals in real-world conditions over a set period. such an example was seen the usa; the reported cases (i.e., diagnosis of clinical symptoms) of mumps declined from > cases per , population before (pre-vaccine era) to cases per , population in , a reduction of % ( , , , ) . to note, clinical efficacy was probably based upon the reduction of the "classical bilateral presentation" rather than the milder mumps presentation. therefore, one could argue that the original vaccine efficacy for clinical manifestations was over estimated. currently the laboratory diagnosis of mumps infection in ireland is based upon two approaches: detection of mumps rna by reverse transcriptase pcr (rt-pcr) in a buccal swab containing saliva, throat swab or urine specimen, and serological detection of immunoglobulin m (igm) using a capture assay ( , ) . both approaches for diagnosis are impacted significantly by the quality and timing of sample collection post-onset of symptoms and also if the subject is mumps naïve or had received mumps containing vaccine ( , , , ) . there are challenges in using standard serological laboratory diagnostic methods to reliably confirm mumps re-infection of individuals who had been previously naturally infected or vaccinated ( , ) . briefly, vaccinated individuals re-infected with muv may only generate a weak or undetectable igm response ( ) . although a rise in igg titer may also not occur in vaccinated individuals ( , ) , numerous studies have documented a rapid, variable increase in mumps-specific igg levels, with neutralization antibody concentrations present up to months post-infection ( , , ) . therefore, reverse transcriptase-polymerase chain reaction (rt-pcr) is recommended ( , ) , and was formally introduced in as the principle diagnostic tool in ireland to detect mumps in oral fluids ( ) . rt-pcr can identify current mumps infection more effectively in vaccinated individuals than serological techniques alone as it identifies the presence of the muv vs. the immunological response (igg, igm), and has been previously shown to % correlate with viral culture results ( , ) . the case numbers of more recent mumps outbreaks should always be assessed with this question in mind; are the number of mumps cases increasing, or/and are we better at diagnosing an acute infection? the latter seems to be the most probable, as many individuals who are being tested do not present with classical symptoms. in addition to enhanced surveillance of mumps cases, further optimizations of technologies are also occurring; the utilization of next-generation sequencing demonstrated that by editing one -fold degenerate nucleotide in the forward primer and three -fold degenerate nucleotides in the probe sequence optimized the fluorescence intensity and clinical sensitivity of the real-time rt-pcr when compared to the cdc-developed and who-recommended rt-pcr target [(np) gene] leading to ∼ % increase in clinical sensitivity (i.e., ct values that were ∼ . cycles lower) ( ) . much is not known about the immunological response to the mumps vaccine strain. however, a number of young adults who were vaccinated as children over the last two decades have demonstrated an increased risk of muv infection with time, which is assumed to be related to a decline of antibodies to sub-protective levels of immunity ( , , , , ( ) ( ) ( ) ( ) . primary vaccine failure is defined as the lack of a sufficient initial antibody response to a vaccine in a recipient resulting in a lack of protective immune responses ( , ) . although this type of vaccine failure may be because of improper storage/handling or administration of the vaccine, impacting its efficacy, it may also be due to the initial immunological response of an individual to the vaccine, which is usually quantified by the presence of antibodies that should be detectable in the weeks following vaccination. primary vaccine failure was attributed to primaryschool outbreaks of both mumps and measles in ireland, which subsequently resulted in reducing the age for the second dose of mmr vaccine from - years in to - years of age ( ) . with the cyclical outbreaks occurring, it has been proposed that primary vaccine failure could again be a factor. how is a response to a vaccine determined? in pre-licensure studies of the jl and urabe mumps vaccines, high seroconversion and low failure rates were observed in children after the first vaccine dose (> and . %, respectively), demonstrating that the vaccine induced an antibody response ( ) ( ) ( ) ( ) ( ) ( ) . a more recent study by ong et al. demonstrated that a ≥ fold increase in mumps antibodies -days post-vaccination was considered to be an adequate response of immunity ( ) . vaccine effectiveness (i.e., seroconversion post-vaccination) of vaccine doses has only been conducted on the jl strain; studies provided a median vaccine efficacy of %. these studies have shown that doses of mmr were more effective (but not statistically significant) than a single mmr dose to combat the incidence of mumps infection ( , , , , , ) . mumps-specific antibodies have been detected - years postvaccination and without substantial decline for years after mumps vaccination, with the immunogenicity and efficacy of the mmr vaccine showing comparable immunogenicity levels to post-vaccination levels at years ( , ) . however, most studies of this vaccine (involving either a mumps-specific vaccine or a combined vaccine) only followed-up to - days postvaccination ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . despite few follow-up studies estimating post-vaccination antibody titers specific to the vaccine mumps strain, the evidence of seroconversion post-vaccination in a number of studies indicate that primary vaccine failure does not seem to be a significant contributor to the outbreaks that have been recently observed ( , , , , , ( ) ( ) ( ) ( ) . it has been noted that a small percentage of the population do not seroconvert post-vaccination; < % who received the mmr vaccine were seronegative - years after the first dose of mmr (n = ) ( ) . poor immune responses to primary vaccination has been shown to be a good indicator of infection susceptibility ( ) . this is in agreement with the correlation of pre-outbreak jl virus neutralization titres and elisa results being significantly lower in individuals who became infected compared to non-infected individuals ( ) . further studies of these individuals may provide insights of which immunological process are integral to develop immunity. the current methods used to determine immunity against mumps cannot discriminate between primary and secondary vaccine failure; only the timing of these tests can assess whether an individual ever mounted an immune response postvaccination or whether the response is detectable years postvaccination. primary vaccine failure encompasses the failure to mount an immune response to a dose of a vaccine, secondary vaccine failure refers to a more gradual loss of immunity after a successful initial response that occurs over a number of years post-vaccination ( ) . several factors have been proposed to be implicated with secondary vaccine failure, such as waning immunity, a lack of cross-neutralization, and natural boosting. waning immunity is defined as a decline in immunological protection proportional to time since vaccination. potential waning immunity has been documented in the current mumps outbreaks seen in europe and the usa, mostly affecting young adults within highly vaccinated populations attending tertiary education who have received two doses of the mmr vaccine in early childhood ( , , , , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) . a number of studies from the usa, where a jl vaccine has been used since have demonstrated waning immunity within the population. the risk of developing clinical mumps was shown to increase by - % for every year post-mmr vaccination ( ) , with the rates of mumps infection rising from . cases per , in those who received the second dose of the vaccine within years of the outbreak, to . cases per , in those who received it over years prior. using a mathematical model with analytical limitations, a recent metaanalysis of six studies estimated that vaccine-derived immune protection to muv wanes about years post-vaccination ( ) . kennedy et al. ( ) also demonstrated a decrease of ∼ % in mumps neutralizing antibody titers over years. in contrast, other studies appear to contradict, these findings, showing no link between mumps protection and time elapsed following administration of mumps vaccine ( , , , , ) . lebaron et al. ( ) and gothefors et al. ( ) demonstrated that - % of individuals still had detectable anti-mumps antibodies ∼ years after initial vaccination. cohen et al. ( ) also demonstrated minimal antibody level decline after two mmr doses - years after second vaccination. neutralizing antibodies against the jl- vaccine strain has also been detected in ∼ % for age groups - years, % for age group - years; and % for age group + years ( ) . implementation of a third dose of the mmr vaccine has been shown to be effective as a stop gap measure in limiting disease spread in outbreak settings situations ( ) . individuals vaccinated for the third time had a % lower risk of contracting mumps, with a decreased attack rate of . vs. . cases per , when compared to those who received a second dose. more than % of those who received a third dose of the mmr vaccine showed a -fold increase in mumps antibody titers ( , , , ) . an increase in mumps igg humoral immunity was also observed post-vaccine administration. however, this immunity boost has been shown to be a transient effect, with mumps antibody titers returning to pre-third dose of mumps-vaccination levels year after vaccination. therefore, as waning immunity is thought to be an important factor facilitating mumps outbreaks, the emphasis placed on the quantity/quality of mumps-specific antibodies may need to be re-assessed. it is yet undetermined if the total loss of detectable antibodies correlates to a loss of clinical protection, as the minimal level of neutralizing antibody required for protection against mumps has not yet been defined ( ). antigenic variation and thus reduced cross-neutralization between the vaccine and circulating strains of different muv genotypes have been cited as possible explanations for mumps outbreaks in highly vaccinated populations ( , , ( ) ( ) ( ) . recent outbreaks in europe and northern america (including ireland) have shown the circulating muv during the current outbreaks to be genotype g ( , , , ) . this muv genotype was first identified in , and has demonstrated intra-genotype diversity of up to % (table ) ( , ) . the jl vaccine strain (genotype a), differs phylogenetically to the circulating muv (genotype g) ( ) . in vitro studies of the genotypic distribution and temporal shift of muv suggest that cross neutralization between wild type and vaccine genotypes may be approximately half the concentration measured against the vaccine strain ( ) . pre-infection neutralization titers in mumps positive cases were also significantly lower against genotype g vs. mumps vaccine strain, potentially due to amino acid differences in b-cell epitopes and/or n-linked glycosylation sites on the hn and also within the f protein ( ) . santak et al. ( , ) also demonstrated that conformational changes within the f protein may lead to immunological escape. despite the decline/scarcity of cross-neutralizing antibodies, different mumps vaccines used worldwide have been shown to prevent significant clinical mumps infection during outbreaks ( , ) . dependent on the strain, a - -fold variation of patient sample titers has been shown to be protective in in vitro plaque reduction neutralizations ( , , ) . although the sera of one of these studies, was collected only weeks after mmr vaccination, a time point that may not signify the concept of waning immunity and antigenic differences, several other groups have shown that the most divergent strains of muv can be neutralized in vitro with only slight variations in titers, supporting the concept that muv is serotypically monotypic ( , , , ) . epitopes of the muv that are presented to cd + t-cells have been shown to be present in not only the circulating strains of virus but also in a number of vaccine strains ( ) . in addition, lewnard et al. ( ) also found no evidence that recent mumps outbreaks were due to the emergence of muv strains escaping vaccine-driven immunological pressure. therefore, the limited data does not suggest that antigenic drift of the muv leading to diminished neutralization capacity of the vaccine strain could fully explain the recent outbreaks ( ) . further studies into the cross-neutralizing capacity of the mumps vaccine strain administered - years previously to the current circulating strain of muv in countries where outbreaks are being observed will allow better deductions to be made. it is possible that differences in the neutralization capacity of vaccine-induced antibodies against different muv strains may be more significant when levels of neutralizing antibody are low and become "overwhelmed" when the mumps viral load challenge is high ( ) . several prominent mmr/mumps vaccine studies were undertaken at a time when there was still a high prevalence of circulating wild type virus, which enabled sub-clinical boosting to occur in an individual. such natural boosting is illustrated in belarus, where a subpopulation of vaccinated individuals only had a small amount of their overall mumps igg antibody levels specific to the vaccine-strain ( ) . neutralization antibodies against iowa-g/usa (the circulating wild type virus) were also present in pre-infection plasma of all mumps cases during a recent outbreak in the us ( ) . this indicates that the mumps vaccine alone is not solely responsible for the high levels of mumps antibodies ( ) , and that longterm antibody persistence or protective efficacy data of the vaccines used may not truly reflect the current circumstance of viral transmission/circulating within a highly vaccinated population ( ) . herd immunity increases the chance for natural mumps boosting for an individual is at a minimum, reducing the potential of the frequency of mumps outbreaks ( , , ) . with less opportunity for subclinical boosting (asymptomatic response to the circulating virus), the impact of other elements of waning immunity may play an increasingly critical role in the re-emergence of mumps outbreaks ( , ) . additionally, as the heterogeneous uptake of vaccines in this modern era is leading to susceptible individuals within the community, future work will need to encompass genotyping of circulating muv to examine how impactful subclinical boosting was on early measures of vaccine efficacy in current populations. why do we consider antibodies to be the best measurement of vaccine efficacy? the evolution of an individual's immune response differs between natural infection and vaccination, in particular the difference in the affinity and specificity of an immunological marker such as antibodies ( ) . true correlates of mumps immunity after vaccination have been poorly characterized; to date, there are no reliable correlates of protection from either symptomatic mumps infection (clinical immunity), or individuals previously exposed to muv ( ) . therefore, a serological surrogate/ substitute is used ( ). mumps vaccine efficacy is quantified by a single measure, igg which may not suffice to evaluate the magnitude of the actual humoral response. borgmann et al. ( ) proposed an increase in mumps-specific igg titer in sera as a diagnostic criteria of mumps reinfection ( ) . it has been suggested that vaccinated individuals have modified b-cell responses to muv that allow for the rapid generation of igg antibodies and a blunted or absent igm response ( , ) . in addition, emerging data in simian immunodeficiency virus studies suggests that not all antibody responses are equal, and qualitative features of antibodies may be key to defining protective immune profiles ( ) . despite its use, the correlation to mumps-specific igg concentrations and neutralization titers against the jl virus is poor, suggesting that igg concentrations do not adequately represent a sufficient surrogate correlate of protection ( ) . this is demonstrated in finland; only % of vaccinees had no detectable mumps antibodies after years ( , ) . data from the european sero-epidemiology network (esen ) project in reported that mmr immunization uptake in ireland in was % ( ), however it was also suggested that only - % of -to -year-olds in ireland had detectable antibodies to muv by either natural immunity or immunization ( ) . in , vaccine coverage of medical students in germany was reported to be . % ( ) . in children between the ages of - years, where . % had been vaccinated with the mmr vaccine at least once, only . % showed prevalence of antibodies ( ) . however, . % showed a prevalence of antibodies to measles and rubella in the absence of mumps-specific antibodies. therefore, previous measurement of anti-mumps-specific igg that represented immunity induced by the mumps vaccine appears to be overestimated ( , ) . antibody levels of other components of the mmr vaccine have seen similar trends. waning rubella antibody titers have been observed, despite the number of acute rubella and congenital rubella syndrome cases not increasing. it has also been shown that college students who received rubella vaccination during childhood and had low/no antibody response were able to mount a secondary response when challenged with rubella indicating that an individual's low antibody levels are not always indicative of susceptibility to infection ( ) . measles antibodies can also be detected for up to a decade post-vaccination, with > % of individuals still measles igg positive at - years of age ( , ) . however, as with mumps and rubella, waning measles antibody titers have been observed ( , ) . despite this, a recent longitudinal study of up to years demonstrates how effective the mmr vaccine has been in preventing diagnosed measles cases during the 's/ 's ( ) . similarly, three doses of the hepatitis b (hbv) vaccine in a cohort of alaskan natives showed > % seroconversion in children and young adult post-vaccination and provided long term and durable protection against chronic hbv infection. although no increase of hbv prevalence were observed % individuals had low to undetectable antibody levels after years. these observations suggest that an individual's antibody levels do not indicate susceptibility to infection, that either an antibody titer lower than recommended guidelines is still protective, or/and is an ineffective surrogate of protection. this is emphasized in a study by amanna et al.; ( ) responses to non-replicating protein antigens (tetanus and diphtheria) were shown to have approximate antibody half-lives of - years. in comparison, antibodies following wild type infection were shown to have half-lives of years or more which was thought until recently to confer a more prolonged lifelong protection ( , , ) . however, reinfections observed in individuals that were previously naturally infected have demonstrated that the quantitative measurement of antibodies do not indicate sterile immunity ( ) . it is also important to stress that seroconversion rates due to immunization/natural infection only reflects a change of antibody status from negative to positive, but not necessarily the intensity of antibody response. in addition, there is no consistency in the timing of sample collected post-vaccination to test vaccine efficacy, and between the serological tests utilized for detecting mumps antibodies. as a result, documented seroconversion rates of the mumps vaccines used vary widely (jl: - %, rit strain: - %, urabe am : - %, rubini: - %). this highlights that the assays used to detect immunity to muv may not always detect an adequate post-vaccination response. only a small number of serological commercial assays such as the detection of hepatitis b surface antibody (anti-hbs) ( ) and rubella igg ( ) have been designed using who reference material as a standard for quantification. however, even utilizing this reference standard demonstrates significant differences in the determined quantification of either anti-hbs or rubella igg depending on the assays used; although a value for anti-hbs of iu/ml is regarded as protective against significant hbv infection, the detection of this anti-hbs is significantly influenced by which anti-hbs assays is used ( ) ( ) ( ) ( ) ( ) . therefore, it is possible that the current assays/tests mechanisms utilized to measure mumps antibodies are too insensitive/inappropriate/crude to identify nuances in the immune response which could correlate with immunity against mumps. in addition, variation within neutralization epitopes i.e., the quality of the antibody present could be a more important correlate than quantity ( , ) . though labor-intensive, neutralizing antibodies are considered to be a better correlate of mumps immunity. antibodies against the haemagglutinin-neuraminidase protein (hn) and nucleoprotein (np) have been shown to neutralize muv, however, repeated attempts to define a titer that provides a protective threshold titer have been inconclusive ( , ) . in older studies, during field evaluations of the jl vaccine, neutralizing antibody titers of : - : in unvaccinated individuals was considered seropositive and protective from mumps infection ( , , ) . using a more contemporary wild-type isolate (iowa-g/usa ), a : neutralizing titer cut off was defined between case patients and exposed patients, despite the fact that no cut-off could fully discern between the two groups ( ) . however, that these results are dependent on the challenge virus strain used in the assay. rasheed et al. demonstrated a fold lower neutralization titer to the g-genotype when compared to the jl vaccine strain in - year olds ( ) . this has also been seen between mumps vaccine strains vs. circulating strains in india and china ( , ) . despite studies in more highly vaccinated populations demonstrating that hn-inhibiting titers after natural disease were : compared to : post-vaccination, neither appeared to prevent reinfection ( , ( ) ( ) ( ) ) . there is increasing evidence that the mumps-specific antibody response is broader than neutralization alone ( ) . avidity testing for virus-specific igg has been proposed ( , , ) . individuals who lack measurable mumps-specific antibody levels may be susceptible to infection but protected from significant illness as they may be protected by cell-mediated immune memory. prolonged t-cell responses are reported after other vaccinations; - years after a single dose of the rubella vaccine ra / , a t-cell proliferative response to neutralizing antibodyinducing peptides suggest t helper and b-cell interactions. this indicates that full vaccine effectiveness could be dependent on mounting both an antibody and cell-mediated immune response ( ) . although cell mediated immunity has not been as wellassessed in mumps infection, a lymphoproliferative response was induced in infants vaccinated at , , or months of age was induced ( ) with antigen-specific t-cells reported to appear within month of infection ( ) . lymphoproliferative responses to measles and mumps vaccine viruses were shown to persist in two thirds of the population at least years after immunization ( ), with t-and b-cell immunity persisting for years post-immunization ( ) . low levels of mumps-specific memory b-cells have also been documented suggesting that mumps infection or vaccination may not generate a robust b-cell memory ( , ) . two principal mechanisms for maintaining long-term humoral immunity have been proposed and reviewed by amanna et al. ( ) : associations between memory b-cell levels and antibody may reflect an epiphenomenon in which serum antibody levels and memory b-cells are equally stable but independently maintained. if memory b-cells and plasma cells are independently regulated, then multiple re-exposures to antigens may cause divergence between memory b-cell levels and antibody levels ( ) . antigens with the highest rates of boosting through vaccination or latent viral infection coincidentally showed the weakest association between memory b-cell titers and antibody titers ( ). although the role and efficacy of t-cell immunity to mumps infection is unclear, there is a possibility that certain muv strains may be capable of escaping vaccine induced t-cell responses, which may not be considered of significance until b-cell waning immunity comes into play ( ) . in individuals who did not respond to vaccination (i.e., had a ≤ -fold of mumps antibody titers days post-vaccination), several genes including those implicated in antigen presenting, processing, t-cell response and function showed significantly increased expression, with mhc class ii hla-drb and hla-dra, and cd induced when compared to responders day post-mmr vaccination. this may indicate that the stimulation of a rapid adaptive immune response limits antigenic presentation and hence prevent the differentiation of memory b-cells to antibody-producing plasma cells ( ) . differences in predicted b-cell and t-cell epitopes between jl vaccine strain and other vaccine strains may also be implicated in the outbreaks witnessed ( ) . although, it has also been shown that natural mumps infection or vaccination do not always induce both cellular and humoral immunity. de wit et al. ( , , ) has shown the presence of th -type cd + t-cells recognizing a muv epitope in a hlr-dr restricted manner. in addition, the response of ifn-γ and tnf producing cd + t-cells specific to muv epitopes are lower in vaccinated individuals when compared to individuals who were naturally infected ( , , ( ) ( ) ( ) . utilizing current knowledge and new technologies may help define a better surrogate correlate of protection and potentially determine a cut-off between the immunity of a vaccinated individual and a secondary mumps infection. this may potentially move the diagnostic preference from serological tests to more comprehensive functional assays. despite the large resurgence of mumps outbreaks, there is insurmountable evidence highlighting the benefit of the mumps vaccine ( table ) . routine childhood mmr vaccination has resulted in a dramatic decrease in the incidence of mumps cases, and has shifted the peak age-specific attack rates from a young children (manifesting between and years) to one that affects young adults, in particular those who have close interaction with other young adults ( - years) ( , ) . additionally, clinical manifestations and severity of disease in vaccinated vs. unvaccinated individuals differ ( , ) . although muv can be clinically asymptomatic in about - % of those who become infected, the vaccine against mumps confers protection in a dose response manner; unvaccinated individuals saw an attack rate of based on the reduction seen upon the introduction of a mumps vaccine, it has been proposed that mmr vaccination also prevents the transmission of the virus. there is limited knowledge regarding the shedding and transmission of muv, but it is thought that close contact and transmission of a certain viral load may induce clinical symptoms ( , , ) . modeling data suggests that infectious muv shedding decreases rapidly after the onset of symptoms, however - % are patients are thought to still be virally shedding days after the onset of symptoms ( ) . this could be the reason why the transmission of muv can be exacerbated by close social situations within a heterogeneously vaccinated population. outbreaks generally occur in situations of intense contact such as college dormitories, boarding schools, and youth summer camps ( ) , with up to a third reporting some contact with a mumps case ( ) . evidence of lower levels of viral replication also suggests a clinical benefit of the vaccine ( , ) . viral load and presence of the mumps vaccine genome in areas of viral replication was lower in vaccinated individuals vs. unvaccinated individuals ( ) . in addition, patients who contracted mumps but had two doses of mmr have been shown to shed less muv in their urine, with fewer experiencing bilateral parotitis or orchitis than unvaccinated individuals ( ), this suggests that immunity induced by mmr vaccination limits virus transmission and complications ( , ) . it should be noted also that individuals who received two doses of mmr, and had a positive correlation between viremia, salivary viral loads and systematic clinical mumps infection may have an increased risk of transmitting virus. these individuals also lacked mature functional responses, with low neutralizing antibody titers and avidity indexes ( ) . overall, evidence demonstrates a clinical advantage to receiving a mumps vaccine ( table ) . currently no global consensus exists for the measurement of mumps antibodies, mumps avidity or neutralizing titers that correlate to vaccine response and protection in healthy individuals. if a biomarker is discovered, it could be utilized as an international diagnostic reference standard to allow global harmonization and evaluation of the relative effectiveness of the different vaccination programs worldwide. such an attempt was conducted by andrews et al. ( ) , who reported on the european sero-epidemiology network project which was established to harmonize the seroepidemiology of five vaccine preventable infections including measles, mumps, and rubella in eight european countries. the study concluded that the development of an international standard for mumps would help in the standardization and comparability of mumps antibodies in the different enzyme immunoassays used in laboratories. however, to date, no international reference standard for mumps has been established. in response to infection, the human immune system launches a series of immunological responses with the goal of controlling or eliminating the pathogen. if the pathogen circumvents the frontline defense of the innate immune system, an adaptive immune response specific for the pathogen will become activated to respond, with the intention to generate humoral-and cell-mediated immunity. humoral immunity, represented by antibodies secreted by b-cells are not effective against pathogens that invade host cells. therefore, cell-mediated immunity instructed by the vaccination aims to stimulate the host immunological process and formation of cell-mediated immunological memory via the use of live-attenuated or of inactivated/subunit vaccine components to promote a cell-mediated immune response. extensive knowledge gaps significantly hinder improvements to the mumps vaccine and prospects for mumps eradication and maintaining proficient population immunity ( , , ) . few studies have collected data that examines different aspects of mumps immunity and are limited in their predictive value for future outbreaks ( ) . for example, the importance of t and b-cell responses in protective mumps immunity and how memory/plasma cell numbers are homeostatically maintained post-infection or vaccination is relatively unknown ( ) . it should be acknowledged that the mechanism of protection of infection may not be the same mechanism of recovery from infection, which may make the identification of a common correlate of protection and recovery difficult ( ) . therefore, if a correlate or surrogate correlate is unobtainable to define an individual's protection to mumps, should we re-consider and re-focus efforts on optimizing the vaccine using available historical clinical and trial data? it has been suggested that wild-type infection could confer a "better quality, " broader and prolonged immuno-activation than vaccine-induced immunity. this is reflected in mean neutralizing antibody titers detected post-mumps vaccination, which were over five times lower than those detected following wild type infection. similarly, hemagglutination-inhibiting titers after natural disease were : compared to : post-vaccination ( , , ) . the use of a live-attenuated virus vaccine is intended to mimic immunological reactions and responses between the host and wild type virus ( ) . the current liveattenuated mmr vaccine is intramuscularly injected, a route that significantly differs from the natural infection mode of transmission. however, emphasized by differing immunological kinetics between immunized and naturally infected individuals when subjected to wild type pathogens, injectable vaccines are considered not to be the best inducer of antigen-specific mucosal immune responses for mucosal pathogens, especially if the mode of administration is not the natural route (the respiratory tract) ( , ) . improvements on a broader range of antigen delivery systems will improve vaccination strategies and potentially prolong the effect of a vaccination by producing a localized immunological response in the relevant tissues ( , ) . mucosal vaccines such as intra-nasal vaccination have advantages over traditional injectable vaccines as they can induce an effective, more robust immune response without any physical discomfort and more closely replicate the natural route of infection for mumps ( , ) . b-cells induced by the mucosal response are also capable of secreting iga class of antibodies in the lumen, where the interaction and neutralization of specific antigens form iga-antigen complexes are easily able to be entrapped in the mucus and eliminated by cilial epithelial cells ( ) . activated mucosal lymphocytes can also reach other mucosal sites via the lymphatic system and have the capability to transfer immunity ( ) . such an example is the intranasal immunization of inactivated influenza. with a - % similar efficacy between the injectable and intranasal influenza in healthy individuals this intranasal vaccine can elicit the secretion of haemagglutinin and neuraminidase specific iga antibodies in the upper respiratory tract, and corresponding igg antibodies ( ) . live, cold adapted attenuated nasal influenza vaccine has been routinely used in russia for over years ( ) . other liquid live-attenuated intranasal vaccines are available; "nasovac r " in india, and "flumist r " in the us, uk and new zealand ( , , ) . inactivated vaccines consisting of heat/chemical or liveattenuating monovalent or multivalent pathogens in animals/cell lines were developed to protect against disease causing microorganisms ( ) . less emphasis was placed on understanding the mechanisms related to conferring immunological memory; the focus lay on the availability, mass production and administration of the vaccine to introduce herd immunity into populations ( ) . currently, the least expensive and time effective method to licensure is the comparison of serologic responses of the new vaccine to an existing licensed vaccine, which can lead to a bias on the development of novel vaccines ( ) . this methodology also does not account for the fact that each vaccine developed elicits its own immunological signature and may need to be considered on an individual basis ( ) . raymond et al. ( ) has suggested that embryonated chicken egg-based vaccines may induce antibodies that are more preferential to egg adapted strains better than wild type virus. amino acid substitutions/differences in key antigenic targets due to the passage of the growing virus within this environment may optimize the growth of the virus, but could lead to differences over time that could affect the immunogenicity or potency of the vaccine ( , , ) . the jl vaccine contains two isolates of the jl strain (jl and jl ) and whilst no immunological differences have been documented, jl grows to higher titers than jl in embryonic eggs and also demonstrates significant sequence variability ( , ) . zost et al. ( ) also demonstrated that an egg selected mutation within a glycosylation site in the - influenza vaccine strain led to the production of poorer neutralizing antibodies to the vaccine strain compared to wild type influenza virus. vaccine rit strain derived from one of the two distinct virus subtypes of the jl vaccine (jl ) showed comparable seroconversion rates despite inducing a significantly lower geometric mean antibody titer when compared to recipients of the jl vaccine, but does not have any longitudinal trials investigating its efficacy, even though there are populations who are currently receiving it ( , ) . the significant time gap between pathogen emergence and vaccine licensure, could potentially lead to antigenic drift. there is potential that modern biotechnologies could be utilized to design novel vaccine platforms ( , , ). clinically derived recombinant muv lacking the expression of the immunomodulatory v or sh protein are currently being investigated ( ) . in china, a vaccine consisting of the prevalent wildtype virus genotype (f) has recently been produced and is currently undergoing trials ( ) . in addition, despite being extremely pleomorphic, utilizing mhc epitopes as potential b-cell and t-cell vaccine candidates are also being investigated ( , , ) . vaccine design has involved the utilization and templating of epitopes that previously induced a b-or t-cell response during natural disease that are considered to be immunogenic enough to induce similar responses if administered in a vaccine. however, the appropriate b-cell and t-cell epitope/peptide candidates to induce a protective immunological response can be difficult to correctly identify and synthesize, as it may differ to the immunodominant epitope and host presentation of that antigen ( , ). prediction of mhc-peptide binding and cleavage has demonstrated mismatches in both vaccine tcell and b-cell epitopes in vaccinated individuals highlighting small number of distinguishing amino acid changes of the jl major strain ( ) . the importance of understanding tand b-cell responses and how antigen-specific memory cells numbers are homeostatically maintained post-infection is crucial to understand to ensure successful vaccine development ( , ) . since the 's, significant progress has also been made in developing flexible, amplifiable, scalable, inexpensive, and cold-chain free rna vaccines, such as synthetic mrna molecules encoding only the antigen of interest and selfamplifying rna (sa-rna) ( ) . such examples include an experimental mrna vaccine candidate (mrna- ) which encodes a stable form of the sars-cov- spike protein and has been accepted as a trial candidate for clinical trials in healthy male and female individuals ( , ) . in addition, sa-rna viruses as gene delivery and vaccine vectors have also demonstrated therapeutic efficacy in a number of preclinical studies. in the context of influenza, sa-rna vaccines have shown comparable results of protection at lower doses than mrna vaccines ( , , ) . exponential developments in the "omic" area has enabled further vaccine development and understanding of the immunological response and challenges surrounding this area ( ) . systems vaccinology, which includes immunoformatics, dna/rnaseq, microarrays, mass spectrometry proteomics, transcriptomics, and metabolomics have all shown huge potential in elucidating differences in vaccine strains, vaccine growth and individual response in depth and on an epigenetic level allowing the identification of new vaccine antigens with increased speed and sensitivity ( , , ( ) ( ) ( ) . adjuvants, a group of biological and chemical compounds could also be considered to enhance and improve the longevity of the immune response of a vaccine such as the mmr. adjuvants have been successful in significantly reducing overall antigen dose in vaccine formulations as well as alter and broaden the host response through epitope spreading and qualitatively shaping the effector function of antibodies through subclass selection ( , ) . the re-purposing of live-attenuated vaccines as tibv are also being investigated. trained immunity based vaccines (tibv) elicit heterologous protective effects by inducing a broader, lasting priming of innate immune cells, in addition to the intended specific immunological response and memory of conventional vaccines [reviewed in ( ) ]. mmr and bcg vaccines have been considered as potential tibv in the context of the current coronavirus disease (covid- ) pandemic ( ) , however further research is needed. the mumps component of a vaccine is an unpurified product whose potency is measured through a biological assay for the substance rather than through evaluation of integrity of physical form (quantitative pcr after cell culture) ( ) . a monovalent mumps vaccine lot is used to characterize the performance of the mumps potency assay with international reference standards. degradation products are neither identified nor quantified ( ) . currently, the minimum potency of the mumps vaccine used varies between brands used [summarized by su et al. ( ) ] ( ) . however, this potency measurement differs to other mmr vaccines strains previously used [reviewed in ( ) ]. in addition, the maximum required potency is not usually specified. atrasheuskaya et al. ( ) demonstrated that the four out of lots of vaccine associated with six cases of viral transmission postvaccination to previously vaccinated contacts were in fact twice as potent as the lots that were not associated with viral transmission post-vaccination ( , ) . this may impact the use and efficacy of specific vaccines. due to their neurovirulence and increased incidence of aseptic meningitis and mumps cases, the urabe am and rubini mumps vaccine strains were discontinued in many countries ( , , ) . comparing alternative culturing technologies and defining a viral potency range for vaccines could help reduce variability within the mmr vaccine ( ) . ensuring the use of a reference sample that had similar replication rate and composition as the virus to be tested will allow accurate determination of the quantity of virus present per lot of vaccine. investigating novel vaccine candidates shown to induce a similar quantity but qualitatively different antibodies will help segregate and reveal potential correlates of protection ( ) . incorporating more modern technologies such as microarray technology or antibody pattern/profiling (rather than single antibody measures) to investigate biomarkers of neutralizing antibody response and/or correlates of protective immunity, in addition to incorporating what has been accomplished in finland will allow further understanding of mumps immunity ( , , , , , ) . the efficacy of a vaccine is defined by disease prevention (sterile immunity, establishment of primary infection and shedding of mature virus particle), or complications associated with infection (orchitis, neurological issues etc.) ( ) . despite the well-documented success of the global immunization programs demonstrating how vaccines significantly attenuate disease and onward transmission of infection, they are rarely totally efficacious (demonstrated in pre-licensure clinical trials) or effective (determined by practical use) ( , , ) . therefore, does "immunity" refer to sterile immunity or solely to protection from symptomatic infection? what defines an effective vaccine, or what constitutes vaccine failure? does the medical profession and the "pro-vaccine" message contribute to the public skepticism regarding immunization? is it time to shift the medical and public perception paradigm from "protection of infection following vaccination" to "protection from serious clinical mumps manifestation"? the lack of definition leads to misinterpretation by health professionals and media of what is truly occurring. such an example is currently observed with influenza; individuals who have recently being vaccinated against influenza and subsequently become infected with influenza, assume that the vaccine has "failed" even though there is a reduction in symptoms. the current assertion that vaccines "protect against" or "eliminate" the risk of infection may contribute to the misperception about what level of protection a vaccine actually provides (vaccination efficacy) perpetuated by the witnessing of visible clinical disease and outbreaks despite vaccination ( , , ) . therefore, definition and consensus of what is termed a true "vaccine failure" is required to inform both the clinical and public perception of what the function of a vaccine is. deciding what the clinical endpoint of a vaccine is i.e., infection with mild clinical symptoms vs. natural infection/disease with its associated complications and assessing the impact of the vaccine in a heterogeneously vaccinated population will allow a better consensus of what is required. a paradigm shift in what is considered to be a good vaccine i.e. one that provides protection against serious clinical sequalae, in addition to identifying a reliable laboratory marker for this protection is required ( ) . by focusing on, and acknowledging that vaccines may not prevent infection but will attenuate the clinical complications/consequences that arise from infection in addition to reducing onward transmission will provide a more realistic view of the benefits of vaccination ( ) . immunity is therefore beneficial but does not necessarily mean protection. if we can decide whether the end point of a vaccine is either the prevention of infection or protection against serious sequalae of infection, its efficacy and impact can be determined and will have enormous implications on how vaccine failure can be studied, quantified and interpreted. this teasing out of the immunological response to muv will ultimately provide potential correlates with robust predictive power, suggest directions for further vaccine improvement, and enable the discovery of potential biomarkers to help create a more efficient diagnostic assay that can discern between different infectious diseases and vaccination vs. disease status. the identification and incorporation of a correlate into diagnostic protocols which can be widely accessible may potentially allow global harmonization of criteria defining immunological protection against mumps. the medical and scientific field needs to inform the public more accurately about what a good vaccine consists of, which may result in a more positive attitude toward vaccines. in the majority of individuals, a vaccine can prevent serious clinical sequalae and associated complications following wild type infections, but also significantly reduce onwards transmission in particular to the cohorts who are not vaccinated due to a contraindication to vaccination. this is the positive and realistic view of vaccination which should be presented rather than the current flawed message of "get the vaccine and be protected from infection." the public deserves, and will appreciate, a more accurate and informed message. ac, jc, and jh contributed to the conception and design of the review. ac wrote the first draft of the manuscript. jc, tl, and jh contributed to manuscript revision. all authors have read and approved the submitted version. this work was 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evaluation of medicines for human use quality of biotechnological products: viral safety evaluation of biotechnology products from cell lines of human or animal origin a framework for research on vaccine effectiveness the urabe am mumps vaccine is a mixture of viruses differing at amino acid of the hemagglutininneuraminidase gene with one form associated with disease studies on live mumps virus vaccine. v. development of a new mumps vaccine "am " by plaque cloning highly parallel characterization of igg fc binding interactions the concept of vaccination failure effective messages in vaccine promotion: a randomized trial it's not all about autism: the emerging landscape of anti-vaccination sentiment on facebook key: cord- - oj xtp authors: khan, ali s.; amara, philip s.; morse, stephen a. title: forensic public health: epidemiological and microbiological investigations for biosecurity date: - - journal: microbial forensics doi: . /b - - - - . - sha: doc_id: cord_uid: oj xtp deliberate dissemination of a biological agent via several different routes presents the latest challenge to global public health security. novel pathogens and transmission methods can easily be exploited to cause disease outbreaks. advancements in molecular biology that make it possible to genetically modify, edit, or disrupt the genome of pathogens increase the disease risk of an accidental or intentional release of pathogens with pandemic potential. the occurrence of a disease at more than an endemic level may stimulate an investigation to determine the source of the disease, who has the disease, when it occurred, and how it spreads. when intentional release of pathogens is suspected, investigators have the additional task of attributing the outbreak not only to a pathogen but also to a human source. the deliberate nature of such dissemination may be obvious. however, some forms of bioterrorism may be more covert, requiring molecular methods to uncover. the field of microbial forensics emerged following the anthrax attack in the united states in to extend epidemiologic principles to aid in the investigation of bioterrorism incidents. microbial forensics combines epidemiology with genomic and microbiologic methods, to identify, characterize, and ascribe the cause of an incident resulting from the intentional or unintentional release of a harmful pathogen. unlike routine epidemiologic investigations, microbial forensic investigations are undertaken when there is a potential crime due to the release of a pathogen with disease-causing potential. the investigation is conducted to attribute cause to a source based on indisputable evidence and is used to support criminal charges against the perpetrator(s). however, because bioterrorism may be unannounced, the initial investigation will start the same as to any public health incident of concern. this chapter discusses how epidemiology integrated with laboratory science can be used to identify the source of diseases caused by microorganisms or toxins—especially for attribution purposes. epidemiology is the study of how disease and injury is distributed in populations and of the factors that influence this distribution (gordis, ) . more broadly, it is the study of the distribution and determinants of health-related states or events in specified populations and the application of the results of this study to control health problems (last, ) . epidemiology is based on the premise that disease, illness, and ill health are not distributed randomly in a population, and that individuals have certain characteristics (e.g., genetic, behavioral, social) that interact with the environment and predispose to, or protect against, a variety of different diseases. the specific objectives of epidemiology (gordis, ) are to (i) determine the extent of disease present in the community; (ii) identify the etiology or cause of a disease and the factors that increase a person's risk for disease; (iii) study the natural history and prognosis of disease; (iv) evaluate new preventive and therapeutic measures and new modes of healthcare delivery; and (v) provide a foundation for developing public policy and regulations. the field of microbial forensics emerged following the anthrax attack in the united states in to extend these epidemiologic principles to aid in the investigation of this and other bioterrorism incidents. microbial forensics combines epidemiology with genomic and microbiologic methods, to identify, characterize, and ascribe the cause of an incident resulting from the intentional or unintentional release of a harmful pathogen (rasko et al., ) . unlike routine epidemiologic investigations, microbial forensic investigations are undertaken when there is a potential crime due to the aforementioned release of a pathogen with disease-causing potential. the investigation is conducted to attribute cause to a source based on indisputable evidence and is used to support criminal charges against the perpetrator(s) (sj€ odin et al., ) . however, because bioterrorism may be unannounced, the initial investigation will start the same as to any public health incident of concern. this chapter discusses how epidemiology integrated with laboratory science can be used to identify the source of diseases caused by microorganisms or toxinsdespecially for attribution purposes. disease has been classically described as the result of an epidemiological triad, where disease results from the interaction between a human host, an infectious agent or toxin, and the environment that promotes the exposure (gordis, ) . in some instances, an animal or an arthropod vector such as a mosquito or tick is involved in the maintenance or transmission of the pathogen. among the assumptions necessary for this interaction to take place is that there is a susceptible host. the susceptibility of the host is influenced by a variety of factors, including genetic, nutritional, and immunological factors. bacteria, viruses, prions, fungi, and parasites responsible for disease can be transmitted either directly or indirectly (table . ). different organisms spread in different ways, and the potential of a given organism to spread and produce outbreaks depends on the characteristics of the organism and the route by which it is transmitted from person to person. diseases can be defined as endemic, epidemic, and pandemic. the usual or expected level of a disease is determined through ongoing surveillance. endemic can be defined as either the habitual presence of a disease within a given geographical area or as the usual occurrence of a given disease within such an area. epidemic can be defined as the occurrence of a disease in a community or region, clearly in excess of what is normally expected, and generally derived from a common source or from a propagated source. epidemic and outbreak are interchangeable linguistic choices used differentially to imply degrees of severity or concern. a cluster also implies an apparent excess of cases that may or may not be normal pending an epidemiological investigation or a circumscribed excess of cases when the expected number is near zero. pandemic refers to a worldwide epidemicdoften involving two or more continentsdand usually infecting numerous people. the excess incidence of cases or their widespread distribution is not synonymous with severity. many factors contribute to the emergence of infectious diseases, including human susceptibility to infection, international travel and trade, microbial adaption and change, changing ecosystems, and intent to harm (smolinski et al., ) . the ability to exploit newly created biological conditions is both the hallmark and the challenge of emerging infections (institute of medicine, ). using several . forensic public health: epidemiological and microbiological investigations for biosecurity different strategies and mechanisms, microorganisms are very efficient at infecting humans. these are exemplified both by the various strategies employed by the pathogen to survive before infecting a host, such as spore formation or survival in drought-resistant mosquito eggs, and by the various modes of transmission, such as direct contact (including large droplets) or indirect contact with fomites, or by insect vectors, and airborne via small particle droplets (heymann, ) . natural outbreaks, however, have highlighted the true diversity in the abilities of microorganisms to infect humans and animals: multistate outbreaks of salmonella linked to contaminated spring pasta salad (centers for disease control, ) and to ice cream made from milk contaminated in a tanker that had previously contained raw eggs (hennessy et al., ) , legionellosis associated with grocery store misters (mahoney et al., ) , and pneumonic tularemia on martha's vineyard from mowing over a rabbit (feldman et al., ) . these few examples are a semblance of the seemingly endless list of novel ways that pathogens are spread. changes in technology can influence pathogen dynamics through the creation of new environments in which microbes thrive (e.g., legionellosis, a disease that emerged from the water distribution systems of large buildings including cooling towers). climate change and human alteration of the ecosystem may contribute to the redistribution of pathogens or disease-causing vectors by impacting their life cycles, distribution, transmission, and survival (wu et al., ) . pathogens have the ability to rapidly alter their genetic make-up, evolve, and develop new strains including antibiotic resistant strains. the influenza virus can vary the spikes or proteins on its outer envelope resulting in the emergence of new strains that can cause disease even in vaccinated individuals (mostafa et al., ) . the outbreak of ebola virus disease (evd) in west africa in demonstrated the impact of global travel on the spread of infectious disease and the need to adopt a coordinated approach to the threat they pose. (rathore et al., ) . many of the biological threat agents are also considered to be reemerging or emerging infectious pathogens. viral hemorrhagic fever viruses are considered high-priority threat agents and are a concern as an emerging disease, as illustrated in the west african ebola outbreak in . studies have shown that most human viruses are zoonotic pathogens. of mammalian viruses, have been detected in humans of which . % are zoonotic, i.e., detected at least once in humans and at least once in another mammalian species (olival et al., ) . for early detection and recognition of emerging infections, it is critical that proper epidemiologic investigations are integrated with laboratory surveillance (feldman et al., ) . the occurrence of a disease at more than an endemic level may stimulate an investigation during which investigators may ask three questions (gordis, ) : who has the disease? the answer to this question will help identify those characteristics of the human host that are closely related to disease risk (last, ) . when did the disease occur? some diseases occur with a certain periodicity. this question is also addressed by examining trends of disease incidence over time (rasko et al., ) . where did the cases arise? answers to the previous questions lead to determining the how and why of an outbreak. as stated previously, disease is not distributed randomly in persons, time, and place. these questions are central to virtually all outbreak investigations. investigation of an outbreak may be primarily deductive (i.e., reasoning from premises or propositions proved antecedently), inductive (i.e., reasoning from facts to a general conclusion), or a combination of both. important considerations in the investigation of acute outbreaks of infectious disease include determining that an outbreak has in fact occurred; defining the population at risk; determining the method of spread and reservoir; and characterizing the agent. steps used commonly for investigating an outbreak are shown in table . . deliberate dissemination of a biological agent via several different routes, including air, water, food, and infected vectors, presents the latest challenge to global public health security. the deliberate nature of such dissemination may be obvious, as in the case of multiple mailed letters containing spores of bacillus anthracis. however, some forms of bioterrorism may be more covert, for example, the deliberate contamination of salad bars with salmonella typhimurium in the dalles, oregon, in , by a religious cult to test their ability to incapacitate the local population before an upcoming election (torok et al., ) . this outbreak, which sickened more than persons, was specifically excluded as bioterrorism during the initial investigation and was only recognized as such following a tip from an informant (torok et al., ; carus et al., ) . given the natural ability of infectious agents to emerge, the oregon outbreak serves to highlight difficulties in determining a characteristic signature for an infectious disease outbreak resulting from covert but intentional introduction. these difficulties in identifying a covert dissemination of a biological agent serve as a caution for public health practitioners, because in the aforementioned investigation of a foodborne outbreak, there was a very unusual pattern with a rare strain of s. typhimurium (torok et al., ) . although the possibility of intentional contamination was considered early in the investigation, it was specifically excluded for the following reasons: (i) such an event had never been reported previously; (ii) no one claimed responsibility; (iii) no disgruntled employee was identified; (iv) no motive was apparent; (v) the epidemic curve suggested multiple exposures, which was presumed to be unlikely behavior for a saboteur; (vi) law enforcement officials failed to establish a recognizable pattern of unusual behavior; (vii) a few employees had onset of illness before the patrons, suggesting a possible inside source of infection; (viii) the outbreak was biologically plausibledeven if highly unlikely; and (ix) it is not unusual to be unable to find a source in even highly investigated outbreaks. although one of the initial reasons to exclude terrorism (i.e., no prior incidents) is no longer applicable, based on similar actions since , determining if an unusual outbreak is biologically plausible will remain a challenge. in this context, it is . forensic public health: epidemiological and microbiological investigations for biosecurity important to remember that the first case of inhalation anthrax identified in florida in was initially thought to be natural exposure. it is clear from the two documented cases of bioterrorism in the united statesdthe oregon salmonella outbreak and the anthrax attackdthat a terrorist will not necessarily announce his/her intentions or take credit for such an attack (torok et al., ; jergnigan et al., ) . research with highly transmissible and virulent pathogens has come under increasing scrutiny due to concerns about biosafety and biosecurity. discomposure about the potential for accidental or deliberate escape of pathogens with lethal or pandemic potential from at least one of the several laboratories engaged in research with such agents is not unwarranted. for example, in , cdc reported two incidents at its main campus in atlanta, georgia: (i) the unintentional release of potentially viable anthrax spores and (ii) the potential exposure of one of its lab staff to noninactivated ebola virus (centers for disease control and prevention, ). another incident was reported in when a private company that received regular shipments of specimens from the department of defense (dod) notified the cdc that supposedly "inactivated" b. anthracis spores in its possession were still viable. cdc investigation revealed that the samples came from a dod facility in utah. furthermore, investigators found that over the past decade, facilities in the united states and other countries had received samples of "inactivated" b. anthracis table . commonly used steps in investigation of infectious disease outbreak. step . verify the diagnosis step . establish a case definition (person, place, and time) step . identify cases step . verify you have an epidemic (descriptive epidemiology) time: look for temporal clustering and timeeplace interactions place: look for geographic clustering person: examine the risk in subgroups of affected population according to personal characteristics: sex, age, residence, occupation, social groups, etc. step . develop hypotheses based on the following: existing knowledge (if any) of the disease analogy to diseases of known etiology step . test hypotheses further analyze existing data (e.g., caseecontrol studies) collect additional data, environmental samples, animal/vectors step . recommend and implement control and prevention measures prevention of future similar outbreaks step . communicate findings deliberate introduction of a biological agent spores that also contained low numbers of viable spores from the same facility (department of defense, ) . although none of these incidents were a threat to public health, it made sense to worry that some accidental releases could pose a significant threat especially since there was precedent in the accidental release of variola virus, sars coronavirus, and the influenza a/h n . based on an assessment of historical data on lab accidents, klotz and sylvester ( ) estimated that the probability of an accidental laboratory release of a pathogen with pandemic potential was . % per laboratory per year. with approximately laboratories worldwide working with pathogens such as sars and h n bird flu, they calculated that there was an % likelihood of at least one accidental release occurring in one of these labs over a -year period (klotz and sylvester, ) . advancements in molecular biology make it possible to genetically modify, edit, or disrupt the genome of pathogens. gene editing may result in a loss of function through knock-out, a change of function through gene replacement, or a gain of function through knock-in techniques (zhang et al., ) . genome editing has important therapeutic benefits and holds enormous potential for improving public health (naldini, ) . for example, gain-of-function research (i.e., research intended to increase the transmissibility and/or virulence of pathogens) can actually improve our understanding of how pathogens interact with their hosts, help us assess the potential of pathogens to cause pandemics, and aid in the development of medical countermeasures and public health preparedness (selgelid, ). the cpispr cas gene editing tool has been successfully used to create a gene driverda genetic system use to hijack a population through the propagation of a gene through multiple generationsdto control the spread of malaria that, in time, could be used to edit the dna of any living organism (selgelid, ) . nevertheless, the publication of the results of a successful attempt by researchers to genetically modify influenza a/h n virus so that it was transmissible by the airborne route in ferrets raised serious biosecurity concerns. by demonstrating that avian a/h n influenza virus could be transmitted by the airborne route between mammals, the researchers highlighted its pandemic potential for humans (herfst et al., ) . critics questioned the potential benefits of the results when compared with the biosafety and potential dual-use risks. concerns have been raised not only over the potential misuse of the results of gain-of-function research but also on research in human germline editing and gene drives and the potential for misuse of emerging gene editing technologies. the risk of intentional or unintentional release of a gene driveemodified organism during research and development, transfer between labs, or due to inadequate containment procedures is small but not zero. newly developed gene editing tools such as zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (crispr-cas) systems are publicly available (dieuliis and giordano, ; maeder and gersbach, ) . the most popular and widely used of these tools are the cpispr systems (crispr-cas , crispr-cpf , and crispr-c c ) (zhang et al., ) . crispr tools for editing prokaryotic and eukaryotic genomes are readily available online at an affordable cost, including user friendly instructions (sneed, ) . in the united states, biohacker boot camps teach basic gene editing skills, and interest in gene editing is growing. just recently, it was demonstrated that mail-order dna could be used to create horse pox virus de novo (kupferschmidt, ; noyce et al., ) . mass casualties could occur if modified strains of a/h n influenza virus with increased virulence and humanto-human transmissibility are produced, aerosolized, and intentionally released. without ignoring the current limitations of gene editing technology for nefarious purposes, a us intelligence community assessment . forensic public health: epidemiological and microbiological investigations for biosecurity stated that genome editing research on pathogens with pandemic potential may pose a national security risk if not regulated. the director of national intelligence in testimony to the us congress in february warned that "given the broad distribution, low cost, and accelerated pace of development of this dualuse technology, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications" (clapper, ) . the european academies science advisory council working group on gene editing acknowledged the potential for misuse but recommended regulating specific applications rather than gene editing itself as a new technology (easac, ) . fortunately, a number of epidemiological clues, alone or in combination, may suggest that an outbreak is deliberate. divining motives behind an attack should be abandoned as a public health tool to assess whether an outbreak is natural or deliberate in nature. it is essential to make this determination not only from a law enforcement standpoint to prevent future such actions but to protect the public health. there is a very short "window of opportunity" in which to implement postexposure prophylaxis for many of the agents likely to be used for bioterrorism (khan et al., ) . therefore, it is critical that all outbreaks be rapidly investigated and assessed for whether they are of deliberate origin. a set of epidemiological clues (table . ) has been proposed by the cdc in collaboration with the federal bureau of investigation (treadwell et al., ) . they are based on distinctive epidemiological and laboratory clues of varying specificity to evaluate whether an outbreak may be of deliberate origin. the clues focus on aberrations in the typical characterization of an outbreak by person, place, and time in addition to consideration of the causative agent. some of the clues, such as a community-acquired case of smallpox, are quite specific for bioterrorism, whereas others, such as a similar genetic type of an organism, may simply denote a natural outbreak. a combination of clues, especially those that suggest suspicious point source outbreaks, will increase the probability that the event is likely due to bioterrorism. although these clues are an important set of criteria to help evaluate outbreaks, no list will replace sound epidemiology to assess an outbreak. it is important to note that forensic investigations are conducted in the context of a rapid and thorough epidemiological investigation. not surprisingly, ongoing surveillance to identify increases in disease incidence is both the first step and the cornerstone of bioterrorism epidemiology. most of the clues described in table . simply suggest an unusual cluster of cases. they have been reorganized by specificity to trigger increasingly broader investigations by state and federal public health officials and to alert law enforcement authorities (tables . and . ). however, even the most specific of clues may signal a new natural disease outbreak. an epidemiological investigation should consider all potential sources and routes of both natural and potential deliberate exposure. for example, the community outbreak of individuals with smallpox-like lesions in the midwest in may, on first blush, have indicated the deliberate release of smallpox virus. however, a thorough integrated epidemiological and laboratory investigation identified the disease as monkeypox, an exotic disease in the united states, which in itself could suggest bioterrorism (centers for disease control, ) . instead, affected individuals were sickened by infected prairie dogs purchased as pets, which had acquired their infection while cohoused with infected giant gambian rats that had been imported from ghana, and not from deliberate dissemination. in , four us soldiers acquired hemorrhagic fever with renal syndrome in the republic of south korea near the demilitarized zone (pasteur et al., ) . despite initial suspicions of deliberate infection, epidemiological and laboratory analysis ultimately linked exposure to rodent hosts at training sites visited by the soldiers (pasteur et al., ) . . single case of disease caused by an uncommon agent (e.g., glanders, smallpox, viral hemorrhagic fever, inhalation, or cutaneous anthrax) without adequate epidemiologic explanation . unusual, atypical, genetically engineered, or antiquated strain of agent (or antibiotic resistance pattern) . higher morbidity and mortality in association with a common disease or syndrome or failure of such patients to respond to usual therapy . unusual disease presentation (e.g., inhalation anthrax or pneumonic plague) . disease with an unusual geographic or seasonal distribution (e.g., plague in a nonendemic area, influenza in the summer) . stable endemic disease with an unexplained increase in incidence (e.g., tularemia, plague) . atypical disease transmission through aerosols, food, or water in a mode suggesting sabotage (i.e., no other possible physical explanation) . no illness in persons who are not exposed to common ventilation systems (have separate closed ventilation systems) when illness is seen in persons in close proximity who have a common ventilation system . several unusual or unexplained diseases coexisting in the same patient without any other explanation . unusual illness that affects a large, disparate population (e.g., respiratory disease in a large heterogeneous population may suggest exposure to an inhaled pathogen or chemical agent) . illness that is unusual (or atypical) for a given population or age group (e.g., outbreak of measles-like rash in adults) . unusual pattern of death or illness among animals (which may be unexplained or attributed to an agent of bioterrorism) that precedes or accompanies illness or death in humans . unusual pattern of death or illness in humans that precedes or accompanies illness or death in animals (which may be unexplained or attributed to an agent of bioterrorism) . ill persons who seek treatment at about the same time (point source with compressed epidemic curve) . similar genetic type among agents isolated from temporally or spatially distinct sources . simultaneous clusters of similar illness in noncontiguous areas, domestic or foreign . large numbers of cases or unexplained diseases or deaths initial investigation at local level a. higher morbidity and mortality than expected, associated with a common disease or syndrome b. disease with an unusual geographic or seasonal distribution c. multiple unusual or unexplained disease entities coexisting in the same patient d. unusual illness in a population (e.g., renal disease in a large population, which may be suggestive of toxic exposure to an agent such as mercury) e. ill persons seeking treatment at about the same time f. illness in persons suggesting a common exposure (e.g., same office building, meal, sporting event, or social event) continued investigation with involvement of state health department and/or centers for disease control and prevention a. at least a single, definitively diagnosed case(s) with one of the following: -uncommon agent or disease -illness due to genetically altered organism b. unusual, atypical, or antiquated strain of agent c. disease with unusual geographic, seasonal, or "typical patient" distribution d. endemic disease with unexplained increase in incidence e. no illness in persons not exposed to common ventilation systems f. simultaneous clusters of similar illness in noncontiguous areas, domestic or foreign g. cluster of patients with similar genetic type among agents isolated from temporally or spatially distinct sources modified from treadwell, t.a., koo, d., kuker, k., khan, a.s., . epidemiologic clues to bioterrorism. public health rep. , e . similarly, the death of a wildlife biologist working for the national park service from yersinia pestis required a thorough epidemiological investigation. the wildlife biologist was found deceased at his home by colleagues and a subsequent postmortem determined cause of death as primary pneumonic plague (wong et al., ). epidemiological, ecological, and laboratory investigations concluded the biologist's source of exposure to y. pestis was most likely during a necropsy that he performed on a mountain lion before his death (wong et al., ) . concerns regarding the potential deliberate use of biological agents such as y. pestis and the presence of emerging infections will continue to complicate efforts to distinguish between naturally occurring disease and disease resulting from deliberate release of a biological agent. the microbiology laboratory has made significant contributions to the epidemiology of infectious diseases. repeated isolation of a specific microorganism from patients with a given disease or syndrome has helped prove infectious etiologies. in addition, isolation and identification of microorganisms from animals, vectors, and environmental sources have been invaluable in identifying reservoirs and verifying modes of transmission. in dealing with an infection, it is often necessary to identify the infecting microorganism and determine its antimicrobial susceptibilities to prescribe effective therapy. many of the techniques that have evolved for such purposes are both rapid and accurate but, in general, do not provide the kind of genetic discrimination necessary for addressing epidemiological questions. historically, the typing methods that have been used in epidemiological investigations fall into two broad categories: phenotypic and genotypic. phenotypic methods are those methods that characterize the products of expressed genes to differentiate strains. for example, the use of biochemical profiles to discriminate between genera and species of bacteria is used as a diagnostic method but can also be used for biotyping. other methods, such as phage typing, can be used to discriminate among groups within a bacterial species. biotyping emerged table . considerations for notifying law enforcement of possible biologic or chemical terrorism initial investigation at local level. a. notification is received from individual or group that a terrorist attack has occurred or will occur b. a potential dispersal/delivery device such as munition or sprayer or questionable material is found notification of the fbi as soon as possible after investigation confirms the following: a. illness due to unexplained aerosol, vector, food, or water transmission b. at least a single, definitively diagnosed case(s) with one of the following: -uncommon agent or disease occurring in a person with no other explanation -illness due to a genetically altered organism notification of fbi after investigation confirms the following (with no plausible natural explanation): a. disease with an unusual geographic, seasonal, or "typical patient" distribution b. unusual, atypical, or antiquated strain of agent c. simultaneous clusters of similar illness in noncontiguous areas, domestic or foreign d. clusters of patients presenting with similar genetic type among agents isolated from temporally or spatially distinct sources e. infection due to novel vehicle or mode of transmission molecular strain typing as a useful tool for epidemiological investigations in the s and early s, while phage typing of bacteria and serological typing of bacteria and viruses have been used for decades. today, the majority of these tests are considered inadequate for epidemiological purposes. first, they do not provide enough unrelated parameters to obtain a good reflection of genotype. for example, serotyping of streptococcus pneumoniae discriminates among only a limited number of groups. in addition, some viruses, such as human cytomegalovirus and measles virus, cannot be divided into different types or subtypes by serology because significant antigenic differences do not exist. second, the expression of many genes is affected by spontaneous mutations, by environmental conditions, and by developmental programs or reversible phenotypic changes, such as high-frequency phenotypic switching. because of this, many of the properties measured by phenotypic methods tend to vary and, for the most part, have been replaced by genotypic methods. the one major exception is multilocus enzyme electrophoresis (mlee) (pasteur et al., ; richardson et al., ) , which is a robust phenotypic method that performs comparably with many of the most effective dna-based methods (pujol et al., ; tibayrenc et al., ) . characteristics of selected phenotypic methods are presented in table . . these methods have been characterized by typeability, the ability of the technique to assign an unambiguous result (i.e., type) to each isolate; reproducibility, the ability of a method to yield the same results on repeat testing of a bacterial strain; discriminatory power, the ability of the method to differentiate among epidemiologically unrelated isolates; ease of interpretation, the effort and experience required to obtain useful, reliable typing information using a particular method; and ease of performance, which reflects the cost of specialized reagents and equipment, technical complexity of the method, and the effort required to learn and implement the method. extremely sensitive and specific molecular techniques have recently been developed to facilitate epidemiological studies. our ability to use these molecular techniques (genotypic methods or proteomic methods for prions) to detect and characterize the genetic variability of infectious agents (bacteria, fungi, protozoa, viruses) is the foundation for most molecular epidemiological studies. the application of appropriate molecular techniques has been an aid in the surveillance of infectious agents and in determining sources of infection. the ability to link isolates to sources has direct implications for investigating both (coleman et al., ) . these molecular techniques can be used to study health and disease determinants in animal (including human) and in plant populations. molecular techniques may also be applied to clinical and environmental samples. it requires choosing a molecular method(s) that can discriminate genetic variants at different hierarchical levels, coupled with the selection of a region of nucleic acid, which is appropriate to the questions being asked (table . ). genotypic methods are those based on an analysis of the genetic structure of an organism. over the past decade, several genotypic methods have been used to fingerprint pathogenic microorganisms (table . ). the methods have been described in detail elsewhere (tenover et al., ; thompson et al., ; soll et al., ; pennington, ; arens, ; foley et al., ) . in general, molecular typing methods can be divided into three general categories: restriction endonucleaseebased methods, amplification-based methods, and sequencebased methods (foley et al., ). among these methods, restriction fragmentelength polymorphism/pulsed-field gel electrophoresis (rflp-pfge) and rflp þ probe and ribotyping have been the most commonly used methods for fingerprinting bacteria (soll et al., ; swaminathan et al., ) . random amplification of polymorphic dna (rapd) and karyotyping have been used for fingerprinting fungi (soll et al., ; soll, ) . mlee, rapd, and polymerase chain reaction (pcr)-rflp have been used for fingerprinting parasitic protozoa (soll et al., ) . multilocus variable number tandem repeat analysis (mlva) has been used to subtype b. anthracis, y. pestis, and francisella tularensis. mlva schemes are now available for most bioterrorism agents (van belkum, ) . single-nucleotide polymorphisms (snps) have been used to analyze strains of b. anthracis and several gram-negative foodborne pathogens (foley et al., ; keim et al., ). an assay used for scoring snps of b. anthracis has been shown to have highthroughput capability and can be performed with small amounts of dna (keim et al., ) . select gene or complete genome characterization, as well as other molecular methods, has been used for viruses (arens, ) . when should fingerprinting be used? strain typing data are most effective when they are collected, analyzed, and integrated into the results of an epidemiological investigation. the epidemiologist must collaborate with the laboratory scientist when investigating a potential outbreak of an infectious disease. microbial fingerprinting should supplement, and not replace, a carefully conducted epidemiological investigation. in some cases, typing data can effectively rule out an outbreak and thus avoid the need for an extensive epidemiological investigation. in other cases, these data may reveal the presence of outbreaks caused by more than one strain. data interpretation is facilitated greatly by an appreciation of the molecular basis of genetic variability of the organism being typed and the technical factors that can affect results. except for whole-genome sequencing (wgs), molecular methods analyze only a small portion of the organisms' genetic complement. thus, isolates that give identical results are classified as "indistinguishable," not "identical." theoretically, a more detailed analysis should uncover differences in the isolates that appeared to give identical patterns but that were unrelated epidemiologically. this is unlikely to occur when a set of epidemiologically linked isolates are analyzed (tenover et al., ) . for this reason, only wgs would provide unequivocal data required for attribution. the power of molecular techniques in epidemiological investigations can be exemplified by a few examples. pulsenet, the national molecular subtyping network for food-borne disease surveillance, was established by the cdc and several state health departments in to facilitate subtyping bacterial food-borne pathogens for epidemiological purposes. twenty-five years ago, most food-borne outbreaks were local problems that typically resulted from improper food-handling practices. outbreaks were often associated with individual restaurants or social events and often came to the attention of local public health officials through calls from affected persons. today, food-borne disease outbreaks commonly involve widely distributed food products that are contaminated before distribution, resulting in cases that are spread over several states or countries. the pulsenet restriction endonucleaseebased methods a. restriction fragmentelength polymorphism without hybridization -frequent cutter ( -to -bp recognition site) coupled with conventional electrophoresis to separate restriction fragments -infrequent cutter (generally -to -bp recognition site) coupled with pulsed-field gel electrophoresis to separate restriction fragments b. rflp with hybridization -frequent cutter ( -to -bp recognition site) coupled with conventional electrophoresis to separate restriction fragments followed by southern transfer to nylon membrane. power and efficacy of typing method depend on the probe. network, which began with laboratories typing a single pathogen (escherichia coli o : h ), achieved full national participation in and includes food safety laboratories of the us food and drug administration (fda) and the us department of agriculture. sister networks have also been established internationally (swaminathan et al., ; gerner-smidt et al., ) . currently, pulsenet usa utilizes standardized pfge protocols for six organisms with mvla as a complementary technique: e. coli o :h , salmonella enterica, shigella spp., thermotolerant campylobacter spp., clostridium perfringens, and vibrio cholerae (gerner-smidt et al., ) . the laboratories follow a standardized protocol using similar equipment so that results are highly reproducible and dna patterns generated at different laboratories can be compared. isolates are subtyped on a routine basis, and data are analyzed promptly at the local level. clusters can often be detected locally that would not have been identified by traditional epidemiological methods alone. pfge patterns are shared between participating laboratories electronically, which increases the ability to link apparently unrelated outbreaks and to identify a common vehicle (centers for disease control, ) . for example, in , pulsenet was critical to facilitating the identification of an s. mbandaka outbreak affecting persons in states in the united states (https://www.cdc.gov/ salmonella/mbandaka- - /index.html). starting in march , cdc and other public health and regulatory officials linked geographically dispersed s. mbandaka isolates from stool samples of symptomatic patients, which had the same pfge pattern. the initial epidemiological investigation revealed that many of the patients reported eating cold cereal, and the vehicle was subsequently identified as contaminated kellogg's honey smacks sweetened puff wheat cereal. additionally, environmental and product samples obtained by the fda at the contract production facility were positive for the outbreak strain of s. mbandaka. without molecular typing, epidemiologists would have found it difficult to identify cases associated with each state cluster and assign attribution to the source. however, the use of pfge subtyping as part of routine surveillance has benefits beyond outbreak detection. for example, the temporal clustering of unrelated cases is not uncommon, and without molecular typing, valuable public health resources would be wasted investigating pseudo or unrelated outbreaks. molecular genotyping of food-borne pathogens continues to evolve. pulsenet has transitioned to the use of wgs for listeria monocytogenes and is expanding wgs to other pathogens to improve the level of resolution. in the future, pulsenet will be evaluating metagenomic approaches and other strategies using nextgeneration sequencing (ngs) technology for direct characterization of patient samples as clinical practice embraces culture-free diagnostic methods. pulsenet remains a powerful tool that can be applied for the early detection of cluster(s) of illness that result from deliberate contamination of food (gerner-smidt et al., ) . another example of the power of molecular techniques is the invaluable information provided during the anthrax attacks. mlva was initially used to subtype isolates obtained from patients, environmental samples, and powders. information from mlva identified the subtype of b. anthracis and was able to link clinical cases to environmental samples and powders, thereby providing information on possible sources of exposure (hoffmaster et al., ) . molecular subtyping also confirmed that clinical cases were caused by the same strain and that suspected cases outside the united states were not linked (hoffmaster et al., ) . both forensic and epidemiological investigations can result in the collection of hundreds of clinical and environmental samples for testing. during this event, mlva assisted with the identification of potential laboratory contamination of samples because of the large number of samples requested to be tested (hoffmaster et al., ) . mlva can be used to reliably and rapidly genotype an isolate within h of receipt by the laboratory. molecular subtyping identified the b. anthracis used in the attack as the ames strain, a strain rarely found in nature (keim et al., ) . this information was a critical epidemiological factor in determining that these cases were most likely the result of a deliberate release (keim et al., ) . additionally, wgs of isolates obtained from spores indicated that the genome and plasmid sequences were identical to those of an ames strain stored at a us army research facility (fricke et al., ) . the utility of molecular typing methodologies was clearly demonstrated in this forensic investigation involving the deliberate release of a biological agent in the united states. in , the cdc was notified of two cases of brucellosis in microbiologists who worked in clinical laboratories in indiana and minnesota (centers for disease control, ). because brucella spp. are considered category b agents (khan et al., ) , infections with brucella spp. should have a thorough epidemiological investigation to determine potential sources of exposure. mlva was utilized to help identify the source of the brucella infections. the cdc compared blood culture isolates from the two microbiologists with the isolates they handled in the laboratory. the epidemiological investigation revealed that the clinical isolate from the infected microbiologist in indiana had been forwarded to the clinical laboratory in minnesota; however, investigation also revealed that the second microbiologist did not handle this clinical isolate (centers for disease control, control, ) . molecular genotyping provided critical confirmation of the source of exposure for these microbiologists and confirmed that these cases resulted from a laboratory exposure. a radical shift in molecular strain typing occurred with the development of technology that allowed for millions of sequencing reactions to be conducted simultaneously on multiple mixed biological specimens. this advancement in sequencing has been termed ngs (behjati and tarpey, ) . the ability to sequence the whole genome, screen mixed dna samples at the same time, detect minor alleles very accurately, and identify causes of disease of unknown etiology has improved the value of dna as evidence in forensic investigations. the throughput diagnostic capacity of ngs technology has the potential to increase the reach and the number of forensic investigations that can be conducted at low cost. ngs is already routinely applied in outbreak investigations to determine the potential source of outbreaks. for example, using dna sequencing, it was determined that the haitian cholera epidemic was associated with the introduction of a strain that was closely related to variant v. cholerae el tor o strains that had been previously isolated in bangladesh in and (chin et al., ) . the e. coli o :h outbreak in europe was epidemiologically linked to seed shipments from egypt that were sent to germany in (grad et al., ) . sequencing capacity was established in liberia during the ebola outbreak to monitor the evolution of the virus during this outbreak (kugelman et al., ) . the technological trend to make portable devices is fueling innovation toward portable ngs devices that are field deployable without the limitations on size, weight, supportive infrastructure, complex sample processing procedures, or need for calibration of sequencing . forensic public health: epidemiological and microbiological investigations for biosecurity machines by field engineers. for example, a pocket-sized, usb-powered sequencer (minion) developed by oxford nanopore was successfully used to rapidly sequence ebola virus at the field diagnostic laboratory in liberia during the ebola virus outbreak in west africa (hoenen et al., ) . advancements in the field of microfluidics also hold promise for the development of lab-on-a-chip systems with capacity to collect and analyze biological specimens on a miniature device. additional advances in molecular laboratory techniques have been used for the rapid detection of antimicrobial resistance. in one prospective study on methicillin-resistant staphylococcus aureus, automated clonal alerts based on real-time subtyping were faster than traditional methods (sintchenko and gallego, ). at present, however, the direct identification of resistance genes by pcr or similar methods is of limited use because only a few resistance genes are strongly associated with phenotypic resistance (jorgensen and ferraro, ) . pcr followed by electrospray ionization mass spectrometry has been used to detect quinolone resistance in acinetobacter spp. (hujer et al., ) . however, this technique must be further evaluated, and limitations must be acknowledged, such as whether detection of a resistance gene indicates that a resistant phenotype is always present (hujer et al., ) . the ability to establish antimicrobial susceptibility patterns rapidly is particularly critical for providing the appropriate antimicrobial agents for treatment or postexposure prophylaxis in a situation where the deliberate dissemination of a potentially engineered drug-resistant organism is being considered. because there are numerous mechanisms for antimicrobial resistance in bacteria, current phenotypic methods will likely continue to be the basis for laboratory determination of antimicrobial susceptibility patterns for the foreseeable future (jorgensen and ferraro, ). unfortunately, molecular genotyping information exists in multiple databases and in a variety of formats. although pulsenet and other systems have web-based access, integration and sharing of data among multiple databases remains a challenge. as information and databases expand, data will also become more challenging to analyze. therefore, there is a need to refine analytic methods including the use of artificial intelligence to improve pattern recognition and integration of multiple streams of epidemiologic and laboratory data so that outbreaks and bioterrorism events can be detected quickly. informatics capacity at local, state, and federal level requires continued investment to maximize the integration of epidemiology and laboratory information. finally, the threat of bioterrorism has initiated the development of mechanisms to quickly identify the presence of biological agents in the environment to rapidly initiate public health and medical response efforts. molecular technologies allow for the rapid identification of genetic material of biological agents from collection devices such as those used for outdoor and indoor air monitoring. public health, forensic, and laboratory assessments must be made based on material collected in a distinct area covered by the monitor or sensor. because these detectors or devices do not preserve the viability of the agent, the assessment cannot indicate that a live organism was released, that individuals were exposed, or that a deliberate release occurred. as a result, it is critical that information from public health and epidemiological investigations be considered when interpreting information from environmental monitors. public health must consider the limits of these new technologies, previous history of environmental detection of a biological agent in each area, and environmental sampling methods. as the recent institute of medicine report on "effectiveness of national bio-surveillance systems: biowatch and the public health system" indicated, the challenge is "understanding the clinical context in which disease detection and reporting occurs and the factors that shape the decision-making process for the state and local public health officials who must interpret the data" from these systems as well as that from traditional public health surveillance systems (institute of medicine and national research council of the national academies, ). with few exceptions, a careful epidemiological investigation will be required to determine whether an outbreak of infectious disease is due to the intentional (or unintentional) release of an agent or is naturally occurring. a number of molecular methods have been developed for subtyping microbes that complement the epidemiological investigation as well as identify related cases. for example, since the establishment of pulsenet, the routine use of molecular subtyping by pfge has improved both the sensitivity and the specificity of epidemiological investigation of food-borne outbreaks at the state and local level (hedberg and besser, ) and mvla was critical in identifying the origin of the anthrax attack. as current subtyping methodologies evolve, applications and uses in the public health response to deliberate releases of biologic agents must be considered and applied. what is next generation sequencing? update: outbreaks of shigella sonnei infection associated with eating fresh parsleydunited states and canada, julyeaugust, . mmwr morb. mortal. wkly. rep. , e . centers for disease control origin of the haitian cholera outbreak director of national intelligence statement for the record, worldwide threat assessment of the us intelligence community senate armed services committee fine-scale identification of the most likely source of a human plague infection. emerg. infect. dis. , e . department of defense gene editing using crispr.-cas : implications for dual-use and biosecurity genome editing: scientific opportunities, public interests and policy options in the european union an outbreak of pneumonic tularemia on martha's vineyard molecular typing methodologies for microbial source tracking and epidemiological investigations of gram-negative bacterial foodborne pathogens the role of genomics in the identification, prediction and prevention of biological threats genomic epidemiology of the escherichia coli o :h outbreaks in europe commentary: cluster evaluation, pulsenet, and public heath practice a national outbreak of salmonella enteritidis infections from ice cream airborne transmission of influenza a/h n virus between ferrets control of communicable diseases manual nanopore sequencing as a rapidly deployable ebola outbreak tool molecular subtyping of bacillus anthracis and the bioterrorism-associated anthrax outbreak, united states effectiveness of national biosurveillance systems: biowatch and the public health system anthrax bioterrorism investigation team. bioterrorism-related anthrax: the first cases reported in the united states antimicrobial susceptibility testing: a review of general principles and contemporary practices anthrax molecular epidemiology and forensics: using the appropriate marker for different evolutionary scales public health preparedness for biological terrorism in the usa the unacceptable risks of man-made pandemic how canadian researchers reconstituted an extinct poxvirus for $ , using mailorder dna a dictionary of epidemiology genome-editing technologies for gene and cell therapy phylogenetic analysis of human influenza a/h n viruses isolated in in germany indicates significant genetic divergence from vaccine strains gene therapy returns to centre stage construction of an infectious horsepox virus vaccine from chemically synthesized dna fragments host and viral traits predict zoonotic spillover from mammals electrophoretic typing parity among the randomly amplified polymorphic dna method, multilocus enzyme electrophoresis, and southern blot hybridization with the moderately repetitive dna probe ca for fingerprinting candida albicans monitoring of ebola virus makona evolution through establishment of advanced genomic capacity in liberia bacillus anthracis comparative genome analysis in support of the amerithrax investigation emerging infectious diseases methods for subtyping and molecular comparison of human viral genomes alloenzyme electrophoresis gain eof-function research: ethical analysis laboratory-guided detection of disease outbreaks: three generations of surveillance systems microbial threats to health: emergence, detection and response mail-order crispr kits allow absolutely anyone to hack dna the ins and outs of dna fingerprinting of infectious fungi laboratory procedures for the epidemiological analysis of microorganisms pulsenet: the molecular subtyping network for foodborne bacterial disease surveillance, united states how to select and interpret molecular strain typing methods for epidemiological studies of bacterial infections: a review for healthcare epidemiologists overview and significance of molecular methods: what role for molecular epidemiology? genetic characterization of six parasitic protozoa: parity between random primer dna typing and multilocus enzyme electrophoresis a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars tracing isolates of bacterial species by multilocus variable number of tandem repeat analysis (mlva) primary pneumonic plague contracted from a mountain lion carcass impact of climate change on human infectious diseases: empirical evidence, evidence and human adaptation progress in genome editing technology and its application in plants forensic public health: epidemiological and microbiological investigations for biosecurity we thank dr. nicki pesik for drafting this chapter for the second edition. key: cord- -b r authors: labrunda, michelle; amin, naushad title: the emerging threat of ebola date: - - journal: global health security doi: . / - - - - _ sha: doc_id: cord_uid: b r ebola is one of the deadliest infectious disease of the modern era. over % of those infected die. prior to , the disease was unknown. no one knows exactly where it came from, but it is postulated that a mutation in an animal virus allowed it to jump species and infect humans. in simultaneous outbreaks of ebola occurred in what is now south sudan and the democratic republic of the congo (drc). for years, only sporadic cases were seen, but in a new outbreak occurred killing hundreds in the drc. since that time the frequency of these outbreaks has been increasing. it is uncertain why this is occurring, but many associate it with increasing human encroachment into forested areas bringing people and animals into more intimate contact and increased mobility of previously remote population. this chapter will navigate ebola in the context of global health and security. there are multiple objectives of this chapter. first is to provide a basic understanding of ebola disease processes and outbreak patterns. second, is to explore the interplay between social determinants of health and ebola. the role of technology in spreading ebola outbreaks will be explained as will ebola’s potential as a bioweapon. readers will gain understanding of the link between environmental degradation and ebola outbreaks. this chapter will be divided into five main sections. these are ( ) a case study; ( ) ebola disease process; ( ) social determinants of health and ebola; ( ) ebola in the modern era, and ( ) the link between ebola and environmental degradation. who contracts ebola. the story will be told from her perspective. she will describe from her why she thinks the outbreak has occurred. her husband has died of ebola despite efforts of traditional healers. she will discuss burial rites in the context of her religious beliefs. the next section looks at the disease itself. the history, epidemiology, transmission, and signs/symptoms will be described. prevention measures including the use of personal protective equipment and vaccination strategies will be discussed. the basics of diagnosis and treatment will be covered. the section will end with a discussion of ebola epidemics. social determents of health play an important role in the epidemiology and transmission of ebola. factors impacting spread include, high population mobility, porous international borders, and ongoing conflict resulting in displaced populations. poverty, cultural beliefs and practices and prior ineffective public health messages have all played a role in the emergence of ebola. the following section will explore ebola in the era of technology. the role of air travel in disease spread and the effectiveness of airport screening measures will be discussed. ebola's potential for use in bioterrorism will also be discussed in this section. the relationship between environmental encroachment and disease emergence will be explored. global warming, and the impact of a growing population in ebola outbreaks will be explored. the chapter will end with a discussion of future directions. in this last section the important of international collaborations for disease prevention and public education programs will be discussed. sia waited nervously in the small one room house where she lives. she was waiting for her brother-in-law to return with the body of her dead husband, saa. he had died yesterday of the bush illness that was killing so many in her community, ebola the outsiders called it. just weeks ago, the world had seemed a different place. sia had sat with the other women of the kissi tribe at church joking and planning for the upcoming rice harvest. yes, they practiced christianity, but also followed the traditions of their ancestors. women in her village prayed to jesus and god, but also to their ancestors. outsiders sometimes questioned how the kissi could follow both christianity and their old traditions, but sia had never seen a problem. ancestors after all, were the ones who communicated with god. when someone in the family died, they were escorted to the realm of the ancestors where they were able to protect the living family and speak to god on their behalf. ancestors continued to live in the village, but in their new form. sia shivered thinking of what happened to those who died and were not escorted to the realm of the ancestors. ceremonies were usually performed by the brother of the deceased. if the ceremonies were not done properly, a loved one would become a wandering ghost instead of an ancestor. wandering ghosts torment the living bringing misfortune to everyone in the village, especially to the family that failed to perform the proper rights. sia did not like to think of such things, but there had been several deaths in a nearby village and she could not help but to wonder if it was the work of a wandering ghost. that was the day it started. saa was fine when he woke up, but while they were at the church, he started to get sick. he got sick so quickly that sia suggested that they return home early so he could rest. it wasn't a far walk, but by the time they arrived home, saa was having chills, headache, nausea, and said his joints hurt. while saa rested, sia prepared a tonic to ease the pain and ward off evil spirits. saa's eyes were red and he felt hot to touch. "a powerful spirit must be involved", sia thought to herself. she couldn't imagine who would have cursed her husband this way. he hadn't argued with anyone that she knew. for days sia cared for her husband with special food, potions, and prayers. she had even sacrificed a chicken, but instead of getting better he started vomiting and having diarrhea. obviously, she needed assistance from someone with greater influence in the spirit realm. kai, a local medicine-man of conservable powerful agreed to help but needed time to make the necessary preparations. by that evening saa had stopped eating altogether and his gums started to bleed. kai belonged to a secret society that added to his powers. sia was not allowed to attend kai's ceremony but was told that saa had cried blood and started to hiccough uncontrollably. kai was notable to defeat the evil spirits even with his most powerful incantations. some of the villagers wanted to take saa to a treatment center set up by some foreigners to see if they could help him. sia was hesitant, but by the next morning saa had developed a yellow color to his skin and was having black diarrhea, so she agreed. after a bunch of questions saa was taken into the camp that the foreigners set up, but they would not let sia or anyone else in the family enter. that was the last time she had seen saa alive. two days later sia was informed that saa had died. he was to be buried in a mass grave and no one was allowed to see his body. saa's brother said that he thinks the foreigners killed him. they weren't really there to help but part of a government plan to destroy the kissi. workers in the camp were removing the internal organs of the sick while they were still alive and selling them. that is why no one was allowed into the camp or to bury the bodies properly. they weren't just attacking the living, but also trying to destroy the ancestors by preventing the death ceremony from happening. luckily saa's brother knew people. it had cost everything that the family owned, but the man driving the truck full of bodies agreed to meet a short distance from the foreigners' camp. he would give them the body there, but there were not to tell anyone. as saa's brother walked into the house carrying saa's body, sia felt an overwhelming sense of relief. all the worry gave her a headache and made her feel weak. now that they had saa's body it will be better. they will do the rituals this evening and burry saa in the morning. he will be able to walk with the ancestors. one of the world's deadliest pathogen, the ebola virus made its first appearance in in not just one but two simultaneous outbreaks. the first of its deadly attacks were in what is now known as nzara, south sudan while the second occurred in a small village community near the ebola river bank in yambuku, democratic republic of congo (drc) [ ] . of the known to be infected, lost their lives. since that time, we have learned much about the ebola virus and the disease it causes. ebola virus is an uncommon virus which infects both human and non-human primates. it belongs to the family filoviridae, a negative stranded rna virus. when magnified, it appears as a filamentous structure fig. . the ebolavirus genus has six known species, zaire, sudan, tai forest (formerly côte d'ivoire ebolavirus), bundibugyo, reston, and the recently described bombali [ ] . reston is highly pathogenic for non-human primates and pigs, and bombali has been discovered in free-tailed bats as part of ongoing research to discover the ebola reservoir. the zaire species was responsible for the first ebola virus outbreak in and is considered to be the deadliest of the six [ ] . initially the disease caused by ebola virus was called ebola hemorrhagic fever, but later studies showed that the hemorrhagic manifestations were less common than initially thought and subsequently the name was changed to ebola virus disease (ebd). until , the ebola virus isolated sporadic outbreaks occurred only in central africa with counts numbering in the hundreds or less, and only lasting days to weeks. however, in march the who confirmed an epidemic of the zaire species of ebola virus emerging in west africa. this outbreak lasted years and grew to be one of the world's deadliest epidemics. there were , case and , fatalities documented by the world health organization (who). the index case of this epidemic is thought to be a -year-old child who became ill in late . the child eventually succumbed to the illness with symptoms of fever, chills, vomiting, and black-tarry stool [ ] . this was in guinea, west africa a country where ebola supposedly did not exist. from here it spread to liberia, sierra leone, nigeria, and mali. the natural reservoir of ebola virus is not known with certainty, although research has suggested that it may be bats. human infection may occur through direct contact with the mystery reservoir or through contact with infected primates. this can occur when hunting and preparing bush-meat or via contact with body fluids from an infected person. ebola is highly transmissible. the disease pattern of evd has shifted over the last years. currently, ebola has been found across central and west africa, with occasional exported cases to other regions. for obscure reasons, outbreaks seem to be occurring with increasing frequency. this may be linked to environmental degradation and increasing mobility of local populations. ebola spread is through contaminated body fluids. unfortunatly, traditional funerary practices across africa put funeral attendees in contact with body fluids from those who have died of ebola. initial international efforts to control ebola spread during outbreaks have often resulted in clashes and conflict as control measures confront tradition. inadequate public health messages, distrust of those providing the health messages, political instability, and regional conflict have allowed ebola to spread and kill thousands when early containment could have been within reach. ebola is one of the most fatal infectious diseases humans have encountered. even with the best medical care the disease is deadly. unfortunatly, the developing countries where evd occurs are not equipped with optimal medical or public health facilities. to complicate the situation further, survivors of evd are not hailed as heroes, but instead may be left with chronic illness and stigmatized in their communities. transmission of ebola disease is still being studied, but it is known that person-toperson contact is the most common form of spread. infection occurs primarily through direct contact with body fluids from infected people or animals (fig. ). viral antigens have been isolated from the skin of those infected suggesting that skin contact alone may be sufficient to spread disease [ ] . it has also been shown that, at least in primates, ebola can be spread through intramuscular injection, and inoculation can occur through contact of the conjunctiva or oral mucosa with infected body fluids [ ] . blood, vomitus, and feces are the body fluid most likely to spread infection because of the frequency with which they are encountered during the course of the illness, but other fluid such as urine, semen, vaginal fluid, tears, sweat, and breast milk also have potential for viral transmission [ , , , , , ] . caring for an infected person with ebola, whether at home or in the hospital has been identified as a high-risk activity for acquiring ebola. household members who provide direct care to an ebola victim are - times more likely to contract ebola than household members who share a residence but do not participate in patient care [ , ] . healthcare workers are also at high risk for acquiring ebola. one study found the risk of developing evd for healthcare workers to be times that of the general community during an outbreak of ebola in sierra leone [ ] . there are many factors contributing to the spread of ebola amongst healthcare workers. the presentation of ebola is non-specific so early on in the disease process it may be diagnosed as malaria, influenza, or other non-specific viral illness. if a patient is initially misdiagnosed, then proper protective measures to limit the spread of ebola will not be initiated. also, the use of personal protective equipment (ppe) including gloves and gowns for routine patient care is less common in developing countries than in more developed countries due to financial restriction. there is a risk of iatrogenic spread of ebola. in the initial outbreak of , health care workers reusing glass syringes and needles in a community clinic may have inadvertently caused spread of infection. the facility consisted of a -bed hospital and a busy outpatient center which treated between and , people per month. at the beginning of each day, nurses were given five syringes each which were reused after a warm water rinse. unfortunatly, this is where ebola made its first appearance. potentially hundreds were exposed from this clinic alone [ , ] . there have been many other instances where hospitals have turned into epicenters for ebola outbreaks [ , ] . early detection and isolation is key to preventing similar incidents in the future. the greatest risk of transmission of evd from human to human occurs when a patient is acutely ill. risk also corelates with severity of illness. the sicker a patient is the more infective she is. in early phase of acute illness, the viral load is relatively low, however it increases exponentially during the latter part of the acute illness, and high viral loads are associated with high mortality rates and infectivity [ ] . those who handle corpses of ebola victims after death also run considerable risk of acquiring the disease. many funerary customs in ebola-prone regions involve extensive physical contact with the dead body. despite the risk of transmission, many still engage in these traditional practices. without these preparations, some local traditions hold that misfortune will plague the living and the dead will not be able to pass into the spirit realm. family who do not engage in expected funerary practice may be viewed negatively in the communities where they live. one funeral ceremony alone has been linked to additional cases of ebola [ ] . transmissibility of ebola virus depends on the phase of infection of the ill-person. the viral load corresponds to the severity of illness [ ] . in other words, the sicker a person is, the higher concentration the concentration viral particles in the blood stream. as an ill person succumbs to ebola, they become more debilitated and require more care. at the same time, the viral load increases as the victim declines. because of this, family caring for the ill are more likely to be infected in the later stages and corpses of those killed by ebola are highly infectious [ ] . even after a person has recovered from ebola and no virus can be isolated from blood, it may still be found in other tissues and able to transmit disease. live virus has been isolated from breastmilk after recovery raising the issue of transmission to mother to infant [ ] . ebola has been isolated from semen up to months after onset of symptoms, in urine for days, sweat for days, aqueous humor of the eye for weeks, and in cerebral spinal fluid for months [ , , , , ] . there has been at least one case where a man who recovered from ebola transmitted the infection to a sexual partner days after his initial illness [ ] . to prevent sexual transmission of ebola, the who recommends systematic testing for ebola virus in semen. for the first months after infection, the semen of male ebola survivors should be assumed to be infectious. three months after the day symptoms started semen testing for ebola should be initiated. if the result is negative, then it should be repeated in week. if the test is positive, then it should be repeated monthly until a negative result is obtained. once two consecutive negative results have been obtained sexual activities can be resumed [ ] . vaginal secretions have been found to contain virus up to days after the initiation of symptoms, but no official testing recommendations exist for vaginal secretions [ , ] . other methods of ebola spread have been postulated, but do not appear to be significant sources of transmission. surfaces contaminated with body fluids produce a theoretical risk of transmission, but no confirmed documented cases of fomite transmission of ebola exist. ebola virus has been shown to persist in the environment supporting the need for close attention to decontamination of surfaces [ , ] . medical procedures can augment disease spread if proper precautions are not taken [ ] . hunting and capturing infected animals for bush meat or for trading in black market as exotic pets can result in exposure and transmission of ebola. there have been numerous instances of human infection resulting from contact with dead primates [ , ] . contact with wild primates, especially those found dead should be avoided to curb the risk of contracting ebola. there is another step in ebola transmission that continues to be elusive. humans and other primates can catch ebola from each other, but they are not the reservoir. the reservoir is not known with certainty, but there is some evidence linking bats to ebola [ ] . the evidence for bats as the ebola reservoir is suggestive but not compelling. antibodies against ebola have been found in bat species, but the significance of this is unclear. antibodies are formed when an organism has been exposed to an infectious organism. this is evidence of exposure and immune response, but not of long-term infection or viral shedding [ ] . only one small study has ever isolated ebola rna from bats [ ] . attempts to infect bats then isolate viral rna or shedding have not met with success [ , ] . as the systematic search for the reservoir continues, negative findings are as important as positive one. plants and arthropods have not been shown to harbor ebola [ , ] . ebola virus disease is an acute febrile illness that has been associated with hemorrhagic manifestations. it has an incubation period of - days, but presentation of symptoms is most common between day and after exposure [ ] . it is unclear whether or not infected people can transmit disease prior to developing symptoms, but those with symptoms should be assumed to be contagious. evd typically begins with abrupt onset of malaise, fever, and chills. it is also common to experience vomiting, headache, diarrhea, and loss of appetite early in the disease course. the diarrhea can be profuse and water losses of up to l per day have been reported [ ] . dehydration and hypovolemic can result. relative bradycardia can also be seen in ebola [ ] . a maculopapular rash commonly develops - days after onset of illness. the rash is not a consistent finding and seems to vary from region to region [ ] . hemorrhage is the most dramatic symptom associated with evd but is not as common as first feared. usually it manifests as gastrointestinal bleeding, but petechia, ecchymosis, bleeding oral mucosa can also be seen [ ] . bleeding is multifactorial and likely due to a combination of thrombocytopenia, coagulopathy from liver involvement, and in some instance disseminated intravascular coagulation (dic). evd can cause involve a number of different organ systems. neurologically, it can cause meningoencephalitis, confusion, chronic cognitive decline, and seizures. neurological symptoms typically occur - days after onset of illness [ , ] . cardiomyopathy and respiratory muscle fatigue have been described [ ] . eye involvement is also common early in the disease course and may persist. patients frequently report blurred vision, photophobia and blindness [ ] . laboratory findings during the course of the infection can include leukopenia, elevated renal profile, abnormal coagulation panel, thrombocytopenia, anemia, and elevated liver function tests [ ] . hiccoughs are common late in the acute phase of illness. symptoms typically abate after weeks of illness. even after the acute illness has resolved, ebola victims can have long term symptoms. these include fatigue, insomnia, headaches, myalgias, arthralgias, cognitive decline, and hair loss. uveitis and hearing loss are both common after recovery from evd [ , ] . even after the resolution of acute evd, new symptoms can develop. in a study looking at early clinical sequela, % of ebola survivors developed arthralgias, % ocular symptoms, % auditory symptoms, and % uveitis [ ] . studies evaluating the long -erm sequela of evd are ongoing. prevention strategies for ebola are numerous, but essentially boils down to avoiding all contact with skin and body fluids that could potentially harbor the ebola virus. of course, this is more easily said than done especially in health care settings, and for families of those infected. health care providers deal with rapidly changing conditions often in limited resource settings and are at high risk for contracting ebola if prevention protocols are not followed. families of ebola victims face similar, but even more daunting challenges. ebola may be found in secretions of those who have recovered for months or even years after the acute illness has resolved. while not common, cases of transmission have occurred months after a person has recovered. active ebola virus can persist in urine, vaginal secretions, breast milk, semen, ocular fluid, and cerebrospinal fluid even after recovery making prevention more challenging. while not heavily researched as an effective prevention strategy, people who eat bushmeat should be encouraged to take precautions to prevent ebola infection. this means avoiding contact with fluids from slaughtered animals as much as possible. ebola virus is inactivated by thorough cooking, so through cooking of bush meat should be encouraged [ ]. ebola is highly pathogenic and easily transmitted. both the who and the center for disease control (cdc) have published detailed guidelines on prevention which are freely available online [ , , ] . the who recommends the following key elements to prevent transmission of ebola virus in the hospital setting: • hand hygiene • gloves • facial protection (covering eyes, nose and mouth) • gowns (or overalls) • sharps safety • respiratory hygiene for both health care providers and patients • environmental cleaning • safe linen transport and cleaning • proper waste disposal • proper sanitation of patient care equipment ebola prevention requires attention to and special training in donning and removing personal protective equipment (ppe). specific instructions and videos for use of this equipment is available at the who prevention cdc websites. health care workers who use ppe equipment properly are safe from ebola infection, but can develop other health issues from the ppe itself. the ppe suits are hot, uncomfortable, and require constant surveillance to ensure that all the equipment remains in place and undamaged. areas prone to ebola outbreaks tend to be hot, humid, and lack resources for air conditioning, wearing ebola suits creates a risk for development of heat related illness and dehydration. the cdc has published guidelines for preventing heat related illness for those providing care to ebola patients in hot african climates [ ] . as previously mentioned, people have survived initial ebola infection may still be able to transmit the disease to others. with proper preventive measures the risk of transmission can be ameliorated. as with other aspects of ebola, both the cdc and who have published extensive guidelines available on their websites. for healthcare workers, no special precautions are needed for basic patient care. the cdc does recommend that additional ppe be used when caring for ebola survivors if contact with testes, urine, breast, breast milk, spinal fluid, or intraocular fluid is anticipated during patient care [ ] . in the home, additional precautions may be needed. cases of transmission through sexual contact and breast milk have been describe in the literature [ , ] . cdc guidelines recommend abstinence from sexual activity of all types including oral, anal, and vaginal. if abstinence is not possible then condoms and avoidance of contact with semen is recommended. the who has recommended that semen be tested months after the onset of disease in men. if the test is negative, then it should be repeated in week. after two negative test sexual activity can be resumed. if the test is positive, it should be repeated every month until a negative test is obtained. once a negative test occurs, it should be repeated in week, and after two negatives sexual activity can be resumed [ ] . maternity issues around ebola are complex. it is unclear when it is safe for a woman to become pregnant after recovering from ebola. some organizations have suggested that a woman wait a few months prior to becoming pregnant, but so far this recommendation has not been supported by clinical data. breastmilk can transmit ebola virus from a mother who has recovered from evd to her child. if feasible, breastfeeding should be avoided. the data on ebola transmission through breasting is limited, and resources in ebola-prone areas make repeat testing of breastmilk impractical. suggested strategies have recommended avoiding breasting feeding for months after recovery [ ] . travel restrictions may occur during ebola outbreaks. it is generally accepted practice that those who have potentially been exposed to ebola virus not travel for days after the last possible day of their exposure. as an alternative for those at low risk, close monitoring with no restrictions on travel may be done. balancing individual rights with community safety creates ethical and regulatory challenges in cases of potential exposure. additional information on monitoring and travel restriction can be found at both the cdc and who websites. vaccination development is in place, but there is currently no federal drug administration (fda) approved vaccination for ebola. currently, there are different clinical trials running with the goal of developing a safe and effective ebola vaccine [ ] . an investigational vaccine called rvsv-zebov is presently being used in drc under "compassionate use". this vaccine is specific for the zaire strain of ebolavirus. this same vaccine was previously administered to , volunteers during an outbreak in . so far, the vaccine appears safe with few side effects, but insufficient data is available for licensing [ ] . preliminary reports suggest an efficacy of %, but duration of protection is currently not known [ ] . even though there are no specific therapies to treat ebola, diagnosis is important to prevent spread and to ensure administration of appropriate supportive care and monitoring. anyone who has had any potential exposure to ebola in the last days should be evaluated if symptoms of ebola develop. while awaiting the result of ebola testing, appropriate infection control practices should be implemented. diagnosis is done by reverse-transcription polymerase chain reaction (rt-pcr). the test should be done days after the onset of symptoms [ ] . false negatives can occur if the lab is collected before h of symptom onset. a positive test confirms ebola virus disease and that the patient is infective. considering repeat testing in patients whose clinical picture is highly suspicious of ebd and have a negative initial test. ebola virus disease has a broad differential, and simultaneous testing for other illnesses should be undertaken as clinically warranted. this differential includes, malaria, lassa fever, typhoid fever, influenza, meningococcal meningitis (neisseria meningitidis), measles, crimean-congo hemorrhagic fever, yellow fever, marburg, and the familiar travelers' diarrhea among many others [ ] . supportive care is the only treatment for ebola. there are no antimicrobial agents proven to be effective in ebd. when possible, care should be provided at a facility familiar with the clinical progression of ebola. supportive care in ebola is no different than for any other critically ill patient. give intravenous fluids to prevent dehydration and shock. patients with ebola suffer from vomiting and diarrhea and may easily dehydrate. if intravenous fluids are unavailable or prohibitively expensive, oral hydration should be undertaken. ebola can lead not only to hypovolemic shock, but also septic shock [ ] so close patient monitoring is warranted. electrolytes will require close monitoring and should be repleted as needed. vasopressors may be required if blood pressure cannot be maintained. ebola can result in significant hematological abnormalities [ , ] . it can also lead to liver failure followed by coagulopathy [ ] . thrombocytopenia, leukopenia, and anemia are all common and treatment should be based on the specific abnormality encountered. other management may include antipyretics, respiratory support, analgesics, antimotility agents for diarrhea, antiemetics for nausea and vomiting, antibiotics, nutritional support and renal replacement therapy. these and other supportive measures must be tailored to the individual patient need. the first reported outbreak of ebola-like illness occurred in in sudan and zaire [ ] [now south sudan and the democratic republic of congo (drc)]. it is probable that sporadic outbreaks happened earlier but were not identified. outbreaks appear to be occurring more frequently than before. this is not only due to improved detection techniques, but also due to environmental encroachment, increasing population mobility, and changing weather patterns. the following section will summarize data on known ebola social determinants of health are the conditions in which a person lives and grows. there is no one list of these factors, but they are generally considered to include influences such as school, (un)employment, the community where one resides, food, and transportation. the factors are driven by forces outside of one's sphere of control such as poverty and war as well as some potentially self-directed choices such as belief system and friend circle. for example, social determinants of health are a way of describing why when a . magnitude earthquake hits haiti buildings collapse and people die and when a . magnitude earthquake and the same earthquake on guam causes no damage. social determinants of health significantly affected how ebola has impacted affected countries. poverty affects every aspect of life for most. according to world bank data, the rate of poverty in sub-sahara africa is trending downwards but is still over % of the population. poverty leads to lack of education, limited medical resources, poor nutrition, and crowded living conditions. people in poverty will eat a dead animal if they find one because it may be all they have to eat. they are unlikely to seek medical care outside of traditional healers because it is all they know and can afford. they may insist on washing the bodies of the dead because their only knowledge of science are traditions passed from generation to generation. all of which contributes to the spread of ebola. anyone who reads the history the countries that make up the peri-equatorial regional of africa will quickly notice that the region has suffered from nearly continuous war since even before the european occupation. there are pockets of stability in the region, but conflict is a way of life for many. conflict leads to destruction of infrastructure, fear, stress, distrust, and population displacement. currently, an ebola outbreak is occurring in drc. refugees from drc continually flee into neighboring countries, especially uganda. conflict driven human movement is a means by which ebola can be spread. no widespread outbreak of ebola has occurred in a refugee camp, but these types of settlements are fertile soil where an outbreak could start and flourish before an alarm is raised. the ugandan government is working with the international federation of the red cross and red crescent societies (ifrc), unicef, and the who collaborating to develop an ebola emergency preparedness plan [ ] . political and economic instability across have resulted in a debilitated medical and public health infrastructure. official data is limited, but media sources have reported that liberia has experienced a severe shortage of trained health workers within the country. media sources list general practitioners, public health specialists, pediatricians, surgeons, obstetrician-gynecologists, ophthalmologists, internists, dentists, psychiatrists, family medicine specialists, orthopedic surgeons, radiologists, pathologist, ear-nose-throat specialist, veterinarian, and dermatologist as comprising the entire formally trained health community (excluding nursing professionals) [ ] . the cia world factbook lists the number of physicians per people to be . for liberia, . for sierra leona, . for guinea, . in drc, and . in uganda [ ] . even some of these numbers are almost years-old making it difficult to assess the actual situation in the region. regardless, it is a safe conclusion that none of these countries are even close to having the recommended physician per residents recommended by the who. each of these countries is unique in the health care challenges it faces, and only are mentioned here because they have all been touched by ebola. infrastructure development is generally associated with improved health and decreased disease burden, but this is not always the case. while lack of infrastructure such as water and sanitation is thought to lead to increased transmission. increased connectivity via road and boat is thought to increase the risk of transmission through increased number of contacts [ ] . one of the most fascinating aspects of ebola occurs at the intersection of culture and public health. for generations, a mixture of traditional beliefs and mainstream religion has served as a cultural foundation in many tribal areas across central and western africa. funerary practices in these tribes are some of the most important in their belief system. it is these practices that have been exploited by the ebola virus allowing it to spread. exposure has been associated with attendance of funerals and contact with dead bodies in multiple countries [ , , ] . as public health and medical personnel tried to curb ebola spread, conflict has occurred. those most at risk for ebola suddenly felt threatened not only by the disease itself, but also by those where were trying to help as their core beliefs were suddenly targeted. from the perspective of the health care workers trying to save lives, the cultural beliefs were generally considered as just another barrier to be surmounted. this lack of understanding between those at risk and the health care workers lead to conflict, distrust, which at times drove ebola victims into hiding rather than seeking care. bribes were made, bodies were stolen, aid workers were attacked, and ebola spread. some of the cultural beliefs common in central and western africa will be discussed here with the goal of fostering cultural understanding of disease. given the diversity of human beliefs, it is likely that future events will again put disease control against traditional beliefs. a good starting point in cultural sensitivity is viewing an idea from the point-ofview of the other party. in the case of ebola, it is important to understand what different groups of people believe to be the etiology of disease. most educated health professionals view disease as an understandable biological process. infections are caused by microbes. in the case of ebola, it is a filovirus. in many traditional african cultures, disease is believed to be due to witchcraft [ ] . consultation with traditional healers is a common practice across africa. in many regions traditional healers are the only locally available medical provider. even if modern medical facilities exist, many will turn to the traditional healers first because they are more trusted, and their beliefs tend to align more closely with those of the community. there are many different traditional healing practices, sometimes traditions are passed down through generations in specific families. one description of a traditional medical ceremony in sudan describes a medicine man and his assistants. first, ritualistic dance and chants are performed. next the medicine man shows his spiritual power by having a large rock placed on his abdomen and broken by an ax while he remains still. once his strength has been established, his attention can be turned to his patient. the medicine man's diagnosis is mental illness caused by evil ancestors who have returned with the purpose of tormenting the patient. incantations are the treatment [ ] . beliefs and practices such as this are common in rural central africa. in these societies, illness is viewed as a disruption in the relationship between god, ancestors, and the person affected. witchcraft, sorcery, angry ancestors, and evil spirits may all be at the root of disease and a powerful medicine man can restore the proper balance in these relationships thus curing disease [ , ] . the individual customs and beliefs associated with the cause and treatment of disease is too long to be included here, but those interested in additional information should read the articles cited in this section for additional details. traditional healers can be a great asset to a community, but there have been unfortunate instances where they actually promoted the spread of ebola. some traditional healers claimed to be able to cure ebola. unfortunatly, their attempts at cure have been known to spread the disease to those in attendance of curative ceremonies as well as to themselves [ ] . traditional healers can also charge a significant amount of money putting a family who is already dealing with the loss of a loved one in additional financial stress [ ] . not all traditional healers seek the good of the community but instead are motivated by personal gain. many societies in central africa practice religious beliefs based on a combination of mainstream religion and ancestor worship. occult ceremonies, secret societies, and rituals are common, and the details of these practices are often covert, only known to a small subpopulation. the ceremonies may be benign such as the one described in the preceding paragraph or may involve animal or human sacrifice [ , ] . while many of these practices involve sacrifice and exposure to blood no studies have been published linking these activities to ebola transmission. it is the traditional funerary practices that have been most closely associated with the spread of ebola. many central and western african cultures view the death ceremony as one of the most important. when people die, they must be guided to the realm of the ancestors. from this realm, ancestors are able to hear the requests and see the needs of the living family and communicate these needs to god. the living family prays directly to the ancestors. if death rights are not done correctly then instead of becoming an ancestor, the deceased may become an angry ghost which torments the family [ ] . a common funerary practice in liberia is for an elder family member to bathe the body of the deceased. it is common for mourners to touch the face and kiss the forehead of the deceased. in some traditions the spouse of the deceased continues to share a bed with the corpse until the time of burial. another tradition involves dance. on the night prior to the funeral, men dance with the dead body while women wail. several traditions involve sacrifice and exposure to the blood of a bull as part of their ceremony [ ] . to prevent the spread of disease the governments in liberia and guinea passed laws requiring safe burial teams or cremation when the number of grave sites was insufficient for the number of bodies. numerous reports of bribing health workers responsible for collecting and properly disposing of the bodies allowed ebola to persist in this region [ ] . people stopped going to the health care facilities, and families would try to hide the cause of death from officials. at the height of the epidemic in sierra leone, the number of ebola care beds was insufficient for the number of patients. many were transferred from facility to facility and their families were not notified. rumors began to spread that the ebola facilities were harvesting organs and killing people [ ] . poor communication resulted in suspicion and distrust. it took thousands of deaths, but finally both sides began to compromise. the government and health care workers started to work with local religious leaders and traditional healers to find solutions that would let the people honor the dead without exposing themselves. many muslim leaders told their followers to abstain from washing bodies until the outbreak ended. bodies were buried with families nearby and although the could not touch the bodies prayers could be said. burial teams started to dress corpses in clothing requested by the family and often placed requested jewelry. once all sides compromised and started working together the epidemic was able to be contained [ ] . even if someone survives ebola the battle is not over. there is poor understanding of disease and disease transmission. survivors may be ostracized and shunned by their communities because there is fear that they can spread disease. survivors have had their houses burned, families attacked, and lost their jobs due to irrational community fear. during the west african ebola outbreak survivors were issued certificates stating that they were no longer contagious in an attempt to combat social stigma. this is not to say that it is all gloom-and-doom in countries that have experienced ebola outbreaks. social determinants of health are not isolated static elements. technology and globalization are bringing health improvements at an unprecedented rate. if one reviews data for the countries where significant ebola outbreaks have occurred, guinea, uganda, drc, south sudan, and liberia. all of these countries have had a decrease in infant mortality rates, decrease in maternal mortality rates, and extreme poverty rate have been steadily dropping over the last years despite the presence of ebola [ ] . anyone interested in additional information on measurable global trends, whether they be economic, or health based is encouraged to visit gapminder (www.gapminder.org). not every country that faces ebola descends into a public health crisis. in july multiple cases of evd were diagnosed in lagos, nigeria. lagos is a densely populated city and the capital of nigeria. the nigerian ministry of health was able to rapidly contain the situation before a full-scale epidemic began. the nigerian government had access to trained health care providers able to do contact tracing, able to mobilize a rapid efficient response, and worked closely in cooperation with the who to implement standardized epidemiologic practices. the epidemic in nigeria was halted before it was able to start [ ] . ebola in the technology era the concept of quarantine was first developed in the fourteenth century to control the spread of plague [ ] . quarantine is a required separation of incoming people or animals prior to mixing with the local population with the goal of preventing the spread of disease. it is one of the oldest and most effective public health measures, but very unpopular with those whose movements are restricted by quarantine. recently, kaci hickcox, a nurse volunteering in sierra leone returned to the us. she possibly had been exposed to the ebola virus. ms. hickcox was placed on a mandatory home quarantine of days, but she defied the quarantine order and proceeded with her day-to-day activities [ ] . in reality, she was at very low risk for developing the disease, and there was essentially no risk for widespread ebola transmission in the us, but her unwillingness to comply with the quarantine brought attention to many public issues surrounding quarantine. specifically, the conflict between individual civil liberty and the well-being of the general public [ ] . since when quarantine laws were first written technology has expanded drastically. surely there exists a technology that allows us to abolish the antiquated quarantine system. whether an intentional act of terrorism or through accidental contagion spread, travelers pose a significant threat to homeland security. various measures have been attempted to try and identify sick travelers with the goal of limiting epidemic spread. the following is a discussion of currently available boarder control measures aimed at preventing the spread of disease, and evaluation of the effectiveness of these measures, and a discussion of technologies that may be of utility in the future in preventing cross-border ebola spread. two-point-five million people fly in or out of the united states every day [ ] and an estimated one-million more per day cross via land and sea [ ] . with millions of border crossings daily, transmission of communicable disease between remote locations is inevitable. the vast majority of communicable diseases spread by travelers are upper respiratory viruses such as the common cold or influenza. generally, these are self-limited illnesses with few long-term consequences. every few years though, something new with greater lethality emerges and threatens the security of the us travelers, their contacts, and the broader population at home. ebola, severe acute respiratory syndrome (sars), and even the relatively benign zika virus have made media headlines with travelers seen as potential harbingers of disease. another factor that must be taken into account is the increasing population density and urbanization. the united nations (un) predicts that % of all people will live in cities by the year [ ] . a megacity is defined as an urban population of over ten million people. the first to reach megacity status was new york city in the 's [ ] . by , the megacity count rose to [ ] . large numbers of people in a small area constitute a vulnerability when looking at epidemic risk assessment. a single ill traveler arriving to a megacity has the potential to start a local chain of infection that could rapidly spread to millions. with the widespread availability and affordability of trains, planes, automobiles, buses, and boats it is easy for microbes as well as humans to travel rapidly across the globe. travel provides individual freedom for pleasure and commerce but, at the expense of national security. small disease outbreaks are continually occurring across the globe. multiple international monitoring systems are in effect and the center for disease control (cdc) has issued official recommendations for travel restrictions for persons with higher-risk exposure to communicable diseases of public health concern [ ] . briefly, these guidelines state that a person who meets the following criteria will have their travel restricted [ ] : be known or likely infectious with, or exposed to, a communicable disease that poses a public health threat and meet one of the following three criteria: . be unaware of diagnosis, noncompliant with public health recommendations, or unable to be located. or . be at risk for traveling on a commercial flight, or internationally by any means. or . travel restrictions are warranted to respond effectively to a communicable disease outbreak or to enforce a federal or local public health order. while the above criteria may be the best legally available option, it leaves a multitude of holes by which a person with a communicable illness could slip into a us city and start a new epidemic. ideally, additional layers of protection would allow potentially ill travelers to be identified and detained prior to entry to the united states. an infectious agent can travel across the globe in h if spread via airplanes [ ] . this has important implications for those trying to prevent disease from spreading. land and boat entry into the united states present other challenges. the sheer number of people crossing by land on a daily basis makes any screening difficult. boat traffic can also present unique screening challenges. a cruise boat, for example, may arrive with thousands of people who all debark within a short period of time. though screens are impractical in these situations. even if screening technology was employed allowing security agents to detect fever there are so many causes of fever that timely interpretation of the data would be difficult. with so much international travel occurring, there is a continual search for ways to improve screening for ill travelers with the goal of preventing importation of disease. many different methods have been tried, most centered around a specific pandemic rather than continual monitoring. none have had great success. these methods have included entry-screens, exit-screens, and post-entry monitoring. the us division of quarantine is not only authorized, but required to identify and detain anyone entering the country with actual or suspected diphtheria, any viral hemorrhagic fever including ebola, cholera, tuberculosis, small pox, plague, novel influenza strains or yellow fever [ , , ] . in theory, this is an excellent regulation, but how can millions of travelers be efficiently screened and detained if needed? after the outbreak of sars in many countries starting using boarder screening to try to identify possibly ill people in hopes of limiting spread of infectious disease, others jumped on board after the h n influenza pandemic. the issue then resurged in the wake of the ebola outbreak in west africa. as with many things, there must be an understanding of the costs, potential benefits and effectiveness of programs aimed at preventing a possible public health disaster. an article by the cdc, published around the same time as the article recommending travel restriction for high-risk individuals, concludes that border screens are expensive and not effective in preventing the spread of disease [ ] . while point-of-care screens are not yet considered an effective means of controlling certain biosecurity threats, progress is being made. temperature screens have been developed with the goal of identifying people with fever. what happens when a fever is detected depends on where a person is traveling to and from, and the current state of outbreaks occurring in the world. there are several types of temperature readers including ear gun thermometers, full body infrared scanners, and hand-held infrared thermometers [ ] . none of these methods is highly effective and most screening devices can be fooled with minimal training and effort. once study found that thermal screens were only about % effective in detecting fever. the authors of this study concluded that temperature screens were ineffective in identifying ill travelers [ ] . the european center for disease control (ecdc) has also investigated the feasibility of using temperature screens to identify ill travelers and came to similar conclusions. this report was done during the ebola of and geared towards diagnosing travelers potentially infected with ebola. they estimate that even under ideal conditions % of symptomatic illness would be missed due to low sensitive of temperature devices [ ] . additionally, it was concluded that those intentionally trying to mask their temperature could easily do so and that those who had not developed symptoms would be missed by the screen. even if fevers screens were accurate and difficult to manipulate that would still be a poor screening measure. first of all, with many illnesses including chicken pox, flu, the common cold and countless others, people can be contagious before a fever starts. it is not yet known if an infected person can spread ebola before symptoms begin. secondly, not all fevers indicate an infectious disease. fevers can be due to drug reactions, blood clots, and even cancer. third, not everyone reacts to an infection the same way. some people naturally tend to have fever and others tend not to. one expression commonly taught in medical schools across the us is, "the older the colder". this is a reminder to students that elderly patients may never have a fever even if they are extremely ill with an infectious disease. lastly, what determines what constitutes a fever? the medical field defines fever as a temperature of degrees celsius ( . f) or higher. are these same numbers valid for travelers or should different cut offs be used? while temperature screens may have their place in emergency settings, they are far from an ideal way of detecting an ill passenger and the day to day use of temperature screens is not generally considered an effective means of identifying ill travelers. when foreign agencies are cooperative screening may be done prior to departure. exit screening was done during the ebola outbreak of for travels from west africa to the united states. the goal of exit screening is to identify those potentially infected with a specific disease and prevent them from departing for the united states until they can be medically cleared. the cdc considers this to be one of the more effective forms of preventing disease importation to the united states [ ] . departure screens are not routinely used except during times of known outbreaks. during the west african ebola outbreak exit screening measures were implemented. the general process used for screening during the outbreak was as follows. travelers were instructed to arrive earlier than they normally would for their travel due to increased processing times. general instructions to travelers instructed them to postpone travel if they were ill. in addition to the regular airport screening, all travelers were required to have their temperature taken and fill out a "traveler public health declaration". travelers who were febrile or considered at risk based on the answers to their health declaration forms were detained and their travel delayed [ ] . during the ebola outbreak the who provided resources for predeparture screening that were detailed yet used easy-to-follow language and including flow charts for those performing the screen. basic information on ebola and its symptoms so that the illness was more well understood and the disease symptoms familiar. directions for using personal protective equipment for those performing the screening. written tools and the public health declaration form were provided. additional resources included a data collection log and a traveler information card that could be distributed to travelers [ ] . the ebola screening was done in two steps, a primary screen and a secondary screen. the primary screen included three questions: ( ) is the traveler febrile?; ( ) is the traveler demonstrating symptoms of ebola?; and ( ) has the traveler marked "yes" to any questions on the health declaration form? an affirmative response to any of these questions resulted in secondary screening. secondary screening involved a public health interview and filling of the secondary health screen form, repeat temperature measurement preferably with an accurate thermometer, and focused medical exam. if the secondary screen found a temperature < . , no risk factors for ebola in the public health interview, and no symptoms of ebola on the public health interview they were allowed to proceed to check-in. if the above criteria were not met, check-in was denied until health clearance could be obtained [ ] . this strategy was considered effective. the limitations include the time and money required to implement the program, frustrating travel delays for travelers, and the inability to identify illnesses other than ebola or similar diseases. its usefulness is limited to known and identified epidemics. this strategy will likely continue to be used in future outbreaks to prevent exportation of disease [ ] . temperature screens have been used during five epidemics to date, dengue, sars, ebola, and influenza during both the entry and exit process. screening for fever in taiwan entry points during a dengue outbreak was reported to be effective. one research study reports that % of imported dengue cases were able to be identified through airport screening [ ] . during the sars outbreak, singapore entry points screened , people and identified no cases, canada entry points screened . million people and identified no cases, and hong kong entry points screened . million people identifying only two cases of sars [ ] . fever screening was used during the - influenza pandemic and even with a low threshold for defining fever was found to have a sensitivity in the . % range. exit screening done in west africa during the ebola outbreak identified fever in out of , travels screened. of these, none had ebola [ ] ). active monitoring is another technique that can be used in preventing disease spread within ebola naive countries such as the united states. it involves allowing a traveler freedom to come into the us, freedom from quarantine, but also allows health authorities to monitor the health status of potentially infected people. if someone begins to develop symptoms then measures can be taken to isolate, diagnose, and treat the ill person. this method is best applied to those who are reliable and at low risk for developing illness. there has not been much experience with widespread use of active monitoring systems with the exception of the western africa ebola outbreak. during this outbreak, travelers from liberia, sierra leone, and guinea to the us were given care (check and report ebola) kits upon arrival to the us [ ] . care kits provided resources to travelers from ebola affected countries. travelers were given information on the signs and symptoms of ebola, educated on the basic pathophysiology of ebola, provided a thermometer with detailed use instructions and given a cell phone to ease the communication process. travelers were allowed to travel freely but were required to check in with public health officials daily. during these check-ins, Àhealth reports were given including the development of any new symptoms, and daily temperature readings for days. ebola has a highly variable incubation period. twenty-one days was the longest interval between exposure and disease presentation to have been reported accounting for its use in both care packages and quarantine [ ] . while the cdc coordinated active monitoring programs, the programs were managed at the state level. all states eventually participated, but with varying start dates. new york, pennsylvania, maryland, virginia, new jersey, and georgia were those to first initiate the program. seventy percent of travelers from west africa enter through these states making them logical starting points for the program [ ] . after much legal debate and unwanted publicity, ms. hickcox mentioned in the introduction, eventually went into active monitoring program which restored most of her personal freedoms while at the same time protecting public interests. currently available technology is considered insufficient to prevent entry of ill individual into ebola naive countries. the general public continues to demand protection of civil liberties that include the freedom to travel and protection of privacy. despite recommendations by the cdc, it is difficult to identify an ill traveler either before a person embarks for the us or at the point-of-entry. post entry monitoring of reliably low risk travels is a socially acceptable alternative to quarantine and considered reliable although not widely tested. screening technologies such as infrared screens may not be considered useful on a daily use basis but may prove of utility under certain circumstances such as an active ebola outbreak. as research continues, technology advances, and better models to study patterns of disease spread are developed, new methods of pointof-entry biosecurity are sure to emerge. bioterrorism is the intentional spread of disease with the goal of destabilizing an opposing group. it is thought to have roots extending back to at least bce when the hittites used infected sheep to spread infection and destabilize their opponents [ ] . since that time, technology has improved and along with it the threat of bioterrorism has augmented. the center for disease control (cdc) divides bioterrorism agents into three separate categories a, b, and c. category a agents are those which are considered to be of highest risk. characteristics group a pathogens are, easy transmission, high mortality rate, protentional for social disruption, and require special action. category b agents are of concern, but considered to have a lower potential for disease than those in group a. this category is comprised of pathogens that are moderately easy to spread, have moderate morbidity, low mortality and require specific diagnostic and surveillance tools. group c are agents of some concern. this group is made of pathogens that are easily available, easy to produce and disseminate, and potentially have significant medical and public health implications. emerging infections also fall within group c pathogens. ebola is considered to be a high threat level a biothreat [ ] . bioweapons are at least as large a threat to homeland security as are traditional weapons. biological weapons are attractive to potential terrorists because they are relatively inexpensive to manufacture, easy to encounter, and easy to distribute [ ] . in the biological weapons convention went into effect. it has been signed by countries and prohibits the development of biological agents for the purpose of warfare. unfortunatly, terrorists fail to abide by this convention, and it is rumored that even some of the countries that signed the convention document continue to engage in clandestine research into biological agents for warfare. characteristics of a pathogen with bioterrorism potential are those with consistent disease induction and progression, high infectivity, are easily transmissible between people, are difficult to diagnose, and have a high mortality rate [ ] . it is also important that the pathogen be stable during production, storage, and distribution [ ] . lack of immunity in the targeted population and diseases that are difficult to diagnoses are also attractive to would-be terrorists. ebola possesses many of these characterizes. ebola possesses many features of an ideal bioterrorism weapon. in the early stages, ebola presents as an acute viral illness. by the time clinical features unique to ebola infection have developed, it is likely that the illness will already have be transmitted to others. particularly vulnerable are those caring for infected patients including family members and health care workers. despite being limited to transmission through body fluids, ebola is highly contagious. ebola has a high mortally rate and is attractive to terrorists because there is already widespread fear associated with ebola infection. reston virus, a non-human pathogen in the ebola family, can be transmitted. there is concern that with genetic manipulation evd could be transformed into an airborne illness and distributed as a bioterrorism weapon [ ] . ebola is one of the many pathogens that could potentially be converted into a biological weapon. preparedness plans at the local, state, and national level all include sections applicable to ebola. all hospitals in the nation have received training on ebola identification and response. continued vigilance and repetitive training sessions are required to ensure that should ebola be used as a biological weapon, it will be rapidly identified and contained. ebola virus is an agent that could be used as a bioterrorism agent. it is deadly, can result in long term infection in survivors, and non-specific clinical presentation make it an attractive choice for would be terrorists. also, for many people, the word ebola creates fear out of proportion to the actual risk of disease. this visceral reaction and exaggerated fear make ebola a tempting agent. on the other hand, the lack of airborne spread and existence of effective vaccine (even if not licensed) are deterrents to its use. it is impossible to know with certainty when the first ebola infection occurred. most likely it was in a remote african jungle and those infected died without a diagnosis other than that provided by the local traditional healer. what can be said with certainty is that the outbreaks are occurring with more frequency. no one knows with certainty why this is. hypothesis tend to center around issues of environmental degradation in association with increased population mobility. increasing population, global warming, and continued human encroachment into forested areas have been put forth as potential contributing factors. increasing population is theorized to be contributing to the increasing frequency of ebola outbreaks. increasing populations, particularly in developing countries, tend to lead to congesting living conditions and rapid disease spread, but this would not explain how the index case in an outbreak becomes infected. experts opinion often lists expanding population as contributing to the ebola outbreak, and intuitively it is credible, but there is little in the way of direct evidence to support this theory. literally hundreds of studies have been conducted on ebola since the outbreak, but none directly addresses the relationship between population growth in africa and increasing frequency of ebola outbreaks. it is likely that the impact of increasing human populations in endemic areas will not be fully understood until the reservoir of ebola has been determined. what we can say with certainty is that once started, ebola spreads more quickly than it did in the past and is killing more people. population level research on ebola has yielded interesting results. for a start, risk of ebola infection has been associated with a higher level of education [ , ] . lower risk for acquisition of ebola at the population level has been associated with urban residence, households with no or low-quality sanitary system, and married men in blue-collar professions in the outbreak in west africa [ ] . other studies have found different results when examining the interplay between population dynamics and the emergence of ebola. for example, in contrast to the study by levy & odoi, ebola transmission has been positively correlated with population density, and proximity to ebola treatment centers in other investigations [ ] . another study found that . % of people who tested positive for ebola cases lived within a -km of roads connecting rural towns and densely populated cities [ ] . basic public health principles hold that increasing population density allows infectious disease to spread more quickly, but it is unclear what the impact is on the emergence of ebola. it is safe that there is a relationship between population density, population distribution, and ebola but the exact nature of that relationship remains elusive. climate change has been cited by mass media sources as the source of emerging disease such as ebola. elevated atmospheric temperature have been associated with the development of evd, but then so have low temperatures [ ] . there does appear to be a relationship between ebola and temperature, but the character of that relationship is not clear. ebola virus is sensitive to high temperatures so intuitively, higher temperatures would not create a more active form of the virus. what may change is the human response to higher temperatures. when it is hot, people sweat more, drink more, and may wear different clothing. it may be that the human response to hot weather is responsible for the noted difference rather than changes in viral activity. it is also possible that temperature changes correlate with other phenomena such as rain storms and that rain, or the response of vegetation to rain somehow impacts the emergence of ebola. climate change, whether due to human activities or natural climatic cycles will change patterns of disease across the globe. how changing weather patterns may affect the distribution and frequency of ebola cases remains to be seen. possibly once the reservoir of ebola virus has been discovered scientists can predict with greater certainty how climate change will impact the emergence of ebola. it is also postulated that ebola is occurring with greater frequency due to increasing human activities within previously untouched natural areas. at least one study has linked deforestation to evd outbreaks [ ] . again, there are limited studies confirming this idea, but logic does suggest that it would be true. expert opinion, and the mass media purport that the increasing frequent outbreaks of ebola are due to environmental encroachment [ ] . as roads are build, forests are cut, and mineral resources exploited humans are in more intimate contact with the forest and its inhabitants including the reservoir for ebola. the reservoir is unknown, but it is probably found in african jungles. a study looking at vegetation cover, population density and incidence of ebola found that vegetation was protective until the population reached people per square km. at this population density vegetation became associated with and increase incidence of evd [ ] . there is a relationship between environmental encroachment and the emergence of ebola, but until the reservoir is found it will be difficult to determine the exact nature of this relationship. the frequency of ebola outbreaks has been increasing. international collaboration is essential to better understand how and why this is occurring. traditional tribal regions do not always follow country lines and both official and unofficial border crossing are common. contact tracing is essential for containment of ebola outbreaks requires countries to coordinate as people cross borders. epidemiological evaluation and experience in treating the disease also require a global rather than country approach. the study of ebola requires systematic evaluation and intercountry coordination to most effectively predict outbreaks and limit their spread once they do occur. the global community would also benefit from international standards for diagnosis, prevention, and treatment. luckily, framework already exists for this collaboration, at least in times of epidemics with pandemic potential. the international health regulations (ihr) agreement is legally binding accord signed by countries. it stipulated that these countries must act to contain the threat if a public health emergency of international concern (pheic) is declared by the who director general. a pheic was declared in august in response to the ebola outbreak in west africa [ ] . the ihr helps to ensure that an appropriate global health response will be made once a public health disaster is well underway. intervention at this level will help curb progression of the disaster. along this same line of thinking, mitigation and preparedness efforts are needed prior to development of a public health disaster. if a pheic is declared, then local measures have failed. improved regional collaboration is needed to help minimize the impact of ebola in the region. many countries at risk for outbreaks of evd would benefit from bolstering of their public health and medical programs. outside assistance is a starting point, but capacity building is required for long term solutions. in countries with weak public health infrastructure international efforts need to focus on programs to develop a sustainable public health system. the challenges are considerable particularly in areas of chronic conflict, but progress has already been made and with continued support will continue into the future. a basic public health infrastructure will help contain ebola as well as whatever threat comes next. when an ebola outbreak hits the general public needs to be educated on how to respond. if ebola preparedness is part of the local education, then lives can be saved. the public can help with surveillance efforts. this would require the population to trust the public health community, believe that their input is useful, and that they be trained to recognize potential ebola in the community. public health education can also assist with limiting spread if an outbreak does occur. this education can be provided through schools, community outreach campaigns, or religious institutions. the education does not 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nan as the world watches the rapid spread of the novel coronavirus ( -ncov) outbreak, it is important to reflect on the lessons that can be learned from this and previous emerging zoonotic viruses (ezv) in a comparative and analytic way. although the source of -ncov is yet to be confirmed, early findings suggest a high possibility of a bat origin. there have been six major ezv outbreaks in the past years caused by proven or suspected bat-borne viruses (table). [ ] [ ] [ ] [ ] [ ] [ ] with these in mind, four major points are worth considering in the context of the -ncov outbreak. first, are koch's postulates still relevant in the era of next-generation sequencing (ngs)? in the heat of the debate about the early response to the -ncov outbreak, insufficient attention was paid to how the initial aetiological evidence came from ngs analysis requested by clinicians. to our knowledge, all previous ezv outbreak investigations started with a live virus isolation, including the middle east respiratory syndrome coronavirus (mers-cov) discovery. the preliminary sequence data indicating the presence of a severe acute respiratory syndrome (sars)-related coronavirus in patients' lung lavage samples were obtained on dec , , by ngs. the chinese authorities ruled out sars and mers, as well as a few other non-coronaviruses, on jan , , and confirmed a novel coronavirus as a potential cause on jan , . however, the genome sequence-crucial for rapid development of diagnostics needed in an outbreak response-was not released until jan , , days after the preliminary sequence data were obtained. these events raise challenging questions. should a national response team report a highly suspected pathogen sequence before confirming an aetiological live agent? are current national and interna tional policies and regulations adequate to deal with a sequence-based outbreak reporting system? while they have evolved over time, the postulates formulated by robert koch and friedrich loeffler in included the isolation of a live agent as a key criterion. we believe that it is time to establish an ngs-based reporting system that can alert to the presence of a new aetiological agent(s) rather than requiring the isolation of aetiological agents. second, clinicians and scientists have a crucial role in responding to such ezv outbreaks. in past ezv outbreak investigations, clinicians have largely had supportive roles. this situation is likely to change now that more clinician scientists are better trained and have academic appointments, especially in china. in fact, it was the clinicians who led to the early detection of and warning about the -ncov outbreak in china. in investigating severe pneumonia cases of unknown cause, clinicians in two hospitals in wuhan independently sent lung lavage samples from patients for ngs analysis by commercial ngs companies. alarm bells rang, not only through the different levels of the official chinese center for disease control and prevention (china cdc) reporting system but also through social media traced back to eight doctors who were wrongly accused of spreading "fake news". these doctors were later cleared of any wrongdoing and praised by the government authorities for their brave action in early alerting. achieving the right balance between information sharing and scientific publication is important during an ezv outbreak response. this is not a new challenge but greatly amplified in the -ncov outbreak when anger in china was directed towards a few leading scientists who were alleged to have held back sharing data about the virus to publish their findings. these unsubstantiated allegations consumed media attention and created media panic that was counterproductive to the outbreak response. clear national and international guidelines are needed on how to achieve the right balance in the leadership provided by public health and research experts facing an outbreak of an ezv. third, a one health approach in ezv outbreak responses and control is vital. in august, , after who declared the end of the sars outbreak, it organised a special mission with international and chinese scientists to investigate the origin and early transmission events of sars-cov. among the eight international experts invited, seven were veterinarians or those working in animal health. by contrast, the six-member chinese team only had one participating veterinarian or animal scientist. while recognising the tremendous effort by the china cdc team in the early response to the -ncov outbreak, the small number of team members trained in animal health was probably one of the reasons for the delay in identifying an intermediate animal(s), which is likely to have caused the spread of the virus in a region of the market where wildlife animals were traded and subsequently found to be heavily contaminated. unfortunately, what animal(s) was involved in transmission remains unknown. there is an urgent need to know the risks associated with the presumed animal to human transmission of -ncov, and the measures that can be taken to prevent such transmission in the future. for example, should the sale of wild animals be restricted in chinese wet markets? we recommend that a comprehensive one health team be involved in all future ezv investigations. indeed, this approach has international implications, with risks of exotic zoonotic diseases associated with the huge quantities of illegal bush meat from central and west africa being imported into europe and north america. finally, naming of a new virus is important not only for virologists in the long term but also for effective communication to the general public. in all the major ezv events over the past years, naming of the new virus has not been straightforward and most went through a renaming process (table) . this is also true for the -ncov outbreak. there has been intensive discussion now among virologists worldwide about an alternative name for -ncov. to continue the tradition of using a syndrome, as in sars and mers, and to avoid the sensitivity of using a city name, we propose to name this new virus han acute respiratory syndrome coronavirus (hars-cov). han is the abbreviation of wuhan in chinese. such a name is, we believe, preferable to the names being used in media headlines, such as "wuhan virus" or "china virus", and it retains the historical fact that the outbreak started in wuhan. now is not a time for blame. rather, there are lessons the global health community can and should learn and act on so that we can better respond to the next ezv event, which is almost certain to happen again. these lessons are definitely not unique to china. programme in emerging infections diseases, duke-nus medical school singhealth duke-nus global health institute a pneumonia outbreak associated with a new coronavirus of probable bat origin a morbillivirus that caused fatal disease in horses and humans nipah virus: a recently emergent deadly paramyxovirus the severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia reflections on early investigations into the ebola virus a novel coronavirus outbreak of global health concern genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding causation and disease: a chronological journey. the thomas parran lecture praise for chinese doctors who coronavirus blew whistle. the australian detection of emerging zoonotic pathogens: an integrated one health approach screening for viral pathogens in african simian bushmeat seized at a french airport key: cord- -k po bzb authors: jean, k.; raad, h.; gaythorpe, k. a. m.; hamlet, a.; mueller, j. e.; hogan, d.; mengistu, t.; whitaker, h. j.; hocine, m. n. title: assessing the impact of preventive mass vaccination campaigns on yellow fever outbreaks in africa : a population-level self-controlled case-series study date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: k po bzb introduction: the eliminate yellow fever epidemics (eye) strategy was launched in in response to the resurgence of yellow fever in africa and the americas. the strategy relies on several vaccination activities, including preventive mass vaccination campaigns (pmvcs). however, by how much pmvcs decrease the risk of outbreak to occur has not yet been quantified. methods: we used the self-controlled case series (sccs) method to assess the association between the occurrence of yellow fever outbreaks and the implementation of pmvcs at the province level in the african endemic region. as all time-invariant confounders are implicitly controlled for, the sccs method is an alternative to classical cohort or case-control study designs when the risk of residual confounding is high. the location and dates of outbreaks were identified from international epidemiological records, and information on pmvcs was provided by coordinators of vaccination activities and international funders. the study sample consisted of provinces that were both affected by an outbreak and targeted for a pmvc between and . we compared the relative incidence of outbreaks before and after the implementation of a pmvc. the sensitivity of our estimates to a range of assumptions was explored, and the results of the sccs method were compared to those obtained through a retrospective cohort study design. we further derived the number of yellow fever outbreaks that have been prevented by pmvcs. results: the study sample consisted of african provinces. among these, outbreaks occurred during the pre-pmvc period in ( . %) provinces versus ( . %) occurring in the post-pmvc period. this corresponded to a significantly reduced incidence rate ratio of . ( % confidence interval . to . ) for the post-pmvc versus pre-pmvc period. this estimate was robust across a range of sensitivity analyses, while the results of the cohort-style analyses were highly sensitive to the choice of covariates included in the model. based on the sccs results, we estimated that pmvcs have reduced the number of outbreaks by % ( % to %) in africa over the study period. conclusion: our estimates provide new empirical evidence of the high preventive impact of pmvcs on yellow fever outbreaks. this study illustrates that the sccs method can be advantageously applied at the population level in order to evaluate a public health intervention. recent years have seen the resurgence of yellow fever outbreaks in africa and latin america. regarding africa specifically, five alerts have been issued for the first semester alone (uganda, south sudan, ethiopia, togo, gabon). as a response to the large-scale angola - outbreak, the world health organization (who) launched the eliminate yellow fever epidemics (eye) initiative in . this strategy aims at preventing sporadic cases sparking urban outbreaks and potentially triggering international spread. it relies on various vaccination activities, including preventive mass vaccination campaigns (pmvcs) that target all or most age groups in a specific area. evaluating the health impact of such campaigns is key to inform further pmvcs within or beyond the eye strategy, to ensure population acceptance and adherence to vaccination campaigns, and to sustain domestic and international efforts for vaccination activities. previous attempts were made in order to estimate the impact of vaccination activities, including pmvcs. [ ] [ ] [ ] these attempts mostly relied on mathematical models to estimate pmvcs impact in terms of deaths or cases prevented on the long term. however, few studies aimed at quantifying the effect of vaccination campaigns on the risk of outbreak. regardless of the number of cases they may generate, outbreaks can possibly lead to healthcare, economic and social destabilizations of entire regions. as an example, the west-african - ebola outbreak strained health systems and generated fear of the disease. this caused excess deaths due to neglected need for malaria control. , when assessed at the population level, the association of vaccination activities and risk of outbreak can be approached within a classical epidemiological perspective. as individuals would be in a cohort study, populations (for instance populations living in well-defined geographical areas) may be followed over time while tracking both exposure (vaccination activities) and events (outbreaks). in such observational studies, a risk of confounding arises when both exposure and event share a same cause. this risk is high when measuring the association between pmvcs and yellow fever outbreaks because pmvcs usually target areas that are assessed at particularly high risk by public health officials, due to the disease circulation in the past or based on expert view or risk assessment. such a risk of confounding is usually overcome in the statistical analysis by conditioning, generally adjusting, on the shared common cause; in this case the baseline risk of yellow fever in the area. however, the environmental or demographic drivers of yellow fever are not fully understood, leading to a situation in which residual confounders may bias the measure of association. the self-controlled case series (sccs) method is a case-only epidemiological study design for which individuals are used as their own control. as all known and unknown time-invariant confounding are implicitly controlled for, the method is a relevant alternative to classical cohort or case-control study designs when the risk of residual confounding is high. the sccs method has successfully been applied at the individual level, comparing exposure vs. non-exposure periods within individual cases. however, to our knowledge, this method has never been used for population-level case series to evaluate the health effects of a public health intervention in specific regions, countries, or other predefined geographical clusters that may be considered as group-level cases. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint here, we illustrate the use of the sccs method at the population level by assessing the association between the implementation of pmvcs and the occurrence of yellow fever outbreaks at the province level in the african endemic region between and . considering the yellow fever vaccine's high level of efficacy, and given the fact that pmvcs target all or most age groups in targeted areas, we expect to detect a substantial preventive effect of pmvc on the risk of outbreak. we also expect to detect this association in a cohort design, providing confounders in the association between exposure to pmvc and outbreak are adequately controlled for (no model misspecification). a sccs model would avoid the risk of residual confounding, at least for time-independent variables, but would reduce statistical power as compared to a cohort-design analysis. we compiled location and dates of yellow fever reported in africa between and from international epidemiological reports, namely the who weekly epidemiological reports (wer) and the diseases outbreak news (don). , locations were resolved at the first sub-national administrative level, thereafter called province, and data were recorded for each outbreak with the date of occurrence. outbreak reports that could not be located at the province level were excluded. we compiled data regarding pmvcs conducted as part of the yellow fever initiative since , and additional campaigns further conducted under the eye strategy. starting dates and locations of pmvcs were collected, and the resulting list of vaccination campaigns was compared with data from the who international coordinating group (icg) on vaccine provision, while resolving any discrepancy. estimates of population-level vaccine-induced protection against yellow fever were obtained from hamlet et al. these estimates were obtained by compiling regularly updated vaccination data from different sources (routine infant vaccination, reactive campaigns, pmvcs) and inputting these into a demographic model. for our main analysis, we used the sccs method to compare to estimate the incidence rate ratio (irr) of yellow fever outbreak after vs. before the implementation of a pmvc. we used the province as unit of analysis, so that the main outcome represents the risk for a province to be affected by an outbreak. as the dependency between potential outbreak recurrences in the same province could not be excluded, we limited the analyses to the first outbreak occurrence per province for the main . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint analysis. we used a conditional poisson model with logit link to model the occurrence of outbreaks. provinces included in the sccs analysis were those both affected by an outbreak and targeted for a pmvc over a study period from st jan to dec . we defined the unexposed period as the pre-pmvc period. previous research found that a single dose of yellow fever vaccine provides a longlasting immunity with high efficacy. , therefore, and given the relatively short observation period of the study ( years), we assumed the exposure period starting at the date of the first pmvc and lasting until the end of the observation period. this assumption was made regardless to estimated achieved coverage or intra-province geographic extent of the campaigns. in other terms, we assumed the campaigns to achieve uniform high coverage in all age groups across provinces. in order to allow for possible variation in coverages achieved across pmvcs, we considered the estimated population-level vaccine coverage as an alternative time-varying, quantitative exposure (considered as categories with % bandwidth). we also used alternative sccs models to assess the influence of several assumptions on our results (table ) . we conducted a sccs analysis considering all outbreaks, instead of the first one only, in order to evaluate the influence of the assumption of non-independent recurrence. additionally, as it is possible that the occurrence of an outbreak could affect subsequent exposure, we conducted a sccs analysis including a -year pre-exposure period. as the precise date of outbreaks and pmvcs start were not always available, we assumed where missing, that outbreaks started in the middle of the year and that exposure to pmvcs started at the end of the year. the influence of these assumptions was explored in sensitivity analysis. to assess whether spatial autocorrelation could affect our results, we conducted multiple resampling. in each re-sampling from the sccs study sample, we only sampled one random province per country and re-estimated the irr of the association between exposure and the event. this implicitly accounts for spatial autocorrelation within, but not across countries. we compared the results obtained using the sccs method with those obtained using a classical cohort design. the study sample was constituted of all provinces belonging to the african countries at high or moderate risk for yellow fever. we used univariate and multivariate poisson regression models with robust variance, considering exposure alternatively as a binary (pre-versus post-pmvc) or continuous (vaccination coverage) time-dependent variable. in a cohort design, the choice of covariates to include is critical to prevent bias due to residual confounding. however, there is currently no clear consensus about the demographical and environmental drivers of yellow fever. we thus considered two (partially overlapping) sets of covariates (supplementary text s ). both sets of variables were documented to reproduce well the . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint presence and absence of yellow fever records at the province level. the first set of covariates was previously used in a statistical model whereas the second was used in a mechanistic model. , statistical models aims to describe the patterns of in the associations between species (including infectious agents species) and environmental variables while mechanistic models aim at explicitly representing biological processes in their occurrence. the association between each covariate and the exposure status was explored using modified poisson regression. for each province , we estimated the expected number of outbreaks averted by pmvc, , using the formula: where is the total time of observation, is the time at which pmvc was implemented (if no pmvc in province , thus = ), is the rate of outbreak occurrence in a poisson process in the absence of pmvc, and irr is the incidence rate ratio after vs. before pmvc implementation. with being the number of outbreaks observed in the province during the pre-pmvc, an estimator of is = ⁄ , which leads to: we obtained % confidence intervals for using bootstrap ( , resampling). for each resampling, a value of was randomly sampled based on the parameters estimated in the sccs analysis. finally, based on and , the total number of outbreaks observed, we obtained the outbreaks prevented fraction, , with: . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint among the provinces within the african endemic or at-risk region for yellow fever, ( . %) from countries (of countries) experienced at least one yellow fever outbreak between and , including provinces experiencing more than one outbreak (total number of outbreaks: ) ; and ( . %) were targeted for at least one pmvc (figure ). the sccs study sample was constituted from ( . %) provinces having experienced both outbreak and pmvc implementation over the study period. temporal trends in the estimated population-level vaccination coverage for this sample are displayed in supplementary material (supplementary figure s ). the median of the difference between the post-and the pre-pmvc estimate of vaccination coverage was . % (interquartile range: . - . %) (supplementary figure s ) . among the sccs study sample, the first outbreak occurred during the unexposed period in ( . %) provinces versus ( . %) occurring in the exposure period ( figure ). under baseline assumptions, this corresponded to a significantly reduced incidence rate ratio of . ( % confidence interval, ci: . - . ) for the exposed versus unexposed periods. a similar protective . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint association was observed when considering all outbreaks instead of the first one only (irr = . , % ci . - . ) or when including a -year pre-exposure period (irr = . , % ci . - . ). considering estimates of population-level vaccine coverage as a categorical variable based on % allowed observing a reduced risk of outbreak for higher levels of coverage (table ). considering vaccine coverage as a continuous linear exposure ensured a better fit of the model (likelihood ratio test: p = . ). doing so, we estimated that a %-increase in vaccine coverage decreased the risk of outbreak by % (irr . ; % ci . - . ). the negative association between exposure to pmvcs and outbreak remained significant across a range of assumptions regarding the imputation of the date (within the same year) of pmvcs implementation and outbreak starting date (when missing) (supplementary table s ). when re-sampling times the sccs study sample while allowing only one sampled province per country, and after excluding re-sampling yielding to random zero in the corresponding contingency table (n= with no outbreak occurring during exposed periods, thus leading to infinite confidence . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint interval surrounding the association measure), we obtained an averaged irr of . ( % ci . - . ). . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint in a cohort design, over the outbreaks (first outbreaks only) that occurred over the study period, occurred during unexposed periods versus occurring in exposed periods. most of the environmental covariates we explored were associated with exposure to pmvcs (supplementary table s ). exposure to pmvcs was associated to a significant reduced risk of outbreak (irr = . , % ci . - . ) when adjusting on the covariates obtained from a statistical model. when adjusting on covariates obtained from a mechanistic model, exposure to pmvc was not significantly associated with the risk of outbreak (irr= . , % ci . - . ) (detailed results in supplementary tables s and s ). for both sets of covariates, we observed an inversed u-shaped association between the estimates of vaccination coverage and the risk of outbreak, with the risk decreasing for lowest and highest values of vaccination coverage ( table ) . based on the value of irr estimated in the main analysis (irr = . , % ci . - . ), we estimated that pmvcs implemented over the study period averted in median ( to ) outbreaks, corresponding to a prevented fraction of % ( % to %). in this paper, using the sccs method, we quantified the preventive effect of pmvcs on the risk of outbreak at the province level, documenting a % ( to %) reduction of the risk of outbreak occurrence for provinces that were targeted by a pmvc. this result was robust over a range of assumptions. when using an estimate of population-level coverage as exposure, we also observed a dose-response preventive effect on the risk of outbreak. considering the scale of pmvcs implementation during the study period, this corresponded to an estimated % to % of outbreaks averted by pmvcs in africa between and . based on a cohort design analysis, the association between pmvc and outbreak was sensitive to the choice of adjustment variables. moreover, we observed a challenging u-shape association between vaccination coverage and the risk of outbreak in the cohort analysis. overall, these results suggest a risk of residual confounding that the sccs method, but not cohort design, could overcome, at least for time-independent confounder. to our knowledge, this is the first time a sccs analysis was conducted at the population level. considering evidence of yellow fever vaccine efficacy at the individual level, a preventive effect of pmvc on outbreak risk was indeed expected. this is why we think that the cohort analysis results may be biased by residual confounding ; whereas we consider the results obtained from the sccs method to be more trustworthy. indeed, the decision of targeting a province for pmvcs partly relies on a risk assessment. for the results of the cohort-design analysis to be valid, one needs to account for all possible confounders in the association between pmvcs and outbreak. this is particularly challenging as the environmental and demographic drivers of yellow fever are not fully understood yet. another result suggesting residual confounding in the cohort-design analysis is the u-shaped . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint relationship between vaccination coverage and outbreak risk. the yellow fever vaccine has not been introduced in large regions of eastern africa yet, as the risk of yellow fever is usually considered as low, though existing (eg. kenya). this setting can actually yield to a spurious negative association between low level of vaccination coverage and outbreak risk when confounders are not controlled for. in the sccs analysis, we did observe a linear relationship in the expected association between vaccination coverage and outbreak risk, which in another evidence for lower residual confounding. previously, in a study setting at important risk for residual confounding, sccs have been documented to outperform cohort or case-control designs. although the sccs method has been originally developed to be conducted at the individual level, we ensured that our analysis complied with all its requirements. , exposure and outcomes were ascertained independently. the list of pmvcs was compiled based on information provided by international funders. outbreak occurrence were compiled from who sources, which themselves compile outbreak notification from countries as per the international health regulation. the observation period was chosen in order to maximize the chance that cases experienced the exposure period. indeed, our observation period started few time before the launch of the first yellow fever initiative, which boosted the use of pmvcs that have been very rare since the s. , the choice of the long and unlimited exposure period was based on evidence regarding the long-lasting protection conferred by the yellow fever vaccine, and the sccs method has been previously used successfully while considering long and unlimited risk periods. under the assumption of causality, the incidence risk ratio we estimate represents the average effect for a province of being targeted by a pmvc, which corresponds to the average treatment effect in the counterfactual framework. this average effect is likely to mask large heterogeneity in the local effect of pmvc. indeed, pmvcs occur in population with various baseline levels of immunity, and they may achieve various levels of post-intervention coverage. the dose-response relationship we observed in the association between vaccination coverage and outbreak risk brought additional evidence for a causal link between pmvc and reduced outbreak risk. when looking at higher values of vaccination coverage, it is notable that several outbreaks (n= ) occurred at estimated levels of vaccination coverage > %, an empirical threshold that has been often suggested as protecting from outbreaks. while keeping in mind all the limitations such province-based estimates of vaccination coverage may have (outbreaks could occur in small pockets with low vaccination coverage even in provinces with high coverage), this can be viewed an argument to ensure high vaccination coverages homogeneously in at-risk areas, and to sustain them after pmvcs by ensuring routine infant vaccination. relying on our estimate of the preventive effect of pmvc, the timing of implementation of these pmvcs and the number outbreaks observed during the study period, we further estimated that pmvcs have averted from to outbreak in africa between and , corresponding to a prevented fraction lying between % to %. garske et al. previously estimated that vaccination campaigns conducted up to averted between to % of yellow fever cases and deaths in africa, while shearer et al estimated that all vaccination activities (including routine infant vaccination) conducted up to have averted to % of cases. , our estimates were in a comparable range, although direct comparison with these model-based estimates is not straightforward. indeed the latter are expressed as proportions of all yellow fever cases, including sylvatic cases that are not linked to outbreaks. preventing outbreaks of epidemic prone diseases is . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint critical for ensuring global health security yet there are few empirical studies that quantify the impact of public health interventions like immunization have on the risk of outbreaks. a main limitation of our study is that it does not account for possible time-varying confounders. environmental changes affecting vector-borne diseases have been documented across tropical africa over the study period, probably the main being changing land-use such as deforestation. , demographic changes, more frequent intrusions of humans into forest and jungles, increasing human mobility between endemic and non-endemic areas, have also been suggested to have affected the yellow fever risk in the recent period. similarly, recent international emphasis about yellow fever may have led to better surveillance of the disease in the recent years. however, these various factors are likely to have increased the risk of outbreaks and the probability of outbreak detection in the recent period, which overlaps with the post-pmvcs period in our study sample. this may have led to an underestimate of the association between pmvc and yellow fever outbreaks. previous quantification of the outstanding health impact of vaccination activities have mainly focused on cases or deaths prevented while relying on mathematical models, which structures and assumptions may be difficult to understand by a non-expert audience, whether it be decision-makers or targeted populations. , here we further document this impact using an empirical, maybe more intuitive approach thus allowing for a triangulation of methods to further document the beneficial impact of yellow fever vaccine campaigns. this method relies on data that are quite easily accessible. thus, our method could be applied to other diseases for which pmvcs are implemented, such as polio, meningitis or cholera. due to the covid- pandemic, who recommended to temporarily suspend preventive campaigns while assessments of risk, and effective measures for reducing covid virus transmission were established. in consequence, regarding yellow fever specifically, four countries postponed vaccination campaigns. our results provide additional evidence to encourage a rapid rescheduling of these vaccine campaigns in order to prevent further outbreaks of preventable disease. evidence before this study in , a systematic review of the literature concluded that a single dose of yellow fever vaccine confers sustained life-long protective immunity (gotuzzo et al). we searched pubmed on june th , using the search terms "yellow fever" [all fields] and "vaccin*" [all fields] and "campaign*" [all fields] without language or date restriction. the search returned results. nine articles evaluated yellow fever mass vaccination campaigns based on secondary criteria, namely postcampaign coverage, adverse events following vaccination, operational campaign costs. two modelling studies evaluated the short-term impact of reactive campaigns conducted during the - outbreak affecting angola and the demographic republic of congo. one study (shearer et al.) estimated the global number of cases averted by the vaccination coverage levels achieved in , thus encompassing all vaccination activities (routine childhood immunization vaccination, outbreak response campaign and preventive mass vaccination campaigns, pmvcs). two studies relying on mathematical models focused specifically on the impact evaluation of pmvcs. jean et al. estimated the long-term number of cases and death averted by hypothetic future pmvcs conducted according to various vaccination scenarios. garske et al. estimated the impact of pmvcs conducted in africa between and . they estimated that pmvcs had reduced the number of yellow fever cases and deaths by % across the african at-risk zone, achieving up to an % reduction in countries targeted by these campaigns. to date, no study has quantified the effect of yellow fever preventive vaccination campaigns on the risk of outbreak occurrence. moreover, to our knowledge, the evidence about the public health impact of yellow fever vaccination available to date stems from mathematical models, whereas few empirical evidence is available. added value of the study based on dates and locations of both yellow fever reported outbreaks and pmvcs conducted in africa between and , we estimated the incidence rate of yellow fever outbreaks at the province level and compare the pre-and post-pmvcs incidence rate. relying on the self-controlled case series (sccs) method, which allows to use each case as its own control and thus eliminates all time invariant confounding, we estimated that pmvc reduces the risk of yellow fever outbreak by % ( % to %) at the province level. we further estimated that pmvcs achieved a % ( % to %) reduction in the number of outbreaks in africa over the study period. implication of all the available evidence beside evidence on efficacy and duration of immunity after yellow fever vaccination and modelbased estimates of yellow fever vaccine impact, our study provides new empirical evidence of the high impact of yellow fever vaccination campaigns in preventing outbreaks. moreover, this study illustrates the potential of the sccs method applied at the population level in order to evaluate public health interventions. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. 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vaccination, : consensus of the informal who working group on geographic risk for yellow fever the seasonal influence of climate and environment on yellow fever transmission across africa self controlled case series methods: an alternative to standard epidemiological study designs relative incidence estimation from case series for vaccine safety evaluation a meta-analysis of serological response associated with yellow fever vaccination tutorial in biostatistics: the self-controlled case series method world health organization disease outbreak news (don) world health organization. the yellow fever initiative: an introduction polici: a web application for visualising and extracting yellow fever vaccination coverage in africa a positive event dependence model for self-controlled case series with applications in postmarketing surveillance efficacy and duration of immunity after yellow fever vaccination: systematic review on the need for a booster every years correlation and process in species distribution models: bridging a dichotomy clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association world health organization. yellow fever key facts pathogen spillover during land conversion risk factors associated with sustained circulation of six zoonotic arboviruses: a systematic review for selection of surveillance sites in non-endemic areas world health organization, unicef, gavi. a global strategy to eliminate yellow fever the equity impact vaccines may have on averting deaths and medical impoverishment in developing countries estimating the health impact of vaccination against pathogens in low and middle income countries from at least million children under one at risk of diseases such as diphtheria, measles and polio as covid- disrupts routine vaccination efforts, warn gavi, who and unicef we are thankful to paddy farrington for helpful discussions. kj, tg and mnh conceived the original idea. kj, ah, kamg and tg collected and compiled numerical data. kj, hr and mnh designed the analysis plan. kj and hr conducted the analysis and produced output figures and tables. all authors contributed to the interpretation of the results. kj wrote the first draft of the article. all authors provided critical feedback and helped shape the research, analysis and manuscript. key: cord- -myjyw ei authors: longtin, jean; marchand-austin, alex; winter, anne-luise; patel, samir; eshaghi, alireza; jamieson, frances; low, donald e.; gubbay, jonathan b. title: rhinovirus outbreaks in long-term care facilities, ontario, canada date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: myjyw ei diagnostic difficulties may have led to underestimation of rhinovirus infections in long-term care facilities. using surveillance data, we found that rhinovirus caused % ( / ) of respiratory outbreaks in these facilities during months in . disease was sometimes severe. molecular diagnostic testing can differentiate these outbreaks from other infections such as influenza. diagnostic diffi culties may have led to underestimation of rhinovirus infections in long-term care facilities. using surveillance data, we found that rhinovirus caused % ( / ) of respiratory outbreaks in these facilities during months in . disease was sometimes severe. molecular diagnostic testing can differentiate these outbreaks from other infections such as infl uenza. r espiratory tract illnesses are a major cause of illness and death among elderly persons, especially those in long-term care facilities. although the most commonly identifi ed viruses have been infl uenza virus and respiratory syncytial virus (rsv) ( ), human rhinovirus (hrv) is being increasingly associated with severe respiratory disease and outbreaks in these facilities ( ) ( ) ( ) ( ) ( ) . clinical diagnosis of hrv by immunofl uorescence and virus culture has been diffi cult because these methods are unreliable ( , ) . moreover, because multiple serotypes of hrv exist, retrospective serologic testing cannot be used to evaluate the prevalence of hrv disease ( ) . as a result, the number of outbreaks caused by hrv in long-term care facilities, and the associated illness and death, may be substantially underestimated. we therefore used surveillance data to estimate prevalence of hrv disease in long-term care facilities. using data from an active surveillance network, we investigated all respiratory outbreaks (as defi ned by the ministry of health) ( ), in long-term care facilities, reported from july through december , , in the province of ontario, canada. the number and timing of specimens collected was left to the discretion of the attending physicians. the regional clinical laboratories cultured specimens (blood, urine, and sputum) for bacteria and performed rapid viral antigen testing for infl uenza a/b and rsv. to facilitate turnaround time during periods of higher demand, we used an alternate multiplex nat kit (seeplex rv; seegene usa, rockville, md, usa) in conjunction with the luminex assay. because the luminex assay cannot differentiate between ent and hrv, we used the seeplex rv kit, which can identify hrv, to confi rm results in a random subset of ent/hrv-positive samples. to type the hrv implicated in outbreaks during which deaths occurred, we amplifi ed and sequenced the hypervariable region of the ′ noncoding region, the entire viral capsid protein (vp) gene, and the ′ terminus of the vp gene; we then constructed phylogenetic trees as described ( , ) . during the surveillance period, respiratory disease outbreaks in long-term care facilities were reported to the ontario public health laboratory; we received samples from facilities (table ) . a total of specimens were tested (average . samples/outbreak). of the ( %) outbreaks for which a pathogen was identifi ed, ( %) pathogens were determined to be ent/hrv (representing positive samples) and were temporally spread throughout the surveillance period. pandemic (h n ) virus and parainfl uenza- virus represented % and %, respectively, of identifi ed pathogens. other viruses were identifi ed for < % of outbreaks. viral co-infection was identifi ed in samples from outbreaks. a subset of samples, representing % of ent/hrv outbreaks, were randomly selected and subsequently tested with the seeplex rv kit to further differentiate ent from hrv; hrv was detected in % of these specimens. deaths were potentially associated with ent/hrv in facilities (outbreaks a-d; table ). samples from patients involved in these outbreaks were confi rmed to contain hrv; no other causative bacteria or viruses were identifi ed. clinical data were available for of of the patients who died; deaths were attributed to pneumonia/ respiratory infection. of the patients who died, ( %) had osteoarthritis, ( %) had cardiovascular conditions, ( %) had dementia, ( %) had diabetes, and ( %) had cancer. the only postmortem lung tissue specimen collected was positive for hrv-c (outbreak d). nucleotide sequences obtained from isolates from outbreaks a, b, c, and d showed homology to hrv-a ( %), hrv-a ( %), hrv-a ( %), and hrv-c n ( %), respectively. we performed multiple sequence alignments of the bp of the ′ untranslated region, vp /vp , and vp and compared them with published representative hrv sequences. we could not obtain a vp sequence from strains isolated during outbreak d. phylogenic trees were constructed, and the vp / vp region tree showed better discriminatory power than did that of the ′ untranslated region (figure) . vp /vp sequence identity was > % within each outbreak. sequences were deposited in genbank under accession nos. gu -gu . we cautiously assume that hrv was the causative organism for ( %) of the respiratory outbreaks in long-term care facilities in ontario during the surveillance period. multiplex molecular methods were crucial for rapid identifi cation of the pathogens involved in these outbreaks. we were able to provide results in a timely fashion for ev-ery outbreak. however, the cost and expertise associated with such technology might be beyond the reach of some clinical laboratories. because of the limitations of the sur- figure. neighbor-joining phylogenetic tree of human rhinoviruses (hrv) isolated from respiratory disease outbreaks with associated deaths in long-term care facilities, ontario, canada. tree was constructed by using a -bp nt region encoding viral capsid protein (vp) /vp , along with strains representative of hrv species a, b, and c. echo is the outgroup. bootstrap analysis used , pseudoreplicate datasets. scale bar represents . % of nucleotide changes between close relatives. boldface indicates sequences deposited in genbank. veillance program, we were unable to assess whether such testing is cost-effective in terms of patient care. of the outbreaks with associated deaths, were attributed to hrv-a and to hrv-c. the link between respiratory disease severity and hrv-c speciation is debatable ( ) . in a study from hong kong, ( %) of adults with hrv-c infection had pneumonia compared with ( %) of adults with hrv-a infection ( ) . however, in the cases we studied, most deaths were associated with hrv-a; a recent study found that hrv-c disease had the same indistinct clinical presentation as did other hrv diseases ( ) . viruses isolated from nasopharyngeal swabs by sensitive nat may represent asymptomatic colonization or nonliving organisms. although postmortem specimens were available for analysis from only outbreak-related case, we identifi ed hrv in the postmortem lung specimen. because we do not know whether hrv was present in the lower respiratory tract of the remaining patients who died, a causal association between hrv and severe disease must be made cautiously. we used the nat assays interchangeably because their reported specifi city is > % for all targets ( ) . sensitivity for each assay differs according to target; compared with the luminex assay, seeplex rv is more sensitive for parainfl uenza, rsv, coronavirus, and adenovirus but less sensitive for hrv ( ) . however, despite limitations for epidemiologic data collection, no pathogens other than hrv could explain these outbreaks and associated deaths. our testing panel did not include human bocavirus or infl uenza c virus, which could be involved in the remaining % of outbreaks that had no identifi ed cause and could even represent confounding factors in the causal relationship of a supposed pathogen. in conclusion, using data from a routine surveillance network, we found high prevalence of hrv during a period that encompassed the fi rst and second waves of pandemic (h n ) . these fi ndings are in accordance with the increasing knowledge that hrv outbreaks cause severe and fatal disease. mortality associated with infl uenza and respiratory syncytial virus in the united states a rhinovirus outbreak among residents of a long-term care facility risk factors for lower respiratory complications of rhinovirus infections in elderly people living in the community: prospective cohort study uncommon(ly considered) manifestations of infection with rhinovirus, agent of the common cold rhinovirus outbreak in a long term care facility for elderly persons associated with unusually high mortality two outbreaks of severe respiratory disease in nursing homes associated with rhinovirus new molecular detection tools adapted to emerging rhinoviruses and enteroviruses human rhinoviruses: the cold wars resume appendix b: provincial case defi nitions for reportable diseases. in: infectious diseases protocol molecular characterization of a variant rhinovirus from an outbreak associated with uncommonly high mortality sequence analysis of human rhinoviruses in the rna-dependent rna polymerase coding region reveals large within-species variation a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants clinical and molecular epidemiology of human rhinovirus c in children and adults in hong kong reveals a possible distinct human rhinovirus c subgroup newly identifi ed human rhinoviruses: molecular methods heat up the cold viruses comparison of commercial multiplex respiratory virus pcr assays and conventional diagnosis assays for detection of respiratory viruses and swine-origin a (h n ) infl uenza virus in children we thank julia hillan, michelle perfect, lisa penney, lindsay mccafferty, erica weir, and beth henning for their help with the epidemiologic investigations of these outbreaks.dr longtin is a medical microbiologist at centre hospitalier universitaire de québec. his research interests include the epidemiology of emerging viruses and the pharmacology of antiretroviral agents. key: cord- -cg j jac authors: gelber, shari e.; ratner, adam j. title: hospital-acquired viral pathogens in the neonatal intensive care unit date: - - journal: seminars in perinatology doi: . /sper. . sha: doc_id: cord_uid: cg j jac hospital-acquired infections caused by viruses are a cause of considerable morbidity and occasional mortality in critically ill neonates. the intensive care environment allows for efficient spread of viral pathogens, and secondary cases among both patients and healthcare workers are frequently observed. we review the common viral causes of hospital-acquired infections in neonates, including rotavirus, respiratory syncytial virus, and others, discuss epidemiology and clinical syndromes, and summarize recommendations for control in outbreak situations. chemoprophylaxis, isolation procedures, and care of affected staff are also addressed. h ospital-acquired infections are a major source of excess morbidity and mortality in the already fragile patient population that inhabits neonatal intensive care units (nicus).i hospital-acquired pathogens add to the difficulty of caring for critically ill neonates and can prolong hospitalization, worsen patient outcomes, increase costs, and, in the case of an outbreak, place considerable strain on physicians, nurses, infection control practitioners, and the clinical microbiology laboratoryy data from the national nosocomial infections surveillance system (nnis) show that bloodstream infections are, by far, the most common hospital-acquired infections in nicus, followed by pneumonias. both of these infection sites had pathology entirely due to bacterial or fungal pathogens in the most recent nnis report. viruses were confined to causing % of episodes of hospital-acquired gastrointestinal infections and . % of eye, ear, nose, and throat infections. congenital infections such as cytomegalovirus (cmv) and herpes simplex virus (hsv), which rarely pose infection control problems, are the more conventional scenarios in which viruses are discussed in neonatal units. why, then, include a section on hospital-acquired viral pathogens in this volume? viruses can cause considerable pathology, often present atypically in nicu patients, may be difficult to detect (many require specific antibody studies or viral isolation techniques, and thus need to specifically considered to be diagnosed), and can spread rapidly within nicus. control of outbreaks caused by viral pathogens often involves prolonged and strict adherence to isolation precautions and may not be achieved until after many patients and/or staff are affected. unlike some bacterial pathogens, hospital-acquired viral infections may affect immune-competent children without traditional risk factors for hospital-acquired infections (eg, indwelling catheters or ventilators) and may be of increased relevance in well-baby nurseries or lower-acuity nicus as well. an understanding of the range of viral pathogens that may be involved in hospital-acquired infections, their modes of spread, and potential methods of control are important to limit the scope of an outbreak. most hospital-acquired viral infections in the nicu are the result of pathogens that are spread via the fecal-oral route. these can cause a range of clinical sequelae, but are nearly universally contained through the use of contact isolation. the centers for disease control & prevention recommendation for each of the viruses listed in this section is to maintain contact isolation (ta-ble ) for the duration of illness. it is important to realize that even after the resolution of symptoms, neonates may continue to shed many of the viral pathogens discussed below and thus may serve as a reservoir for further spread. documentation of viral clearance prior to removal of isolation precautions may be of benefit in this population. rotavirus (rv) was isolated in > % of the cases of hospital-acquired viral gastroenteritis reported to nnis. while other viral pathogens (eg, enteric adenoviruses, calicivirus, astrovirus) appear to be capable of causing clusters of disease in neonates, it is clear that the greatest burden comes from this single agent. rv is a worldwide public health threat and causes > , deaths annually. however, symptomatic neonatal rv infection is relatively uncommon. , maternal antibodies passed transplacentally are thought to afford some protection from symptomatic infection, s, effective protection from passive antibody acquired via breast-feeding has been less consistently shown. ~ infection early in life, even with only mild or no symptoms, has been shown to be protective against later disease, but neonatal rv may be acutely associated with electrolyte disturbances and poor weight gain. reports of co-occurrence of rv with either necrotizing enterocolitis or apnea and bradycardia exist in the literature, but the significance of these associations remains unknown. the epidemiology of rv can be confusing. although there is a well-described seasonal variation in rv in the general population, rates of disease in nurseries may not correspond to community trends. ill healthcare workers are often the initial source of rv infection, but this reservoir is not always clearly implicated. some have raised the possibility that the relatively constant temperature and humidity within the nicu blunt these seasonal trends. some nurseries show fluctuating rates of rv with increases in the colder months and fewer infants shedding the virus in the warmer months, and other studies show constant rates of shedding. there may also be variation among units in the rate of symptomatic infections compared to asymptomatic carriage. rv may be introduced into the nicu by several routes. reports of high levels of viral excretion during the first two days of life provide some evidence for vertical transmission of rv. , any of the wide variety of non-newborns (physicians, nurses, hospital staff, family members) who come in contact with infants in the nicu may contribute to rv spread. infant-toinfant transfer of rv via the hands of personnel or direct contact with people (especially ill healthcare workers) excreting the virus are possible mechanisms. although airborne infection, as fomites, and contaminated formula are potential mechanisms of spread, there are no reports of nicu transmission through these means. once rv has been introduced to a nicu, it may be difficult to prevent spread. fecal excretion of virus may begin prior to the onset of clinical illness (if present). affected infants may excrete a large viral load with to viral particles per gram of stool. in one study of rv in neonates, an infant with convulsions was transferred to a premature ward that had been rv free. ~ this child was later found to be infected with rv. subsequently, % of the infants in that ward and % of infants in the nursery were found to be rv positive. some infections occurred as early as hours after the index case was diagnosed. the average time to diagnosis was days after admission to the hospital or detection of the index case. of note, all cases of rv in this outbreak were identical by molecular typing, indicating nosocomial spread. one week after the index case was admitted, infection control procedures were instituted. although this decreased the number of new cases, it took weeks for the outbreak to subside. because asymptomatic and prolonged shedding of rv is common, vigilance regarding hand washing and standard precautions are necessary to prevent, outbreaks. these infection control practices must be in place routinely and adhered to continually, and not just when a case has been identified. regular disinfection of surfaces and of potential fomites (eg, stethoscopes) may help in preventing spread as rv may remain viable on inanimate surfaces for prolonged periods. alcohol-based disinfectants and hand cleansers are important resources in the interruption of rv transmission. rv should be included in the differential diagnosis of a neonate with diarrhea and should be tested for promptly so that contact precautions, which should be instituted at the onset of diarrhea, and further case investigation can begin. infections with hepatitis a virus (hav) are rare in nicus, and affected infants usually have subclinical illness. however, the nicu appears to provide an excellent environment for the propagation of spread of hav to other infants and health-care workers. there are multiple reports of hav outbreaks in nicus. ~ in these, the index cases were infected through various means including vertical transmission, blood transfusion, and undetermined causes. ai-though each of these modes of transmission is rare, the common factor in each of these outbreaks was the rapidity of spread and the longevity of hav in a nicu environment. in each case, hav spread through the nursery to both infants and caregivers, and, in some cases, transfer of neonates to other facilities increased the extent of the outbreak. all neonatal infections in these descriptions were subclinical, and the outbreaks were detected as a result of clinical symptoms in caregivers. once hav has been introduced, several aspects of the nicu setting appear to encourage spread of virus: ) the likelihood that affected neonates may be asymptomatic; ) fecal-oral spread by personnel who care for multiple patients with tasks that may include the changing of diapers and the placement or manipulation of enteral feeding equipment; ) lack of adherence to hand washing and glove wearing; and ) increased duration of viral shedding among infants. in a study of risk factors for transmission during an outbreak, rosenblum et al ~ noted that in addition to "nurse-sharing" between cases and uninfected infants, breaks in infection control procedure including drinking beverages in the nicu and not wearing gloves while manipulating intravenous tubing were associated with higher rates of spread. outbreak control is best attained by strict adherence to contact precautions designed to prevent fecal-oral spread. exclusion of symptomatic healthcare workers from patient care duties may be warranted. one outbreak of hav has been described in which the index case was thought to have acquired the infection vertically. -~ although vertical transmission is rare and disease in infants is usually subclinical, some experts recommend giving a single dose of immunoglobulin to an infant whose mother developed symptoms during the period from weeks prior to delivery through week postpartum. s in an outbreak setting, personnel with significant exposure should receive immunoglobulin. s although there is no published recommendation regarding treatment of potentially exposed neonates with immunoglobulin during an outbreak, this intervention has been described by at least group. -~ there is no role for postexposure hepatitis a vaccine in children under years of age, and the vaccine has not been studied for postexposure prophylaxis of adults in an outbreak setting. since all of the described nicu outbreaks of hav involved healthcare workers, education of that population as well as occupational health providers about the importance of screening exposed infants if a worker develops hepatitis a disease may be helpful in the early recognition of an outbreak. vaccination of all nicu workers against hav is not routinely recommended but merits study. whereas hepatitis a is rare and often asymptomatic in infants, the nonpolio enteroviruses (including enteroviruses, coxsackie viruses, and echoviruses) are common and may be associated with substantial morbidity and mortality in this population. the most common presentation of enteroviral infection is a nonspecific febrile illness; however, entero~iruses may be responsible for sepsis-like syndromes, myocarditis, meningitis, hepatitis or death. '. enteroviruses may spread via fecal-oral and respiratory routes as well as via fomites. introduction of enteroviruses into a nicu frequently occurs as a result of transmission from an infected mother (often with a nonspecific febrile illness during the summer months) to her newborn infant. neonatal infections are relatively common s~ and many outbreaks in nicus have been described, sl- some with high rates of serious disease. viral shedding may occur without signs of active infection, and although respiratory tract shedding generally lasts for a week or less, fecal viral shedding can continue for several weeks. in temperate climates, outbreaks may occur in the general population yearlv most often in the summer and autumn? ~ icu cases may parallel community outbreaks. :~ .:~ in healthy infants, some data suggest that breast-feeding may protect against developing infection? ~ however, this has not been described in neonatal intensive care populations. eisenhut et al :~ recently reported a fatal case of coxsackie a infection caused by myocarditis in a full-term infant that occurred during an outbreak. :~s infection control measures and the use of pooled human immunoglobulin appear to have been effective in halting spread. an outbreak of echovirus (ev ) infection occurred in a newborn unit and involved patients during an ll-day period. of these, patients devel-oped meningitis, developed coagulopathy, and died. the level of maternal antibody to ev appeared to be a predictor of severity of illness. similar outbreaks with multiple infants developing systemic symptoms within days of the index case have been described with other echoviruses. , however, in other cases, the outbreak occurred weeks after admission of the index patient, while the patient was still excreting virus. , although some enteroviruses can be passed transplacentally, the more common means of maternal-infant transmission appears to be after birth via fecal-oral or respiratory spread. spread among patients likely occurs more efficiently via the fecal-oral route than via the respiratory route, and prolonged shedding in the stool of patients and healthcare workers may facilitate the continuation of an outbreak as described above for rv. while there is no widely accepted treatment for enteroviral disease, several authors have described the use of immunoglobulin (mg) in outbreak settings and in life-threatening infections. abzug et al showed more rapid resolution of viremia and viruria in patients who received mg with high titers of neutralizing antibodies against the specific type of enterovirus with which they were infected. pasic et al. described the use of prophylactic mg during a nicu outbreak of echovirus. this decreased the risk of symptomatic viral infection from % in the untreated group to % in the group receiving ivig. however, larger studies would be required before immunoglobulin could be routinely recommended for this use. pleconaril is an antiviral agent with activity against enteroviruses. while some data regarding treatment of severe enteroviral infections in neonates are available, as its role in the control of in-hospital spread of enteroviruses is unknown. respiratory viruses comprise the other major group of hospital-acquired viral pathogens affecting hospitalized infants, and while the causative agents are many of the same ones that affect other pediatric populations, largely during the winter months, the clinical presentations may be quite different. nonspecific clinical findings (eg, apnea, feeding intolerance) and a low index of suspicion leading to failure to order specific viral tests likely contribute to a delay in the institution of proper isolation and to the propagation of outbreaks. although the target organ of these viruses is the respiratory tract, control of the spread of respiratory syncytial virus (rsv), the most common respiratory virus affecting neonates, is achieved via contact isolation. some other viral respiratory pathogens spread via droplets and require precautions to prevent that means of spread (table ). although rsv was known to be an important pediatric pathogen for several years prior, it was not until that hall et a described the role of rsv in neonatal intensive care units. neonatal rsv was found to be a protean disease, affecting premature infants far more frequently than had previously been appreciated, capable of causing considerable pathology, and involving a high percentage of nicu staff. since then, numerous reports of outbreaks in nicus have confirmed these findings, - ~ and rsv currently represents a major infectious cause of disease among critically ill neonates. symptomatic rsv disease is less common in term neonates than in preterm infants, presumably due to transplacental acquisition of maternal antibodies. numerous nicu outbreaks have shown that prematurity is a significant risk factor for acquisition of hospital-acquired rsv infection. , there is strong evidence that compliance with contact precautions (gowning and gloves) prevents nosocomial spread of this virus. , however, despite increased vigilance, there continue to be hospital-acquired rsv outbreaks in nicus with high attack rates and considerable morbidity. in addition, several reports exist of concurrent outbreaks of rsv and other respiratory pathogens (including rhinovirus, echovirus, and parainfluenza) in nicus, - adding to difficulties in diagnosis, isolation, and containment of spread. spread of rsv within hospitals occurs largely on the unwashed or insufficiently washed hands of healthcare workers. cessation of outbreaks by enforcement of compliance with hand hygiene has been described, and the use of gowns and gloves may corifer additional benefit. the high rate of transmission of rsv is also thought to be related to its ability to survive on inanimate surfaces for minutes to hours. even if hand washing takes place around the time of patient contact, the hands of caregivers may become contaminated by touching environmental surfaces. this can lead to spread to other patients and, often, to the caregiver. affected caregivers are major components of many published outbreaks and contribute to inter-patient spread. the development of antigen-based rapid diagnostic tests has contributed to the tracking and control of outbreaks. a targeted infection control program has been shown to decrease the amount of hospitalacquired rsv in a pediatric hospital and to be cost effective. ~ the measures undertaken in that particular program included education of staff, cohorting of infective patients and the nursing staff caring for them, maintenance of a high index of suspicion for new cases, contact precautions, and regular surveillance. this study included nicu patients, although the program was used in other pediatric populations as well. a strict infection control policy proved effective at decreasing spread during a nicu rsv outbreak. in this study, cases of rsv were separated from other infants, and a separate team of nurses and physicians was assigned to that nursery. a policy of strict wearing of gowns, masks, and gloves during the handling of infected infants was observed. the nursery was cleaned and fumigated. eight cases were found prior to the institution of these infection-control policies, but no new cases of rsv developed once they were in place. while these measures exceed those generally used to combat transmission of rsv in a nicu, they may be justified during an outbreak. in addition to strict infection control measures, pharmacologic means have been explored to prevent the spread of rsv in the nicu. infants meeting criteria laid out by the american academy of pediatrics routinely receive palivizumab to prevent severe rsv disease; however, the data regarding prevention of nosocomial spread of rsv by palivizumab are limited. cox et a recently studied the use of palivizumab to prevent hospital-acquired rsv in infants at high risk for rsv (defined as infants <= weeks gestation or those with bronchopulmonary dysplasia) during an outbreak. palivizumab administration to susceptible infants correlated with the end of an outbreak after increased infection control had failed. however, it is difficult to determine the role of palivizumab in ending the outbreak as there were a variety of measures in place. controlled studies directed toward this question are needed. outbreaks of influenza in nicus are rarely reported, and cases in neonates are generally mild in part due to the presence of maternal antibody. - however, severe disease can occur, especially in premature infants. diagnosis is important to ensure rapid institution of appropriate control measures as the short incubation period and droplet transmission by neonates may allow for rapid spread. s rapid diagnosis may be made by direct immunofluorescence of nasopharyngeal aspirates. the presence of influenza in the general population should alert nicu personnel to suspect influenza in their patients. sagrera et a described outbreaks of influenza a over a -month period in separate neonatal units in barcelona, spain. in all, of infants in nicus were found to be infected with influenza a, of whom ( %) developed symptoms. risk factors for infection included low birth weight (mean birth weight g among cases, g among unaffected patients), low gestational age (mean gestational age weeks among cases, weeks among unaffected patients), twin pregnancy, and mechanical ventilation. an attack rate of % was documented in a retrospective study of an outbreak in a canadian nicu. while annual vaccination is recommended for nursery personnel as well as parents/visitors to nurseries, actual vaccination rates among hospital staff are often very low. when nicu personnel were surveyed during outbreaks, rates ranged from % to %. ' amantadine prophylaxis has been used for staff in outbreak settings but is not approved for use in infants. neuraminidase inhibitors may hold some promise as prophylaxis or treatment during outbreaks, but studies in nicu populations are not available. the most effective means of outbreak control is likely to be the routine vaccination of healthcare workers. vaccination of healthcare workers, screening of asymptomatic infants, droplet isolation of cases, limitation of sibling visitation during community outbreaks, and exclusion of affected adults from the nicu may all be of value in limiting the scope of outbreaks. adenovirus infection is easily transmissible and there have been several reported nicu outbreaks. -v neonates are thought to gain some protection from maternally acquired antibodies; however, when infection does occur it can disseminate rapidly and is associated with a poor outcome. factors that play a role in transmission include the difficulty of eliminating viral particles from environmental surfaces, long incubation period, and the ability to transmit virus through aerosols and direct and indirect contact. infection in the neonate may have high morbidity and be confused with bacterial sepsis. other manifestations can include uri symptoms, lower respiratory tract symptoms, conjunctivitis, gastroenteritis (caused by specific serotypes, generally and ), and fever. in neonates, disseminated disease including pneumonia, meningitis, or encephalitis may also occur. although long incubation periods may make outbreaks difficult to detect, early recognition of adenoviral infection may allow for limitation of viral spread. coinfection of patients with adenovirus and other viral pathogens has contributed to delayed diagnosis (due to attribution of symptoms to another virus) with subsequent spread to staff members and other patients. ~ another report of adenovirus spread within a nicu described a lower attack rate and less disseminated disease. significantly, healthcare workers were affected in that outbreak as well as in one of adenoviral conjunctivitis related to contaminated ophthalmology equipment. control measures for adenovirus disease include contact and droplet precautions, strict enforcement of hand washing, proper disinfection of ophthalmologic and other medical equipment, cohorting of patients in outbreak situations, and exclusion of affected staff and parents from the unit. protective eyewear for healthcare workers may be of use when caring for patients with adenoviral conjunctivitis to provide an additional barrier to patient-to-caregiver spread. severe outbreaks may result in unit closure. ~ other respiratory viruses such as parainfluenza, , - rhinovirus, and coronavirus - may cause clusters of cases in nicu settings. these are generally associated with milder disease than rsv, and control follows the general principles outlined above. neonatal varicella can occur via vertical transmission or hospital-acquired infection. transmission of varicella zoster virus (vzv) occurs via direct contact with lesions or less commonly by aerosolized droplets. a long incubation period ( - days) and a period of maximum infectivity that lasts from to days before until days after the onset of lesions make control of outbreaks difficult. fortunately, such outbreaks seem to be rare and hospital-acquired disease is generally mild. the risk of horizontal transmission in nurseries is thought to be low because of physical barriers (such as isolettes) as well as high rates of passive immunity; only % to % of women born in the united states are thought to be susceptible to varicella, ~ and there is good transplacental passage of varicella antibody. nonetheless, there are several reports of varicella outbreaks in nicus. s~ premature infants may be at increased risk because of decreased levels of antibody, although antibody may still be detectable in many of these infants. , b the cornerstone of infection control management is to place infants who have had exposure on airborne isolation and provide passive immunization to high-risk infants with varicella zoster immunoglobulin (vzig). candidates for vzig, according to the recommendations of the american academy of pediatrics, are all hospitalized premature infants born at less than weeks' gestation or g, those weeks or greater if the mother has no reliable history or serologic evidence ofvaricella immunity, and those whose mother developed varicella between days prior to and hours after delivery. however, several reports show negative vzv antibody status and/or cases of varicella in infants of to weeks' gestation despite a positive maternal history of vzv. ,s ,s therefore, testing or empiric treatment in that subgroup may be justified. all nicu healthcare workers should be vaccinated against varicella or show evidence of immunity. of note, some commercially available serologic tests have low sensitivity and specificity for vzv antibodies in immunized adults. in an outbreak setting, postexposure vaccine may be of benefit in exposed people over year of age (eg, healthcare workers, family members). with the increasing use of varicella vaccine in the community and a demonstrated decrease in disease, it is likely that nicu exposures will be even less common in the near future. while hsv is a common and significant cause of disease in the neonatal period, the vast majority of cases are acquired at the time of birth. spread of hsv from caretakers with oral lesions or herpetic whitlow has been described, but outbreaks are rare. , contact precautions and exclusion of caretakers with whitlow or with large oral lesions are generally sufficient to prevent spread. workers with small oral lesions may continue to work provided that the lesions are adequately covered and proper infection control procedures are followed. greater than % of children excrete cmv in the neonatal period (and the number may be greater in populations with high rates of maternal immunity to cmv), ~ making it one of the most common congenital infections. shedding in the urine or the saliva can be prolonged in neonates, but transmission in a nicu setting is rare. child-to-child transmission of cmv is well described in the daycare environment. however, routine hand washing seems to prevent spread in the nicu. hospital-associated transmission has been documented by molecular techniques, z but a multiyear study by adler et a showed that the most common means of hospital-acquired cmv acquisition in neonates is via red blood cell transfusion. exclusion of pregnant caretakers from the care of cmv-excreting infants is not recommended, as healthcare workers frequently care for cmv-excreting children without an increased risk of acquiring cmv infection. -~ standard precautions are recommended for children known to be shedding cmv. hiv, hepatitis b, and hepatitis c are of concern in the postnatal period mostly because of congenital infection. transmission of these and other blood-borne pathogens is possible via transfusion of blood products, but current screening methods make this extremely unlikely. secondary spread within a nicu has not been described, and standard precautions for patients with hiv, hepatitis b, and hepatitis c are indicated. a wide variety of viral pathogens may be spread within neonatal units. reported outbreaks and studies using video surveillance and dna markers '~"i show an enormous capacity for spread of infectious organisms in this environment. low gestational age and birth weight, incomplete transfer of maternal antibody, and atypical clinical presentations put these patients at increased risk of complications from viral infections. in addition, aspects of the nicu environment itself may predispose to rapid spread of these agents among patients, with healthcare workers as a common means of transmission. clinical suspicion, rapid diagnosis, and prompt institution of proper infection control precautions, including occupational health service evaluation and possible exclusion of affected staff and family members from patient care areas, are critical components of an infection control program that can limit the impact that hospitalacquired viral infections have on nicu populations. epidemiolo~' and control of nosocomial viral infections nosocomial infections among neonates in high-risk nurseries in the united states. national nosocomial infections surveillance system microorganisms responsible for neonatal diarrhea the magnitude of the global problem of diarrhoeal disease: a ten-year update rotavirus infections of neonates banatvalaje: asymptomatic endemic rotavirus infections in the newborn lack of maternal antibodies to p serotypes may predispose neonates to infections with unusual rotavirus strains protective effect of naturally acquired homotypic and heterotypic rotavirus antibodies observations questioning a protective role for breast-feeding in severe rotavirus diarrhea modulation of rotavirus enteritis during breast-feeding. implications on alterations in the intestinal bacterial flora rotavirus infections in infants as protection against subsequent infections an outbreak of rotavirus-associated neonatal necrotiziug enterocolitis rotavirus infection and bradycardia-apnoea-episodes in the neonate comparison of human rotavirus disease in tropical and temperate settings a search for faecal viruses in new-born and other infants infections acquired in the nursery: epidemiology and control aerosol transmission of experimental rotavirus infection survival of enteric viruses on environmental fomites incidence and diagnosis of rotavirus infection in neonates: results of two studies nosocomial rotavirus infections in neonates: means of prevention and control interruption of rotavirus spread through chemical disinfection posttransfusion hepatitis a in a neonatal intensive care unit nosocomial hepatitis a. a multinursery outbreak in wisconsin vertical transmission of hepatitis a resulting in an outbreak in a neonatal intensive care unit hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants studies on the maternal-infant transmission of the viruses which cause acute hepatitis report of the committee on infectious diseases profile of enterovirus disease in the first two weeks of life epidemiology of neonatal enterovirus infection nosocomial infection with echo virus type in a neonatal intensive care unit an outbreak due to echovirus type in a neonatal unit in france in : usefulness of pcr diagnosis usefulness of nested pcr and sequence analysis in a nosocomial outbreak of neonatal enterovirus infection severe neonatal echovirus infection during a nursery outbreak a new-born baby outbreak of echovirus type infection a community and intensive care nursery outbreak of coxsackievirus b meningitis coxsackie b virus epidemiology and neonatal infection in belgium fatal coxsackie a virus infection during an outbreak in a neonatal unit nosocomial respirator , syncytial virus infections in an intensive care nursery: rapid diagnosis by direct immunofluorescence nosocomial respiratory svncvtial ~irus infections: the costeffectiveness and cost-benefit of infection control prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of rsv-igiv the use of palivizumab monoclonal antibody to control an outbreak of respirator" syncytial ~irus infection in a special care baby unit outbreaks of influenza a virus infection in neonatal intensive care units outbreak of influenza in a neonatal intensive care unit an outbreak of influenza a in a neonatal intensive care unit influenza a virus outbreak in a neonatal intensive care unit hong kong influenza in a neonatal unit epidemiology and prevention of pediatric viral respiratory, infections in health-care institutions adenovirus wpe conjunctivitis outbreak in a neonatal intensive care unit an epidemic of adenovirus a infection in a neonatal nursery: course, morbidity, and management description of an adenovirus type outbreak in hospitalized neonates born prematurely neonatal adenovirus infection: four patients and review of the literature outbreak of parainfluenza virus type in an intermediate care neonatal nursery outbreak of parainfluenza ~'irus type in a neonatal nurseu parainfluenza ~ e viral outbreak in a neonatal nursery neonatal nosocomial respiratory infection with coronavirns: a prospective study in a neonatal intensive care unit nosocomial infections due to human coronaviruses in the newborn coronavirus-related nosocomial viral respiratory infections in a neonatal and paediatric intensive care unit: a prospective study antibody to varicella-zoster virus in parturient women and their offspring during the first year of life outbreak and control of varicella in a neonatal intensive care unit outbreak of varicelia in a newborn intensive care nursery transplacental immunity to varicella-zoster virus in extremely low birthweight infants antibody to varicella zoster virus in low-birth-weight newborn infants varicella exposure in a neonatal intensive care unit: emergency management and control measures persistence of immunity to varicella-zoster virus after vaccination of healthcare workers varicella disease after introduction of varicella vaccine in the united states natural history of neonatal herpes simplex virus infections in the acyclovir era transmission of herpes-simplex virus type in a nursery for the newborn. identification of viral isolates by d.n.a. "fingerprinting an outbreak of herpes simplex virus type in an intensive care nursery congenital cytomegalovirus infection in preterm and fullterm newborn infants from a population with a high seroprevalence rate molecular epidemiology of cytomegalovirus: a study of factors affecting transmission among children at three day-care centers transmission of cytomegalovirus among infants in hospital documented by restriction-endonuclease-digestion analyses molecular epidemiology of cytomegalovirus in a nursery: lack of evidence for nosocomial transmission occupational risk for primary cytomegalovirus infection among pediatric health-care workers high rate of hand contamination and low rate of hand washing before infant contact in a neonatal intensive care unit detection of pathogen transmission in neonatal nurseries using dna markers as surrogate indicators the authors thank richard hodinka, phd for assistance ~ith issues of ~iral diagnosis. key: cord- -mwuix tv authors: inkster, t.; ferguson, k.; edwardson, a.; gunson, r.; soutar, r. title: consecutive yearly outbreaks of respiratory syncytial virus in a haemato-oncology ward and efficacy of infection control measures date: - - journal: j hosp infect doi: . /j.jhin. . . sha: doc_id: cord_uid: mwuix tv background: respiratory syncytial virus (rsv) causes significant respiratory tract infection in immunosuppressed patients. aim: to describe two consecutive yearly outbreaks of rsv in our haemato-oncology ward. methods: haematology patients presenting with respiratory symptoms were screened by polymerase chain reaction for viral respiratory pathogens using a saline gargle. findings: none of our patients had undergone bone marrow transplant but all had underlying haematological malignancies. eight patients were affected in the first outbreak (mortality rate: . %) and patients were affected in the second (mortality rate: . %). extensive infection control measures were implemented in both outbreaks and were successful in preventing further cross-transmission. conclusion: there was significant learning from both outbreaks and actions implemented with the aim of reducing the likelihood and impact of future outbreaks. respiratory syncytial virus (rsv) is an important cause of viral lower respiratory tract infection in infants and children worldwide and is a significant pathogen in immunocompromised hosts. the incubation period of rsv is typically two to eight days [ ] . route of transmission is person to person via droplets or through direct/indirect contact with contaminated hands or surrounding environment. in patients with underlying haematological conditions rsv may lead to higher mortality and prolonged viral shedding [ ] . progression to lower respiratory tract infection is estimated to occur in % of patients who have had chemotherapy for leukaemia [ ] . prior to the last outbreak of rsv in haemato-oncology patients in our health board occurred in [ ] . we describe two consecutive winter outbreaks of rsv in a haematology ward occurring in december and again in december . both outbreaks took place on a -bedded haematooncology ward in the beatson west of scotland cancer centre (bwoscc). the unit opened in and is the uk's second largest centre for specialist, non-surgical oncology and scotland's largest. the haematology ward cares for patients with haematological malignancies. allogeneic bone marrow transplant patients are nursed in a neighbouring ward and were unaffected by these outbreaks. the ward layout comprises five single rooms with en suite, one double room with shared en suite and the remainder of the accommodation is provided in three four-bedded bays with shared en-suite rooms. it is standard practice in this ward to screen haematology patients presenting with respiratory symptoms for viral respiratory pathogens using a saline gargle. patients who are unwell are told to report directly to the haematology unit rather than attend the accident and emergency department. all samples were extracted on the siegen mix using the siam viral rna kit (siegen, crawley, uk). the samples were pre-lysed and ml of the sample extracted, and nucleic acid was eluted into ml. the case definitions employed were the same for both outbreaks and are listed in box . there is variation in the published literature regarding the definition of nosocomial rsv, the interval between hospital admission and symptom onset varying from two to eight days because of the length of the possible incubation period [ , ] . we applied the lower limit of two days in our outbreak policy, taking account of our high-risk patient group. in december three patients on the haematology ward with respiratory symptoms tested positive for rsv in a h period. each of the patients had an underlying haematological malignancy. at the time of initial laboratory referral and subsequent investigation by the infection prevention and control team (ipct), one patient case had been discharged home with two remaining on the ward. one of the two remaining patients, whose symptoms had resolved by the time of referral to the ipct, was being nursed in a four-bedded bay; the other had respiratory symptoms and was in a single side room with droplet and contact precautions in place. as there were three confirmed cases (two nosocomial) linked in time, place and person, an outbreak was declared and the ward closed to admissions/transfers. on the day of ward closure a fourth patient with respiratory symptoms tested positive for rsv and was isolated with precautions in place. an outbreak control team (oct) was established. the index case was community onset and had been admitted feeling unwell, complaining of cough and green spit, and with an unwell child at home. the patient improved and was discharged home prior to the positive sample result being reported. screening of all patients and staff on the ward by pcr on gargles took place over the course of the outbreak, which lasted nine days. in total eight patients and two healthcare workers tested positive for rsv. of the patients who tested positive for rsv three were asymptomatic. three of the patient cases who tested positive for rsv required treatment with antiviral (ribavirin) and immunoglobulin. three of the confirmed patient cases died over the course of the outbreak with rsv cited on death certification. although only two staff members tested positive for rsv, a total of seven staff reported symptoms over the course of the outbreak, and this, along with ward closure, led to service disruption in this highly specialist area. patient characteristics of this outbreak are listed in table i . the majority of patients were male (six out of eight). the average age was years (range: e ) and the mortality rate was . % (three of eight patients). a full list of infection control measures employed in both outbreaks is listed in box . precautions remained in place for patient cases until two negative viral gargle samples were achieved h apart. symptomatic staff were advised to remain off duty until h asymptomatic. a patient information leaflet was produced for distribution to all patients on the ward. over the course of the outbreak the ward was visited twice daily as a minimum by a member of the ipct and this allowed for observational audit of staff practice, including use of personal protective equipment and informal teaching. the ipct completed formal infection prevention and control audit, nosocomial rsv any patient with respiratory symptoms and a positive respiratory sample for rsv if patient was hospitalized two or more days before the onset of symptoms. confirmed case of rsv any patient or staff member with respiratory symptoms and a positive respiratory sample for rsv probable case of rsv any patient or staff member with respiratory symptoms asymptomatic carrier any patient or staff member in whom rsv was detected on screening in the absence of respiratory symptoms or fever measuring both standard and transmission-based infection control precautions at the time of ward reopening, and a training package was put in place for ward staff. the end of the outbreak was declared after nine days. in december the ipct was alerted to four patients testing positive for rsv on the haematology ward over a fiveday period. again these were nosocomial infections and linked in time, place, and person; therefore an outbreak was declared and an oct established. at the time of referral two patients had been sent home well and the other two cases, both of whom were symptomatic, were cohorted together in a four-bedded bay with the remaining two beds blocked. a fifth patient tested positive prior to the first outbreak meeting and was isolated in a single side-room with precautions in place. staff recalled a positive patient seven days previously who had been discharged home. this was also determined to be a nosocomial infection and it was likely that this patient was the index case, taking the total numbers at this point to six patients. screening of the remaining patients was undertaken and a further three cases were identified, all of whom were asymptomatic. during the course of the outbreak a further three symptomatic cases were detected, taking the total number of patients to . one patient died with rsv cited on death certification. one patient was treated with ribavirin and immunoglobulin and a further three patients were given infection control measures implemented for both outbreaks À ward closed to admissions/transfers. À isolation of symptomatic cases in single side-room or cohorted with other respiratory syncytial virus-positive patients. À increased environmental cleaning: twice daily with chlorine-based detergent (actichlorÔ plus). À cough etiquette emphasized. À use of personal protective equipment (gloves, aprons, surgical masks, visors) emphasized and adequate supplies obtained. À hand hygiene emphasized. À screening of all patients. À screening of all staff ( outbreak only). À restriction of patient and staff movement. À access to adjoining ward (bone marrow transplant) restricted and entry via alternative route agreed. À reduced visiting hours and visitor numbers (no more than two per patient). if possible no child visitors aged < years. media statements released which reinforced this. À symptomatic staff to refrain from duty until h symptom-free. À enhanced observation of the ward by the infection prevention and control team and education. À frequent meetings with infection control, clinical and management staff. À written communication, so all staff were aware of situation. À psychological and practical support to ward staff dealing with patients and relatives from infection control staff. immunoglobulin alone. the end of the outbreak was declared after days. no staff screening was undertaken but symptomatic staff were excluded from work. patient characteristics are displayed in table i . male patients were predominantly affected ( out of patients). the average age of patients was years (range: e ), and the mortality rate was . % (one out of patients). we describe two outbreaks of rsv in our haematology ward, which have occurred in the last two consecutive years during the month of december. all patients in both outbreaks had underlying haematological malignancies but none had had autologous or allogeneic bone marrow transplants. the outbreaks coincided with seasonal outbreaks of rsv in the community and increased admissions in the paediatric setting. from timelines that were created, and particularly during the december outbreak, there were opportunities for crosstransmission between patients in the same bed bays. however, this did not explain the full picture, as some rsvpositive patients had no contact with other positive cases (figures and ). our hypothesis for both outbreaks is that rsv was introduced from the community by a patient, a staff member or a relative and cross-transmission then occurred in the ward setting between patients themselves, and staff members with mild symptoms. this appeared to be the case in the first outbreak where the index case was admitted symptomatic from the community. this pattern has been demonstrated in other rsv outbreaks. jensen et al. described an rsv outbreak in haematology patients involving patients and one staff member. sequencing of the isolates was consistent with transmission occurring on the ward and introduction of rsv from the community [ ] . in a e outbreak involving haematology patients, investigations showed single introduction of the outbreak strain from the community; this strain subsequent spread among patients into the unit [ ] . in addition to direct contact with symptomatic patients or staff, asymptomatic patients and prolonged excretion may have contributed to continued transmission within the unit. viral shedding in this patient group is known to occur for several weeks after the resolution of symptoms, and has been reported to be seven to days in one study [ ] . in both outbreaks we detected asymptomatic patients on screening. we also noted patients who continued to be pcr positive following resolution of symptoms and who became positive again after having negative pcr results. both outbreaks were relatively short, so it was not possible to determine for how long patients were continuing to excrete the virus. whether these patients could shed virus in sufficient amounts to contribute to further transmission is unknown. outbreak investigators in the paediatric setting have detected asymptomatic patients and have postulated that these patients may shed rsv and cause onward transmission [ , ] . due to our high-risk population we employed patient screening to detect those who were asymptomatic in both outbreaks. further research investigating the efficacy of this measure is required. during a large outbreak of rsv in a german haematology unit, % of rsv patients had recurrent positive tests even after two consecutive negative pcr tests. this led the authors to conclude that it might be appropriate to treat patients as positive for their duration of stay [ ] . mortality rates in haemato-oncology patients as a result of rsv are high. the mortality rate in outbreak was higher at . %. average age in this outbreak was also higher at years, which might have been a factor in the mortality rate. a retrospective cohort study of adult patients attending the emergency department with rsv identified lower respiratory infection, chronic lung disease and bacterial co-infection as independent predictors of life-threatening infection [ ] . risk factor analysis specific to haematology patients is difficult due to small numbers but sharing a room with a positive patient was identified as a risk factor from one study [ ] . one of the larger studies examining risk factors involved haematology patients. hypogammaglobulinaemia was identified as a significant risk factor for morbidity and mortality and was not reversible by treatment with polyvalent immunoglobulin [ ] . preexisting lung disease was also thought to be a factor but the finding was not statistically significant [ ] . in haematopoietic cell transplant recipients with rsv, lymphopenia was associated with progression to lower respiratory disease [ ] . the majority of our patients in both outbreaks were noted to be lymphopenic (table i) although this is not a rare finding in this patient population. a range of infection control precautions were employed during both outbreaks. on both occasions the ward was closed to admissions in an attempt to control the outbreak, to prevent exposure of other haematology patients and to limit the reintroduction of virus from the community. the implementation of broad precautions applicable to the entire unit is recommended during rsv outbreaks in preference to those focusing only on specific patients [ ] . a recent systematic review of control measures implemented in rsv outbreaks supported the use of multi-component measures. these measures reduced the transmission risk by %. it was not possible, however, to assess the effects of individual components [ ] . in the first outbreak in several staff members exhibited symptoms compatible with rsv infection. screening was therefore undertaken for all groups of staff in the unit. two were positive, both of whom were displaying symptoms. staff screening was not performed in the second outbreak. fewer staff were symptomatic and our experience from the outbreak the preceding year was that only the symptomatic staff tested positive. similarly, in an outbreak of rsv in adult stem cell recipients asymptomatic healthcare workers were screened and all tested negative [ ] . had the outbreak control measures failed we would have proceeded with staff screening in . during both outbreaks healthcare workers with mild symptoms remained at work and this has been described by others [ ] . human resource policies in relation to sickness absence and concerns about ward staffing may mean that staff are reluctant to take time off when symptoms are mild. when caring for rsvpositive patients our staff wore surgical masks. implementation of a universal surgical mask policy, whereby all staff in direct contact with patients wore a mask, led to a significant reduction in respiratory viral illness in a haemopoeitic stem cell unit [ ] . prophylaxis in paediatric outbreaks of rsv is well described; however, studies into its use in adults are lacking [ ] . prophylactic administration of palivizumab was administered during a nosocomial outbreak involving five stem cell transplant patients in . sixteen patient contacts were designated high risk and administered prophylaxis with intravenous palivizumab, none of whom went on to develop rsv [ ] . further studies into the benefits of prophylaxis in this patient group are needed. given that the last outbreak of rsv in haematology patients in our health board was in we were surprised to experience two significant outbreaks two years in succession. although both outbreaks were relatively short-lived there was significant morbidity, mortality and disruption to our haematology service. a review of both outbreaks has been undertaken and a number of measures implemented as a result. rsv is highly transmissible and rapid detection in this susceptible patient group is essential. we are limited by accommodation with only five single rooms; in addition our virology laboratory is situated off site. near-patient testing done at ward level for rsv and other respiratory viruses has now been implemented. this will enable prompt detection and isolation or cohorting, depending on results. human resources have agreed that staff members who are excluded during a confirmed outbreak will not have the sickness absence recorded e it is hoped that this will encourage staff members to refrain from duty when symptomatic. an early warning trigger has been implemented to inform the ward and infection control team when rsv cases in the community start to increase. consideration is to be given to admitting haematology patients to other areas when presenting with respiratory symptoms, provided specialist haematology care is not required. our board rsv policy was reviewed and now includes specific information relevant to rsv outbreaks in adults; the previous emphasis had been on the paediatric setting where outbreaks are more frequent. a report was produced following each outbreak and provided summary information as well as recommendations including: staff education, local audits of hand hygiene, and standard infection control precautions. a full staff debrief was undertaken after the first outbreak as there was naturally staff anxiety both in relation to patient outcomes and as to whether staff had been implicated in the outbreak. haematology units should be alert to the possibility of rsv outbreaks, especially during periods of high incidence in the community. both outbreaks were relatively short-lived and the initial infection control measures implemented were effective in preventing further cross-transmission. infection control measures we felt were key in managing these outbreaks were: À ward closure À isolation/cohorting of positive patients À rapid exclusion of symptomatic staff À hand hygiene and personal protective equipment. infection control measures which may be useful but require further evaluation include: À isolation of positive patients for their duration of stay À screening to detect asymptomatic patients with subsequent isolation À universal application of surgical masks. respiratory syncytial virus outbreak on an adult stem cell transplant unit contributing and terminating factors of a large rsv outbreak in an adult haematology and transplant unit respiratory syncytial virus infection in patients with haematological diseases; single centre study and review of the literature control of an outbreak of respiratory syncytial virus infection in immunocompromised adults outbreak of respiratory syncytial virus in immunocompromised adults on a haematology ward molecular characterisation of a respiratory syncytial virus outbreak in a haematology unit in heidelberg respiratory syncytical virus infection in recipients of allogeneic stem cell transplantation: a retrospective study of the incidence, clinical features and outcome transmission of respiratory syncytial virus at the paediatric intensive care unit: a prospective study using real time pcr respiratory syncytial virus outbreak in neonatal intensive care unit: impact of infection control measures plus palivizumab use factors predicting life threatening infections with respiratory syncytial virus in adult patients risk factors and containment of respiratory syncytial virus outbreak in a haematology and transplant unit respiratory syncytical virus in hematopoietic cell transplant recipients;factors determining progression to lower respiratory tract disease risk of nosocomial respiratory syncytial virus infection and effectiveness of control measures to prevent transmission events: a systematic review universal mask usage for reduction of respiratory viral infections after stem cell transplant: a prospective trial detection and control of a nosocomial respiratory syncytial virus outbreak in a stem cell transplantation unit: the role of palivizumab we would like to thank all the nursing and medical staff in the haematology unit at the beatson oncology centre. none declared. none. key: cord- -kxhp my authors: hansen, s.; stamm-balderjahn, s.; zuschneid, i.; behnke, m.; rüden, h.; vonberg, r.-p.; gastmeier, p. title: closure of medical departments during nosocomial outbreaks: data from a systematic analysis of the literature date: - - journal: journal of hospital infection doi: . /j.jhin. . . sha: doc_id: cord_uid: kxhp my summary a total closure of an affected medical department is one of the most expensive infection control measures during investigation of a nosocomial outbreak. however, until now there has been no systematic analysis of typical characteristics of outbreaks, for which closure was considered necessary. this article presents data on features of such nosocomial epidemics published during the past years in the medical literature. a search of the outbreak database ( nosocomial outbreaks in file) revealed a total of outbreaks that ended up with some kind of closure of the unit (median closure time: days). closure rates (crs) were calculated and stratified for medical departments, for causative pathogens, for outbreak sources, and for the assumed mode of transmission. data were then compared to the overall average cr of . % in the entire database. wards in geriatric patient care were closed significantly more frequently (cr: . %; p < . ) whereas paediatric wards showed a significantly lower cr ( . %; p = . ). pathogen species with the highest cr were norovirus ( . %; p < . ) and influenza/parainfluenza virus ( . %; p < . ). if patients were the source of the outbreak, the cr was significantly increased ( . %; p = . ). infections of the central nervous system were most often associated with closure of the ward ( . %; p = ). a systematic evaluation of nosocomial outbreaks can be a valuable tool for education of staff in the absence of an outbreak, but may be even more helpful for potentially cost-intensive decisions in the acute outbreak setting on the ward. summary a total closure of an affected medical department is one of the most expensive infection control measures during investigation of a nosocomial outbreak. however, until now there has been no systematic analysis of typical characteristics of outbreaks, for which closure was considered necessary. this article presents data on features of such nosocomial epidemics published during the past years in the medical literature. a search of the outbreak database ( nosocomial outbreaks in file) revealed a total of outbreaks that ended up with some kind of closure of the unit (median closure time: days). closure rates (crs) were calculated and stratified for medical departments, for causative pathogens, for outbreak sources, and for the assumed mode of transmission. data were then compared to the overall average cr of . % in the entire database. wards in geriatric patient care were closed significantly more frequently (cr: . %; p < . ) whereas paediatric wards showed a significantly lower cr ( . %; p ¼ . ). pathogen species with the highest cr were norovirus ( . %; p < . ) and influenza/parainfluenza virus ( . %; p < . ). if patients were the source of the outbreak, the cr was significantly increased ( . %; p ¼ . ). infections of the central nervous system were most often associated with closure of the ward ( . %; p ¼ ). a systematic evaluation of nosocomial outbreaks can be a valuable tool for education of staff in the absence of an outbreak, but may although most nosocomial infections occur endemically, still outbreaks may cause tremendous problems for health care systems. , the consequences of such nosocomial outbreaks may affect the individual patient, the medical department, or even the entire hospital: ( ) affected patients may suffer from possible infections due to the outbreak strain. the morbidity and the risk of mortality may increase. additional antimicrobial treatment can become necessary and the duration of hospital stay may be prolonged. ( ) on the affected ward, the recognition of an outbreak often causes uncertainty about the outbreak's origin, the transmission route, and about appropriate infection control measures required to bring the outbreak to an end. furthermore, almost every nosocomial outbreak will increase the costs for the affected medical department especially when a total closure of the unit is considered. that is why a total closure is performed only if all previous infection control measures have failed to control the pathogen's spread. this closure of the unit may comprise the immediate cessation of new admissions to the ward until disinfection of the ward has been carried out, but it may also include temporary cancellation of scheduled surgical operations or restriction of certain diagnostic procedures. e sometimes the extent of a closure may vary within the course of one single outbreak. ( ) publication of a nosocomial outbreak in public media may represent a threat for the reputation of the entire healthcare facility. even after the successful termination of the outbreak following the closure of the ward, the contribution of this specific infection control measure remains unknown. until now, there has been no systematic analysis of outbreak descriptions in the medical literature with respect to the impact of restrictions on new admissions on the affected ward. this information could be very valuable when such an expensive measure is considered in an outbreak situation. this systematic review provides an overview on nosocomial outbreaks published in years of medical literature. collection of outbreak descriptions was performed by a search of the 'outbreak database' (http:// www.outbreak-database.com) in august . this database is freely assessable via the internet and contains detailed descriptions of numerous nosocomial outbreaks. all of these outbreaks are filed in a systematic manner that allows the user a quick and convenient query for the parameter of interest (e.g. causative pathogen, number of affected patients, or implemented infection control measures). the development of the database has been described in more detail elsewhere. meanwhile, this database includes approximately % of all nosocomial outbreaks ever published in pubmed. there were no restrictions with respect to a minimum number of patients involved in the outbreak, to the type of publication (editorial, letter, case report, or original article), or to language. an intervention considered as a 'closure' was defined as any partial or total closure of an affected location, regardless of its duration or complexity. for all outbreaks in which 'closure' was applied, the following data were obtained: (a) the type of medical department; (b) the degree of closure, e.g. part of the unit, the entire unit, or multiple units; (c) the species of the nosocomial pathogen; (d) the most probable source of the outbreak; (e) the route of transmission; (f) the distribution of outbreak-associated nosocomial infections. closure rates (crs) were calculated stratified by each of the parameters listed above. the cr of each stratified parameter was then compared to the average cr in the whole database using fisher's exact test (p < . ) using epiinfo â . . software. overall there were outbreaks filed in the outbreak database, in of which some kind of closure had been performed as an infection control measure. the exact duration of closure was described in outbreaks. in these outbreaks the median closure time was days (range: e days). the distribution of the main affected medical departments and corresponding cr are shown in table i in more detail. highest crs were reported from geriatric patient care ( . %), and from orthopaedic departments ( . %). table ii shows the cr with respect to different nosocomial pathogens. viral infections especially, such as norovirus ( . %) and influenza/parainfluenza virus ( . %), were associated with closure of the unit. only of the analysed outbreaks provided detailed information on the degree of closure in the particular outbreak setting. in the vast majority ( of outbreaks; . %), the entire unit was closed during the epidemic. entire facilities had been closed in outbreaks due to influenza virus (three outbreaks), sars coronavirus (two), s. pneumoniae (two), norovirus (one), shigella spp. (one), and rotavirus (one). besides closure of the ward, several additional infection control measures were described. the most frequent interventions were isolation of infected or colonized patients ( . %), screening cultures and surveillance of patients ( . %) and staff ( . %), as well as enforced hand hygiene ( . %) and reprocessing of devices (sterilization or disinfection; . %). other less common infection control measures comprised education of healthcare workers ( . %), restriction of the work load ( . %), or vaccination if available ( . %), e.g. for the prevention of infection by hepatitis b virus or by s. pneumoniae. tables iiiev summarize the data on the source of the outbreak, the mode of pathogen transmission, and the distribution of nosocomial infections that finally led to closure of the ward. cr was high especially when patients had been the source of the outbreak ( . %; table iii ) and when the pathogen had been acquired by inhalation or by contact ( . and . % respectively; table iv ). the highest cr were recorded when infection of the central nervous system ( . %) or infections of eye, ear, nose, throat or mouth ( . %) occurred (table v) . apart from these two classes of infection, there was no significant difference between the average cr ( . %) and that of any other class. as stated before, a total closure of a medical department is an extremely cost-intensive measure in a nosocomial outbreak setting. however, outbreak management is always a multi-task procedure and the exact costs for the closure are difficult to determine. in a retrospective cost analysis of a four-month outbreak caused by extended-spectrum beta-lactamase-producing (esbl) k. pneumoniae in a neonatal intensive care unit, approximately onethird of the total outbreak costs could be referred to the lost revenue from blocked patient beds. to avoid unnecessary expenses during an outbreak it is important to implement evidence-based and effective infection control recommendations to limit pathogen spread at the earliest possible stage. knowledge of certain characteristics that will lead to closure of the unit in a large proportion of outbreaks may be useful when deciding whether to close the ward at an earlier time point. our analysis demonstrates that such an expensive measure is likely to be necessary in viral infections of the gastrointestinal (norovirus) or respiratory (influenza/parainfluenza) tract (table ii) . this may reflect the high transmissibility and low infectious dose of these pathogens. , in addition, prolonged survival time of the outbreak strain in the environment may contribute to the likelihood of transmission, as it has been proposed in outbreaks due to acinetobacter spp. closure of a department is usually considered much more often when it cares for older patients but less so on paediatric wards (table i) . this can easily be explained by the confounding fact that most norovirus outbreaks take place on geriatric wards. in geriatric patients, it is especially difficult to implement sufficient infection control measures such as isolation in private rooms, and also to achieve a high compliance with alcohol-based hand rub. in terms of the outbreak's source, we found that contaminated medical devices led significantly less often to the closure of the ward. most probably these kinds of outbreaks stopped as soon as the device was identified as the source of the outbreak and were removed. by contrast, there was no such option for outbreaks in which infectious patients were responsible for the spread of the pathogen (table iii) . a similar explanation might be applicable for the findings on transmission by contact vs an invasive technique (table iv) . there are limitations to our analysis that must be borne in mind. ( ) when performing a systematic analysis on medical literature, one has to rely on published data. however, most probably the majority of nosocomial outbreaks will not be published in the medical literature or will not even be recognized. thus there will be some bias towards extraordinary species or towards common species that show a more antimicrobial-resistant phenotype. we believe that the large number of outbreaks filed already in the outbreak database balances this publication bias at least to some extent. ( ) some characteristics need a more detailed differentiation. for example, we cannot distinguish between the different kinds of hepatitis viruses, the various types of environmental source, or the sort of contact that occurred (direct or indirect by contaminated surfaces). more systematic analysis of nosocomial outbreaks needs to be performed to gain a better insight into the speciality of certain pathogens, possible sources of nosocomial outbreaks, and effective infection control measures. the outbreak database happens to be a very valuable tool for obtaining a quick overview on all kinds of outbreaks. it can therefore be used for education of staff to prevent the occurrence of an outbreak in the first place, but it may also be helpful when quick decisions need to be made during the investigation of a current epidemic. hospitalacquired infections in intensive care unit patients: an overview with emphasis on epidemics how frequent are outbreaks of nosocomial infection in community hospitals? a predominantly clonal multi-institutional outbreak of clostridium difficile-associated diarrhea with high morbidity and mortality the immediate psychological and occupational impact of the sars outbreak in a teaching hospital postoperative endophthalmitis caused by an enterobacter species direct costs associated with a nosocomial outbreak of adenoviral conjunctivitis infection in a long-term care institution a simultaneous outbreak on a neonatal unit of two strains of multiply antibiotic resistant klebsiella pneumoniae controllable only by ward closure how outbreaks can contribute to prevention of nosocomial infection: analysis of , outbreaks attributable costs and length of stay of an extended-spectrum beta-lactamaseproducing klebsiella pneumoniae outbreak in a neonatal intensive care unit lessons learned from a norovirus outbreak in a locked pediatric inpatient psychiatric unit lessons from a nursing home outbreak of influenza a survival of acinetobacter baumannii on dry surfaces risk groups for clinical complications of norovirus infections: an outbreak investigation a grant for the general implementation of the outbreak database was provided by schülke & mayr gmbh, norderstedt, germany. key: cord- - kbq v w authors: heath, joan a.; zerr, danielle m. title: infections acquired in the nursery: epidemiology and control date: - - journal: infectious diseases of the fetus and newborn infant doi: . /b - - - / - sha: doc_id: cord_uid: kbq v w nan neonates, especially premature neonates, requiring intensive care support constitute a highly vulnerable population at extreme risk for nosocomial or health care-associated infections. it has been estimated that as many as % to % of infants who survive or more hours in a high-risk nursery or neonatal intensive care unit (nicu) acquire a nosocomial infection."* although nosocomial infections have long been recognized in nicus, only recently have data on rates been documented in the literature. as technology and treatments have advanced to significantly diminish mortality and morbidity among critically ill neonates, especially infants of very low birth weight (less than g), this vulnerability has only increased, as a result of both more profound immune system immaturity and more frequent use of invasive interventions that bypass skin and mucous membrane barriers. ' nosocomial infections in neonates carry high attendant morbidity and mortality and health care costs. prevention and control of these infections, although highly desirable, present a formidable challenge to health care professionals. because control over birth weight-the most significant predictor of nosocomial infection risk-is limited, proper nicu customs, environment, and procedures (e.g., hand hygiene, antimicrobial usage, catheter-related practices, skin and cord care, visitation policies, unit design, and staffing) can reduce the risk for infection in the nicu. understanding the epidemiology of nosocomial infections in neonates and methods for their prevention and control is critical to minimizing poor outcomes. this chapter describes the epidemiology, etiology, and clinical characteristics of neonatal nosocomial infections as well as the methods required for effective infection prevention and control. it is well recognized that the immune system of the newborn infant, especially the premature infant, is functionally inferior to that of older infants, children, and adults (see chapter ). the lineages of the cells that will develop into the immune system are present at the beginning of the second trimester. the major components of the neonatal immune system, including t cells, neutrophils, monocytes, and the complement pathways, are functionally impaired, however, when compared with those in older infants and adults. for example, neonatal neutrophils show decreased chemotaxis, diminished adherence to the endothelium, and impaired phagocyto~is~~~; neonatal complement levels and opsonic capacity also are reduced, particularly in the premature ne nate. '~ in addition, neonatal t cell lymphokine production, cytotoxicity, delayed-type hypersensitivity, and help for b cell differentiation all are inferior when measured against those in adults! antigenic naivete may account for many of these differences; however, inherent immaturity also appears to account for certain inequities. for example, neonatal t cells are delayed in their ability to generate antigen-specific memory function after hsv infection, even in comparison with naive adult t cells. ' passively acquired maternal immunoglobulin g (igg) is the sole source of neonatal igg. soon after birth, maternal igg levels begin to fall; weeks later, production of immunoglobulins by the neonate commences. neonatal igg levels reach about % of adult levels by year of age. unfortunately, because much of the maternal igg is not transferred to the infant until the last to weeks' gestation, premature infants start with significantly lower levels of serum igg than in their term counterparts, which persist throughout most of the first months of life. other issues specific to the premature neonate also affect the functional immune system. for instance, the immature gastrointestinal tract (lack of acidity worsened by use of histamine h blockers and continuous feedings) and easily damaged skin constitute open potential portals of entry for pathogens or commensals. in addition, like other intensive care unit populations, the nicu population frequently experiences extrinsic breeches of the immune system through use of intravascular catheters as well as other invasive equipment and procedures used to care for critically ill patients. it is generally accepted that colonization with "normal flora" prevents, to some degree, colonization by pathogenic organisms. the neonate begins life essentially sterile. in the healthy term neonate, colonization occurs within the first few days of life. the organisms involved by site are a-hemolytic streptococci in the upper respiratory tract, staphylococcus epidermidis and other coagulase-negative staphylococci (cons) on the skin, and gram-negative bacilli and anaerobes in the gastrointestinal tract. this process of colonization with normal flora is disrupted in infants cared for in an nicu in part because of exposure to the nicu environment, the hands of health care workers (hcws), antimicrobial agents, and invasive procedures. as a result, the microflora of infants in the nicu can be markedly different from that of healthy term infantses multiple antimicrobial agent-resistant cons, klebsiella, enterobacter, and citrobacter species colonize the skin and the respiratory and gastrointestinal tracts of a high proportion of nicu neonates by the second week of hospitali~ation.'~-'~ in addition, neonates in the nicu become colonized not only with candida albicans but also with non-albicans candida species and malasse~ia.'~-' ' because colonization of the neonate with pathogenic organisms is a prelude to invasive infection from the same pathogens? measures to prevent such colonization need to be considered. first, as a result of abnormal colonization, infants in the nicu themselves serve as an important reservoir of potential pathogens. second, contamination of the hands of hcws during routine patient care has been well documented.'* thus, careful attention to hand hygiene before and after contact with patients and their environment, as well as decontamination of potential fomites, are crucial measures in preventing spread of colonization and infection. nosocomial infections in healthy term infants are uncommon unless other conditions require that they be cared for in the nicu for several days to weeks. on the other hand, these other conditions are frequent in neonates of very low birth weight (less than g), who require prolonged nicu care. understanding the epidemiology of nosocomial infections in nicus can be challenging, because reported rates vary dramatically by institution. this variation probably results from use of nonstandard definitions of nosocomial infection and from differences in patient populations, such as mean gestational age, birth weight, and severity of underlying illness, which significantly affect the incidence of nosocomial infection." the national nosocomial infections surveillance (nnis) system is a national surveillance system of the centers for disease control and prevention (cdc) that uses standardized surveillance protocols and the involvement of multiple medical centers to provide benchmark data for the epidemiology of nosocomial nicu infections. using standardized definitions, "is reported in that , nosocomial infections occurred between and in , neonates in nicus.~' in this study, rates of intravascular catheterassociated bloodstream infection, the most frequent nosocomial infection, ranged from fewer than infections per umbilical or central catheter days in infants with a birth weight greater than g to almost infections per catheter days in the lowest-birth-weight group (less than another national, multicenter surveillance study, the pediatric prevention network's (ppn) point prevalence survey, was undertaken in to determine the point prevalence of nosocomial infections in nicus and to define risk factors associated with development of these infections." this study included infants from nicus. of the infants, ( . %) had an active nosocomial infection on the day of the survey. bacteremia accounted for % of infections; lower respiratory tract infections, ear-nose-throat infections, and urinary tract infections accounted for %, %, and %, respectively (table - ) . in contrast with the nicu setting, the frequency of nosocomial infection in well-baby nurseries has been estimated to be between . % and . %? - in general, non-lifethreatening infections such as conjunctivitis account for a majority of infections in the well-baby population. the remainder of this chapter focuses almost entirely on nosocomial infections in and control measures for the nicu setting. g). / ( . ) / ( ) / ( ) for purposes of surveillance and tracking, all infections occurring in hospitalized newborns could be considered nosocomial. infections that are manifested in the first few days of life, however, usually are caused by pathogens transmitted vertically from the maternal genital tract. unfortunately, no precise time point perfectly distinguishes maternally acquired neonatal infections from those transmitted within the nicu. nnis has attempted to address this issue by stratifying infections according to whether they are likely to be maternally acquired. in % of neonates who had an infection thought to be maternally acquired, onset occurred within hours of birth. use of a cutoff period of hours or less to designate maternally acquired infections allowed . % of bacteremias and . % of pneumonias to be considered as originating from a maternal source. maternally acquired bloodstream infections were more likely to be caused by group b streptococci, other streptococci, and escherichia coli, whereas those not maternally acquired usually were caused by coagulase-negative staphylococci. in general, nonmaternal routes of transmission of microorganisms to neonates are divided into three categories: contact (from either direct or indirect contact from an infected person or a contaminated source), droplet (from large respiratory droplets that fall out of the air at a maximum distance of feet), and airborne (from droplet nuclei, which can remain suspended in air for long periods and as a result travel longer distances). specific microorganisms can be spread by more than one mechanism; in most instances, however, a single mode of spread predominates. the cdc has developed a system of precautions for the control of nosocomial infections that is based on these modes of transmi~sion.~~ contact transmission of bacteria, viruses, and fungi on the hands of hcws is arguably the most important yet seemingly preventable means of transmission of nosocomial infection. spread of infection by this means can occur either by transmission of the hcw's own colonizing or infecting pathogens or, more often, by transmission of pathogens from one patient to another. that the hands of hcws become contaminated even in touching intact skin of patients has been well demonstrated.'* poor compliance with hand hygiene is another means by which the hands of hcws can spread organisms from one patient to another. furthermore, hands of hcws have been implicated in multiple outbreaks with a variety of different organisms; through experimental studies, a causal link between hand hygiene and nosocomial infection has been established. contact transmission by means of fomites also can occur and has been described as a potential mechanism of spread of pathogens in multiple nicu outbreaks. as described later in this chapter, implicated items have included linens, medical devices, soap dispensers, and breast pumps, to name a few. these observations highlight the need for careful attention to disinfecting items shared between infants. spread through large respiratory droplets is an important mode of transmission for pertussis and infections due to neisseria meningitidis, group a streptococci, and certain respiratory viruses, whereas airborne transmission by means of droplet nuclei is relevant for measles, varicella, and pulmonary tuberculosis. for large droplet or droplet nuclei transmission, usually an ill adult, either an hcw or a parent, is the source of infection in an nicu setting. in general, these organisms are rare sources of outbreaks. infusates, medications, and feeding powders or solutions can be intrinsically or extrinsically contaminated and have been reported as the source of outbreaks due to a variety of different pathogens. it is important when possible to mix infusates in a controlled environment (usually the pharmacy), to avoid multiuse sources of medication, and to use bottled or sterilized feeding solutions when breast milk is not available. of course, nosocomial infection also can arise from endogenous sources within the neonate. the "abnormal flora" of the neonate residing in the nicu, however, is determined at least in part by the nicu environment and hcws' hands. with use of molecular techniques, even organisms typically considered to originate solely from normal flora (e.g., cons) have been shown to have clonal spread in the hospital setting, suggesting transmission by means of the hands of hcws.~~,~' as discussed earlier, infants in nicus have intrinsic factors predisposing them to infection, such as an immature immune system and compromised skin or mucous membrane barriers. in addition, multiple extrinsic factors play important roles in the development of infection, such as presence of indwelling catheters, performance of invasive procedures, and administration of certain medications, such as steroids and antimicrobial agents. birth weight is one of the strongest predictors of risk for nosocomial infection. for instance, "is data demonstrate that compared with larger infants, low-birth-weight infants are at higher risk of developing bloodstream infections and ventilator-associated pneumonia, even after correction for central intravascular catheter and ventilator use." similarly, in the ppn's point prevalence survey, infants weighing g or less at birth were . ( % confidence interval [ci] . % to . %; p < . ) times more likely to have an infection than those weighing more than g. ' the relationship between birth weight and nosocomial infection is complicated by multiple other factors that accompany low birth weight and also increase risk for nosocomial infection. low birth weight, however, has been shown to be an independent predictor for nosocomial infection, after adjustment for use of vascular catheters, parented alimentation, and mechanical ~entilation.~~ it is likely that birth weight also is a surrogate marker for other unmeasured factors, such as immune system immaturity. central venous catheters (cvcs) increase the risk for development of nosocomial bloodstream infections. in a study by chien and colleagues , infants admitted to nicus in canada, nosocomial bloodstream infections were found to occur at a rate of . to . infections per catheter days, depending on the type of catheter, versus . infections per noncatheter days. other studies have demonstrated that the association between cvcs and bloodstream infection is independent of birth weight. ' mechanisms for cvc-related nosocomial bloodstream infections probably involve colonization of the catheter by means of the catheter hub, colonization of the skin at the insertion site? or hematogenous spread of pathogens from distant sites of infection or colonization. bloodstream infections also can result from contaminated intravenous fluids, which have the potential for intrinsic or, especially with use of multiuse vials, extrinsic contamination. factors related to the management of cvcs influence the risk of infection. disconnection of the cvc and the frequency of blood sampling through the catheter increase the frequency of catheter-related infection^.^^ by contrast, administration of a solution with heparin and exit-site antisepsis decreased infection. lower frequency of cvc tubing changes (every hours versus every hours) was associated with increased catheter contamination, suggesting a potential for increased risk of infecti n. ~ cvc management techniques, including use of antiseptic-impregnated dressings, antimicrobialcoated catheters, and avoidance of scheduled replacement of cvcs, are discussed in the most recent cdc recommendations, summarized in "guidelines for the prevention of intravascular catheter-related infection," published in and prepared by the hospital infection control practice advisory c~m m i t t e e .~~ it has been suggested that use of peripherally inserted central catheters (piccs) may be associated with a lower rate of infection than for other cvcs. studies based in nicus have yielded conflicting results. in a study by chien and colleagues?' the relative risk of bloodstream infection, after adjustment for differences in infant characteristics and admission illness severity, was . per catheter days for umbilical venous catheters, . for piccs, and . for broviac catheters, compared with no catheter ( p < . ). another study also documented similar rates of infection for broviac catheters and for piccs.~~ by contrast, a higher rate of infection with broviac catheters than with piccs was suggested by brodie and co-w~rkers.~~ further study of different cvcs in nicu infants is needed to delineate infection risks for individual catheter types. parented alimentation and intralipids have been shown to increase risk of bloodstream infection in premature infants even after adjustment for other covariables such as birth weight and cvc use. etiologic agents often associated are cons, candida species, and malassezia species. the pathogenesis of this association remains unclear. potential hypotheses are many. intralipids, for example, could have a direct effect on the immune system, perhaps through inhibition of interleukin- . alternatively, as with any intravenous fluids, parented alimentation has the potential for intrinsic and extrinsic contamination, and intralipids especially may serve as a growth medium for certain bacteria and fungi. finally, total parented alimentation and intralipids delay the normal development of gastrointestinal mucosa because of lack of enteral feeding, encouraging translocation of pathogens across the gastrointestinal mucosa. it is well accepted that mechanical ventilation is an important risk factor for nosocomial lower respiratory tract infection. a large multicenter study of neonates found that mechanical ventilation was a risk factor for bloodstream infection as well, even after adjustment for a number of covariables such as birth weight, parented nutrition, and umbilical catheterization:' clinically obvious respiratory infection appeared to precede some but not all cases of bloodstream infection associated with mechanical ventilation. the study authors suggested that the increased risk of mechanical ventilation could be attributed to colonization of humidified air, as well as to physical trauma from the endotracheal tube and its suctioning. a number of medications critical to the survival of infants in the nicu increase risk of infection. broad-spectrum antimicrobial agents, especially with prolonged use, are important in the development of colonization with pathogenic micro-organism~.~ the widespread use of broad-spectrum antimicrobial agents has been associated with increased colonization with resistant organisms in many settings, including nicus." in addition to colonization, antimicrobial agents also have been shown to increase risk of infection with resistant bacteria ' and with fungal pathogens!' other medications also appear to play a role in nosocomial infection. for instance, infants who receive corticosteroids after delivery are at approximately . to . times higher risk for nosocomial bacteremia in the subsequent to weeks than that observed for infants who do not receive this in addition, colonization and infection with bacterial and fungal pathogens have been shown to increase with the use of h, blocker^.'^"' measures of illness severity have been developed, in part, in an effort to account for variations in birth weight-adjusted mortality scores between nicus. the score for neonatal acute physiology (snap) was developed and validated by richardson and ass ciates, ~ and the clinical risk index for babies (crib) was developed by the international neonatal network.% these scores are highly predictive of neonatal mortality even within narrow birth weight strata and are predictive of nosocomial infection. thus, in investigating potential risk factors for nosocomial infection, it is important to consider adjusting for illness severity using such measures, in addition to adjusting for other potential confounders. other risk factors related to infection include poor hand hygiene and environmental issues, such as understaffing and overcrowding. b these and related issues are discussed later in this chapter under "prevention and control." nosocomial infections can affect any body site or organ system and manifest in a multitude of different ways. "is and ppn data demonstrated that bloodstream infections are the most common manifestation of nosocomial infection and account for % to % of infections (table - ; see also table - ). ,'' respiratory infections and eye, ear, nose, or throat infections are second and third in frequency, whereas gastrointestinal infections, urinary tract infections, surgical site infections, meningitis, cellulitis, omphalitis, septic arthritis, and osteomyelitis are reported less frequently."*" bloodstream infections are the most common and one of the most potentially serious nosocomial infections that occur in nicu patients. factors discussed earlier, including birth weight, intravascular catheters, mechanical ventilation, use of parented alimentation, and steroids, all have been shown to be associated with an increased risk of bloodstream infection. the most common pathogen associated with nosocomial bloodstream infections is cons (see table - ). staphylococcus aureus, enterococcus, candida species, e. coli, enterobacter species, klebsiella pneurnoniae, and pseudomonas aeruginosa also play important roles and are associated with higher morbidity and mortality rates than those associated with cons?^,^" in one study, the frequency of fulminant sepsis (fatal within hours) was estimated to be % ( % ci % to %) when the bloodstream infection was caused by pseudomonas species, whereas it was only % ( % ci % to %) when infection was caused by cons.^" the difficulty of assigning an etiologic role to cons on the basis of one blood culture that could be contaminated probably accounts for some distortion of the incidence and mortality data related to this organism, and this problem is discussed in detail in chapter . pneumonia accounts for % to % of nicu nosocomial infections" and has been associated with prolonged hospital stay and increased mortality. organisms most commonly associated with nosocomial pneumonia include cons, s. aureus, and i? aeruginosa (see table - ). mechanical ventilation and birth weight are important risk factors for nosocomial respiratory infection^.^^ diagnosis of nosocomial respiratory infections requires correlation of microbiologic results with clinical findings and can be challenging in lowbirth-weight infants because of the mostly nonspecific associated signs of illness and often misleading results of radiologic ~tudies.~' eye, ear, nose, and throat infections account for approximately % to % of infections, depending on birth weight." common etiologic organisms include cons and s. aureus, although gram-negative organisms, such as e. coli, e! aeruginosa, and k. pneumoniae, also can be isolated from these sites (see table - ). conjunctivitis appears to be the most common of these infections, accounting for % to %, depending on birth weight?' risk factors for neonatal conjunctivitis identified in a study from nigeria included vaginal delivery, asphyxia, and prolonged rupture of membranes. in the nnis review, gastrointestinal infections were estimated to account for % to % of nosocomial infections, depending on birth weight. necrotizing enterocolitis (nec) was the most common presentation.'" nec carries high morbidity and mortality rates. a review of nec epidemics estimated that surgery was required for a mean of % (range, % to %) of infants, and death occurred in a mean of % (range, % to y ) .~~ in controlled studies, identified risk factors for nec have included young chronologic age, low gestational age, low birth weight, and young age at first feeding. implication of specific pathogens is complex, requiring careful selection of an appropriate control population and attention to how and where specimens are collected. pathogens associated with nec outbreaks have included pseudornonas species, salmonella species, e. coli, k. pneumoniae, enterobacter cloacae, s. epidermidis, clostridium species, coronavirus, and r~t a v i r u s .~~'~~ the importance of infection control methods such as strict attention to hand hygiene and cohorting patients in the nicu is suggested by the observation that their implementation has been followed by resolution of the outbreak. a detailed discussion of the cause of nosocomial sepsis and meningitis is found in the chapter on bacterial sepsis (chapter ) and chapters describing specific etiologic agents. s. aureus is a colonizing agent in neonates and has been a cause of nosocomial infection and outbreaks in well-baby nurseries and nicus. methicillin-resistant s. aureus (mrsa) has become a serious nosocomial pathogen, and outbreaks have been reported in many areas of hospitals, including n~rseries.~~-~' in addition to the usual manifestations of neonatal nosocomial infection (conjunctivitis, bloodstream infections, and pneumonia), nosocomial s. aureus infections can manifest as skin infection^?^ bone and joint infections,@' parotitis:' staphylococcal scalded skin syndr me, ~*~~ toxic shock syndrome? and disseminated sepsis. the role of the hands of hcws in transmitting and spreading pathogenic organisms among infants was demonstrated with s. aureus in the ~."*~~ currently, in a majority of instances, s. aureus transmission is thought to occur by direct contact. thus, it is not surprising that understaffing and overcrowding have been associated with s. aureus outbreaks in n i c u s .~~.~ the potential for airborne transmission, however, has been suggested by the occurrence of "cloud babies? described by eichenwald and colleagues in . "cloud" hcws also have been described; in such cases, the point source of an outbreak was determined to be a colonized hcw with a viral respiratory infe~tion.~~'~' in one of these studies, dispersion of s. aureus from the implicated hcw was found to be much higher after experimental infection with rhinovirus. more recently, molecular techniques not only have defined outbreaks but also have demonstrated that transmission to infants probably occurs from colonized hcws, * and sometimes from colonized parents. nasal mupirocin ointment has been used to control outbreaks of both methidin-susceptible s. aureus and mrsa. , the pharynx, rather than the anterior nares, however, may be a more common site of colonization in neonates and infants," and eradication of the causative organisms with nasal mupirocin may be more difficult in this site. since the early s, cons has been the most common cause of nosocomial infection in the nicu. ' this finding suggests that a portion of cons infections may be preventable by strict adherence to infection control practices. the fact that a hand hygiene campaign was associated with increased hand hygiene compliance and a lower rate of cons-positive cultures supports this ~ontention.'~ enterococcus has been shown to account for % of total nosocomial infections in neonates, % to % of bloodstream infections, % to % of cases of pneumonia, % of urinary tract infections, and % of surgical site sepsis and meningitis are common manifestations of enterococcal infection during nicu outbreak^'^,^^; however, polymicrobial bacteremia and nec frequently accompany enterococcal sepsis. identified risk factors for enterococcal sepsis, after adjustment for birth weight, include use of a nonumbilical cvc, prolonged presence of a cvc, and bowel resection?' because enterococcus colonizes the gastrointestinal tract and can survive for long periods of time on inanimate surfaces, the patient's environment may become contaminated and, along with the infant, serve as a reservoir for ongoing spread of the organism. the emergence of vancomycin-resistant enterococci (vre) is a concern in all hospital settings, and vre have been the cause of at least one outbreak in the nicu setting ' in the neonate, resistant strains appear to cause clinical syndromes indistinguishable from those due to susceptible enteroco~ci.'~ the conditions promoting vre infection, such as severe underlying disease and use of broad-spectrum antimicrobial agents, especially vancomycin, can be difficult to alter in many nicu settings. guidelines for the prevention and control of vre infection have been published; these focus on infection control tools such as rapid identification of a vrecolonized or vre-infected patient, cohorting, isolation, and barrier precautions. historically, before the recognized importance of hand hygiene and the availability of antimicrobial agents, group a streptococci (gas) were a major cause of puerperal sepsis and fatal neonatal sepsis. although less common now, gas continue to be a cause of well-baby and nicu outbreak^.'^-'^ gas-associated clinical manifestations include severe sepsis and soft tissue infections. one report described a high frequency of "indolent omphalitis"; in this outbreak, the umbilical stump appeared to be an important site of gas colonization and an ongoing reservoir of the organism." routine cord care included daily alcohol application. after multiple attempts, the outbreak finally was interrupted after a -day interval during which bacitracin ointment was applied to the umbilical stump in all infants, and affected infants received intramuscular penicillin. molecular techniques have enhanced the ability to define outbreaks, and use of these techniques has suggested that transmission can occur between mother and infant, between hcw and infant, and between infantsprobably indirectly on the hands of hcws.",~~ in one recurring outbreak, inadequate laundry practices appeared to be a contributing factor. nnis data have shown that group b streptococci (gbs) infections account for less than % of non-maternally acquired nosocomial bloodstream and pneumonia infections." a number of studies from the s and s demonstrated nosocomial colonization of infants born to gbs-negative ~o m e n .~~-~o these studies suggested a rate of transmission to babies born to seronegative mothers as high as % to / . ~,~' a recent case-control study evaluating risk factors for lateonset gbs infection demonstrated that premature birth was a strong predictor?' in that study, % of the infants with late-onset gbs infection were born at less than weeks of gestation (compared with % of controls), and only % of the mothers of these infants were colonized with gbs, suggesting possible nosocomial transmission of gbs during the nicu stay. the hands of hcws are assumed to account for the transmission of most cases of nosocomial gbs infection. breast milk also has been implicated as a potential mode of acquisition, however. in one report, gbs probably was transmitted from breast milk to one set of premature triplets between days and of life. two maternal vaginal swabs taken before delivery did not grow gbs, but repeated cultures of the mother's breast milk yielded a pure growth of gbs (greater than ' colony-forming units [ cfu] /ml) despite no evidence of mastitis. in this report, antimicrobial therapy administered to the mother appeared to eradicate the organism. the enterobacteriaciae family has long been recognized as an important cause of nosocomial infection. neonatal infection can be manifested as sepsis, pneumonia, urinary tract infections, and soft tissue infections; morbidity and mortality rates frequently are enterobacter species, k. pneumoniae, e. coli, and serratia marcescens are the members of the family enterobacteriaciae most commonly encountered in the nicu. enterobacter species have been estimated to account for % of bloodstream infections, % of cases of pneumonia, and % of surgical site infections in the nicu setting (see table - ). outbreaks due to enterobacter species in nicus have been associated with thermometer^?^ a multidose vial of d e x t r o~e~~ intravenous fluids,% and powdered formula? as well as with understaffing, overcrowding, and poor hand hygiene practice^.'^ in one outbreak in which contaminated saline was linked to the initial cases, subsequent ongoing transmission was documented, presumably by means of the hands of hcws and the environment." in that study, early gestational age, low birth weight, exposure to personnel with contaminated hands, and e. cloacae colonization of the stool were associated with e. cloacae bacteremia, whereas use of cvcs and mechanical ventilation was not. k. pneumoniae has been estimated to account for a similar proportion of infections in the nicu setting to that identified for enterobacter species. investigations in outbreaks involving klebsiella species have implicated contaminated breast milk, oo infusion therapy practices,"' intravenous dextrose,io cockroaches, di~infectant,"~ incubator humidifier^,'^' thermometers, oxygen saturation probes,io and ultrasonography coupling ge .io in a surveillance study of nicu infants in brazil, % became colonized with kleb~iella.'~ in this study, colonization was associated with use of a cephalosporin and aminoglycoside combination therapy, as well as with longer duration of the nicu stay. e. coli has been estimated to cause % of bloodstream, % of gastrointestinal, and % of surgical site infections. e. coli also has been responsible for outbreaks of pyelonephritis,io ga~troenteritis,'~'*"o and nec. s. marcescens is an opportunistic pathogen that survives in relatively harsh environments. disease due to s. marcescens often is manifested as meningitis, bacteremia, and pneumonia.'" s. marcescens infections have a high potential for morbidity and mortality." ,' s. marcescens outbreaks have been associated with, but not limited to, contaminated soap, multiuse bottles of theophylline," formula,"' enteral feeding additives,l breast pumps,' ",'i and transducers from internal monitors.ii although point source environmental contamination is important in serratia outbreaks, in many of these outbreaks and in reports in which no point source was identified,"' patient-to-patient spread of the organism by means of the hands of hcws appeared to be an important mechanism of spread.i extended-spectrum p-lactamases (esbls) are plasmidmediated resistance factors produced by members of the enterobacteriaceae family. esbls inactivate third-generation cephalosporins and aztreonam. they most commonly occur in k. pneumoniae and e. coli but have increasingly been found in other gram-negative bacilli. colonization with esblproducing organisms has been associated with administration of certain antimicrobials and longer duration of hospitalization, whereas infection has been associated with prior colonization and use of cvcs.i that the esbl-containing plasmids can be transmitted to other enterobacteriaceae organisms has been demonstrated in nicu outbreaks in which the implicated plasmid spread from klebsiella species to e. coli, e. cloacae, and citrobacter fieundii.' s'zl the gastrointestinal tract in neonates and the hands of hcws serve as reservoirs for members of the enterobacteriaceae family. thus, in general, measures aimed at controlling spread of organisms in this family have focused on attention on hand hygiene, cohorting of patient and staff, and observation of isolation precautions.' " i? aeruginosa, an opportunistic pathogen that persists in relatively harsh environments, frequently has been associated with nosocomial infections and outbreaks in the nicu setting. nosocomial i! aeruginosa infections vary in their clinical presentation, but the most common manifestations are respiratory, ear, nose, or throat and bloodstream infections.*' from the ppn data it has been estimated that j? aeruginosa species account for . % of total pathogens, % of bloodstream infections, and % of respiratory infections. l ? aeruginosa infections, particularly bloodstream infections, have been associated with a very high mortality rate.' feeding intolerance, prolonged parented alimentation, and long-term intravenous antimicrobial therapy have been identified as risk factors for pseudomonas infe~ti n.l~~ outbreaks due to i! aeruginosa have been linked with contaminated hand lotion,' respiratory therapy solution, ' a water bath used to thaw fkesh-frozen plasma,' a blood gas analy~er,'~' and bathing sources. in one case, neonatal pseudomonas sepsis and meningitis were shown by pulsed-field gel electrophoresis to be associated with shower tubing from a tub used by the infant's mother during labor.i ' of importance, hcws and their contaminated hands also have been linked with pseudomonas infections in the nicu setting. in a study of a new york outbreak, recovery of pseudomonas from the hands of hcws was associated with older age and history of use of artificial nails. ' this and other studies suggest that the risk of transmission of pseudomonas to patients is higher among hcws with onychmycosis or those who wear long artificial or long natural nail^.'^^,'^^ as a result of these and other findings, the cdc revised its hand hygiene recommendations to include a recommendation against the presence of hcws with artificial fingernails in intensive care units.' bordetella pertussis is a rare cause of nosocomial infection in neonates. when b. pertussis infection occurs, parents and hcws typically are the source. a parent was the source of an outbreak involving three neonates and one nurse in a special care nursery in a~stralia.'~' in in knoxville, tennessee, an outbreak involving six neonates probably was due to transmission of infection by an hcw."' as a result of the tennessee outbreak, infants received erythromycin prophylaxis. subsequently, an increase in infantile hypertrophic pyloric stenosis was noted by local pediatric surgeons. results of a cdc investigation suggested a causal role of erythromycin in the cases of hypertrophic pyloric steno~is.'~~~~" erythromycin remains the recommended agent of choice for prophylaxis after pertussis exposure, but parents should be informed of the risk and signs of hypertrophic pyloric stenosis, and cases associated with erythromycin use should be reported to medwat~h.'~~ newborn infants are particularly prone to infection and disease following exposure to mycobacteriurn tuberculosis. a cluster of multidrug-resistant m. tuberculosis infections was noted in three infants born during a -week period in one new york h spita .l~~ investigation implicated an hcw who visited the nursery several times during that period. pulmonary and extrapulmonary disease occurred in three infants to months after exposure, highlighting the vulnerability of the newborn p~pulation.'~~ tuberculosis screening of hcws, ultraviolet lighting, and a high number of air exchanges appear to be effective methods in preventing nosocomial tuberculosis infe~ti n.i~' the cdc's "guidelines for preventing the transmission of mycobacteriurn tuberculosis in health-care settings" emphasizes ( ) use of engineering controls and personal protective equipment, ( ) risk assessments for the development of institutional tuberculosis control plans, ( ) early identification and management of individuals with tuberculosis infection and disease, ( ) tuberculosis screening programs for hcws, ( ) hcw education and training, and ( ) evaluation of tuberculosis control prograrns.l * candida species are an increasingly important cause of nosocomial infection in nicu patients and have been estimated to account for . % of bloodstream infections and % of urinary tract infection^.^^^"^ prospective studies have estimated colonization rates with candida to be % to % in low-birth-weight neonate^,'^"^^-'^' and colonization has been associated with subsequent invasive disease. ' the mortality rate can be high in invasive candidiasis. in one study of patients with fungemia due to candida species, a case-fatality rate of % was r e~ r t e d . i~~ risk factors for fungal infections in neonates are similar to risk factors for bacterial infections; low birth weight and gestational age are important predictors. in addition, a prospective, multicenter study of infants found that use of a third-generation cephalosporin, presence of a cvc, intravenously administered lipids, and hz blocker therapy were associated with candida colonization after adjusting for length of stay, birth weight of g or less, and gestational age less than weeksl candida parapsilosis appears to be the most frequent species associated with nosocomial candida infection in nicu infants. both cross-contamination and maternal reservoirs are sources of nosocomial candida albicans infection, as demonstrated in studies using molecular typing method^.'^-'^^ malassezia species, lipophilic yeasts, frequently colonize nicu patients. in one french study, of preterm neonates ( %) became colonized with malassezia fit+r. malassezia pachydermatis, a zoonotic organism present on the skin and in the ear canals of healthy dogs and cats, also has been associated with nosocomial outbreaks in the nicu setting. , in one report, the outbreak appeared to be linked to colonization of hcws' pet dogs.i ' pichia anornala, or hansenula anornala, a yeast found in soil and pigeon droppings, and on plants and fruits, also can colonize the human throat and gastrointestinal tract. in general, it is an unusual cause of nosocomial infection in neonates, but it was the cause of two reported outbreaks in this ~e t t i n g . '~~, '~~ in both reports, carriage on the hands of hcws appeared to be a factor. invasive mold infections are a rare cause of nosocomial infection in neonates, but when they occur, they are associated with high mortality rate. aspergillus infections may manifest as pulmonary, central nervous system, gastrointestinal, or disseminated disease. a cutaneous presentation, with or without subsequent dissemination, appears to be the most common presentation for hospitalized premature infants without underlying immune defi~iency.'~'.'~~ often, skin maceration is the presumed portal of entry. in a series of four patients who died of disseminated aspergillus infection that started cutaneously, a contaminated device used to collect urine from the male infants was impli~ated.'~' similarly, contaminated wooden tongue depressors, used as splints for intravenous and arterial cannulation sites, were associated with cutaneous infection due to rhizopus microsporus in four premature infants.' in addition to preterm birth, use of broad-spectrum antimicrobial agents, steroid therapy, and hyperglycemia are thought to be risk factors for mold infection. even zoophilic dermatophytes have been described as a source of nosocomial infection in neonates. in one report, five neonatal cases in one unit were traced to an infected nurse and her cat. prolonged therapy for both the nurse and her cat was necessary to clear their infections. although many pathogens can cause nosocomial gastroenteritis, rotavirus is responsible for % or more of viral infections in high-risk nurseries, including the nicu." in one longitudinal study, rotavirus infection developed during hospitalization in of neonates ( ? ).'~~ in this study, rotavirus was manifested as frequent and watery stools in term infants and as abdominal distention and bloody, mucoid stools in the preterm neonates. a high titer of virus is excreted in stool of infected persons, and the organism is viable on hands and in the environment for relatively prolonged periods of time.' " attention to hand hygiene and disinfection of potential fomites are crucial in preventing spread of infection. this concept is illustrated by the results of one study in which rotavirus infection was associated with ungloved nasogastric tube feeding. respiratory viruses including influenza a virus, parainfl uenza virus, coronavirus, respiratory syncytial virus, and aden )virus have been reported to cause nosocomial infections in qicu patient^.'^^-'^' associated clinical findings include rhino rrhea, tachypnea, retractions, nasal flaring, rales, and wheezir g, but illness also can be manifested as apnea, sepsis-like i lness, and gastrointestinal symptoms. ', * identified risk f ictors for acquisition vary from study to study but have includl id low birth weight, low gestational age, twin pregnancy, mech anical ventilation, and high crib s~o r e . '~~-'~* contact and d :oplet transmission are the most common modes of sprcad of infection, again highlighting the importance of scrul (dous hand hygiene in delivery of patient care for this popul, tion. numerous nursery and nicu outbreaks of enterovii a infection have been r e p~r t e d . '~~"~ in the neonate with e iteroviral infection, clinical manifestations can range fron mild gastroenteritis to a severe and fulminant sepsis-like sync home or meningitis/encephalitis. the latter presentation c m be associated with a high mortality rate.lw in index cas :s, the patient may have acquired disease vertically, with subst quent horizontal spread leading to outbreak^'^^'^^; with othe r viral pathogens, virus can be shed into the stool for prolnged periods, enabling patient-to-patient transmission by the hands of hcws when hand hygiene procedures are impr iperly performed. congenitally acquired cytomegalovirus (cmv) infecti )n is a cause of morbidity and occasionally death, whereas postnatally acquired cmv infection follows a benign col rse in virtually all healthy term infants. postnatal cmv infi ction, however, can cause considerable morbidity and death i n premature infants. hepatitis, neutropenia, thrombocyto penia, sepsis-like syndrome, pneumonitis, and developmi nt of chronic lung disease each have been associated with postnatal acquisition of cmv in premature infant^.'^^''^^ w th the routine use of cmv-seronegative blood products in these neonates, a majority of postnatal cmv infections ap ear to be acquired through breast milk.' it has been estinated that transmission by this mode occurs in approximate y % of breast-fed infants of mothers with cmv detec ed in breast milk. ' in one study, approximately % of these infants had clinical features of infection, and % pre iented with a sepsis-like syndrome. nosocomial person-to-] ierson transmission has been d o~u m e n t e d , '~'~'~~ but the exl ent to which this occurs is contr~versial.'~~ at present, no p :oven, highly effective method is available for removing cml ' from breast milk without destroying its beneficial compc nents. some data, however, suggest that freezing the breas: milk before use may decrease the cmv titer, thereby liniting subsequent transmission."* in a majority of cases, neonatal herpes simplex virus hsv) infection is acquired vertically from the mother. nursery transmission of hsv infection is rare but has been describe( . [ ] [ ] [ ] in each of these cases, hsv- was involved. in one infa it, the source of virus was thought to be a patient's father, wl had active herpes labiali~.'~~ subsequent spread of virus from this first infant to a second infant was thought to have occurred by means of the hands of an hcw. in another report, the source of hsv for the index case, an infant who died of respiratory distress in whom evidence of hsv infection was found at postmortem examination of the brain, was un- the hands of hcws were implicated in the spread of hsv to three subsequent cases, however. in another report, direct spread from an hcw was thought to be responsible for transmission of hsv to three infants over a period of approximately years.' studies of adults with herpes labialis suggest a high frequency of recovery of virus from the mouth and the hands ( % and %, re~pectively).'~~ in this same study, hsv was shown to survive for to hours on skin, cloth, and plastic. implementing contact precautions for infants with hsv and instructing hcws with active herpes labialis regarding control measures, such as covering the lesion, not touching the lesion, and using strict hand hygiene, are reasonable means to prevent nosocomial transmission of hsv. if there are concerns that an hcw would be unable to comply with control measures or if the hcw has a herpetic whitlow, such persons should be restricted from patient contact. nosocomial transmission of varicella in the nicu setting, although unusual, has been de~cribed.'~~ large-scale outbreaks in nurseries and nicus are rare, most probably because of the high rate of varicella-zoster virus (vzv) immunity in hcws and pregnant women. premature infants born at less than weeks of gestation are unlikely to have received protective levels of vzv igg from their mothers, so their potential risk is significant if an exposure occurs. transmission is most likely to occur from an adult with early, unrecognized symptoms of varicella. in such instances, the potential risk for vzv-seronegative exposed infants and hcws is substantial, especially if the patient in the index case is an hcw.'" for this reason, it is recommended that hcws be screened for prior varicella infection by history, with subsequent immunization as indicated. hepatitis a is a rare cause of nosocomial infection in nicus, but a number of outbreaks in this setting have been r e p~r t e d . '~' . '~~ in most instances, disease in neonates is clinically silent. neonatal cases often are detected only through recognition of the symptomatic secondary adult cases. in one report, disease was acquired by patients in the index cases through blood transfusion from a donor with acute hepatitis of note, the virus subsequently spread to another infants, nurses, and other hcws. overall, hepatitis a affected % of the patients and % of the nurses. lapses in infection control practices and the prolonged shedding of the virus in infants stool probably contributed to the rapid spread and high attack rate documented in the outbreak. outbreaks such as this one are unlikely because of current blood product practices to eliminate transmissible agents from donor blood. an effective infection control program that focuses on reducing risk on a prospective basis can decrease the incidence of nosocomial infection^.'^"^^ the principal function of such a program is to protect the infant and the hcw from risk of hospital-acquired infection in a manner that is cost-effective. activities crucial to achieving and maintaining this goal include collection and management of critical data relating to surveillance for nosocomial infection, and direct intervention to interrupt the transmission of infectious diseases. reducing the incidence of nosocomial infection for neonates must begin with surveillance for these events. surveillance has been defined as "a comprehensive method of measuring outcomes and related processes of care, analyzing the data, and providing information to members of the health care team to assist in improving those outcomes."' essential elements of a surveillance program include the following: defining the population and data elements as concisely collecting relevant data using systematic methods consolidating and tabulating data to facilitate evaluation analyzing and interpreting data reporting data to those who can bring about changeia surveillance systems necessarily vary, depending on the population; accordingly, a written plan, based on sound epidemiologic principles,ls should be in place to track rates of infection over time. because new risks can emerge, such as new interventional technology or drugs, changing patient demographics, and new pathogens and resistance patterns, the plan should be reviewed and updated the joint commission on accreditation of healthcare organizations (jcaho) recommends that hospitals have a written infection control plan that includes a description of prioritized risks; a statement of the goals of the infection control program; a description of the hospital's strategies to minimize, reduce, or eliminate the prioritized risks; and a description of how the strategies will be evaluated. the jcaho further recommends that hospitals identify risks for transmission and acquisition of infectious agents (table - system provides high-risk nursery-specific data collection methods as well as denominator data and allows external benchmarking of infection rates for this populati~n.'~~,'~' the nnis system defines a nosocomial infection as a localized or systemic process that results from adverse reaction to the presence of an infectious agent(s) or its toxin(s) and that was not present or incubating at the time of admission to the hospital. nnis also recognizes as special situations, and defines as nosocomial, some infections in neonates that result from passage through the birth canal but do not become clinically apparent until several or more days after birth. it does not, however, consider infections that are known or proved to have been acquired transplacentally to be noso-~omial.'~' distinction between maternal and hospital sources of infection is important, although difficult at times, because control measures designed to prevent acquisition from hospital sources will be ineffective in preventing perinatal acquisition of pathogen^.'^' surveillance for infections in healthy newborns also is challenging because of the typically short length of stay. infections can develop after discharge, and these are more difficult for infection control practitioners (icps) to capture. methods for postdischarge surveillance have been developed, but because most neonatal infections that occur following discharge are noninva~ive,'~~ such surveillance has not been widely implemented, because of concerns about the cost-effectiveness of these labor-intensive processes. the ultimate goal of surveillance is to achieve outcome objectives (e.g., decreases in infection rates, morbidity, mortality, or cost).is baseline infection rates for an inpatient unit must be established so that the endemic rate of infection can be understood and addressed. in the nicu, concurrent surveillance (initiated while the infant is in the hospital) should be conducted by persons trained to collect and interpret clinical information. typically, such persons are icps working closely with hcws and using various data sources (table - ) . using nnis or other accepted definitions, the icp should collect data regarding cases of nosocomial infection in the nicu population as well as population-specific denominator data. denominators must be carefully chosen to represent the population at risk. attempts to stratify risk should take into account both underlying infant-specific risks and those resulting from therapeutic or diagnostic interventions.' risk stratification techniques that attempt to control for distribution of risk have included severity of illness score, intensity of care required, and birth weight. because the risk for developing nosocomial infection is greater for lower-birthweight infants:' the nnis system breaks down data collection and analysis into birth weight categories (tables - and - ).' ' the use of invasive devices, however, also is an important factor to consider. the appropriate denominator for an infection related to the use of a medical device, such as a cvc-related primary bloodstream infection, according to nnis, would be total device days for the population during the surveillance period. the formula generally used for calculating nosocomial infection rates is (x/y)k, where x equals the number of events (infections) over a specific time period, y equals the population at risk for development of the outcome, and k is a constant and a multiple of . rates can be expressed as a percentage (k = loo), although device-related infections usually are expressed as events per device days (k = ). a value should be selected for k that results in a rate greater than because use of invasive devices is such a significant risk factor both for bloodstream infection and ventilatorassociated pneumonia, assessing nicu practices with device use may be warranted. "is provides a benchmark for nicu device utilization broken down into birth weight categories. an nicu device utilization ratio can be calculated using the following formula: in those units with device utilization ratios above the nnis th percentile, investigation into the practices surrounding use of invasive devices may be ~a r r a n t e d . '~~ calculating monthly and annual rates to employ as benchmarks can assist in identification of a potential problem in device-related procedures. surveillance data must be arranged and presented in a way that facilitates interpretation, comparison both directed internally and with comparable external benchmarks, and dissemination within the organization. quality improvement tools (e.g., control and run charts) can be useful for these purposes. statistical tools should be used to determine the significance of findings, although statistical significance should always be balanced with the evaluation of clinical ~ignificance."~ external benchmarking through interhospital comparison is a valuable tool for improving quality of are'^,'^^ but should be performed only when surveillance methodologies (e.g., case definitions, case finding, data collection methods, intensity of ~urveillance)'~~ can reasonably be assumed to be consistent between facilities. few overall infection rates in nicus are available, but a small study done in children's hospitals performing nicu nosocomial infection surveillance reported a median nosocomial infection rate of . infections per patient days (range, . to . ). ' nnis does not provide a benchmark for overall infection rates within nicus. instead, nnis provides birth weight-stratified device-associated infection rates for umbilical and central intravascular line-associated bloodstream infections. the most recent rates for catheterrelated bloodstream infections ( to nicus reporting) and ventilator-associated pneumonias ( to nicus reporting) are summarized in table e~ . l~~ once arranged and interpreted, nosocomial infection data must be shared with personnel who can effect change and implement infection control interventions. written reports summarizing the data and appropriate control charts should be provided to the facility's infection control committee, unit leaders, and members of the hospital administration on an ongoing basis. the interval between reports is determined by the needs of the institution. in addition to formal written reports, face-to-face reports are appropriate in the event of identification of a serious problem or an outbreak. icps can serve as consultants to assist nicu or neonatology service leaders in addressing infection rate increases or outbreak management. surveillance activities typically identify endemic nosocomial infections (i.e., those infections that represent the usual level of disease within the nursery or nlcu).' although the rate can fluctuate over time, in the absence of interventions that successfully reduce risk of infection, the difference rarely is statistically significant. establishing an nicu's endemic infection rate and expected variation around that rate allows the icp to rapidly identify unusual increases in rates that may indicate on outbreak (epidemic) of a particular infection. using baseline surveillance data along with aggregate data from sources such as the "is system allows the icp to develop meaningful threshold rates for initiating outbreak investigation.is alternatively, hcws can be the first to sense an increase in infections, which then can be confirmed or refuted by surveillance data? even a single case of infection due to an unusual and potentially dangerous pathogen (e.g., salmonella) can constitute the index case for a subsequent outbreak and thus merits rapid and comprehensive investigation. outbreaks may need to be reported to health authorities, depending on local and state requirements as well as the organism involved. numerous studies have described nursery and nicu epidemics caused by a variety of pathogens (table - ) , and most such epidemics have required the coordinated efforts of icps, nicu leadership, staff, and hospital administration outbreak investigation and intervention should be approached systematically, applying sound epidemiologic principles. in general, the process should include the follo~ing'~~~~''": for resolution. , , , , i j i, ,zo - confirming that an outbreak exists, by comparing the outbreak infection rate with baseline data (or with rates reported in the literature if baseline data are not available), and communicating concerns to stakeholders within the institution (and to those in other agencies if notification of health authorities is necessary) assembling the appropriate personnel to assist in developing a case definition and in planning immediate measures to prevent new cases performing active surveillance using the case definition to search for additional infections and collecting critical data and specimens characterizing cases of infection by person, place, and time, including plotting of an epidemic curve (to facilitate identification of shared risk factors among involved patients, such as invasive devices, proximity to other infected patients or temporal association with infection in such patients, common underlying diagnoses, shared medical or nursing staff, surgery, and medications, including antimicrobial agents) formulating a working hypothesis and testing this hypothesis (if the severity of the problem warrants this level of study, and provided that the institution has and can commit the necessary resources), with use of analytic approaches, including case-control and cohort studies, as appropriate to determine the likely cause of the outbreak instituting and evaluating control measures, which can be implemented anywhere in the foregoing process (more directed measures become possible as more is learned about the outbreak, and efficacy of control measures can be judged on whether the outbreak resolves, as indicated by return of number of cases to endemic levels or by cessation of occurrence of infections) reporting findings to appropriate personnel, including unit staff, hospital administration, and public health authorities (if involved in management of the outbreak), in comprehensive written reports, including summaries of how the outbreak was first recognized, study and analysis methods used, interventions implemented to resolve the epidemic, results, and a discussion of any other important outcomes or surveillance and control measures identified interventions used to control and limit outbreaks usually have consisted of isolation and cohorting of infected or colonized infants to prevent transmission of organisms. transmission-based precautions, a system developed by the cdc, can be used to determine the most effective barrier precautions to use with affected patients. cohorting, or placing infants infected or colonized with the outbreak organism together in geographically segregated areas and assigning dedicated staff and equipment to their care, also has been used successfully to halt outbreaks in nurseries and nicus. in extreme cases, closure of an nicu to admissions has been necessary to bring an outbreak under ~o n t r o l .~~~'~~, '~~ every attempt should be made to identify the source of a nursery outbreak, although this is not always possible. sources implicated in nicu outbreaks have included medications, equipment, and enteral feeding solutions; person-to-person transmission and environmental reservoirs also have been efforts to identify the source may include culturing of specimens from hcws, equipment, and the environment, although careful consideration should be given to the potential benefits before initiating these measures. culture of samples from the environment and equipment, in view of the vast number of objects that could be contaminated, usually is not helpful in identifying the source of an outbreak unless specific case characteristics or microbiologic data strongly suggest the location. culture of specimens obtained from hcws when person-to-person transmission is suspected may be more likely to identify the source of an outbreak, but it must be remembered that an hcw whose culture specimen yields the outbreak organism may have been transiently colonized while working with an affected infant, rather than constituting the source of the infection. management of culture-positive hcws (possible furlough, treatment, and return to work criteria) should be planned in advance of widespread culture surveillance and should involve supervisors of affected employees and occupational health services.'" reported. , , , , , the most widely accepted guideline for preventing the transmission of infections in hospitals was developed by the cdc. most recently revised in , the system contains two tiers of precautions. the first and most important, standard precautions, was designed for the management of all hospitalized patients regardless of their diagnosis or presumed infection status. the second, transmission-based precautions, is intended for patients documented or suspected to be infected or colonized with highly transmissible or epidemiologically important pathogens for which additional precautions to interrupt transmission are needed. standard precautions are designed to reduce the risk of transmission of microorganisms from both recognized and unrecognized sources and are to be followed for the care of all patients, including neonates. they apply to blood; all body fluids, secretions, and excretions except sweat; nonintact skin; and mucous membranes. components of standard precautions include hand hygiene and wearing gloves, gowns, and masks and other forms of eye protection. hand hygiene plays a key role for caregivers in the reduction of nosocomial infection for patient^'^.^'^ and in prevention of nosocomial or health cart+associated infections. hand hygiene should be performed before and after all patient contacts; before donning sterile gloves to perform an invasive procedure; after contact with blood, body fluids or excretions, mucous membranes, nonintact skin, and wound dressings; in moving from a contaminated body site to a clean body site during patient care (ie., from changing a diaper to performing mouth care); after contact with inanimate objects in the immediate vicinity of the patient; after removing gloves; and before eating and after using the re~troom.'~~ when hands are visibly soiled or contaminated with proteinaceous materials, blood, or body fluids, and after using the restroom, hands should be washed with antimicrobial soap and water. soaps containing % to % chlorhexidine gluconate or . % t r i~l o s a n '~~ are recommended for hand washing in n~rseries.'~~ when hands are not visibly soiled, alcohol-based hand rubs, foams, or gels are an important tool for hand hygiene. compared with washing with soap and water, use of the alcohol-based products is at least as effective against a variety of pathogens and requires less time, and these agents are less damaging to skin. the cdc "guideline for hand hygiene in the health care setting" calls for use of alcohol hand rubs, foams, or gels as the primary method to clean hands, except when hands are visibly soiled.i l programs that have been successful in improving hand hygiene and decreasing nosocomial infection have used multidisciplinary teams to develop interventions focusing on use of the alcohol rubs in the settin of institutional commitment and support for the initiativetj ~ hcws should wash hands and forearms to the elbows on arrival in the nursery. a -minute scrub has been suggested?l but consensus on optimal duration of initial hand hygiene is lacking. at a minimum, the initial wash should be long enough to ensure thorough washing and rinsing of all parts of the hands and forearms. routine hand washing throughout care delivery should consist of wetting the hands, applying product, rubbing all surfaces of the hands and fingers vigorously for at least seconds, rinsing, and patting dry with disposable t we s.l~~ wearing hand jewelry has been associated with increased microbial load on hands. whether this results in increased transmission of pathogens is not known. many experts, however, recommend that hand and wrist jewelry not be worn in the in addition, the cdc guideline states that staff who have direct contact with infants in nicus should not wear artificial fingernails or nail extenders."' only natural nails kept less than y.. inch long should be allowed. clean, nonsterile gloves are to be worn whenever contact with blood, body fluids, secretions, excretions, and contaminated items is anticipated. the hcw should change gloves when moving from dirty to clean tasks performed on the same patient, such as after changing a diaper and before suctioning a patient, and whenever they become soiled. because hands can become contaminated during removal of gloves, and because gloves may have tiny, unnoticeable defects, wearing gloves is not a substitute for hand hygiene. hand hygiene must be performed immediately after glove removal. personnel in nurseries including the nicu historically have worn cover gowns for all routine patient contact. the practice has not been found to reduce infection or colonization in neonates and is u n n e c e~s a r y ? '~~~~~ instead, cdc guidelines recommend nonsterile, fluid-resistant gowns to be worn as barrier protection when soiling of clothing is anticipated and in performing procedures likely to result in splashing or spraying of body substance^.^^ possible examples of such procedures in the nicu are placing an arterial line and irrigating a wound. the perinatal guidelines of the american academy of pediatrics and the american college of obstetricians and gynecologists recommend that a longsleeved gown be worn over clothing when a neonate is held outside the bassinette by nursery personnel.'" nonsterile masks, face shields, goggles, and other eye protectors are worn in various combinations to provide barrier protection and should be used during procedures and patient care activities that are likely to generate splashes or sprays of body substances and fl~ids.'~ standard precautions also require that reusable patient care equipment be cleaned and appropriately reprocessed between patients; that soiled linen be handled carefully to prevent contamination of skin, clothing, or the environment; that sharps (i.e., needles, scalpels) be handled carefully to prevent exposure to blood-borne pathogens; and that mouthpieces and other resuscitation devices be used, rather than mouth-to-mouth methods of re~uscitation.'~ in addition to standard precautions, which must be used for every patient, the cdc recommends transmission-based precautions when the patient is known or suspected to be infected or colonized with epidemiologically important or highly transmissible organisms. always used in addition to standard precautions, transmission-based precautions comprise three categories: contact precautions, droplet precautions, and airborne precautions. contact precautions involve the use of barriers to prevent transmission of organisms by direct or indirect contact with the patient or contaminated objects in the patient's immediate e n~i r o n m e n t .~~ sources of indirect contact transmission in nurseries can include patient care equipment such as monitor leads, thermometers, isolettes, breast pumps,le toys, and instruments and contaminated hands. the patient requiring contact precautions should be placed in a private room whenever possible but, after consultation with an infection control practitioner, can be cohorted with a patient infected with the same microorganism but no other infection. many nurseries, however, have few if any isolation rooms. the american academy of pediatrics states that infected neonates requiring contact precautions can be safely cared for without an isolation room if staffing is adequate to allow appropriate hand hygiene, a -to -footwide space can be provided between care stations, adequate hand hygiene facilities are available, and staff members are well trained regarding infection transmission modes.'" hcws should wear clean, nonsterile gloves when entering the room or space of a patient requiring contact precautions and should wear a cover gown when their clothing will have contact with the infant, environmental surfaces, or items in the infant's area. a cover gown also should be worn when the infant has excretions or secretions that are not well contained, such as diarrhea or wound drainage, which may escape the diaper or dressing. infant care equipment should be dedicated to the patient if possible so that it is not shared with thers. ~ examples of conditions in the neonate that require contact precautions include neonatal mucocutaneous herpes simplex virus infection, respiratory syncytial virus infection, varicella (also see airborne precautions), infection or colonization with a resistant organism such as mrsa or a multiple drug-resistant gram-negative bacillus, and congenital rubella syndrome. droplet precautions are intended to reduce the risk of transmission of infectious agents in large-particle droplets from an infected person. such transmission usually occurs when the infected person generates droplets during coughmg, sneezing, or talking, or during procedures such as suctioning. these relatively large droplets travel only short distances and do not remain suspended in the air, but can be deposited on the conjunctiva, nasal mucosa, andfor mouth of persons working within feet of the infected patient. patients requiring droplet precautions should be placed in private rooms (see earlier discussion of isolation rooms in nurseries in the paragraph on contact precautions), and staff should wear masks when working within feet of the patient. examples of conditions in the neonate that necessitate droplet precautions are pertussis and invasive n. meningitidis infection. airborne precautions are designed to reduce the risk of airborne transmission of infectious agents. because of their small size, airborne droplet nuclei and dust particles containing infectious agents or spores can be widely spread on air currents or through ventilation systems and inhaled by or deposited on susceptible hosts. special air-handling systems and ventilation are required to prevent transmission. patients requiring airborne precautions should be placed in private rooms in negative air-pressure ventilation with to air changes per hour. air should be externally exhausted or subjected to high-efficiency particulate air (hepa) filtration if it is recirculated. examples of conditions in the neonate for which airborne precautions are required are varicella-zoster virus infections and measles. susceptible hcws should not enter the rooms of patients with these viral infections. if assignment cannot be avoided, susceptible staff members should wear masks to deliver care. if immunity has been documented, staff members need not wear masks. airborne precautions also are required for active pulmonary tuberculosis, and although neonates are rarely contagious, the cdc recommends isolating patients while they are being e~aluated.~'~ a more important consideration is the need to isolate the family of a suspected tuberculosis patient until an evaluation for pulmonary tuberculosis has been completed, because the source of infection frequently is a member of the child's before the s, well-baby nurseries and many nicus were constructed as large, brightly lit open wards with rows of incubators surrounded by equipment. sinks could be provided in such rooms only around the periphery, limiting access to hand hygiene facilities for staff and families. in these nicus, parents' time with their infant was severely restricted, and the units were designed for the convenience and function of the hcw. more recently, perinatal care professionals have come to understand that neonates (and especially preterm infants) can benefit from a quiet, soothing atmosphere and protection from unnecessary light, noise, handling, uncomfortable positioning, and sleep disruptions? if infants are kept in a central nursery rather than roomingin with mothers, at least square feet of floor space should family. ,z be provided per neonate, and bassinets should be at least feet apart. teams designing units delivering higher levels of perinatal care, including nicus, should plan individual bed areas large enough for families to stay at the bedside for extended periods of time without interfering with the staffs ability to care for the child. if individual rooms cannot be provided, at least square feet of floor space should be allowed for each neonate in an nicu, incubators or overhead warmers should be separated by at least to feet, and aisles should be at least feet a scrub sink with foot, knee, or touchless (electronic sensor) controls should be provided at the entrance to every nursery and should be large and deep enough to control splashing. sinks in patient care areas should be provided at a minimum ratio of sink for at least every to stations in the well-baby nursery and sink for every or stations in higher-level nurseries, including the nicu.'i every bed position should be within feet of a hand-washing sink and accessible for children and persons in wheelchairs. for nicus composed of individual rooms, a hand-washing sink should be located in each room near the door to facilitate hand hygiene on entering and leaving the room. environmental surfaces should be designed so that they are easy to clean and do not harbor microorganisms. sink taps and drains, for instance, have been implicated in outbreaks of infection. z installing sinks with seamless construction may minimize this risk by decreasing areas where water can pool and microorganisms proliferate. faucet aerators have been implicated in outbreaks of infection and should be avoided in the intensive care unit. although carpeting can reduce noise levels in a busy nicu, the cdc "guidelines for environmental infection control in health-care facilities" recommend against use of carpeting in areas where spills are likely, including intensive care units. the guidelines further recommend against upholstered furniture in nicus.~~' if, for reasons of noise reduction and developmentally appropriate care, porous surfaces such as carpeting and cloth upholstery are selected for the nicu, cleaning must be performed carefully. carpet should be vacuumed regularly with equipment fitted with hepa filters, and upholstered furniture should be removed from inpatient areas to be cleaned. attention also should be paid to air-handling systems. according to the perinatal guidelines, minimal standards for inpatient perinatal care areas include six air changes per hour, and a minimum of two changes should consist entirely of outside air. air delivered to the nicu should be filtered with at least % efficiency. in addition, nurseries should include at least one isolation room capable of providing negative pressure vented to the outside, observation windows with blinds for privacy, and the capability for remote m~n i t o r i n g .~~~'~~~ floors and other horizontal surfaces should be cleaned daily by trained personnel using environmental protection agency (epa)-registered hospital disinfectantddetergents. these products (including phenolics and other chemical surface disinfectants) must be prepared in accordance with manufacturers' recommendations and used carefully to avoid exposing neonates to these products. phenolics should not be used on surfaces that come in direct contact with neo-nates' skin. high-touch areas, such as counter tops, work surfaces, doorknobs, and light switches, may need to be cleaned more frequently because they can be heavily contaminated during the process of delivering care. hard, nonporous surfaces should be "wet dusted" rather than dry dusted, to avoid dispersing particulates into the air, and then disinfected using standard hospital disinfectant^.'^^ sinks should be scrubbed daily with a disinfectant detergent. walls, windows, and curtains should be cleaned regularly to prevent dust accumulation, but daily cleaning is not necessary unless they are visibly soiled. bassinets and incubators should be cleaned and disinfected between infants, but care must be taken to rinse cleaning products from surfaces with water before use. care units should not be cleaned with phenolics or other chemical germicides during an infant's stay. instead, infants who remain in the nursery for long periods of time should periodically be moved to freshly cleaned and disinfected units. ' patient care equipment must be cleaned, disinfected, and, when appropriate, sterilized between patients. sterilization (required for devices that enter the vascular system, tissue, or sterile body cavities) and higher levels of disinfection (required for equipment that comes in contact with mucous membranes or that has prolonged or intimate contact with the newborn's skin) must be performed under controlled conditions in the central processing department of the hospital. examples of patient care equipment that require these levels of processing are endotracheal tubes, resuscitation bags, and face masks. , , low-level disinfection is required for less critical equipment, such as stethoscopes or blood pressure cuffs, and usually can be performed at point of use (e.g., the bedside), although this type of equipment should be dedicated to individual patients whenever possible. requirements for linen handling and management for neonates do not vary appreciably from those for other hospitalized patients. although soiled linen can contain large numbers of organisms capable of causing infections, transmission to patients appears to be rare. studies suggesting linen as a source of infection often have failed to confirm it as the source of infection. at least one report, however, has implicated linen in the transmission of group a streptoco~ci.~~ investigation of this outbreak revealed that clothing worn by the neonates was being washed in the local hospital "mini laundry," rather than being processed under the usual laundry contract. investigation of the dryers revealed extensive contamination with the outbreak organism. this case illustrates the importance of having standard hospital laundry protocols and ensuring that appropriate water and dryer temperatures are maintained. when such protocols are followed, the mechanical actions of washing and rinsing, combined with hot water and/or the addition of chemicals such as chlorine bleach, and a final commercial dryer and/or ironing step significantly reduce bacterial few hospitals in the united states use cloth diapers, but regardless of type used, soiled diapers should be carefully bagged in plastic and removed from the unit every hours. hcws caring for neonates have the potential both to transmit infections to infants and to acquire infections from vaccine should be considered for all hcws, including those born before , who have no proof of immunity (receipt of doses of live vaccine on or after first birthday, physician-diagnosed measles, or serologic evidence of immunity). hcws believed t o be susceptible can be vaccinated; adults born before can be considered immune. hcws, both male and female, who lack documentation of receipt of vaccine on or after first birthday or serologic evidence of immunity should be vaccinated; adults born before can be considered immune, except women of childbearing age. hcws without a reliable history of varicella or serologic evidence of varicella immunity should be vaccinated. patients. educating hcws about infection control principles is crucial to preventing such transmission. hospitals should provide education about infection control policies, procedures, and guidelines to staff in all job categories during new employee orientation and on a regular basis throughout employment. the content of this education should include hand hygiene, principles of infection control, the importance of individual responsibility for infection control, and the importance of collaborating with the infection control department in monitoring and investigating potentially harmful infectious exposures and outbreaks. transmission of infectious organisms between patients and hcws has been well documented. several studies have indicated that a high proportion of hcws acquire rsv ( % to %) when working with infected children, and these workers appear to be important in the spread of the illness within hospital^.^^'.^^^ although % of the infected hcws in one of these rsv studies were asymptomatic, staff should be aware of the importance of self-screening for communicable disease. they should be encouraged to report personal infectious illnesses to supervisors, who in turn should report them to occupational health services and infection control. in general, hcws with respiratory, cutaneous, mucocutaneous, or gastrointestinal infections should not deliver direct patient care to neonates. i in addition, seronegative staff members exposed to illnesses, such as varicella and measles, should not work during the contagious portion of the incubation period. staff members with hsv infection rarely have been implicated in transmission of the virus to infants and thus do not need to be routinely excluded from direct patient care. those with herpes labialis or cold sores should be instructed to cover the lesions and not to touch their lesions, and to comply with hand hygiene policies. persons with genital lesions also are unlikely t o transmit hsv so long as hand hygiene policies are followed. however, hcws who are unlikely or unable to comply with the infection control measures and those with herpetic whitlow should not deliver direct patient care to neonates until lesions have healed. acquisition of cmv often is a concern of pregnant hcws because of the potential effect on the fetus. approximately % of newborn infants in most nurseries and a higher percentage of older children (up to % of children to years of age in child-care centers) excrete cmv without clinical manifestation^.'^^ the risk of acquiring cmv infection has not been shown to be higher for hcws than for the general for this reason, pregnant caregivers need not be excluded from the care of neonates suspected to be shedding cmv. they should be advised of the importance of standard precautions. hcws in well-baby nurseries and nicus should be as free from transmissible infectious diseases as possible? and ensuring that they are immune to vaccine-preventable diseases is an essential part of a personnel health program. the cdc recommends several immunizations for health care personnel (table - ) . staffing levels in a patient care setting also can affect patient outcomes. a number of studies suggest that as patient-tonurse ratios in intensive care units increase, so do nosocomial infections and mortality rate^.^^,'^^,'^ although optimal staffing ratios have not been established for nicus and will vary according to characteristics of individual units, one study demonstrated that the incidence of clustered s. aureus infections was times higher after periods when the infantto-nurse ratio exceeded : . decreased compliance with hand hygiene during a period of understaffing frequently is cited as contributing to nosocomial infection rate increases." further study is necessary to determine best practice surrounding staffing levels in nicus. the first nicus in the late s grouped infants together in large, brightly lit rooms with incubators placed in rows. parents were allowed very little time with their babies and even less physical contact. in the decades since, it has been recognized that "the parent is the most important caregiver and constant influence in an infant's life" and that hcws working in nicus should encourage parents to become involved in the nonmedical aspects of their child's care. principles of family-centered care also include liberal nicu visitation for relatives, siblings, and family friends and the involvement of parents in the development of nursery policies and programs that promote parenting skills. care must be taken, however, to minimize risk of infection for the neonate. mothers can transmit infections to neonates both during delivery and post partum, although separation of mother and newborn rarely is indicated. in the absence of certain specific infections, mothers, including those with postpartum fever not attributed to a specific infection, should be allowed to handle their infants if the following conditions are met: they feel well enough. they wash their hands well under supervision. a clean gown is worn. contact of the neonate with contaminated dressings, a mother with a transmissible illness not requiring separation from her infant should be carefully educated about the mode of transmission and precautions necessary to protect her infant. personal protective equipment, such as cover gowns, gloves, and masks, and hand hygiene facilities should be readily available to her, and she should perform hand hygiene and don a long-sleeved cover gown before handling her infant. if wounds or abscesses are present, drainage should be contained within a dressing. if drainage cannot be completely contained, separation from the infant may be necessary. care should be taken to prevent the infant from coming in contact with soiled linens, clothing, dressings, or other potentially contaminated items. the mother with active genital hsv lesions need not be separated from her infant if the foregoing precautions are taken. those with herpes labialis should not kiss or nuzzle their infants until lesions have cleared; lesions should be covered and a surgical mask may be worn until the lesions are crusted and dry, and careful hand hygiene should be stressed. mothers with viral respiratory infections should be made aware that many of these illnesses are transmitted by contact with infected secretions as well as by droplet spread, that soiled tissues should be disposed of carefully, and that hand hygiene is critical to transmission prevention. masks can be worn to reduce the risk of droplet t r a n s m i s s i~n .~~~'~~~ as previously mentioned, although very few infections require separation of mother and infant, women with untreated active pulmonary tuberculosis should be separated from their infants until they no longer are contagious. mothers with group a streptococcal infections, especially when involving draining wounds, also should be isolated from their infants until they no longer are contagious. less certain is the necessity of separating mothers with peripartum varicella (onset of infection within days before or days after delivery) from their uninfected infants. the perinatal guidelines recommend that such infants remain with their mothers after receiving varicella-zoster immune globulin (vzig) but caution that infant and mother must be carefully managed in airborne and contact precautions to prevent transmission within the nursery. some experts recommend separating these mothers from their infants until all lesions are dried and crusted. numerous studies support the value of human milk for infants (see chapter ). besides providing optimal nutritional content for infants, it has been shown to be associated with a lower incidence of infections and sepsis in the first year of linen, clothing, or pads is avoided. although contraindications to breast-feeding are few, mothers who have active untreated tuberculosis, human immunodeficiency virus (hiv) infection, breast abscesses (as opposed to simple mastitis that is being treated with antimicrobial therapy), or hsv lesions around the nipples should not breast-feed. mothers who are hepatitis b surface antigen positive may breast-feed, because ingestion of an infected mother's milk has not been shown to increase the risk of transmission to her child, but the infant must receive hepatitis b virus immune globulin (hbig) and vaccine immediately after birth. because systemic disease may develop in preterm infants with low concentrations of transplacentally acquired antibodies to cmv following ingestion of milk of cmv-seropositive mothers, decisions regarding breast-feeding should consider the benefits of human milk versus the risk of cmv transmission. freezing breast milk has been shown to decrease viral titers but does not eliminate cmv; pasteurization of human milk can inactivate cmv. either method may be considered in attempts to decrease risk of transmission for breast-feeding nicu neonates. neonates in the nicu frequently are incapable of breastfeeding because of maternal separation, unstable respiratory status, and immaturity of the sucking reflex. for these reasons, mothers of such infants must use a breast pump to couect milk for administration through a feeding tube. pumping, collection, and storage of breast milk create opportunities for contamination of the milk, and for cross-infection if equipment is shared between mothers. several studies have demonstrated contamination of breast pumps, contamination of expressed milk that had been frozen and thawed, and higher levels of stool colonization with aerobic bacteria in infants fed precollected breast milk. , * consensus is lacking on the safe level of microbiologic contamination of breast milk, and most expressed breast milk contains normal skin flora. although breast milk containing greater than cfu/ml of gram-negative bacteria has been reported to cause feeding intolerance and to be associated with suspected sepsis, routine bacterial culturing of expressed breast milk is not recommended. v instead, efforts to ensure safety of expressed milk should focus on optimal collection, storage, and administration techniques. cleaning and disinfection of breast pumps should be included in educational material provided to nursing mothers (table - ). in addition, mothers should be instructed to perform hand hygiene and cleanse nipples with cotton and plain water before expressing milk in sterile containers. expressed breast milk can be refrigerated for up to hours and can be safely frozen (- " c f °c [- " f f . " f]) for up to months. it can be thawed quickly under warm running water (avoiding contamination with tap water) or gradually in a refrigerator. exposure to high temperatures, as may be experienced in a microwave, can destroy valuable components of the milk. thawed breast milk can be stored in the refrigerator for up to hours before it must be discarded. to avoid proliferation of microorganisms, milk administered through a feeding tube by continuous infusion should hang no longer than to hours before replacement of the milk, container, and for mothers who choose not to breast-feed, commercial infant formula is available. most hospitals now use sterile, ready-to-feed formulas provided by the manufacturer in bottles, with sterile nipples to attach just before use. nipples each mother is supplied with a personal pumping kit. nursing staff instruct mothers in techniques of milk expression and appropriate procedures for cleaning breast pump parts: wipe all horizontal surfaces at the pumping station with hospital disinfectant before and after pumping. wash hands with soapy water before and after pumping. wash all parts of the breast pump kit that have been in contact with milk in hot water and dish detergent or in a dishwasher. expressed milk is collected in sterile, single-use plastic (polycarbonate or polypropylene) containers. breast milk containers are labeled with infant's name and the date and time of collection. administration containers (bottle or syringe) are similarly labeled when breast milk is transferred from collection containers. all hcws wear gloves when handling and administering breast milk. two persons check t h e labeled administration container against the infant's hospital identification band before administering breast milk (may be two hcws or one hcw and a family member). hcw. health care worker. from infection control policy, children's hospital and regional medical center, seattle, are best attached at the bedside just before feeding, and the unit should be used immediately and discarded within hours after the bottle is ~ncapped.'~' specialty and less commonly used formulas may not be available as a ready-to-feed product, and breast milk supplements do not come in liquid form. after a recent report of a case of fatal enterobacter sakazakii meningitis in a neonate fed contaminated powdered infant formula: concerns have risen about the safety of these products. although powdered formulas are not sterile, preparation and storage practices can decrease the possibility of proliferation of microorganisms after preparation. the cdc, the food and drug administration, and the american dietetic association offered updated recommendations on the safe preparation and administration of commercial formula after the recall of the product linked to the e. sakazakii case. these recommendations instruct the care provider as follows: use alternatives (ready-to-feed or concentrated formulas) to powdered infant formula whenever possible. prepare formula using aseptic technique in a designated formula preparation room. refrigerate prepared formula so that a temperature of " to " c is reached by hours after preparation, and discard any reconstituted formula stored longer than hours. limit ambient-temperature hang time of continuously infused formula to no longer than hours. use hygienic handling techniques at feeding time, and avoid open delivery systems. have written guidelines for managing a manufacturer's recall of contaminated formula. the fda also recommended that boiling water be used to prepare powdered formulas, but concerns about this recommendation include potential damage to formula components from the high temperature of the water, a lack of evidence that using this method would lull potential pathogens in the formula, and risk of injury to persons preparing the f rmula. ~' the concept of co-bedding, or the bunlung of twin infants (or other multiples) in a single isolette or crib, is being explored in nicus for the potential benefits offered to the babies. co-bedding as a component of developmentally supportive care is based on the premise that extrauterine adaptation of twin neonates is enhanced by continued physical contact with the other twin. potential benefits need further study but may include increased bonding, decreased need for temperature support, and easier transition to home. it is certainly possible, however, for one of a set of multiples to be infected while the others are not, and for parents to be implicated as vectors in infection transmission. it also is possible for invasive devices and intravascular catheters to be dislodged by close contact with an active sibling. therefore, exclusion criteria for co-bedding infants should include clinical findings suggesting infection that could be transmitted to a sibling (e.g., draining wound) and the need for drains and central venous or arterial line^.*^^-'^^ the principles of family-centered care encourage liberal visitation policies, both in the well-baby nursery (or roomingin scenario) and in the nicu. parents, including fathers, should be allowed unlimited visitation to their newborns, and siblings also should be allowed liberal visitation. expanding the number of visitors to neonates may, however, increase the risk of disease exposure if education and screening for symptoms of infection are not implemented. written policies should be in place to guide sibling visits, and parents should be encouraged to share the responsibility of protecting their newborn from contagious illnesses. the perinatal guidelines regarding persons who visit newborns are listed in table - . adult visitors to neonates, including parents, have been implicated in outbreaks of infections including p aeruginosa infection, pertussis, and salmonella i n f e c t i~n . '~'~~~~~~~~ ac cordingly, the principles for sibling visitation should be applied to adult visitors as well. they should be screened for symptoms of contagious illness, instructed to perform hand hygiene before entering the nicu and before and after touching the neonate, and should interact only with the family member they came to the hospital to visit. families of neonates who have lengthy nicu stays may come to know each other well and serve as sources of emotional support to one another. nevertheless, they should be educated about the potential of transmitting microorganisms and infections between families if standard precautions and physical separation are not maintained, even though they may be sharing an inpatient space. sibling visits should be encouraged for healthy and ill newborns. parents should be interviewed at a site outside the nursery to establish that the siblings are not ill before allowing them to visit. children with fever or other symptoms of an acute illness such as upper respiratory infection or gastroenteritis, or those recently visiting children should visit only their sibling. children should be prepared in advance for their visit. visitors should be adequately observed and monitored by hospital staff. children should carefully wash their hands before patient contact. throughout t h e visit, siblings should be supervised by parents or another responsible adult. exposed to a known communicable disease such as chickenpox, should not be allowed to visit. bathing the newborn is standard practice in nurseries, but very little standardization in frequency or cleansing product exists. if not performed carefully, bathing actually can be detrimental to the infant, resulting in hypothermia, increased crying with resulting increases in oxygen consumption, respiratory distress, and instability of vital signs. although the initial bath or cleansing should be delayed until the neonate's temperature has been stable for several hours, removing blood and drying the skin immediately after delivery may remove potentially infectious microorganisms such as hepatitis b virus, hsv, and hiv, minimizing risk to the neonate from maternal infection. when the newborn requires an intramuscular injection in the delivery room, infection sites should be cleansed with alcohol to prevent transmission of organisms that may be present in maternal blood and body for routine bathing in the first few weeks of life, plain warm water should be used. this is especially important for preterm infants, as well as full-term infants with barrier compromise such as abrasions or dermatitis. if a soap is necessary for heavily soiled areas, a mild ph-neutral product without additives should be used, and duration of soaping should be restricted to less than minutes no more than three times per week. few randomized studies comparing cord care regimens and infection rates have been performed, and consensus has not been reached on best practice regarding care of the umbilical cord stump. a review published in described care regimens used for more than decades, including combinations of triple dye, chlorhexidine, % alcohol, bacitracin, hexachlorophene, povidone-iodine, and "dry care" (soap and water cleansing of soiled periumbilical skin) and found variable impact on colonization of the stump. the study authors suggested that dry cord care alone may be insufficient and that chlorhexidine seemed to be a favorable antiseptic choice for cord care because of its activity against gram-positive and gram-negative bacteria. they went on to stress, however, that large, well-designed studies were required before firm conclusions could be drawn. the current perinatal guidelines do not recommend a specific regimen but warn that use of alcohol alone is not an effective method of preventing umbilical cord colonization and ~mphalitis.'~~ the perinatal guidelines further recommend that diapers be folded away from and below the stump and that emollients not be applied to the although blindness resulting from neonatal conjunctivitis is rare in the united states, with a reported incidence of . % or less, the rate among the million infants born annually throughout the world is as high as %. chlamydia trachornatis has been the most common etiologic agent in the united states, but other organisms such as neisseria gonorrhoeae, s. aureus, and e. coli also can cause ophthalmia neonatorum. use of % silver nitrate drops, at one time the agent of choice, is no longer recommended because of concerns about associated chemical irritation. agents thought to be equally efficacious and now recommended include % tetracycline and . % erythromycin ophthalmic ointments, administered from sterile single-use tubes or vials. ~ povidone-iodine ( . %) ophthalmic solution also can be used and in one study was shown to be more effective than silver nitrate or erythromycin in the prevention of ophthalmia neonatorum. bacterial resistance has not been seen with this agent, it causes less toxicity than either silver nitrate or erythromycin, and it is less expensivea definite consideration in developing countries. whatever the agent selected, it should reach all parts of the conjunctival sac, and the eyes should not be irrigated after application. ophthalmic agents will not necessarily prevent ocular or disseminated gonorrhea in infants born to mothers with active infection at time of delivery. these infants should be given parenteral antimicrobial therapy as well as ocular p r o p h y l a~i s . '~~,~~~ some experts also advise giving infants born to mothers with untreated genital chlamydia infections a course of oral erythromycin beginning on the second or third day of life. primary bloodstream infections (defined by the cdc nnis system as being due to a pathogen cultured from one or more blood specimens not related to an infection at another site) account for a large proportion of infections in nicu infants:' and most are related to the use of an intravascular catheter. peripheral intravenous catheters (pivs) are the most frequently used devices for the neonate for intravenous therapy of short duration. when longer access is necessary, nontunneled cvcs such as umbilical catheters and piccs most commonly are the most recent data available conduct surveillance in nlcus to determine catheter-related bloodstream infection rates, monitor trends, and identify infection control lapses. investigate events leading to unexpected life-threatening or fatal outcomes. select the catheter, insertion technique, and insertion site with the lowest risk for complications for the anticipated type and duration of intravenous therapy. use a cvc with the minimal number of ports essential f o r management of t h e patient. designate one port for hyperalimentation if a multilumen catheter is used. educate hcws who insert and maintain catheters, and assess their knowledge and competence periodically. use aseptic technique and maximal sterile barriers during insertion of cvcs (cap, mask, sterile gown, sterile gloves, and a large sterile barrier). do not routinely replace cvcs, piccs, or pulmonary artery catheters to prevent catheter-related infections. do not remove on the basis of fever alone. in pediatric patients, leave peripheral venous catheters in place until intravenous therapy is completed unless a complication (e.g., phlebitis, infiltration) occurs. remove intravascular catheters promptly when no longer essential. observe proper hand hygiene procedures either by washing with antiseptic-containing soap and water or use of waterless alcohol-based products before and after working with intravascular lines. disinfect skin with an appropriate antiseptic before catheter insertion and during dressing changes. a % chlorhexidine-based preparation is preferred. do not use topical antibiotic ointment or creams on insertion sites, except when using dialysis catheters. use either sterile gauze or sterile, transparent, semipermeable dressing to cover t h e catheter site. replace gauze dressings on short-term cvc sites every days and transparent dressings at least weekly, except in pediatric patients, in whom the risk of dislodging the catheter outweighs the benefit of changing the dressing. change if damp, loosened, or visibly soiled. replace dressings on tunneled or implanted cvc sites no more than once per week until the insertion site has healed. chlorhexidine sponge dressings are contraindicated in neonates younger than days or those born at a gestational age of less than weeks. clean injection ports with % alcohol or an iodophor before accessing the system. use disposable transducer assemblies with peripheral arterial catheters and pressure monitoring devices. keep all components of such systems sterile, and do not administer dextrose-containing solutions or parenteral nutrition fluids through them. from nnis (august ) revealed that the mean umbilical catheter-and cvc-associated bloodstream infection rates for nicus ranged from . per catheter days for infants whose birth weight was less than g to . per catheter days in infants whose birth weight was g or more.' the cdc recommends implementing strategies to reduce the incidence of such infections that strike a balance between patient safety and cost-effectiveness. few large studies of risks related to intravascular devices have been performed in nicu patients. as a result, intravascular device recommendations for neonates are based on those developed for adults and older pediatric patients (table - ) . several differences in their management should be considered. although the cdc recommends, in certain circumstances, using antimicrobialor antiseptic-impregnated cvcs in adults whose catheters are expected to remain in place more than days, these catheters are not available in sizes small enough for neonates. of more importance, studies to evaluate their safety in neonates, especially premature neonates of very low birth weight, have not been performed. in addition, although the cdc recommends changing the insertion site of pivs at least every to hours in adults, data suggest that leaving pivs in place in pediatric patients does not increase the risk of complications. the cdc guidelines recommend that pivs be left in place in children until therapy is completed, unless complications occur. careful skin antisepsis before insertion of an intravascular catheter is critical to prevention of intravascular devicerelated bacteremia, although care in the selection of a product for use on neonatal skin is required. chlorhexidine preparations are recommended by the cdc because these products have been found to be superior to povidone-iodine in reducing the risk for peripheral catheter colonization in neonates. residues left on the skin by chlorhexidine prolong its half-life, providing improved protection for catheters in neonates that must be left in place for longer periods of timef ' umbilical veins and arteries are available for cvc insertion only in neonates and are typically used for several days; thereafter, the cvc is replaced with another, nontunneled cvc or picc if continued central venous access is required. the umbilicus provides a site that can be cannulated easily, allowing for collection of blood specimens and hernodynamic measurements, but after birth, the umbilicus quickly becomes heavily colonized with skin flora and other microorganisms. colonization and catheter-related bloodstream infection rates for umbilical vein and umbilical artery catheters are similar. colonization rates for umbilical artery catheters are estimated to be % to %; the estimated rate for umbilical artery catheter-related bloodstream infection is %? colonization rates are from % to % for umbilical vein catheters; rates for umbilical vein catheter-related bloodstream infections are % to ? .~~ a summary of the cdc recommendations for management of umbilical catheters is presented in table - . as mentioned earlier, nnis data indicate that nosocomial pneumonia is the second most common infection type in cleanse umbilical insertion site with an antiseptic before catheter insertion. avoid tincture of iodine; povidone-iodine can be used. add low doses of heparin to fluid infused through umbilical artery catheters. remove and do not replace umbilical catheters if signs of catheter-related bloodstream infection, vascular insufficiency, or remove umbilical catheters as soon as possible when no longer needed or if any sign of vascular insufficiency to the lower umbilical artery catheters should not be left in place for longer than days. umbilical venous catheters should be removed as soon as possible when no longer needed but can be used for up to nicu patients. risk factors for ventilator-associated pneumonia can be grouped as host-related (prematurity, low birth weight, sedation or use of paralytic agents), devicerelated (endotracheal intubation, mechanical ventilation, orogastric or nasogastric tube placement) and factors that increase bacterial colonization of the stomach or nasopharynx (broad-spectrum antimicrobial agents, antacids, or h, b l o c k e r~) . ~,~"~~~ ventilator-associated pneumonia generally refers to bacterial pneumonia that develops in patients who are receiving mechanical ventilation. aspiration and direct inoculation of bacteria are the primary routes of entry into the lower respiratory tract; the source of these organisms may be the patient's endogenous flora or transmission from other patients, staff members, or the e n~i r o n m e n t .~~'~~~ few studies have been performed to assess the effectiveness of prevention strategies in pediatric patients. strategies to prevent ventilator-associated pneumonia in the nicu patient are therefore based primarily on studies performed in adults (table - ) . hand hygiene remains critical to the prevention of ventilator-associated pneumonia, and hcws should consistently apply the principles of standard precautions to the care of the ventilated patient, wearing gloves to handle respiratory secretions or objects contaminated by them, and changing gloves and performing hand hygiene between contacts with a contaminated body site and the respiratory tract or a respiratory tract device. because mechanical ventilation is a significant risk factor for the development of nosocomial infection or ventilatorassociated pneumonia, weaning from ventilation and removing endotracheal tubes as soon as indication for their use ceases are key infection control strategies. as an alternative to endotracheal intubation, noninvasive nasal continuous positive airway pressure (cpap) ventilation avoids some of the common risk factors for ventilator-associated pneumonia and has been used successfully for neonate^?^^"^^ respiratory care equipment that comes in contact with mucous membranes of ventilated patients or that is part of the ventilator circuit should be single use (discarded after one-time use with a single patient) or be subjected to sterilization or high-level disinfection between patients. wet heat pasteurization (processing at oc for minutes) or chemical disinfectants can be used to achieve high-level disinfection of reusable respiratory equipment. ventilator circuits should be changed no more frequently than every hours, and evidence suggests that extending the length of time between changes to days does not increase the risk of ventilator-associated pneumonia.z s circuits should be monitored for accumulation of condensate and drained periodically, with care taken to avoid allowing the condensate, a potential reservoir for pathogens, to drain toward the sterile fluids should be used for nebulization, and sterile water should be used to rinse reusable semicritical equipment and devices such as in-line medication nebulizers. basic infection control measures, such as hand hygiene and wearing gloves during suctioning and respiratory manipulation, also can reduce the risk of nosocomial pneumonia. both open, single-use and closed, multiuse suction systems are available. if an open system is used, a sterile single-use catheter should be used each time the patient is suctioned. closed systems, which do not need to be changed daily and can be used for up to have the advantage of lower costs and decreased environmental cross-contamination but have not been shown to decrease the incidence of nosocomial pneumonia when compared with open systems. v although not well studied in pediatric patients, aspiration of oropharyngeal secretions is believed to contribute to development of ventilator-associated pneumonia in adults. placing the mechanically ventilated patient in a semirecumbent position or elevating the head of the bed in an attempt to minimize aspiration is recommended unless medically contraindicated. also, placement of enteral feeding tubes should be verified before their to prevent regurgitation and potential aspiration of stomach contents by the sedated patient, overdistention of the stomach should be avoided by regular monitoring of the patient's intestinal motility, serial measurement of residual gastric volume or abdominal girth, reducing the use of narcotics and anticholinergic agents, and adjusting the rate and volume of enteral fee ding^.^^^,^^^ oral decontamination, with the intent of decreasing oropharyngeal colonization, has been studied in adults and seems to lower the incidence of ventilatorassociated pneumonia (although not duration of ventilation or mortality but further work is needed to determine whether this is an effective strategy in neonates. in addition, medications such as sucralfate, as opposed to histamine h, receptor antagonists and antacids, which raise gastric ph and can potentially result in increased bacterial colonization of the stomach, have been used to prevent development of stress ulcers and have been associated with lower incidence of ventilator-associated pneumonia in adults. two studies suggest, however, that this approach is of no benefit in pediatric patients, but the authors stress that additional studies with larger sample sizes are needed to confirm these nosocomial infections in a neonatal intensive care unit: incidence and risk factors. am infect control bektas s, goetze b, speer cp. decreased adherence, chemotaxis and phagocytic activities of neutrophils from preterm neonates surgery, sepsis, and nonspecific immune function in neonates. pediatr surg - , . stiehm er. the physiologic immunodeficiency of immaturity diminished interferongamma and lymphocyte proliferation in neonatal and postpartum primary herpes simplex virus infection importance of the environment and the faecal flora of infants, nursing staff and parents as sources of gram-negative bacteria colonizing newborns in three neonatal wards use of human milk in the intensive care nursery decreases the incidence of nosocomial sepsis colonization and infection associated with malassezia and candida species in a neonatal unit. hosp infect - requirements for infrastructure and essential activities of infection control and epidemiology in hospitals: a consensus panel report. society for health care epidemiology of america guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee effectiveness of a hospitalwide programme to improve compliance with hand hygiene skin hygiene and infection prevention: more of the same or different approaches? molecular epidemiology of staphylococcus epidermidis in a neonatal intensive care unit over a three-year period nosocomial staphylococcus epidermidis septicaemia among very low birth weight neonates in an intensive care unit a randomized trial of -versus -hour intravenous tubing set changes in newborns receiving lipid therapy. infect control hosp epidemiol - occurrence of nosocomial bloodstream infections in six neonatal intensive care units effect of lipid emulsion on il- production by mononuclear cells of newborn infants and adults risk factors for nosocomial sepsis in newborn intensive and intermediate care units extended-spectrum plasmid-mediated beta-lactamases neonatal suppurative parotitis: a study of five cases molecular epidemiology of staphylococcal scalded skin syndrome in premature infants a double outbreak of exfoliative toxinproducing strains of staphylococcus aureus in a maternity unit acquisition of staphylococci by newborns. direct versus indirect transmission transmission of staphylococci between newborns. importance of the hands to personnel the role of understaffing and overcrowding in recurrent outbreaks of staphylococcal infection in a neonatal special-care unit the"c oud baby": an example of bacterial-viral interaction a cloud adult: the staphylococcus aureus-virus interaction revisited nosocomial transmission of methicillin-resistant staphylococcus aureus from a mother to her preterm quadruplet infants control of a methicillin-resistant staphylococcus aureus outbreak in a neonatal intensive care unit by unselective use of nasal mupirocin ointment preferential pharyngeal colonization of methicillin resistant staphylococcus airreus in infants nasal mupirocin treatment of pharynx-colonized methicillin resistant staphylococcus aureus: preliminary study with carrier infants a ten year, multicentre study of coagulase negative staphylococcal infections in australasian neonatal units coagulasenegative staphylococcal bacteremia among very low birth weight infants: relation to admission illness severity, resource use, and outcome effect of an evidence-based hand washing policy on hand washing rates and false-positive coagulase negative staphylococcus blood and cerebrospinal fluid culture rates in a level nicu streptococcus faecium outbreak in a neonatal intensive care unit neonatal enterococcal bacteremia: an increasingly frequent event with potentially untreatable pathogens outbreak of vancomycin-resistant enterococcusfuecium in a neonatal intensive care unit centers for disease control and prevention. recommendations for preventing the spread of vancomycin resistance: recommendations of the hospital infection control practices advisory committee (hicpac) group a streptococcal infections in newborn nurseries an outbreak of m serotype group a streptococcus in a neonatal intensive care unit mother-to-infant vertical transmission and cross-colonization of streptococcus pyogenes confirmed by dna restriction fragment length polymorphism analysis clinical laboratory and epidemiological investigations of a streptococcus pyogenes cluster epidemic in a newborn nursery infection and hospital laundry nosocomial transmission of group b streptococci in a newborn nursery nosocomial transmission of group b streptococci epidemiology of the group b streptococcus: maternal and nosocomial sources for infant acquisitions nosocomial transmission of group b streptococci unusual occurrence of an epidemic of type ib/c group b streptococcal sepsis in a neonatal intensive care unit a d a m k. prematurity is the major risk factor for late-onset group b streptococcus disease neonatal group b streptococcal disease associated with infected breast milk analysis of three outbreaks due to klebsielh species in a neonatal intensive care unit enterobacter cloacae outbreak in the nicu related to disinfected thermometers enterobacter cloacae and pseudomom ueruginosa polymicrobial bloodstream infections traced to extrinsic contamination of a dextrose multidose vial enterobacter sakazakii infections associated with the use of powdered infant formula-tennessee outbreak of enterobacter cloacae related to understaffing, overcrowding, and poor hygiene practices outbreak investigation of nosocomial enterobacter cloacae bacteraemia in a neonatal intensive care unit contaminated breast milk: a source of klebsiella bacteremia in a newborn intensive care unit klebsiella pneumoniae bloodstream infections in neonates in a hospital in the kingdom of saudi arabia identification of an iv-dextrose solution as the source of an outbreak of klebsielh pneumoniae sepsis in a newborn nursery invasive disease due to extended spectrum beta-lactamase-producing klebsiella pneumoniae in a neonatal unit: the possible role of cockroaches disinfectant contaminated with klebsiella oxytoca as a source of sepsis in babies neonatal intensive care unit outbreak caused by a strain of klebsielh oxytoca resistant to aztreonam due to overproduction of chromosomal beta-lactamase nosocomial outbreak of klebsiella pneumoniae producing shv- extended-spectrum betalactamase, originating from a contaminated ultrasonography coupling gel epidemic outbreaks of acute pyelonephritis caused by nosocomial spread of p fimbriated eschm'chia coli in children enteropathogenic escherichia coli (epec) and enterotoxigenic (etec) related diarrhoeal disease in a neonatal unit an outbreak of gastroenteritis due to escherichia coli h in a neonatal department molecular epidemiology of an outbreak of serratia marcescens in a neonatal intensive care unit nosocomial outbreak of serratia marcescens in a neonatal intensive care unit serratia marcescens infections in neonatal departments: description of an outbreak and review of the literature serratia marcescens outbreak associated with extrinsic contamination of / chlorxylenol soap investigation of a nosocomial outbreak due to serratia marcescens in a maternity hospital an outbreak of serratia marcescens transmitted by contaminated breast pumps in a special care baby unit a bacteriological examination of breast pumps use of pulsed-field gel electrophoresis to investigate an outbreak of serratia marcescens infection in a neonatal intensive care unit molecular epidemiology of an shv- extended-spectrum beta-lactamase in enterobacteriaceae isolated from infants in a neonatal intensive care unit. c l i infect dis a hospital outbreak of extendedspectrum beta-lactamase-producing klebsielh pneumoniae investigated by rapd typing and analysis of the genetics and mechanisms of resistance outbreak of nosocomial sepsis and pneumonia in a newborn intensive care unit by multiresistant extended-spectrum beta-lactamase-producing klebsiella pneumoniae: high impact on mortality pseudomonas aeruginosa infection in very low birth weight infants: a case-control study pseudomonas aeruginosa outbreak in a neonatal intensive care unit: a possible link to contaminated hand lotion nosocomial pseudomonm pickem'i colonization associated with a contaminated respiratory therapy solution in a special care nursery neonatal infections with pseudomonas aeruginosa associated with a water-bath used to thaw fresh frozen plasma pseudomonas aeruginosa outbreak associated with a contaminated blood-gas analyser in a neonatal intensive care unit sepsis in a newborn due to pseudomonas aeruginosa from a contaminated tub bath endemic pseudomonas aeruginosa infection in a neonatal intensive care unit a prolonged outbreak of pseudomonas aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission? guideline for hand hygiene in healthcare settings. recommendations of the health care infection control practices advisory committee and the hicpacishenapiciidsa hand hygiene task force. society for health care epidemiology of association for professionals in infection control/infectious diseases society of america pertussis: adults as a source in health care settings centers for disease control and prevention. hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study red book: report of the committee on infectious diseases a continuing outbreak of multidrug-resistant tuberculosis, with transmission in a hospital nursery nursery exposure of newborns to a nurse with pulmonary tuberculosis guidelines for preventing the transmission of mycobacterium tuberculosis in health-care facilities prevalence of candida species in hospitalacquired urinary tract infections in a neonatal intensive care unit association of fungal colonization and invasive disease in very low birth weight infants candida tropicalis in a neonatal intensive care unit: epidemiologic and molecular analysis of an outbreak of infection with an uncommon neonatal pathogen low rate of candida parapsilosisrelated colonization and infection in hospitalized preterm infants: a one-year prospective study when to suspect fungal infection in neonates: a clinical comparison of candida albicans and candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia evidence of nosocomial spread of candida nlbicans causing bloodstream infection in a neonatal intensive care unit vertical and horizontal transmission of unique candida species to premature newborns outbreak of candida afbicans fungaemia in a neonatal intensive care unit malassezia pachydermatis fungaemia in a neonatal intensive care unit an epidemic of malassezia pachydermatis in an intensive care nursery associated with colonization of health care workers' pet dogs pichia anomah outbreak in a nursery: exogenous source? outbreak of pichia anomah infection in the pediatric service of a tertiary-care center in northern india invasive pulmonary aspergillosis in a critically ill neonate: case report and review of invasive aspergillosis during the first months of life outbreak of systemic aspergillosis in a neonatal intensive care unit nosocomial infection with rhizopus microsporus in preterm infants: association with wooden tongue depressors nosocomial ringworm in a neonatal intensive care unit: a nurse and her cat clinical manifestations of rotavirus infection in the neonatal intensive care unit interruption of rotavirus spread through chemical disinfection an outbreak of diarrhea in a neonatal medium care unit caused by a novel strain of rotavirus: investigation using both epidemiologic and microbiological methods adenovirus type conjunctivitis outbreak in a neonatal intensive care unit neonatal nosocomial respiratory infection with coronavirus: a prospective study in a neonatal intensive care unit an outbreak of influenza a in a neonatal intensive care unit outbreak of parainfluenza virus type in an intermediate care neonatal nursery outbreaks of influenza a virus infection in neonatal intensive care units clinical and epidemiological aspects of an enterovirus outbreak in a neonatal unit severe neonatal echovirus infection during a nursery outbreak an outbreak due to echovirus type in a neonatal unit in france in : usefulness of pcr diagnosis cytomegalovirus infection in a neonatal intensive care unit. subsequent morbidity and mortality of seropositive infants transmission of cytomegalovirus to preterm infants through breast milk cytomegalovirus infection and bronchopulmonary dysplasia in premature infants cytomegalovirus infection of extremely low-birth weight infants via breast mdk epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding molecular epidemiology and significance of a cluster of cases of cmv infection occurring on a special care baby unit transmission of cytomegalovirus among infants in hospital documented by restriction-endonuclease-digestion analyses nosocomial cytomegalovirus infections within two hospitals caring for infants and children prevention of postnatal cytomegalovirus infection in preterm infants transmission of herpes-simplexvirus type in a nursery for the newborn. identification of viral isolates by dna ''fingerprinting an outbreak of herpes simplex virus type in an intensive care nursery two outbreaks of herpes simplex virus type nosocomial infection among newborns shedding and survival of herpes simplex virus from 'fever blisters varicella exposure in a neonatal medical centre: successful prophylaxis with oral acyclovir varicella exposure in a neonatal intensive care unit: case report and control measures nosocomial hepatitis a. a multinursery outbreak in wisconsin vertical transmission of hepatitis a resulting in an outbreak in a neonatal intensive care unit hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants the efficacy of infection surveillance and control programs in preventing nosocomial infections in us hospitals prevention of nosocomial infections in the neonatal intensive care unit recommended practices for surveillance. association for professionals in infection control and epidemiology, inc. surveillance initiative working group af'ic text for infection control and epidemiology hospital epidemiology and infection control pre-publication edition. oak brook terrace, ill national nosocomial infections surveillance system (nnis): description of surveillance methods cdc definitions for nosocomial infections epidemiology of neonatal infections: experience during and after hospitalization. pediatr infect dis j . centers for disease control and prevention, division of health care quality promotion. national nosocomial infections surveillance the newborn nursery improving hospital-acquired infection rates: the cdc experience hospital-acquired infections in the united states. the importance of interhospital comparisons nosocomial infection rates in us children's hospitals' neonatal and pediatric intensive care units af'ic text for infection control and epidemiology outbreak investigation in a neonatal intensive care unit outbreak of necrotizing enterocolitis associated with enterobacter sakamkii in powdered milk formula outbreak of acinetobacter spp. bloodstream infections in a nursery associated with contaminated aerosols and air conditioners nosocomial neonatal outbreak of serratia marcescen+analysis of pathogens by pulsed field gel electrophoresis and polymerase chain reaction an outbreak of epidemic keratoconjunctivitis in a pediatric unit due to adenovirus type a five year outbreak of methicillin-susceptible staphylococcus aureus phage type , in a regional neonatal unit outbreak of invasive disease caused by methicillin-resistant staphylococcus aureus in neonates and prevalence in the neonatal intensive care unit infection due to extended-spectrum beta-lactamase-producing salmonella enterica subsp. enterica serotype infantis in a neonatal unit an outbreak of necrotizing enterocolitis associated with a novel clostridiurn species in a neonatal intensive care unit flavobacterium) rneningosepticum outbreak associated with colonization of water taps in a neonatal intensive care unit a nursery outbreak of staphylococcus aureus pyoderma originating from a nurse with paronychia parainfluenza w e viral outbreak in a neonatal nursery an organizational climate intervention associated with increased handwashing and decreased nosocomial infections improving adherence to hand hygiene practice: a multidisciplinary approach american academy of pediatrics and american college of obstetricians and gynecologists. inpatient perinatal care services the effect of rings on microbial load of health care workers' hands impact of ring wearing on hand contamination and comparison of hand hygiene agents in a hospital gowning does not affect colonization or infection rates in a neonatal intensive care unit gowning on a postpartum ward fails to decrease colonization in the newborn infant guidelines for perinatal care infection control for hospitalized children guideline for preventing the transmission of mycobacterium tuberculosis in health care fac tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children's hospital single-room infant care: future trends in special care nursery planning and design the principles for family-centered neonatal care recommended standards for newborn icu design: report of the fifth consensus conference on newborn icu design. consensus committee to establish recommended standards for newborn icu design reservoirs of pseudomonas in an intensive care unit for newborn infants: mechanisms of control multi-resistant pseudomonas aeruginosa outbreak associated with contaminated tap water in a neurosurgery intensive care unit aerators as a reservoir of acinetobacter junii: an outbreak of bacteraemia in paediatric oncology patients guidelines for environmental infection control in health-care facilities. recommendations of cdc and the health care lnfection control practices advisory committee (hicpac) newborn nursery and neonatal intensive care unit association for professionals in infection control and epidemiology apic guideline for selection and use of disinfectants central services, linens, and laundry the inanimate environment guidelines for environmental infection control in health-care facilities. chicago, ill, american society for health care engineering and the american hospital association nosocomial respiratory syncytial virus infections neonatal respiratory syncytial virus infection control of nosocomial respiratory syncytial viral infections herpes simplex red book risk of cytomegalovirus infection in nurses and congenital infection in their offspring cytomegalovirus infection among employees of a children's hospital. no evidence for increased risk associated with patient care the role of understaffing in central venous catheter-associated bloodstream infections american academy of pediatrics and american college of obstetricians and gynecologists. perinatal infections fetal and neonatal varicella-zoster infections breast-feeding reduces incidence of hospital admissions for infection in infants human milk report of the committee on infectious diseases american academy of pediatrics and american college of obstetricians and gynecologists. care of the neonate bacterial contaminants of collected and frozen human milk used in an intensive care nursery preventing contamination of breast pump kit attachments in the nicu infant formula safety. pediatrics - co-bedding twins: a developmentally supportive care strategy co-bedding of twins in the neonatal intensive care unit parents as a vector for nosocomial infection in the neonatal intensive care unit a parent as a vector of salmonella brandenburg nosocomial infection in a neonatal intensive care unit role of antimicrobial applications to the umbilical cord in neonates to prevent bacterial - , . colonization and infection: review of the evidence a controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum ocular applications of povidoneiodine peripheral intravenous catheter complications in critically ill children: a prospective study guidelines for prevention of nosocomial pneumonia risk factors for nosocomial infections in critically ill newborns: a -year prospective cohort study nosocomial pneumonia hospital-acquired pneumonia: perspectives for the health care epidemiologist the prevention of ventilator-associated pneumonia non-invasive mandatory ventilation in extremely low birth weight and very low birth weight newborns with failed respiration ventilator-associated pneumonia with circuit changes every days versus every week cost analysis and clinical impact of weekly ventilator circuit changes in patients in intensive care unit weekly versus daily changes of inline suction catheters: impact on rates of ventilator-associated pneumonia and associated costs incidence of colonization, nosocomial pneumonia, and mortality in critically ill patients using a trach care closed-suction system versus an open-suction system: prospective, randomized study prevention of ventilatorassociated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia. a randomized, placebo-controlled, double-blind clinical trial stress ulcer prophylaxis in critically ill patients. resolving discordant meta-analyses occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole ventilator-associated pneumonia and upper airway colonisation with gram negative bacilli: the role of stress ulcer prophylaxis in children rr- ):l- key: cord- -lmf h oc authors: light, r. bruce title: plagues in the icu: a brief history of community-acquired epidemic and endemic transmissible infections leading to intensive care admission date: - - journal: critical care clinics doi: . /j.ccc. . . sha: doc_id: cord_uid: lmf h oc the ability to diagnose and treat infectious diseases and handle infectious disease outbreaks continues to improve. for the most part, the major plagues of antiquity remain historical footnotes, yet, despite many advances, there is clear evidence that major pandemic illness is always just one outbreak away. in addition to the hiv pandemic, the smaller epidemic outbreaks of legionnaire's disease, hantavirus pulmonary syndrome, and severe acute respiratory syndrome, among many others, points out the potential risk associated with a lack of preplanning and preparedness. although pandemic influenza is at the top of the list when discussing possible future major infectious disease outbreaks, the truth is that the identity of the next major pandemic pathogen cannot be predicted with any accuracy. we can only hope that general preparedness and the lessons learned from previous outbreaks suffice. intensive care, the epitome of the application of modern technology to medicine, arguably began as a response to the increasing numbers of older children and young adults developing paralytic polio during the early s. severe paralytic polio itself turns out to have been among the products of increasing modernity in the western world. clinical recognition of the syndromes associated with the polio virus date back about years. the fact that the disease was caused by a transmissible viral particle was demonstrated by . until early in the twentieth century the virus was readily transmitted throughout the population almost continuously by personal contact and by the fecal-oral route via water. the result was that most people's first exposure to the virus occurred in infancy. at this age most infections resulted in a clinically unapparent infection, in part due to partial protection by maternal antibody, after which lifelong immunity was established. only a few suffered a paralytic episode with the infection, at the time termed ''infantile paralysis.'' as hygienic standards of the advanced economy nations rose throughout the first half of the century, early childhood exposure to the virus declined. an increasing fraction of the population had their first exposure in late childhood or during young adulthood. in these age groups the likelihood that the infection will cause a paralytic syndrome is greatly increased, so both the incidence of clinically recognized infection and that of paralysis rose. by the early s clinically recognized cases had reached - annually for every , people in the united states, making it a major public health concern and a source of a great deal of fear in the general populace. more than % of polio virus infections are asymptomatic. however, at the more severe end of the clinical spectrum are the paralytic syndromes which range from paralysis of one or more limbs (''spinal polio'') to syndromes with respiratory muscle or bulbar paralysis (''respiratory polio'' or ''bulbospinal polio'') with loss of respiratory or upper airway muscle function or both. these more severe outcomes rise in incidence from about . % in infants to more than % in older children and adults. in the early part of the century development of polio with bulbar involvement was associated with a death rate of greater than %, generally from respiratory failure. use of a mechanical respirator to try to avert death was first attempted at the children's hospital in boston in , using an ''iron lung.'' the machine was basically a sealed box with a hole at one end for the patient's head to protrude, attached to two vacuum cleaners. the motors were then cycled to alternately create vacuum inside the box, expanding the patient's chest and causing the patient to inhale through the mouth (outside the box), then allowing air back into the box to permit exhalation. the design was further improved in , and the machines came into increasingly broad use throughout north america and europe during the severe outbreaks of the s. adoption of this therapy resulted in a significant reduction in mortality during these years. iron lungs, however, were cumbersome, difficult to use when trying to provide nursing care, and expensive. a more cost-effective and user-friendly approach to providing respiratory support was clearly needed. this finally came by bringing the positive pressure ventilation (ppv) concept out of the operating room. ppv was first used for respiratory support for polio victims at blegdam hospital in copenhagen, denmark, an innovation attributable to danish anesthetist bjorn ibsen. during this large outbreak in , some medical students were put to work hand-ventilating dozens of patients through tracheostomies until the worst of the paralytic phase of the illness had passed, often several weeks. the concept quickly spread elsewhere and was widely adopted, yielding substantial reductions in mortality. for reasons of efficiency and convenience, patients needing respiratory support were often grouped in a single location where the necessary expertise and equipment were available. the introduction of ppv into a defined area of the hospital used to support respiratory failure was the genesis of the modern icu and represents a signal event in the development of the field of critical care medicine. the introduction of effective vaccines, the salk (inactivated) vaccine in and later the sabin (live attenuated oral) vaccine in , immediately and dramatically reduced the incidence of polio to less than one per , population by the early s and the incidence continued to fall thereafter. the last case of wild strain polio in north america was reported in , and since that time the only cases of paralytic polio have been rare instances of disease due to variants of the live oral vaccine strain. polio does, however, still contribute to illnesses that may require intensive care in the form of the ''post-polio syndrome.'' this occurs in patients who survived paralytic polio decades ago and who, over the years, develop a gradual decline in function in the originally affected nerves and muscles which can years later once again threaten them with disability and, in some cases, respiratory failure requiring intensive care. in july , american legion members attending a convention at a hotel in philadelphia suddenly began falling ill with an acute febrile illness with pneumonia, often associated with extrapulmonary symptoms such as myalgia or diarrhea. many developed acute respiratory failure requiring mechanical ventilatory support in icu. over were affected and died, an alarming mortality rate, especially since physicians caring for the patients had no idea what was causing the illness. conventional microbiologic investigations yielded no convincing pathogens despite intensive investigation for the usual bacteria and viruses and other potential pathogens. epidemiologic and various biologic investigations were quickly implemented by local health authorities and by the centers for disease control and prevention (cdc). these showed that the disease was likely airborne and that it occurred more frequently in older individuals who had underlying lung disease, smoked, or were relatively immunocompromised. analysis of the likelihood of death revealed that those who received tetracyclines or macrolide antibiotics were more likely to survive than those who received only betalactams. however, no causal agent was uncovered, though many potential causes were excluded-most known bacteria and viruses, many biologic toxins and many environmental agents such as toxic chemicals and metals. in , joseph mcdade and charles shepard of the cdc reported the isolation of a novel fastidious gram-negative bacillus from the available clinical specimens. they named it legionella pneumophila. this discovery was quickly followed by an explosion of knowledge about the organism and its ecology, antimicrobial susceptibility, and of other bacteria within the genus. over time, demonstration that it was a widely occurring colonizer of brackish water, particularly in air conditioners, cooling towers, and water heaters and pipes, led to the implication of these reservoirs in several hundred outbreaks of the disease worldwide, especially in hospitals and other public health institutions, and hotels. thus began widespread development of regulations and guidelines for limiting the degree of colonization of these water sources by legionella, resulting in a reduction in the size, number, and scope of subsequent outbreaks. since the initial description of the disease, legionella has, of course, been shown to be one of the major causes of community-acquired pneumonia (cap), particularly in the more severe subset requiring icu care; this fact underlies the major lesson from plagues in the icu the outbreak-the nearly universal recommendation for inclusion of antimicrobial therapy for legionell spp in any treatment regimen for severe cap without another obvious cause. although we now know that no amount of continuing effort can completely eliminate this organism from our environment, and that we will continue to see endemic cases, we also know that clusters of cases should trigger an investigation into finding the point source of the outbreak, a situation that continues to occur several times a year somewhere in the world. in addition, the philadelphia outbreak that defined ''legionnaire's disease'' was the first in the modern icu era to demonstrate that major unknown infectious disease syndromes of severe consequence still exist, presaging the new infectious disease syndromes to be discovered in the years that followed. in the late s, emergency rooms and icus throughout north america began to see an increasing number of young menstruating women presenting with a previously little-known syndrome characterized by sudden onset of a high fever, often associated with vomiting and diarrhea, quickly followed by severe hypotension. early in the course most patients developed a diffuse macular rash, often with mucous membrane inflammation, with subsequent desquamation during convalescence. patients frequently required massive fluid resuscitation because of systemic capillary leak, as well as vasopressor support, mechanical ventilation for adult respiratory distress syndrome, and even renal replacement therapy for acute renal failure, complicating the shock episode. one of the early clusters of observed cases was reported in , and the term ''toxic shock syndrome'' was coined based on the isolation of an exotoxin-producing staphylococcus aureus from mucosal surfaces or the site of a minor infection in the absence of bacteremia. as the case numbers rapidly increased case definitions for the syndrome were formulated and epidemiologic studies mounted. by , over cases had been formally reported to the cdc. the case fatality rate was reported to be as high as % in the more severe cases included in the earliest reports, falling to about %- % as recognition of the syndrome improved. by this time there were clear epidemiologic links between the syndrome and menstrual use of high-absorbency tampons which were often left in place longer than less absorbent products. colonization of the tampon with staphylococcus aureus was also implicated, consistent with the postulated toxin-mediated disease mechanism. within months of these revelations the main manufacturer of the implicated tampons withdrew them from the market and women began changing tampons with greater frequency or stopped using them at the urging of public health authorities. the incidence of the syndrome immediately began to fall and within a few years, with the changing of use patterns of tampons and changes in their manufacture, toxic shock syndrome disappeared, for the most part, but not entirely, from the icu. even at the height of tss incidence in the united states, about % of the cases reported were nonmenstrual and % were in males. subsequent development of the knowledge that the clinical syndrome was due to strains of staphylococcus aureus that secrete a particular toxin (toxic shock syndrome toxin , or tsst- ), which is both absorbable from mucosal surfaces and capable of producing a profound shock syndrome even in the absence of significant invasive infection, soon led to the more widespread recognition of the nonmenstrual toxic shock syndrome. this syndrome, which was almost certainly extant before but little-recognized, was perhaps the main lesson from the outbreak: even trivial staphylococcal skin or wound infections light or mucosal surface colonization in the presence of a foreign body such as a nasal pack for nosebleed can lead to a severe shock syndrome if the organism is present and produces this toxin or one of several related ones. the recognition of the staphylococcal toxic shock syndrome also led to increasing understanding of the role of ''superantigens'' as a mechanism of disease-bacterial toxins capable of activating a large fraction (up to %) of the total t-lymphocyte population. such superantigens have since been implicated in a number of other disease syndromes, among them the streptococcal toxic shock syndrome (see below). over the past two decades, the incidence of menstrual and nonmenstrual staphylococcal tss has been about one per , population in most areas. busy icus will, therefore, continue to see occasional cases. however, there is some recent evidence that case numbers may be on the rise again in at least some areas, possibly because of a resurgence in the prevalence of toxin-producing strains in the community. in , physicians working in infectious diseases and critical care medicine thought they knew all about pneumocystosis. the organism, then thought to be a protozoon, had been first described in by carlos chagas in brazil, and since then had been clearly implicated as a cause of interstitial pneumonia in debilitated and malnourished children (in the aftermath of world war ii) and, later, a cause of severe opportunistic pneumonia in immunocompromised patients, usually those being treated with highdose corticosteroids for connective tissue diseases or lymphoreticular neoplasms. in these patients it caused an impressively aggressive bilateral pneumonia leading to acute respiratory failure. this pneumonia was notoriously difficult to definitively diagnose, requiring bronchoscopy or open lung biopsy to demonstrate the small numbers of characteristic pneumocystis organisms on special silver stains of clinical specimens. the mainstay of treatment at that time was pentamidine, generally given intramuscularly, giving way to trimethoprim/sulfamethoxazole after the publication in of a randomized clinical trial showing that it was at least as effective and generally better tolerated. in the early s, a new form of the infection began to be seen with regularity. young men began to present to hospital with a rather more indolent diffuse bilateral pneumonia that nevertheless went on to cause respiratory failure and which, when investigated, proved to be due to pneumocystis. the course of the disease was quite different from what physicians had been used to up to then. it began more gradually, progressed at a slower pace and was associated with a much lesser systemic inflammatory response. microscopy of respiratory specimens revealed exponentially more organisms than previously seen, such that many patients could be diagnosed from sputum specimens rather than bronchoscopy, and biopsy was virtually never needed. nobody had any idea why this was happening, although it quickly became apparent that the underlying cause of the infection was a new form of severe deficiency of cell-mediated immunity. epidemiologic investigations were soon underway. patterns began to emerge. many of the young men were haitian or had been to haiti. many were homosexual, bisexual, or had worked in the sex trade; others had abused intravenous drugs. the many fewer women with the disease had similar exposures. theories proliferated. was it immunologic exhaustion from exposure to too many microbial stresses? toxins? drugs used in the sex trade? multiple and synergistic viral infections? through the early s, the case load grew. icus throughout north america and, later, in europe and elsewhere, saw increasing numbers of young people, mainly men, plagues in the icu with severe respiratory failure due to pneumocystis pneumonia. by they were being called patients with acquired immunodeficiency syndrome (aids) on the basis of demonstration of low numbers of cd lymphocytes in the blood, but the cause remained unclear. then, in , montagnier and barre-sinoussi at the pasteur institute in france isolated a viral pathogen that they named lymphadenopathy-associated virus (lav). at the national institutes of health in the united states, gallo demonstrated that the virus (which he referred to as human t-cell leukemia virus iii, based on an unproven relationship to other viruses he had previously discovered) definitively caused aids. the virus, now called human immunodeficiency virus (hiv)- was isolated and described and the first diagnostic kits devised, resolving the mystery of causation. montagnier and barre-sinoussi would eventually win the nobel prize in medicine in for their contribution. during the s, patients continued to present with severe pneumonia requiring respiratory support and intensive antimicrobial therapy, often with less than satisfactory results. as knowledge progressed, hiv-associated pneumocystis infection in the icu changed its face several times over the years. at the beginning of the epidemic, most patients presenting for care with hiv/aids and pneumocystosis were severely ill with diffuse pneumonia and hypoxemic respiratory failure and many died, %- % in most centers, prompting widespread debate about whether such patients should even be admitted to icu for mechanical ventilatory support. however, as experience with the disease developed it became clear that an early and aggressive approach could improve prognosis. it was found that in the aids population even minor respiratory symptoms with few or no abnormalities on chest radiograph could be due to pneumocystis infection in the earlier stages, and that even modest degrees of arterial oxygen desaturation signaled impending respiratory failure. earlier bronchoscopy for diagnosis followed by prompt antimicrobial therapy, with pentamidine predominantly in the early s and later primarily with trimethoprim/sulfamethoxazole, led to overall mortality rates falling to the %- % range by the middle of the decade. the advent of systemic corticosteroids therapy for early respiratory failure in aidsassociated pneumocystosis was then shown to further reduce the numbers of patients progressing to advanced respiratory failure, leading to reductions in the numbers of cases needing icu admission and further reducing overall mortality rates to the %- % range. but for patients requiring icu care mortality rates were as high as before the use of steroids and often higher, likely related to the fact that most patients developing respiratory failure had already failed to improve or had progressed despite intensive antimicrobial and corticosteroid therapy. along with these developments in management of the disease, progress was being made on hiv itself. following identification of the virus in , there soon followed increasingly reliable diagnostic tests for the infection, leading to earlier identification of cases and monitoring of cd lymphocyte counts. by the early s, studies supporting widespread use of chemoprophylaxis against pneumocystis in all patients with cd counts < /mm were available and became standard public health agency recommendations. pneumocystosis, which in the s and s was one of the principal causes of hypoxemic respiratory failure in many icus in north america and western europe, began to decline rapidly in incidence, becoming relatively uncommon even before the widespread adoption of highly active antiretroviral therapy, which has, since the mid- s, caused the disease to all but disappear from our icus. although many lessons can be drawn from the battle against aids-related pneumoncystis pneumonia during the s and s, for icu and infectious diseases practitioners one of the main ones comes from the sad fact that once patients had developed full-blown hypoxemic respiratory failure even the best intensive care could only deliver % survival rates. the really large gains in survival came not from better icu technology but from pre-empting the disease on multiple fronts, including earlier diagnosis of hiv infection, early diagnosis and antimicrobial treatment of pneumonia, steroid treatment of early respiratory failure, antimicrobial prophylactic regimens and, later, effective antiretroviral therapy. until , the only members of the bunyaviridae family of viruses known to cause disease in north america were members of the genus bunyavirus, all causing mosquito-borne viral encephalitis, mainly in children (california encephalitis). other members of the family were known to cause serious febrile illnesses, encephalitides and hemorrhagic-fevers in africa and asia (rift valley fever, crimean-congo hemorrhagic fever, hemorrhagic fever with renal syndrome). however, in the spring of wetter-than-usual conditions in the american southwest led to increased availability of food for deer mice, leading to a population explosion and increasing movement of rodents into human-occupied spaces, increasing the chance that humans might be exposed to the rodents and their excreta. in rapid succession, several previously healthy young people, mainly navajos, presented to health care institutions in the four corners area of the southwestern united states, all with fulminant illnesses leading to shock and acute respiratory failure requiring icu care. by early june that year, cases had been identified and had died. in most cases the illness had started with fever and widespread myalgia, soon followed by cough, then by cardiovascular collapse due to a severe systemic capillary leak syndrome and by acute respiratory failure due to low-pressure pulmonary edema. in some cases the time from onset to icu or death was as little as hours, in others a few days. remarkably, although no pathogen was initially identified from blood or tissues, in less than a month after the first report of a possible outbreak, serologic testing had demonstrated antibody cross-reactivity with a range of known pathogens of the hantavirus group, suggesting that the disease was due to a previously unknown member of this group. shortly thereafter exposure to deer mice and their excreta was implicated as the likely source of the infection. the mortality rate for the early cases of hantavirus pulmonary syndrome (hps) was extremely high- % in the initially reported group of patients-mostly due to intractable shock and unsupportable hypoxemic respiratory failure due to acute respiratory distress syndrome (ards). however, this improved with clinical experience as it became evident that administration of large amounts of intravenous fluids in the face of profound capillary leak only resulted in much worse generalized and pulmonary edema, with little improvement in the shock state and only worsening of the respiratory failure. management changed to an approach limiting the amount of fluid administered early in the course together with earlier institution of inotropic support, resulting in a much improved survival rate of about %, generally with minimal or no long-term sequelae in survivors. in subsequent years development of increasingly specific serologic and virologic testing has demonstrated that this disease had been present but unrecognized throughout north and south america long before this outbreak, and that there are several related viruses, each associated with a particular rodent, causing endemic disease and the occasional outbreak. by the mid- s, over cases were reported in states, mainly in the southwest, and cases have since been reported plagues in the icu in small numbers in most other states, canada, mexico, and south america, where several outbreaks have occurred. whereas occasional cases continue to be seen in icus in all these areas, no further major outbreaks have yet occurred in the united states or canada, though clearly remaining a threat under the right conditions; the only currently available preventive measure is avoiding rodent contact. steven simpson, md, one of the intensivists at the health sciences center in albuquerque, new mexico, who was closely involved in the initial four corners outbreak, points out that the event highlights several trends in subsequent disease outbreaks in north america. one is the extreme rapidity with which novel pathogens and potential pharmacotherapeutic agents can now be identified. whereas the pathogen in the legionnaire's outbreak took almost a year to identify, researchers identified the hps pathogen and its source in just months. computerized access to data and data analysis along with virtually instantaneous electronic transmission of information plays a central role in this development. the initial hps outbreak has several icu-related lessons to teach us. while the aforementioned treatment strategies effective in a systemic capillary leak syndrome have been absorbed by the critical care community, it appears that one lesson taken to heart by the local icu teams failed to disseminate to the broader icu community. the initial outbreak was accompanied by a marked element of fear and concern among health care workers, including those in the icu, and a significant level of panic in the local community; a combination of this fear, the requirement for rigorous quarantine precautions, and a marked increase in transfers to the icu of any severely ill patients with symptoms remotely compatible with hps resulted in some compromise of icu operations, due to being completely overwhelmed. this might potentially have been avoided by an awareness that for an effective epidemic response, it is essential to include both hospital and icu operations in each locale. the outbreak also reinforces the principle that nearly all old and most new epidemic infectious diseases have their origin in close contact between humans and other species of animal, both wild and domestic, and new kinds and quantities of such contact are likely to cause new, or newly recognized, disease syndromes. streptococcus pyogenes was one of the first bacteria ever to be conclusively linked to human disease (puerperal infection associated with childbirth). however, over the past years the nature of the diseases stemming from it has changed dramatically on several occasions. at the turn of the last century, it was well known as a cause of streptococcal pharyngitis, erysipelas, and wound infections. it also caused severe septicemic illnesses that frequently led to death. osler knew streptococcus pyogenes as a principal cause of thoracic empyema following pneumonia or severe cases of scarlet fever, and also as a major cause of primary bacteremia with sepsis. these more severe manifestations of streptococcal infection became increasingly uncommon as the twentieth century progressed, particularly after the arrival of antibiotics mid-century. notably, osler did not mention streptococcus as a cause of necrotizing fasciitis or being associated with soft tissue necrosis in wound infections. this syndrome was first described by meleney in ; at that time, it was characteristically a slowly evolving gangrenous infection, usually of surgical wounds, which often responded well to debridement and was associated with a mortality rate of only %. for over a generation after the advent of the modern antibiotic era, streptococcus pyogenes was seldom a problem that led to critical illness-soft tissue infections and light the occasional bacteremia were generally very amenable to treatment; extensive surgery or drainage was seldom required, and cases requiring icu support for shock or respiratory failure were rare. beginning in the mid- s, medical practitioners in centers across north america and europe began seeing previously unknown forms of severe streptococcal disease, soon labeled streptococcal necrotizing fasciitis and streptococcal toxic shock syndrome. streptococcal toxic shock syndrome (strep tss) is any infection with streptococcus pyogenes that is associated with a rapidly progressing systemic toxic response characterized by early onset of high fever and myalgia, often with prominent gastrointestinal symptoms, and by rapid progression to hypotension and multiple organ system failure. the illness usually requires icu support for massive fluid resuscitation, vasopressor and inotropic support and mechanical ventilation. although some cases have primary bacteremia, many others have a localized focus of infection, most often in soft tissues, that only becomes clinically apparent after the onset of shock. streptococcal necrotizing fasciitis is often associated with strep tss and, as mentioned, is often only correctly diagnosed after the onset of shock. the most characteristic story is presentation to a physician or an emergency room with abrupt onset of severe pain, often in an extremity with minimal or no evidence of cutaneous injury. at this stage severe systemic toxicity is usually not present and, since examination of the painful site is also at this stage quite unremarkable, patients are frequently sent home with analgesics and reassurance. over the next - hours pain at the site of infection continues to increase, soft tissue swelling and redness appear above the deeper tissues that are undergoing ongoing necrotizing infection, eventually resulting in full-thickness necrosis evidenced by ecchymosis, cutaneous necrosis, and bullae formation. early or later in this course strep tss frequently occurs. when these cases first began to appear, clinicians' approach to both the sepsis and the tissue necrosis was essentially the same as that used for apparently similar syndromes caused by other bacteria. a broad spectrum antimicrobial was started, fluid resuscitation begun and imaging studies ordered to better define the source of infection causing pain or localized swelling. imaging frequently demonstrated only soft tissue swelling consistent with cellulitis, so surgery was often deferred until superficial signs of tissue necrosis became obvious, and then when surgery was done it was often performed using the conventional approach of trying to conserve as much tissue as possible. the result was that treatment was often too little and too late, with mortality rates exceeding % in many reported series. with the realization that treatment, to be successful, must be swift and aggressive, approaches to therapy changed. emergency physicians were increasingly alerted to the fact that severe pain at any body site, even with relatively minimal localized physical findings and particularly if accompanied by signs of systemic inflammation, could represent necrotizing fasciitis. surgeons began to be consulted much earlier, and any localized pain with swelling more often led to diagnostic surgical exploration rather than imaging and waiting. antimicrobial strategies changed. addition of clindamycin to the usual penicillin or other beta-lactam therapy was advocated and widely adopted, based on results from animal models of the syndrome and on pharmacologic and physiologic considerations, including its ability to inhibit bacterial protein (ie, toxin) synthesis, penetrate necrotic tissues, and inhibit inflammatory cytokine synthesis. toxin neutralization using pooled intravenous gamma globulin was also advocated with the support of primarily historical case-control studies. in most centers, implementation of these approaches has led to dramatic reductions in mortality rates to about %- % although, in the absence of any adequate controlled trials, it remains unclear what the relative contribution of each of these measures has been to the improved outcome. unlike several of the other ''plagues'' discussed above, this is one that is still very much with us. the streptococcus pyogenes strains most strongly associated with severe invasive disease (m-protein types and ) have increasingly been supplanting those associated with less severe disease resulting in an endemic sporadic case-rate for severe disease of one to cases/ , population yearly, with intermittent larger-scale community outbreaks, both of which will continue to require vigilance and an aggressive therapeutic stance from the critical care community. the first case of this apparently novel severe viral respiratory infection occurred in guangdong province in southern china in november . the victim, a farmer, died of an undiagnosed ''atypical pneumonia.'' over the ensuing weeks several more cases of severe respiratory syndromes began to appear in the region, also undiagnosed. by the end of november there had been enough such cases to generate considerable alarm among the medical community in china, generating internet communications between institutions which were picked up by international monitoring agencies. this led to a request from the world health organization (who) for information about the outbreak, but no information was forthcoming from chinese authorities. the first official report about the outbreak was made to public health authorities in guangdong in early january , with a later report to the who in february that, in retrospect, did not fully make clear either the nature or the scale of the problem. transmission of the disease within china continued to occur, leading to rapidly increasing numbers of cases in south china, then throughout the country and to the capitol beijing (where one of the largest outbreaks occurred). exposure of chinese travelers and visitors to the country was inevitable, given the scale of the outbreak. one exposed individual was a physician from mainland china who, incubating the disease during his travel, stayed at the metropole hotel in hong kong in early march. later investigations showed that he transmitted the virus to at least other guests at the hotel, who then carried it by international air travel to taiwan, singapore, vietnam, and canada. one of these contact cases was an american businessman headed for singapore. becoming ill while in transit, he stopped in hanoi where he was admitted to hospital with a severe pneumonia, to which he eventually succumbed. soon after, a number of health care workers who had been in contact with him also became acutely ill. fortunately for the course of the outbreak, one of the consultants on the case was an italian physician working with the who in vietnam, dr. carlo urbani. he immediately recognized that this was a previously unknown severe atypical pneumonia that was relatively easily transmissible and reported it to the who; this led to immediate mobilization of investigative efforts and worldwide alerts about the threat. unfortunately, in the course of caring for the victims of the disease in hanoi, dr. urbani himself contracted the infection and died of it later. as information from china became more available, it became clear that by this time there had already been hundreds of cases and numerous deaths. the majority of the initial wave of cases were noted to have occurred primarily in farmers and food handlers, particularly those working in food markets where live wild animals were kept and sold for food. the second large wave of those affected were health care workers exposed in hospital to patients with the disease. the illness was characterized by fever and myalgia with gastrointestinal symptoms in the initial phase, occurring an average of days after exposure (range - days). many cases got no worse than this, but others went on to develop dyspnea associated with radiographic evidence of a diffuse, patchy pneumonitis which, in some, progressed to ards. an average of light % required mechanical ventilatory support, and when the data were all in from later phases of the outbreak, mortality rates averaged about % overall, worse in the aged and debilitated, lower in the young and healthy. the largest outbreak outside asia occurred in toronto, canada. the index case, a visitor to china, returned to canada and died of pneumonia at home, undiagnosed, in early march . shortly thereafter, one of his sons was admitted to hospital with a severe respiratory illness and died a few days later. by this time, four other family members had become ill and had been admitted to hospital; the first cases of affected health care workers appeared soon after among those who had cared for the dying son of the index case. within days, other instances of transmission from undiagnosed contacts of the initial cases in hospitals, doctors' offices, emergency rooms, and at social events were leading to admission of cases to several hospitals throughout toronto. the response of the public health authorities, beginning soon after the who global alert and coincident with the recognition of the first local cases, was quick and vigorous, including closure of the main affected hospital, intensive follow-up of probable contacts, quarantine of suspected cases based on a fairly inclusive case definition and strict institution of barrier contact protection for health care workers. by mid-april the number of new cases was rapidly declining, although there was one cluster of late cases related to exposure of a large number of health care workers during the resuscitation and difficult intubation of a critically ill patient. a later cluster of cases also occurred in a rehabilitation hospital, where it appeared that unrecognized contacts from the first phase of the outbreak had been transferred and transmitted the disease to other patients and staff. the worldwide outbreak was essentially over by july . there were a total of reported cases from countries, with deaths. intensive epidemiologic and laboratory study of the disease by investigators and laboratories worldwide led to unprecedented rapid growth in knowledge about the causative agent. the virus, more or less simultaneously characterized at a number of laboratories around the world, proved to be a previously unknown coronavirus (severe acute respiratory syndrome [sars]-cov) with capacity to infect and spread from a variety of wild animals to humans. epidemiologic, serologic, and virologic evidence was developed linking human cases to exposure to infected wild animals, including masked palm civets, raccoon dogs, ferrets and ferret badgers, all being sold for human consumption in markets in china. control of their transport and sale and exposures to humans by chinese health authorities was probably one of the major factors in bringing the first outbreak under control, the partial failure of which later led to a second, much smaller outbreak late in . although the initial speculation was that one or more of these wild animals were the reservoir in nature for the infection, it now appears more likely that the viral reservoir is actually bats, with crosstransmission of the virus between bats, food animals, and humans in crowded markets leading to development of strains with the capacity to transmit between humans. public health authorities worldwide learned much from sars about the importance of effective international communication in developing a rapid and effective response to outbreaks of novel viruses, and more about how to go about containing such infections within communities and hospitals. several intensivists involved in the outbreak credit e-mail communications from other international outbreak sites for effective advice on critical elements of disease protection (eg, powered air purifying respirators and full contact rather than droplet precautions) and therapy. for the critical care community, perhaps one main lesson was the importance of ''super-spreading incidents'' in propagating the disease in hospitals. many of these occurred in critically ill patients undergoing resuscitation with difficult or traumatic intubation, generating aerosols in closed spaces which contained many superfluous and inadequately protected health care workers. handling these situations safely depends crucially on identifying the potential risk and undertaking the resuscitation and intubation using the most experienced operators available, adequately protected with basic barrier precautions (eye protection, gloves and surgical face-masks), using sedation or paralysis as necessary to minimize trauma and aerosol generation, and with only essential and adequately protected staff in the room. this likely applies to many other situations with potential for disease transmission to health care workers. unfortunately, this epidemic again points out the primary lesson that was not absorbed from the earlier hps outbreak, namely, the need for detailed preplanning and preparation for a major infectious disease epidemic that is inclusive of hospital and icu operations in each locale. according to participants, the sars outbreak demonstrated many of the same early icu operational problems that plagued the hps outbreak albeit on a larger scale. in the icu era, there has yet to occur a true influenza pandemic with a high attack rate in all age groups and associated high hospitalization and mortality rates, as was seen in the great pandemic. in that worldwide disaster, it is estimated that % of all people became ill with the virus and an estimated - million died. minor recent pandemics in and had less than one twentieth of the impact of the influenza, not greatly different from the yearly interpandemic influenza the world has been experiencing in the years since. interpandemic influenza epidemics since have been caused primarily by h n and h n influenza viruses, to which most of the population has developed some degree of immunity from prior infection or vaccination. the result is what public health authorities have become used to seeing: each year a slightly different influenza a appears in asia with minor antigenic changes in the ha or na surface proteins (termed drift), making it infectious once again for humans whose immune systems have yet to be exposed to the new variant, and a new epidemic is launched. when the ''flu'' arrives in an area, cases begin to appear suddenly and there is rapid spread in the population, usually with %- % becoming infected over a -week period with a peak in case numbers at week two or three. about half of those infected will seek medical attention, many more than once, and one to about per thousand infected will be admitted to hospital with a respiratory syndrome such as pneumonia, chronic obstructive pulmonary disease exacerbation, asthmatic attack, or cardiac failure, the rate depending on age and underlying comorbidities. overall, about . % of those infected die, with mortality rates among those with major comorbidities up to %. these latter cases constitute most of the increase in the icu case load which most units experience every winter. the load is sometimes taxing but usually not overwhelming. a true pandemic is unlikely to play out this way. how different it would be depends on a number of factors: the antigenic difference in the new influenza virus compared with the old (ie, the antigenic ''shift'' to a different one of ha or na protein subtypes due to introduction of a variant from another influenza-susceptible species), how transmissible the new virus is, how virulent it is, how susceptible it is to antiviral drugs, and whether the world is prepared for it with drug availability and vaccines. the prototype severe pandemic was the spanish influenza of , an h n virus. the most recent circulating influenza virus just before that time was an h n that had arrived in . current evidence suggests that an avian influenza virus underwent a period of evolutionary adaptation, possibly in another susceptible species such as swine, fitting it for transmission to humans, which it then did. , this h n virus had not been previously experienced by any segment of the population except the very old, so nearly everyone, particularly non-elderly adults and children, was without immunity and was at risk of severe infection. attack rates, as noted earlier, were extremely high everywhere as were rates of primary influenza pneumonia, complicating bacterial pneumonia, and death. in the united states, death rates were more than -fold higher than in any influenza pandemic since. an outbreak of influenza on this scale, if unchecked by effective antiviral therapy or vaccines, would render icu care such as mechanical ventilatory support for respiratory failure irrelevant. even today, with maximal respiratory support, most patients with diffuse primary viral pneumonia complicated by respiratory failure cannot be saved, and the numbers presenting for such care in a short space of time, if comparable to the pandemic, would overwhelm our current icu capacity within days. currently the main apparent threat of a new pandemic comes in the form of the h n influenza virus. this virus is now present nearly worldwide in migratory and, intermittently, domestic bird populations. from time to time, transmission of the virus from birds to humans occurs, generally from close contact situations. who data indicate that there have been laboratory-confirmed cases of such transmission from to mid- . the mortality rate has exceeded %, although it is likely that many less severe cases do not come to medical attention and are therefore not counted as confirmed case survivors. to date no instances of transmission to humans by humans or other mammals has been documented. however, the threat remains that if this virus were to become capable of human-to-human transmission by adaptation in another susceptible mammalian host such as swine, a pandemic on the order of the event could occur. with no true pandemic for over years, including all of the icu era, health authorities worldwide are deeply engaged in trying to learn the lesson of this new ''plague'' before it actually occurs. it is clear that we will need excellent international communication, rapidly enactable containment and quarantine plans and, if possible, effective antivirals and vaccines to deal with the h n virus. if it evolves as feared and becomes easily transmissible while retaining its current virulence; modern life-sustaining technology alone will be no shield at all. the last years have seen remarkable advances in the ability to diagnose and treat infectious diseases and handle infectious disease outbreaks. for the most part, the major plagues of antiquity remain historical footnotes. however, despite these advances, there is clear evidence that major pandemic illness is always just one outbreak away. in addition to the hiv pandemic, the smaller epidemic outbreaks of legionnaire's disease, hantavirus pulmonary syndrome, and sars, among many others, points out the potential risk associated with a lack of preplanning and preparedness. although pandemic influenza is at the top of the list when discussing possible future major infectious disease outbreaks, the truth is that the identity of the next major pandemic pathogen cannot be predicted with any accuracy. we can only hope that general preparedness and the lessons learned from previous outbreaks suffice. a history of poliomyelitis polio: an american story an apparatus for the prolonged administration of artificial respiration the physiologic challenges of the copenhagen poliomyelitis epidemic and a renaissance in clinical respiratory physiology post-poliomyelitis syndrome legionnaire's disease: description of an epidemic of 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region of china/vietnam public health measures to control the spread of the severe acute respiratory syndrome during the outbreak in toronto isolation and characterization of viruses related to the sars coronavirus from animals in southern china bats are natural reservoirs of sars-like coronaviruses critically ill patients with severe acute respiratory syndrome influenza: the mother of all pandemics molecular basis for the generation in pigs of influenza a viruses with pandemic potential who-epidemic and pandemic alert and response (epr) key: cord- -q hqra authors: paul, kishor kumar; salje, henrik; rahman, muhammad w.; rahman, mahmudur; gurley, emily s. title: comparing insights from clinic-based versus community-based outbreak investigations: a case study of chikungunya in bangladesh date: - - journal: int j infect dis doi: . /j.ijid. . . sha: doc_id: cord_uid: q hqra abstract background outbreak investigations typically focus their efforts on identifying cases that present at healthcare facilities. however, these cases rarely represent all cases in the wider community. in this context, community-based investigations may provide additional insight into key risk factors for infection, however, the benefits of these more laborious data collection strategies remains unclear. methods we used different subsets of the data from a comprehensive outbreak investigation to compare the inferences we make in alternative investigation strategies. results the outbreak investigation team interviewed , individuals from homes. ( %) of individuals had symptoms consistent with chikungunya. a theoretical clinic-based study would have identified % of the cases. adding in community-based cases provided an overall estimate of the attack rate in the community. comparison with controls from the same household revealed that those with at least secondary education had a reduced risk. finally, enrolling residents from households across the community allowed us to characterize spatial heterogeneity of risk and identify the type of clothing usually worn and travel history as risk factors. this also revealed that household-level use of mosquito control was not associated with infection. conclusions these findings highlight that while clinic-based studies may be easier to conduct, they only provide limited insight into the burden and risk factors for disease. enrolling people who escaped from infection, both in the household and in the community allows a step change in our understanding of the spread of a pathogen and maximizes opportunities for control. infectious disease outbreaks have the potential to place a significant burden on public health resources. understanding who is at risk of becoming infected is critical for the focused targeting of interventions. due to relative ease of access and limited cost requirements, outbreak investigations typically focus on cases that present at formal healthcare centers such as hospitals or community clinics. for example, data collection performed as part of epidemiological investigations during the recent epidemics of ebola, zika and mers focused on quantifying the number of cases and their characteristics. (al-abdallat et al., , lu et al., , teixeira et al., these case-counting exercises provided key insights into fundamental epidemiological parameters such as the basic reproductive number and case fatality rates, and allowed the projection of the future course of the epidemic. (aylward et al., , lessler et al., , lewnard et al., , yamin et al., however, without information on the underlying population, and especially characteristics of individuals who avoid infection, these approaches limit our ability to make mechanistic insights, quantify burden of disease, and identify risk factors for infection, hampering efforts to develop targeted control strategies. cases that present at healthcare centers may only represent a small minority of all cases. in addition, some individuals are more likely to visit formal healthcare providers than others, including those with more severe illness, and differences in healthcare seeking can vary by age, gender and socioeconomic status. (chowdhury et al., , nikolay et al., , pandey et al., household-based outbreak investigations, where investigation teams visit affected j o u r n a l p r e -p r o o f communities, permit a more comprehensive understanding of pathogen spread that limits the impact of healthcare seeking patterns. (france et al., ) however, these investigations are usually still focused on identifying individuals that got sick. (boore et al., , france et al., without also understanding who is avoiding infection in a community, it is difficult to identify the key risk factors for infection, limiting potential inferences. the possible insights from alternative investigation strategies have not previously been systematically compared. here, we use the results of a detailed chikungunya outbreak investigation from bangladesh as an example to consider the inferences made under different investigation scenarios. chikungunya virus is a mosquito-borne alphavirus transmitted to humans by aedes mosquitoes causing acute fever, joint pain, and skin rash. (aubry et al., ) chikungunya fever was first recognized in in tanzania. (lumsden, ) since then, outbreaks of chikungunya have been regularly identified across the tropics and sub-tropics. the first chikungunya outbreak in bangladesh was identified in in two northwestern districts bordering india.(icddr) since then regular outbreaks have been detected. (khatun et al., , salje et al., b here we use the results from a detailed investigation of an outbreak of chikungunya virus in a village in tangail, bangladesh where the outbreak team visited every household in the community and interviewed all members in each household. the comprehensive household investigation captured both those who did get infected and those that escaped from infection. the objective of this study was to compare our approach, in terms of the inferences about the outbreak, to more limited investigation strategies. in late november , a local health official of gopalpur sub-district in tangail households in the village consented to being enrolled in the study. questionnaires were administered in all households to identify suspected cases, identify demographic characteristics, and travel histories of individuals within households. suspect cases were defined as residents with acute onset of fever with rash or joint pain within months prior to beginning the investigation. study staff administered questionnaires to household heads about household members' demographic data and history of illness, water source, construction materials, and mosquito control measures in the household. potential mosquito breeding containers in and around the participating households with stored water were inspected for presence of larvae. suspected cases were asked about their symptoms with onset date and specifics about their treatment seeking behavior. the gps location of all homes was also recorded. determining the etiology of the outbreak all household members, irrespective of their suspected case status, were asked to provide a single ml blood specimen for laboratory testing. blood specimens were spun in the field to separate serum, which were then stored on ice and transported to the virology laboratory of iedcr. the serum samples were tested for igm antibodies against chikungunya by enzyme linked immunosorbant assay (elisa) (standard diagnostics, inc., south korea). suspected casepatients who had igm antibodies against chikungunya in their serum were termed laboratory confirmed cases. we created four different datasets that allowed us to consider different outbreak investigation strategies: this dataset consisted of all suspect cases that reported that they visited a formal healthcare setting (defined as government or non-government primary healthcare center/clinic/hospital) following the onset of symptoms. this dataset consisted of all suspect cases, irrespective of their healthcare seeking behaviors. this dataset consisted of all suspect cases plus controls consisting of household members of these cases. this dataset consisted of all members of all households in the community, regardless of symptoms. the epidemic curve was constructed using symptom onset date of chikungunya cases. gps locations of households with and without chikungunya cases were used to prepare spatial distribution maps. for the case-only datasets (datasets a and b), we compared the age and sex distribution of the cases with that for the district from the census (bangladesh bureau of statistics, ) . for the datasets with information on individuals who escaped from infection (datasets c and d), we initially used simple logistic regression to compare the demographics, typical apparel worn, travel history within the last six months, and household characteristics of cases with non-cases. we then built multivariable logistic regression models to identify adjusted risk factors for chikungunya fever. we initially placed all variables with a p-value of < . in the unadjusted analysis into a multivariable model. we then used backward stepwise selection using the akaike information criterion (aic) (sauerbrei et al., ) to identify the best model. not all individuals who get infected will present with symptoms. we attempted to capture these individuals by asking for blood samples from all community members. to assess the impact of j o u r n a l p r e -p r o o f misclassifying asymptomatically infected individuals as controls in datasets c and d, we conducted sensitivity analyses where these individuals were reclassified as cases. all participants provided written informed consent prior to interviews and blood specimen collection and the ministry of health and family welfare, government of bangladesh reviewed and approved the outbreak investigation plan. the ninety-five suspect cases reported visiting a formal healthcare facility for symptoms consistent with chikungunya between july and november, with the peak number of cases occurring in j o u r n a l p r e -p r o o f october (figure : panel a). cases sought care in three different centers: sought care in a government run community clinic, in a government run sub-district health complex and in a private clinic. the median age was years (interquartile range (iqr) = - years) and the majority ( %) were female (table ). if we used the age and sex distribution of the district from the national census, we find that there is an increased risk of disease in those between the ages of - compared to those aged below years (or . , % . - . ) and that females were at increased risk of infection compared to males (or of . , % ci: . - . ) ( table ) . an additional suspect cases were identified in the community who did not seek care in formal healthcare facilities. of these, individuals visited a local pharmacy and individuals visited the informal sector (unlicensed medical practitioner, traditional healer, and homeopath). the distribution of dates of symptom onset for all cases was nearly identical to the distribution for those that visited clinics (spearman correlation of . ) ( figure a ). the proportion of suspect cases visiting a clinic varied between % in - years age group and % in ≤ years age group ( figure b) . the conclusions about age, sex, educational levels, use of mosquito controls and clinical presentation of suspect cases were similar when using datasets of all cases or only those that sought care in clinics (table ) , however, those who presented to clinics were more likely to travel outside the district ( % vs %, p-value . ). cases who attended formal healthcare settings also appeared to come from similar parts of the community as cases who did not (figure a-b) . similar to the analysis using clinical cases only, using data from the national census identified increasing risk among females for being a case (table ) . inference from community cases plus controls from same household j o u r n a l p r e -p r o o f incorporating controls from the households where cases reside allowed us to assess additional potential risk factors for being a case. consistent with inferences using census data, logistic regression models that used household controls also identified increased risk among females (aor . , % ci . - . ) ( table ). in addition, this analysis showed that cases were significantly less likely to have secondary (aor . , % ci . - . ) or more formal (higher secondary) education (aor . , % ci . - . ) compared to the household controls. incorporating data from the entire community showed that the chikungunya outbreak was largely constrained to the center of the village, with few households affected on the east and west borders but virtually all households affected in the center ( figure c ). this is despite the entire community only being a few hundred meters wide. the expanded dataset also allowed us to understand the risk factors for infection in the wider community. as with the previous analyses, females had an increased risk of being a case (or: . , % ci . - . ) ( table ), although the difference by sex was concentrated in adults with no difference among children ( figure c ). further individuals who reported usually wearing clothing that exposed both limbs had . the odds of being a case compared to individuals wearing clothing that exposed upper limbs only ( % ci . - . ). those who had travelled outside tangail district within the last six months also had increased odds of being a case (aor . , % ci . - . ). individuals who had higher secondary or more formal education (aor . , % ci . - . ) were less likely to be a case than individuals without formal education. we did not identify any household characteristics that were associated with being a case, including presence of mosquito larvae (aor . , % ci: . - . ), daily use of anti-mosquito coil (aor . , % ci: . - . ), number of j o u r n a l p r e -p r o o f household members (aor . , % ci: . - . ), and number of rooms in the household (aor . , % ci: . - . ). fifty-two individuals without symptoms tested positive for chikv. we found no significant demographic differences between symptomatic suspected cases and igm-confirmed asymptomatic cases in those who gave blood (table s ). in sensitivity analysis, we removed these individuals from the 'control' population and included them in the 'case' populations. risk factors for being a case identified in the previous analysis remained similar in both scenarios where we considered household contacts as controls and individuals from all community households as controls (supplementary information, table s ). however, we found important differences in the probability of providing blood. those with symptoms were . times more likely to provide blood than those without symptoms. further, among asymptomatic individuals, only % of children - years provided a sample compared to % among those - (table s ). there were also significant differences by sex ( % of asymptomatic males gave blood compared to % of females, p-value < . ) and educational level with more educated people less likely to provide samples (table s ). outbreak investigations are central to informed responses to public health emergencies caused by the emergence of an infectious pathogen. however, outbreak investigations currently largely revolve around case-counting exercises that limit our ability to identify who is at risk for j o u r n a l p r e -p r o o f infection and who is not. here, by using the results of a comprehensive outbreak investigation, we have been able to explicitly explore the impact of different investigation strategies in the same outbreak. we found that a clinic-based study that used data from all the formal healthcare settings would have identified a quarter of all cases and, using census data, have correctly identified female sex as an important risk factor for disease. however, it is only through the recruitment of people who did not get sick that we could identify the importance of travel history, educational level and apparel usage in determining who gets sick. controls from the wider community were also required to demonstrate which household-level characteristics were important for risk, showing that the use of mosquito coils was not protective, and to map spatial heterogeneity in risk, key to intervention development and deployment. this study highlights the significant heterogeneity in healthcare seeking. even in a small community such as this, cases visited nine different sources of healthcare, three of which could be considered formal healthcare settings. infectious disease surveillance activities are unlikely to be able to collate datasets from this diverse range of healthcare sources, even among only those within formal sector, suggesting that outbreak investigations that rely on cases that seek healthcare likely substantially underestimate the magnitude of outbreaks. using the results of our study, we provide our assessment of the ability of different investigation strategies to capture key characteristics of an outbreak (table ). in practice, the decision to expand outbreak investigations beyond information available from healthcare systems will depend on the resources available. where outbreak teams are already performing communitybased case-investigations, the additional time and effort to also collect data on those without symptomsboth from case-households as well as neighboring householdsmay be marginal. this comprehensive outbreak investigation employed ten field-based investigators and took seven days to complete. an investigation strategy only focused on cases in the community would have taken only marginally less person-time as finding cases in the community anyway typically requires comprehensive door-to-door surveys. our findings highlight how this additional data collection effort can help reveal the drivers of transmission, allowing mechanistic insight into pathogen spread and maximizing opportunities to control, many of which would not be possible from case-based investigations (table )..where it is collected, an additional major benefit of the comprehensive dataset is that it can inform mathematical models that reconstruct entire outbreaks, allowing us to estimate the mean transmission distance (previously estimated here at meters) (salje et al., b) . travelling outside tangail district within the six months before the outbreak was associated with increased chikungunya fever risk. human movement can introduce chikv into new areas, causing epidemics (chretien and linthicum, ) . no other areas of bangladesh were reporting outbreaks of chikv at this time, though outbreaks may have been missed due to poor surveillance. although individuals of all ages were affected by chikungunya in this outbreak, incidence increased with age among females, potentially linked to increased time women spend at home compared to males, increasing their risk of being bitten by the largely home-dwelling aedes mosquito (salje et al., b) . in this outbreak, household use of mosquito coils was not protective against chikungunya, which is consistent with the findings from a recent meta-analysis on household level risk factors for dengue, which is also spread through aedes mosquitoes (bowman et al., ) . serum samples have the potential to provide important information about the level of asymptomatic infection during an outbreak, as has previously been shown during previous chikv outbreaks (salje et al., a , sissoko et al., . in addition, this outbreak investigation was carried out six months after the outbreak began and community members may have been unable to reliably recall their symptoms or the date their symptoms started, particularly for milder illnesses, which may have led to an underestimation of suspected cases. serological confirmation could help detect any missing infections. however, our study highlights how some caution needs to be taken when interpreting serological data. firstly, while we sought to obtain blood samples from all participants, only one in five individuals agreed. we found that the probability of agreeing to provide blood depended strongly on having had chikungunya symptoms (individuals who had symptoms were more likely to provide samples). children, women and those with a high educational level were less likely to give blood. secondly, the sensitivity of the commercial assay we used has been estimated to be < % in individuals where igm is still circulating (johnson et al., ) and is likely to be even lower here, as the blood draw occurred after igm antibodies would have waned to undetectable levels for many infected individuals (kam et al., ) . future studies should consider underlying biases in who is providing blood as well as considering the use of complementary igg assays to help improve the interpretability of serological findings. this investigation suggests that chikungunya virus has become an emerging public health problem in bangladesh, and outbreak investigations of emerging infections often have the objective of estimating attack rates of diseases and identifying the risk factors that lead to infection. our analysis suggests that the optimal strategy for attaining these objectives during an outbreak is to conduct case finding, testing, and data collection in communities. many recent j o u r n a l p r e -p r o o f outbreaks of emerging infections have suffered due to a lack of detailed information about attack rates and risk for infection, due to their limited investigation strategies (ahmed et al., , ballera et al., , khatun et al., . future investigations of emerging infection outbreaks should consider using these more intensive strategies, at least in a subset of investigations, to improve our understanding of these infections and our public health response. according to institutional data policy of the international centre for diarrhoeal disease research, bangladesh (icddr,b), summary of data can be publicly displayed or can be made publicly accessible. to protect intellectual property rights of primary data, icddr,b cannot make primary data publicly available. however, upon request, institutional data access committee of icddr,b can provide access to primary data to any individual, upon reviewing the nature and potential use of the data. requests for data can be forwarded to: this work was supported by centers for disease control and prevention (cdc), atlanta, usa [cooperative agreement no: u ci ]. in addition, the government of bangladesh, canada, sweden and the uk provided core/unrestricted funding support for this work. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. chikungunya virus outbreak hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description chikungunya outbreak ebola virus disease in west africa--the first months of the epidemic and forward projections investigation of chikungunya fever outbreak in laguna bangladesh population and housing census added value of a household-level study during an outbreak investigation of salmonella serotype saintpaul infections is dengue vector control deficient in effectiveness or evidence?: systematic review and meta-analysis delivery complications and healthcare-seeking behaviour: the bangladesh demographic 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outbreak: similarities in the early epidemics and prediction of future trends date: - - journal: chin med j (engl) doi: . /cm . sha: doc_id: cord_uid: ug pare nan emerging infectious diseases represent a serious threat for human public health worldwide. [ , ] the novel coronavirus ( -ncov) caused a pneumonia outbreak, which is spreading around the country and has affected provinces and regions of china as of january , . [ , ] countries outside china, including japan, the united states, thailand, and south korea, have also reported cases imported from other countries. [ ] with the joint efforts of chinese scientists, health workers, and related departments, the pathogen causing this epidemic was quickly identified as a new type of coronavirus, days after the first official report. after confirming the pathogen, specific detection methods were rapidly developed, with improvement in etiological diagnosis. as of january , , it has been confirmed that the new coronavirus came from wild bats and belonged to group b of the beta coronavirus, which includes severe acute respiratory syndrome-associated coronavirus (sars-cov). [ ] although -ncov and sars-cov belong to the same sub-group of beta coronaviruses, the similarity at the genome level is only %, [ , ] meaning that the new virus is genetically different from sars-cov [supplementary figure a , http://links. lww.com/cm /a ]. rapid discovery of the causative agent and development of diagnostic reagents demonstrated that technology has greatly improved in the years since the sars outbreak. however, no effective anti-viral medication or vaccines are available for this new virus, and many of its aspects remain to be explored. similar to the sars outbreak, this outbreak also occurred during the spring festival, the most important of the chinese traditional festivals, when billion people travel throughout the country. [ ] this unexpectedly provides beneficial conditions for the transmission of this highly infectious disease and correspondingly poses great challenges for the prevention and control of the outbreak. although technology has greatly improved since the sars outbreak, the basic laws and characteristics of the occurrence and development of infectious diseases have not fundamentally changed. [ ] therefore, the epidemic laws and characteristics of the sars outbreak and the painful lessons we learned in responding to the epidemic are of great value currently and in the future. due to concerns about controlling the impact of the epidemic and the relatively less developed information exchange tools of that time, the early epidemics and characteristics of the early sars cases were not reported. however, as we had participated in the epidemiological investigations of early sars cases in , we had collected important data about the early stages of the outbreak. using these valuable data, we analyzed the characteristics of the early sars cases and the progression of the outbreak. by comparing the epidemic situations of the two outbreaks, we found some strikingly similar characteristics and trends, providing lessons for better responses to the present and future epidemics. on january , , a hospital in heyuan city, guangdong province, reported two strange cases of severe pneumonia, which were then transferred to a larger hospital for further treatment. several days later, seven medical staff members in the department that treated these patients developed symptoms. retrospective investigation found that a hospital in foshan had treated a similar case on november , [supplementary figure a , http://links. lww.com/cm /a ]. this patient developed symptoms on november , , and subsequently, five family members also developed symptoms. this indicated that sars-cov emerged with high human-to-human transmission capability, characterized by familial and medical staff infections. [ , ] an investigation of family clustering identified clusters involving patients, in families with two or more family members in guangzhou. the largest cluster was derived from a female patient. a total of persons were infected due to visiting or nursing the female patient, and two of these people died [ ] [supplementary figure b , http://links.lww.com/cm /a ]. this indicated that the super virus spreader emerged at the earliest stage of the outbreak, confirming the high infection capability of the virus. [ , ] subsequent case investigations also showed that sars-cov had the capability to multiply and continuously undergo human-to-human transmission [supplementary figure c , http://links.lww.com/cm / a ]; at least four generations of cases were identified from one original patient. among the clusters of cases, healthcare workers were common victims. [ ] as of april , , a total of medical institutions had medical staff with sars-cov infection, and medical institutions in guangzhou reported a total of cases. the incidence among medical staff in the respiratory care department of a university affiliated hospital in guangzhou was . % ( / ), that is, more than half of the medical staff were infected while treating their patients. [ ] as for the -ncov outbreak, the first patient with unexplained pneumonia was identified on december , . on december , , cases of viral pneumonia were officially announced; seven of these patients were in a severe condition. [ ] respiratory infectious diseases, including influenza, sars, and middle east respiratory syndrome, were screened for and excluded. [ ] on january , , only week later, a new type of coronavirus was discovered. the identification of pathogenic nucleic acids was completed on january , [ ] and on january , the world health organization officially named the new coronavirus the " novel coronavirus." it took less than days from the first official announcement to the identification of the pathogen. in contrast to that of sars-cov, the discovery of human-to-human transmission of -ncov came relatively late. on december , , confirmed pneumonia cases were officially reported, no human-to-human transmission case was identified. [ ] on january , , a cluster of cases, including healthcare workers, were confirmed to have been infected via patients, confirming that -ncov also has humanto-human transmission capability. [ ] based on these results, it was concluded that -ncov also has high human-to-human transmission capability. it remains unclear whether earlier cases also showed this capability, and if so, how many victims were not identified. the close contacts of these unidentified patients might act as new infection sources and could become super-spreaders. the incidence and development process of the sars outbreak has valuable implications for the -ncov outbreak. after discovering the earliest case identified on november , , the incidence remained low until january , . the peak of the incidence was observed between january and february , , and the number of cases accounted for . % of the total cases (wikipedia). according to the case numbers and the developmental characteristics, the sars epidemic can be roughly divided into four stages: stage , from november , both outbreaks happened in the winter, when the two provinces have similar climate patterns suitable for virus survival and spread. temperature and weather are risk factors of natural infectious diseases, and those in wuhan and guangzhou seem to be suitable for disease transmission. given previous trends, this is unlikely to be the incidence peak of this new virus outbreak. the daily counts of -ncov cases were higher than the daily counts of sars cases during its peak in , implying a possibly higher number of cumulative cases. [ ] we analyzed the transportation between different and large cities. high frequency transportation is mainly distributed among megacities [supplementary figure e , http://links.lww. com/cm /a ]. the highest ranked cities include beijing, guangzhou, and shanghai. [ ] wuhan has a population of million and is also a major hub of the spring festival transportation network. [ ] the predicted number of passengers traveling during the spring festival is . because we are now in the early stage of the outbreak, we must be prepared for subsequent larger-scale outbreaks and predict the scale of the outbreak. since -ncov is highly similar to sars-cov, some important characteristics of sars-cov could be used for this prediction. by combining the reported daily counts of -ncov cases and data from the sars outbreak, we constructed a logistic model and predicted the incidence of -ncov over time. during the sars outbreak, a total of cases were reported. [ ] with this data and the present situation, we predict that the cumulative number of -ncov cases might be , to , . logistic models were fitted to these data, and the cumulative and daily counts of -ncov cases were predicted. as shown in supplementary figure b and c, http://links.lww.com/ cm /a , we also calculated the time needed to reach the peak of incidence under different scenarios. setting the upper limit of cumulative incidence (k) to , , , , or , , the end date of incidences will be in days (march , ), days (march , ), or days (march , ), respectively. using valuable epidemiological data from the sars outbreak, we systematically evaluated and compared the characteristics of the -ncov and sars-cov outbreaks. the two outbreaks share many similarities, and the ongoing -ncov outbreak situation seems to be a repetition of the sars-cov outbreak situation. fortunately, the chinese government is implementing many efficient measures, including shutting down public transportation in wuhan and other cities, reducing population migration, and encouraging personal protection such as face maskwearing. with these measures, case numbers could be reduced significantly. however, due to the lack of awareness regarding the human-to-human transmission capability of -ncov in the early stages, there is a possibility that super-spreaders exist. 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(sars-cov- ) infected pneumonia (covid- ): preliminary evidence obtained in comparison with -sars infection control and sars transmission among healthcare workers risks to healthcare workers with emerging diseases: lessons from mers-cov, ebola, sars, and avian flu epidemiological analysis on sars clustered cases in guangdong province (in chinese) super-spreaders in infectious diseases the role of super-spreaders in infectious disease an epidemiological study on the index cases of severe acute respiratory syndrome occurred in different cities among guangdong province epidemiological study of sars in guangdong province (in chinese) clinical features of patients infected with novel coronavirus in wuhan, china a novel coronavirus genome identified in a cluster of pneumonia cases -wuhan genomic and protein structure modelling analysis depicts the origin and infectivity of -ncov the ncov outbreak joint field epidemiology investigation team. notes from the field: an outbreak of ncip ( -ncov) infection in china-wuhan hubei province baidu migration data statistical communique on national economic and social development of wuhan epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong people's republic of china, in february a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster from severe acute respiratory syndrome-associated coronavirus to novel coronavirus outbreak: similarities in the early epidemics and prediction of future trends the authors thank the collaborators who participated in the original investigations during the to sars outbreak. none. key: cord- -lakwurn authors: mondor, luke; brownstein, john s.; chan, emily; madoff, lawrence c.; pollack, marjorie p.; buckeridge, david l.; brewer, timothy f. title: timeliness of nongovernmental versus governmental global outbreak communications date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: lakwurn to compare the timeliness of nongovernmental and governmental communications of infectious disease outbreaks and evaluate trends for each over time, we investigated the time elapsed from the beginning of an outbreak to public reporting of the event. we found that governmental sources improved the timeliness of public reporting of infectious disease outbreaks during the study period. the study database consisted of unique human infectious disease outbreak events collected from disease outbreak news, published online by the world health organization during - ( ) . for each outbreak, we defi ned the initial source or sources of the fi rst public communication as the individual, organization, or website that fi rst publicly communicated information regarding the disease threat (locally or internationally, orally or in writing). the corresponding date of communication was identifi ed by using outbreak reports disseminated by promed-mail ( ) . all outbreaks were categorized as having been fi rst communicated by > nongovernmental or governmental source, or simultaneously by both types of sources. when an outbreak was simultaneously fi rst communicated by nongovernmental and governmental sources (n = ), the outbreak was repeated in the dataset and each source was given credit. this adjustment increased the number of outbreak events to . to characterize the timeliness of outbreak communications, for each reporting source of an event, we calculated the median time in days, and bootstrapped % ci, from outbreak start to public communication (table ) . median reporting times were calculated for the entire study period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ), before and after public recognition of severe acute respiratory syndrome (sars) (march , ) , and for each who-defi ned geographic region. the effect of the initial reporting source on the timeliness of outbreak communication was quantifi ed by using negative binomial regression after adjusting for geographic region and whether the outbreak occurred before or after sars. these variables were included in the model on the basis of a priori assumptions that public health infrastructure can vary by geographic and political region and that new pandemic preparedness strategies, including use of informal information to initiate public health responses, were developed in response to the sars epidemic ( ) . interaction terms between each variable were examined but were not included in the fi nal model because none reached statistical signifi cance (p> . ). temporal trends were assessed by using univariate negative binomial regression models, stratifi ed by source category. these models included covariate for the year of outbreak start. of all initial outbreak reports identifi ed, were excluded from analysis for ≈ of the following reasons ( figure ): ( %) of the excluded reports were missing information on the estimated outbreak start date; ( %) were not found in the promed-mail archives; and ( %) outbreak estimated start date occurred after the date of public communication of the outbreak. of the ( %) outbreaks included in analysis, ( %) were fi rst publicly communicated by governmental sources, and ( %) were fi rst communicated by nongovernmental sources. chi-square tests showed no signifi cant differences in the proportions of governmental and nongovernmental sources included in the analysis versus those excluded (p = . ). the median time from estimated outbreak start to initial public communication was days shorter for nongovernmental sources ( days, % ci - ) than for governmental sources ( days, % ci - ), although this difference was not signifi cant according to the wilcoxon rank-sum test (p = . ) ( table ) . additionally, multivariate modeling showed no signifi cant difference after covariates were adjusted for (incidence rate ratio [irr] . , % ci . - . ) ( table ). the effect of missing data was assessed in sensitivity analyses for all outbreaks for which we had an estimated outbreak start date ( of ). when we used the who disease outbreak news communication date, our results did not change when crediting either governmental sources (irr = . , % ci . - . ) or nongovernmental sources (irr = . , % ci . - . ). examination of temporal trends over the study period ( figure ) showed that nongovernmental sources generally communicated outbreak signals to the public faster after , although the trend did not reach statistical signifi cance (irr = . , % ci . - . ). governmental sources, in contrast, made signifi cant improvements in lessening the time in which they publicly communicated initial outbreak signals (irr = . , % ci . - . ). our data suggest that, from through , outbreaks reported initially by nongovernmental sources were communicated publicly an average of days earlier than those reported initially by governmental sources. though the differences varied, nongovernmental sources tended to report outbreaks faster than governmental sources when we compared outbreaks before and after sars, or by who-defi ned region. the lack of statistically signifi cant differences in initial communication timeliness by source is probably attributable to a lack of statistical power rather than a lack of effect. our results also provide support for the international health regulations revisions that allow who to use unoffi cial information to request verifi cation from member states. slightly more than one-third of all unique infectious disease outbreaks in the who disease outbreak †categories for exclusion are not mutually exclusive; ‡health offi cials, ministries of health, laboratories, hospitals, etc.; §included in sensitivity analysis; ¶includes nongovernmental organizations, individual accounts, promed requests for information, and multiple sources. news during this -year period were initially reported by informal information sources. traditional governmental public health reporting mechanisms remain an integral source for outbreak information, accounting for almost two-thirds of all initial reports over this period. our results also show that these sources made statistically signifi cant improvements in reporting early warnings of outbreak threats more rapidly to the public, which might result in part from a shift toward automated, electronic methods that improve the timeliness of communication ( , ) . it is possible that enhancements in nongovernmental outbreak reporting systems also contributed to improvements in governmental outbreak reporting timeliness over the study period, but we were unable to test this assumption with the current data. this study has potential limitations. we encountered diffi culty in selecting and consistently applying criteria to determine the initial source of public communication from promed-mail reports, which could have resulted in misclassifi cation bias. although other reporting systems that use informal information exist, they either lack a publicly available archive (for example, global public health intelligence network) ( ) or their database did not cover the entire study period (for example, healthmap) ( ) . according to heymann, et al., % of outbreaks recognized by who are fi rst identifi ed by informal sources ( ), a proportion we did not fi nd. some outbreak reports were excluded because of missing data. we were able to internally validate the data that remained, but these exclusions limited the study's statistical power. finally, use of outbreak reports collected from the who disease outbreak news might limit the generalizability of our fi ndings to all infectious disease outbreaks. despite these limitations, our data highlight the value of nongovernmental sources as an integral resource for providing timely information about global infectious disease threats, and demonstrate the signifi cant improvements in the timeliness of outbreak reporting made by governmental sources. emerging infectious diseases • www.cdc.gov/eid • vol. , no. , july world health organization. the world health report-a safer future: global public health in the st century. geneva: the organization evaluation of reporting timeliness of public health surveillance systems for infectious diseases digital disease detectionharnessing the web for public health surveillance hot spots in a wired world: who surveillance of emerging and re-emerging infectious diseases world health organization. international health regulations early detection of disease outbreaks using the internet information technology and global surveillance of cases of h n infl uenza rumors of disease in the global village: outbreak verifi cation global capacity for emerging infectious disease detection promed-mail: an early warning system for emerging diseases global surveillance, national surveillance, and sars a comparison of the completeness and timeliness of automated electronic laboratory reporting and spontaneous reporting of notifi able conditions electronic reporting improves timeliness and completeness of infectious disease notifi cation, the netherlands the global public health intelligence network and early warning outbreak detection: a canadian contribution to global public health healthmap: global infectious disease monitoring through automated classifi cation and visualization of internet media reports this research was supported by a grant from google.org and by the national institutes of health grants r lm and g lm . group. his research interests include timely disease detection, infectious disease epidemiology, and health care data analysis. key: cord- -u o eitu authors: colubri, andrés; kemball, molly; sani, kian; boehm, chloe; mutch-jones, karen; fry, ben; brown, todd; sabeti, pardis c. title: preventing outbreaks through interactive, experiential real-life simulations date: - - journal: cell doi: . /j.cell. . . sha: doc_id: cord_uid: u o eitu operation outbreak (oo) is a simulation platform that teaches students how pathogens spread and the impact of interventions, thereby facilitating the safe re-opening of schools. in addition, oo generates data to inform epidemiological models and prevent future outbreaks. before sars-cov- was reported we repeatedly simulated a virus with similar features, correctly predicting many human behaviors later observed during the pandemic. introduction introduction introduction as countries shut down by sars-cov- reopen, decision-makers are debating how best to resume all levels of education to mitigate further spread of the virus (vogel and couzin-frankel ; edmunds ) . public health officials and school administrators have championed a wide range of interventions, including mask usage, social distancing, and small classes. the efficacy of these interventions depends on two key factors that are as yet unknown: ( ) how likely each intervention is to modify behavior and transmission and ( ) whether students and other stakeholders are educated, equipped, and empowered enough to remain compliant. here we present a new way to address both problems in an integrated manner. operation outbreak (oo) is an educational curriculum and simulation platform that uses bluetooth to spread a virtual "pathogen" in real-time across smartphones in close proximity. students engage with oo by first learning about key topics in outbreak prevention and response. they then participate in an appfacilitated outbreak simulation designed to vividly illustrate what they have learned. finally, we j o u r n a l p r e -p r o o f administer post-simulation reflection and analytical exercises to reinforce key points that can inform students' future responses to real outbreaks. oo simulations at sma. clockwise, from top left: "sick" student presenting to a health responder, epidemiologists analyzing outbreak data, members of the public health team bringing an "infected" student to the treatment center, "recovered" student showing her immune health status. b. components of the oo platform. transmission model defines the parameters dictating the probabilistic spread of the virtual virus among participant phones. during simulated outbreaks, the oo platform automates real-time contact tracing by recording all "transmission events" between phones, as well as observable changes in behavior that result. this automation yields critical data that are often missing from standard real-life outbreak datasets. the data are accessible via a web-based dashboard where users can visualize real-time information on simulated infection and transmission patterns or view raw data for analysis. weeks before sars-cov- was first identified in humans (andersen et al. ) , we ran several oo simulations that mimicked outbreaks of a very similar sars-like virus in which pre-symptomatic carriers caused a significant fraction of transmissions. other epidemiological parameters representing early sars and mers outbreaks (e.g., basic reproductive number, r , of - ) were also programmed into the app. seeking to complicate traditional transmission dynamics (where participants know if they are sick), we built in asymptomatic transmission with high transmissibility to allow the virus to spread widely at the beginning of the simulations. these simulations took place in both school and conference settings, with hundreds of participants in close proximity. the app-generated data from these simulations represented the "ground truth" of the mock outbreaks, captured several essential features of sars-cov- , and allowed us to observe behavioral changes among participants--many of which are now being mirrored in real life. in this article, we describe the predictive power of our oo simulations, share the resulting epidemiological data, and propose ways to use oo to bring students back to campus safely by j o u r n a l p r e -p r o o f teaching them the fundamentals of pandemic response--a critical effort in fighting the current pandemic and preparing for the next one. initial design and use of oo. initial design and use of oo. initial design and use of oo. initial design and use of oo. we created oo in collaboration with sarasota military academy (sma) preparatory school in as a two-week curriculum in pandemic preparedness, culminating in a class-wide outbreak simulation. we initially used stickers to "transmit disease." in late , we introduced the oo app and platform, which triggers infection and recovery events using probabilities that can be flexibly configured, offering virtually limitless possibilities to simulate additional elements such as falsepositive cases, clinically-diverse strains and personal protective equipment (ppe). the oo platform includes three interconnected components ( figure ): ( ) the mobile app uses the proximity and location-sensing capabilities of smartphones to propagate the virtual pathogen. the app currently supports the use of bluetooth low energy (ble) beacons and qr codes, which can be used to represent zoonotic infectious sources, protective items (e.g., facemasks and hazmat suits), and other interventions that attenuate pathogen transmission (vaccines or therapies). ( ) an administrator website enables organizers of simulations to set parameters for each simulation (e.g., number of participants, duration, symptoms, outcomes). ( ) a graphical dashboard retrieves data from simulated outbreaks (e.g., number of cases, transmission events, participant health status), and allows for visualizations, calculations, and other activities that develop skills in data science. the dashboard data can also be extracted for more sophisticated computational analyses. our oo app-based simulations at sma over the last five years have involved more than eighthgrade students who took on roles as general population, clinical workers, epidemiologists, and government officials. their goal: to "win the game" by preventing the virtual pathogen from infecting more than a predetermined threshold of players. oo allows organizers to parameterize different outbreak scenarios with known pathogens, de novo pathogens based on real microbes, or even fictional diseases. for our simulation at sma, we chose ebola as the pathogen and configured the symptoms and fatality rate accordingly. in , given reported risks of emerging respiratory viruses (cui et al. ), we simulated a coronavirus modeling the sars r of - (lipsitch et al. ) and the clinical symptoms of mers (assiri et al. ). we added one more key parameter: a period of asymptomatic transmission (twice the duration of the symptomatic period), to allow the virus to spread widely at the beginning of the game. in early december , we simulated outbreaks of the sars-cov- -like virus at sma ( participants) and the annual retreat of the broad institute of mit and harvard ( participants). we also simulated this virus in february at the day-long florida undergraduate research conference (furc); of the attendees installed the app to run an unsupervised simulation for the full conference. realistic outbreak scenarios predict population behavior and increase engagement. realistic outbreak scenarios predict population behavior and increase engagement. realistic outbreak scenarios predict population behavior and increase engagement. realistic outbreak scenarios predict population behavior and increase engagement. the socio-behavioral parallels between our past simulations and the current pandemic are striking. notably, oo simulations have repeatedly foreshadowed the political distrust and altercations that have increased alongside covid- in the us. they have vividly illustrated that viral outbreaks reveal and exacerbate existing rifts in society (kim and bostwick ) . for example, in one simulation, students acting as "government officials" tried to spread disinformation to manipulate public behavior. this strategy backfired when students acting as "media" discovered the truth and informed the general population. "citizens" who had previously complied with "government" orders immediately broke quarantine, further driving viral transmission. the government's refusal to properly "fund" its epidemiology team also drew widespread criticism--portending similar arguments now being made about fiscal allocation at all levels of the us government. in another simulation, a member of the student "police" was approached by a classmate who refused to comply with orders to disclose his infection status (as indicated on the app). the officer "shot" the student (with a nerf gun) for non-compliance. similar real-life incidents have been reported in multiple countries (snyder et al. ; hayes and seucharan ) . we have also consistently observed that student "family units" with fewer in-game "credits" (simulated money) are more likely to be infected and die than their more privileged counterparts. this functional inequality is likely because the less fortunate "families" regularly spend their tokens on periodic "food distribution," leaving little left over to purchase "ppe." we have simulated many of the interventions currently being considered for covid- , such as face masks, ppe, and even vaccines. in some cases, these interventions initially caused problems of their own. for instance, when masks were first introduced, a group of students "bought" them in bulk and tried to sell them at higher prices, only relenting under "public pressure" (precisely as was observed with the hoarding of medical-grade masks, toilet paper, and disinfectants at the start of the covid- pandemic). however, in the long run, all three measures reduced infection transmission in the simulation, especially when given to highly-vulnerable participants (e.g., "healthcare workers"). students themselves have proved to be an organic test of other proposed initiatives. in each simulation, without prompting, they implemented social distancing and a form of "remote work" (photographing and sharing educational material online to limit physical interaction). they also developed a way to assess players' health status and limit movements accordingly, paralleling the real-world use of health/immunity passports and containment strategies. however, as trust in the "government" eroded, some students tried to "game" the game by faking their health status screenshots. active learning exercises like oo have been repeatedly shown to improve stem learning outcomes (balicer ; freeman et al. ). our preliminary pedagogical data suggest this is true for oo. average test scores for the oo unit are higher than those for other units at sma, across all genders and ethnicities. for the past three years, post-simulation survey data have shown that oo is the most anticipated lesson by all classes in any subject. students have been especially eager to play the roles of epidemiologists and triage workers. in the last two years, of students signed up for this role; over half were female and % were underrepresented hispanic or black minorities. the role of simulation in exploring outbreak dynamics. the role of simulation in exploring outbreak dynamics. the role of simulation in exploring outbreak dynamics. the role of simulation in exploring outbreak dynamics. realistic simulated outbreaks provide a unique opportunity to capture not only behavioral changes in response to viral spread, but also the "ground truth" of transmission, i.e., documentation of every single event (fuller ) . the oo app produces real-time anonymous "contact tracing" data using bluetooth, recording who "infects" whom and when, and the subsequent series of events for each participant, ending in "recovery" or "death." this data reflects the spread of the virtual pathogen among the participants with a granularity that is nearly impossible to replicate in the real world--and it can be used like real outbreak data for epidemiological modeling and visualization. it also allows us to quantitatively explore the effects of changing parameters (e.g., r ) and the impact of containment and prevention measures (e.g., social distancing and vaccination). our sma ebola simulation first showed how student social-distancing could affect an "outbreak's" trajectory ( figure a more detailed data from the simulation allowed us to reconstruct transmission chains over time and identify important features of the outbreak, such as the existence of two super-spreaders causing and secondary infections early in the game ( figure c ). as with covid- (kupferschmidt ), these super-spreader events accounted for a significant fraction of cases--in the simulation, % of all secondary infections were caused by these two participants. the simulation at furc using sars-like parameters allowed us to explore the effect of herd immunity. only % of conference attendees installed the app, leaving susceptible players buffered from each other by non-participants--just as vaccinated or otherwise immune individuals buffer the more vulnerable from the transmission of real diseases. consistent with this observation, simulated transmission levels peaked throughout the day but never showed the exponential growth expected in an entirely susceptible population. the furc data were particularly revelatory when paired with the conference program. the effective reproductive number as a function of time, rt, remained below --again, consistent with a population with significant herd immunity--but spiked during activities that required attendees to be in close proximity to each other: two presentation sessions (posters and oral), a workshop session, and lunch ( figure d ). a roadmap for the near future: pandemic education, preparedness, and data gen a roadmap for the near future: pandemic education, preparedness, and data gen a roadmap for the near future: pandemic education, preparedness, and data gen a roadmap for the near future: pandemic education, preparedness, and data generation. eration. eration. eration. the covid- pandemic presents a unique opportunity to rethink the way we educate students and other stakeholders about outbreak response--and to do so in a way that can facilitate the students' return to the classroom. we envision oo as playing two key roles: ( ) as a pedagogical platform for teaching fundamentals of pandemic response that are vital for the public to understand and ( ) as a novel system for simulating outbreaks and evaluating real-world mitigation strategies, including those needed to restart in-person education. we have already begun to leverage oo to help mitigate the covid- pandemic. in summer , we partnered with the one summer chicago program to train , students as social distancing ambassadors. as part of the training, the ambassadors integrated the app into their daily lives over a seven-day period. each of three regions of the city was randomly seeded with the same number of index cases, while the app tracked social contacts and transmission events. the simulation results and post-simulation survey demonstrated that the students retained the knowledge they learned and had a significantly increased interest in public health careers after the program. to further increase oo's realism, we are enhancing the platform with components specifically informed by and focused on sars-cov- . these include: • a multi a multi a multi a multi----faceted "health score." faceted "health score." faceted "health score." faceted "health score." this feature aggregates physical movement (quantified by a step counter or changes in gps location), social interactions (quantified by bluetooth proximity measurements), and infectious disease knowledge (quantified by quizzing users about outbreak science). this score influences participants' risk and recovery probabilities based on behaviors and responses during the simulation--effectively gamifying oo and incentivizing behaviors and responses that are beneficial during real-life pandemics, especially those in which underlying health conditions play an important role in determining outcomes. • tools to evaluate response readiness. tools to evaluate response readiness. tools to evaluate response readiness. tools to evaluate response readiness. we are adding features that allow students and stakeholders to evaluate their mitigation strategies in real-time based on changing data. one new feature lets stakeholders choose which individuals can be "diagnosed" given available in-j o u r n a l p r e -p r o o f game funding, and assess resulting efforts to track and trace. we will also allow for simulated changes in pathogen genetics. this feature will generate more realistic data on pathogen transmission and evolution, and will support oo's use in more advanced classes (e.g., genetic epidemiology courses). • comprehensive educational curriculum on outbreak science. comprehensive educational curriculum on outbreak science. comprehensive educational curriculum on outbreak science. comprehensive educational curriculum on outbreak science. we are developing a robust, modular, scalable curriculum on outbreak science in the form of an online and print textbook, online lectures, learning assessments, and an online video series. we are currently working on two curricula: one for middle schools and another for high schools and colleges. we have already begun pilots at schools across the us. • remote learning capabilities, including add remote learning capabilities, including add remote learning capabilities, including add remote learning capabilities, including add----ons to existing multiplayer online games. ons to existing multiplayer online games. ons to existing multiplayer online games. ons to existing multiplayer online games. to account for the dramatically increased numbers of students now in remote learning--and to mimic disease transmission in close quarters--we have created options for people to play oo with family members at home. we also are working on an online multiplayer version of oo, inspired by the so-called "corrupted blood incident," a virtual--and unintended--pandemic in world of warcraft (wow) that occurred in due to an error in the game's code. epidemiologists later found many correlations between players' reactions to the virtual pandemic and documented historical responses to real outbreaks (balicer ) , including failed quarantine attempts and a high potential for rapid global spread. conclusions. conclusions. conclusions. unprecedented times yield unprecedented opportunities. the covid- pandemic has rendered the traditional in-person school experience impossible without mitigation strategies, and such measures, from masks to hybrid learning, may combine to make the coming school year 'less than' what would have been. yet the pandemic also presents a unique opportunity. we know that students engage most deeply with topics that affect them directly and daily--those they care about most. if we give students a new way to actively learn about epidemiology and public health through the lens of the pandemic, we can train them to play important roles in mitigating its spread and transitioning from lockdowns to reopening. we can also give them a 'more than' experience--one that ignites their interest in stem and other education and gives them agency to prevent future pandemics. declaration of interests declaration of interests declaration of interests declaration of interests p.c.s. is a co-founder and shareholder of sherlock biosciences, and is a non-executive board member and shareholder of danaher corporation the proximal origin of sars-cov- epidemiological, demographic, and clinical characteristics of cases of middle east respiratory syndrome coronavirus disease from saudi arabia: a descriptive study modeling infectious diseases dissemination through online role-playing games origin and evolution of pathogenic coronaviruses finding a path to reopen schools during the covid- pandemic. the lancet. child & adolescent health active learning increases student performance in science, engineering, and mathematics what's missing in pandemic models ontario man dies in police shooting after mask dispute in grocery store social vulnerability and racial inequality in covid- deaths in health education & behavior : the official publication of the society for public health education statistical inference for partially observed markov processes via the r package pomp why do some covid- patients infect many others, whereas most don't spread the virus at all? transmission dynamics and control of severe acute respiratory syndrome three family members charged in shooting death of security guard who told a customer to put on a face mask should schools reopen? kids' role in pandemic still a mystery key: cord- -istz iql authors: nan title: procedures to investigate waterborne illness date: - - journal: procedures to investigate waterborne illness doi: . / - - - - _ sha: doc_id: cord_uid: istz iql humanity could not survive without a reliably clean, safe, and steady flow of drinking water. since the early s when typhoid fever and cholera were frequently causes of waterborne illness in developed countries, drinking water supplies have been protected and treated to ensure water safety, quality, and quantity. having access to safe drinking water has always been one of the cornerstones of good public health. not only safe water is limited to drinking water, but recreational water can also be a source for waterborne illness—both from treated waters such as in swimming pools, whirlpools, or splash pads and from non-treated surface waters such as lakes, rivers, streams and ponds. recreational waters may cause illness not only from ingestion of pathogens, but also when in contact with eyes, ears, or skin. some pathogens in water can be acquired by inhalation of aerosols from water that is agitated or sprayed such as in humidifiers, fountains, or misting of produce. this poses a potential risk to those exposed, particularly if they are immunocompromised. humanity could not survive without a reliably clean, safe, and steady flow of drinking water. since the early s when typhoid fever and cholera were frequently causes of waterborne illness in developed countries, drinking water supplies have been protected and treated to ensure water safety, quality, and quantity. having access to safe drinking water has always been one of the cornerstones of good public health. safe water is not limited to drinking water, since recreational water and aerosolized water can also be sources for waterborne illness, from treated waters such as in swimming pools, whirlpools, or splash pads and from non-treated surface waters such as lakes, rivers, streams and ponds. recreational waters may cause illness not only from ingestion of pathogens, but also when in contact with eyes, ears, or skin. some pathogens in water can be acquired by inhalation of aerosols from water that is agitated or sprayed such as in humidifiers, fountains, or misting of produce. this poses a potential risk to those exposed, particularly if they are immunocompromised. often when an outbreak is first suspected, the source is not clear, i.e., food, water, animal contact. investigation is usually needed to find the common source. in some outbreaks the food may first be identified as the source, such as with produce, but the ultimate source could be contaminated irrigation water. investigators have to keep an open mind until laboratory and/or epidemiologic evidence links cases to the primary source. although we frequently think of waterborne illness originating from a microbiological agent, we should be aware that water may also be contaminated by pesticides, fertilizers, and other chemicals which may enter through industrial discharge, agriculture runoff, or deliberate contamination. waterborne illness acquired from microorganisms may be classified as: • toxin-mediated infections caused by bacteria that produce enterotoxins or emetic toxins that affect water, glucose, and electrolyte transfer during their colonization and growth in the intestinal tract; • infections caused when microorganisms invade and multiply in the intestinal mucosa, eyes, ears, or respiratory tract, or contact the skin; • intoxications caused by ingestion of water containing poisonous chemicals or toxins produced by other microorganisms manifestations range from slight discomfort to acute illness to severe reactions that may terminate in death or chronic sequelae, depending on the nature of the causative agent, number of pathogenic microorganism or concentration of poisonous substances ingested, and host susceptibility and reaction. the public relies on public health regulators to investigate and mitigate waterborne illness. mitigation depends upon rapid detection of outbreaks and a thorough knowledge of the agents and factors responsible for waterborne illness. public health and law enforcement agency officials should always be alert to the rare possibility of an intentional contamination of water supplies by disgruntled employees or terrorists. the purposes of a waterborne illness investigation are to stop the outbreak or prevent further exposure by: • identifying illness associated with an exposure and verifying that the causative agent is waterborne • detecting all cases, the causative agent, and the place of exposure • determining the water source, mode of contamination, processes, or practices by which proliferation and/or survival of the etiological agent occurred • implementing emergency measures to control the spread of the outbreak • gathering information on the epidemiology of waterborne diseases and the etiology of the causative agents that can be used for education, training, and program planning, thereby impacting on the prevention of waterborne illness • determining if the outbreak under investigation is part of a larger outbreak by immediately reporting to state/provincial/national epidemiologists in the instance of a bottled water outbreak, halting of distribution and sale of product and recall of product, some of which may already be in consumers' homes, are necessary to prevent further illness. as epidemiologic data accumulate, information will indicate the source of the problem, whether a municipal water treatment plant, bottled water manufacturing plant, or recreational water exposure, and suggest methods for controlling and preventing waterborne illness. this information will guide administrators in making informed decisions to provide the highest degree of waterborne safety. a flowchart, sequence of events in investigating a typical outbreak of waterborne illness (fig. ) shows the sequential steps, as presented in this manual, in investigating a typical outbreak of waterborne illness and illustrates their relationships. a description of each step is presented in this manual. can be recognized at any point during the outbreak investigation. if intentional contamination is suspected follow your notification scheme in emergency response plans (this could include law enforcement, emergency management and other government agencies) the primary purpose of a waterborne disease surveillance system is to systematically gather accurate information on the occurrence of water-related illnesses in a community, thus allowing development of a rational approach for the detection, control and prevention of waterborne illness. other purposes are to (a) determine trends in the incidence of waterborne diseases, (b) characterize the epidemiology of waterborne diseases, (c) gather and disseminate information on waterborne diseases, and (d) develop a basis for evaluating control efforts. it may be useful to coordinate this system with, or integrate it into a foodborne disease surveillance system. however, while the procedures are quite similar from an epidemiologic viewpoint, they may differ with respect to personnel or agencies involved. an effective disease surveillance system is essential for detection of disease caused by either unintentional or intentional contamination of food. an effective waterborne disease surveillance system consists of: • early reports of enteric and other illnesses that may be related to water exposure or consumption • coordinated effort between local and state public health partners, water utility and water recreation staff • systematic organization and interpretation of data • timely investigation of identified outbreaks or clusters of illness • dissemination of outbreak reports and surveillance summaries to all appropriate stakeholders many types of reporting systems may already exist at the local or state/provincial level, and these should be incorporated into a waterborne disease surveillance program. these include (a) mandatory (or voluntary) laboratory-or physician-based reporting of specific infectious diseases, (b) national-based surveillance systems such as calicinet (cdc ) or nors (cdc in the us, (c) physician office, hospital emergency, and urgent-care clinic medical records, (d) public complaints made to health agencies and/or local water utilities, (e) school illness and absentee records, (f) absentee records of major employers, (g) water treatment records kept by water utilities (e.g., turbidity, disinfection levels, occurrence of coliforms), (h) increased sales of antidiarrheal drugs and anti-nausea medications, and (i) source water quality data kept by environmental agencies (e.g., departments of natural resources and geological survey agencies). another type of surveillance mechanism that may supplement or enhance existing reporting systems is a daily log of illness and water quality complaints. agency contemplates initiation or development of a waterborne illness surveillance program, give top priority to identification of appropriate financial, political, strategic, and administrative support. then, identify a key person to create, implement, and manage the system. this person takes responsibility for: • reviewing the types of reporting systems that already exist in your agency or in other agencies that could be incorporated into a waterborne illness surveillance system • identifying the types of information that cannot be obtained from existing reporting systems but that need to be collected or addressed by the waterborne illness surveillance system • identifying ways to merge or integrate the data collected by existing systems with data gathered in the waterborne illness surveillance system • identifying collaborating agencies and staff • develop a mechanism to communicate and update all stakeholders (may be by blast e-mail or periodic conference calls) • providing training in surveillance methods for agency staff and other partners to enhance cooperation • assembling materials that will be required during an outbreak investigation • evaluating the effectiveness of the system. develop procedures to seek and record complaints about waterborne illnesses, water supplies, and water recreational sites. for example, list the telephone number of the waterborne illness investigation unit prominently on local and state public health and water utility websites. to be most effective, have this number monitored / by staff or an answering service. if possible, the utilization of social media such as facebook or twitter should be considered and monitored as many large municipalities (including drinking water utilities) and recreational facilities have an internet presence. if your agency has social media accounts, consider using this vehicle to further disseminate information regarding waterborne illness clusters or outbreaks. identify medical care facilities and practitioners and seek their participation. direct educational activities, such as newsletters and talks at meetings, to stimulate participation in the program. encourage water treatment utilities and operators of recreational water sites to report suspected complaints of waterborne illness to the appropriate local agencies. also, encourage private and hospital laboratories to report isolations of parasitic agents (e.g., giardia, cryptosporidium), viruses (e.g., norovirus and hepatitis a virus), bacteria (e.g., e. coli (pathogenic), salmonella, shigella, vibrio cholerae), and other agents that may be waterborne. develop a protocol for notification and coordination with agencies that might cooperate in investigational activities, including -h-a-day, -days-a-week contacts. a comprehensive contact list should be constructed and updated at least twice a year as individuals may change. notify and coordinate with state/provincial or district agencies, national agencies that have surveillance and water regulatory responsibilities, and other national and international health agencies, as appropriate. for example, it may be useful to find out the level of participation within a certain jurisdiction in national-level outbreak surveillance programs such as nors (cdc, ) or other national surveillance system. delegate responsibility to a professionally trained person who is familiar with epidemiologic methods and with the principles of water treatment and recreational water protection. this person will (a) direct the surveillance program, (b) take charge if waterborne and enteric outbreaks are suspected, and (c) handle publicity during outbreaks. delegate responsibility to others who will carry out specific epidemiologic, laboratory and on-site investigations. if an intentional contamination event is suspected, local and national law enforcement agencies will likely become the lead agency responsible for the investigation. with this in mind, it is critical to identify appropriate individuals and include them in communication and any practice drills that may occur. if a relationship has been established prior to any event, the investigation may run more smoothly. enlist help from a team of epidemiologists, microbiologists, sanitarians/environmental health officers/public health inspectors, engineers, chemists, nurses, physicians, public information specialists, and other (e.g., toxicologists) as needed. free flow of information and coordination among those participating in waterborne disease surveillance and investigation are essential, particularly when several different agencies are involved. water-related complaints are equally likely to be directed at health departments or water utilities but also perhaps to different jurisdictions. therefore, it is essential that these complaints be registered by an agency and that the information is rapidly shared within and perhaps outside of a particular jurisdiction as part of an integrated surveillance system. whenever possible, share the information with participating parties by rapid means such as e-mail and by calling / contact phone numbers. if an intentional contamination event is suspected, contact emergency response and law enforcement for their early involvement. select staff members who will participate in the waterborne disease surveillance program on the basis of interest and ability. inform them of the objectives and protocol of the program. emphasize not only the value of disease surveillance, but also the value of monitoring water quality and treatment performance. if possible, provide printed learning material that can be referenced later. encourage the use of epidemiologic information and approaches in routine disease surveillance and prevention activities. develop their skills so that they can carry out their role effectively during an investigation, and teach them how to interpret data collected during investigations. conduct seminars routinely and during or after investigations to update staff and keep agency personnel informed. train office workers who will receive calls concerning waterborne illnesses to give appropriate instructions. those who participate in the investigation will learn from the experience and often are in a position to implement improvements after completion of the investigation. assemble and have readily available kits with forms and equipment as specified in table a (equipment useful for investigations). restock and maintain kits on a schedule recommended by, and in cooperation with, laboratory staff to ensure their stability and sterility. verify expiration dates, and use kits before this date or discard and reorder. assemble a reference library on waterborne illnesses, investigation techniques, and control measures from reference books, scientific journal articles, manuals, and reputable internet sources (e.g., www.cdc.gov, www.who.int/en/, www.hc-sc.gc.ca/ index-eng.php, www.gov.uk/topic/health-protection/infectious-diseases); make it available to the staff in an easy-to-access format. (see further reading for suggestions). organize a multiagency team with representatives from public health agencies, regulatory agencies, and water utilities and with local political officials to review and exercise existing emergency response plans in the event of a large scale waterborne disease outbreak or other disaster likely to result in waterborne illnesses. local public health agencies have the primary responsibility for the restoration and protection of health of a community following an outbreak event or other emergency. emergency operational procedures should include the following: • an emergency notification list that includes phone numbers and e-mail addresses of key persons/agencies that need to be informed about possible outbreaks and that should receive emergency press releases. every state/province has an emergency management agency and depending upon the scale of the event, it may be useful to coordinate efforts. • clear guidelines for household water consumption following an event. for example, boil-water advisories or instructions to drink only bottled water. statements should be reviewed to ensure current relevance and updated to reflect the most current knowledge. • a plan for dissemination of information to the public; select a coordination point to which all news media and outside agencies will be directed, and designate one person or one telephone number as the contact. (more than one contact person can create confusion). • alternative drinking water sources to be used in cases of emergency and plans for the distribution of this water, if necessary. these include alternative munici-pal systems, bottled water supplies, portable filtration and/or disinfection devices and home treatment units. (special attention should be given to backup supplies for hospitals, nursing homes and other places where lack of safe water would be immediately life-threatening). • identification of specialty laboratories at the state/provincial and national level that are capable of performing (and willing to perform) procedures not routinely done at local laboratories (e.g., large volume water sampling and processing for pathogenic parasites and viruses, serotyping, electron microscopic examination of stool samples, molecular and immunodiagnostic tests for pathogens in environmental and clinical samples). one or more of these tests may be necessary to identify the causative agents in an outbreak and confirm their transmission route. • a plan to exercise procedure with tabletop exercises involving all pertinent partners on a regular basis and implement any necessary adjustments based upon review of after-action findings. notification of a suspected outbreak is often received by health authorities from a laboratory report or a family physician and can be documented on a log such as form a (foodborne, waterborne, enteric illness complaint report). public health investigators will then interview cases and persons at risk who are well (controls) to make epidemiologic associations to find a common source. from here a hypothesis can be formed. further investigation will involve: • collecting clinical samples and water samples • conducting an on-site investigation at the facility alleged to be responsible to determine the mode of contamination or process failure, e.g., low disinfectant level • characterizing the etiologic agents by laboratory analysis using various typing schemes. dna profiling or pulsed-field gel electrophoresis (pfge), of isolates from clinical and water samples to "fingerprint" and link strains of the etiologic agent among cases and to the source prompt handling and referral of water-related complaints, rapid recognition of the problem, and prevention of further illnesses are the foundations of a successful investigation. complaints of water problems are as likely to be reported to a water utility as to a health department. communication is essential between these agencies. this first contact with the public is a vital aspect of an investigation of a potential outbreak and needs to begin by public health professionals as quickly as possible, usually within hours, sometimes by putting less urgent activities aside. as indicated earlier, any action respecting a potential deliberate contamination of water will generate a specific approach to further action. upon receiving a complaint or an alert about a water supply or water exposure or illness potentially attributed to these sources, record the information on form a. alerts may be initiated by reports from physicians, laboratories, or from hospital emergency rooms. alerts may also include an increase in a particular pfge pattern from clinical isolates. an investigation may be initiated to determine if there is a common water exposure among patients with the pfge pattern. the pattern may be compared with similar pfge patterns in pulsenet databases to determine if there are similar occurrences of the pattern in water and clinical isolates nationwide or internationally, e.g., for food that might have been contaminated with water, bottled water. the form provides information upon which to decide whether an incident should be investigated. form a is not difficult to fill out and can be completed by a public health professional, a trained water utility staff member, or trained office worker. assign a sequential number to each complaint. if additional space is needed to record information, use the reverse side or attach additional sheets. always ask the complainant to provide names of other persons at the event, or using the water supply or recreational water under suspicion, whether or not ill, and names of any other persons who are known to be ill with the same symptoms. follow up by contacting these additional persons. emphasize to the persons making alerts or complaints the need to retain a sample of the suspect water and to save clinical specimens (vomitus and stool) from ill persons using a clean utensil in a clean jar or plastic bag and to seal tightly and label clearly with the name of the person and date, and store in a refrigerator (do not freeze). also consider family members not ill for case-control studies. advise complainants to collect a liter (quart) of water immediately, preferably in sterile containers but otherwise in jars that have been boiled or in plastic bags, or if this is not feasible, in other clean containers. tell the complainant to save any ice cubes or refrigerated water, either in their present containers or in unused plastic bags, in the refrigerator or freezer (if already frozen) where they are normally kept. instruct the ill person to hold all clinical specimens and water samples until the health agency evaluates the epidemiological evidence and arranges, if necessary, to collect them. if it is determined that the specimen or sample is not necessary, notify the complainant and advise on proper disposal of the material. unfortunately, the specific etiologic agent cannot be identified in a large proportion of waterborne outbreaks because water samples and clinical specimens (a) were not collected in an appropriate time-frame (not early enough during illness), investigate outbreaks (b) are too old, (c) are too small in volume, especially for giardia and viruses which require liters, (d) have not been examined for the appropriate agent. contaminants may be in the water system for only a short time, and concentrations of toxic substances and numbers of microorganisms may decrease significantly because of dilution or disinfection. if there is a cluster of cases, monitor reports from physicians, complaints about water, or records of laboratory isolation of enteric pathogens that may suggest outbreaks of disease or contributory situations. collect clinical specimens and water as soon as practicable according to the section obtain clinical specimens in this book. extract key information (see* and † entries) from form a and enter it onto form b (foodborne, waterborne, enteric illness and complaint log). record time of onset of the first symptom or sign of illness, number of persons who became ill, predominant symptoms and signs, whether ice or water was ingested, and the name of the water supply or recreational water alleged to have caused the illness, and whether a physician had been consulted, and/or had taken feces or emesis samples, and/or prescribed antibiotics. also, enter on form b names of the places or common gatherings (other than home) at which the stricken persons ingested water during the weeks before onset of illness (see table for an example). enter a code for the water source (e.g., community, non-community, individual well, bottled, stream/ lake, vended, or untreated) . under "history of exposures" column indicate whether the afflicted person had recent domestic or international travel, attended a child care facility, or had recent contact with ill persons or animals. under "comment" column, enter notations of type of agent isolated, results of specimen tests, places where water was consumed during travel, names and locations of restaurants or other foodservice facilities, and other pertinent information including hospitalization, occupation, or place of employment. at this phase of the investigation it will probably not be known whether the illness is waterborne, foodborne, or person-toperson spread. this log can be kept either in hardcopy or in electronic format. see table (below) as an example of a log. interpretation of table . entry -get further details on the patient's symptoms and seek other cases. the report of foreign travel suggests an infection that may have been acquired outside the country. follow-up of such cases may identify an outbreak of international scope. if so, inform state/provincial and national authorities concerned with surveillance of waterborne disease about the situation. entry -possibly food associated; alert food safety officials. entry -initiate investigation; the two cases of conjunctivitis suggest the possibility of a common-source outbreak associated with the motel pool. entry -initiate investigation; cases indicate an outbreak that has a common time-place association. entry -this could be related to entry , because this person reported swimming in the same pool. exposure history: dt domestic travel (out of town, within country); it international travel; cc child care; ci contact with ill person outside household or visitor to household; a an exposure to ill animal; c contact with ill person within household responsible for the investigation, if this was not done when the surveillance protocol was established. delegate sufficient authority and provide resources to the head investigator so that the investigation tasks can be accomplished effectively and efficiently. inform all outbreak investigative team members that any findings are to be reported to this delegated authority. a list of all team members and additional contacts such as administrative contacts, sanitarians/environmental health officers/ public health inspectors, local and regional contacts, physicians, clinical laboratories, or other persons who may become involved in outbreak investigations should be assembled. before beginning the investigation, check the supply of forms and the availability of equipment suggested in table a (equipment useful for investigations) and obtain any needed materials or additional equipment. general resource materials describing signs and symptoms, incubation times, and specifics regarding specimen collection and appropriate kits to be used should be maintained and readily available to those processing the initial calls, which may help to formulate the initial hypothesis. if the alert or complaint suggests a possible outbreak, inform laboratory personnel of the type of outbreak and estimated quantity and arrival time of clinical specimens and water samples collected. this information will give laboratory managers time to prepare laboratory culture media, prepare reagents, and allocate personnel. at a minimum, the laboratory should have six to eight stool culture kits on hand or readily available, since in many cases, stool specimens must be collected within h of onset of illness to isolate and identify certain pathogens (e.g., campylobacter spp., and salmonella spp.). consult laboratory personnel about proper methods for collecting, preserving, and shipping environmental samples and clinical specimens if such information is needed. obtain appropriate specimen containers and sample submission (chain of custody forms) from them. once the investigation is underway, the proper clinical specimens should be collected as soon as possible before patients recover and become less likely to submit specimens. all suspected waterborne outbreaks should be examined and a determination made regarding the feasibility of conducting a thorough investigation even if the time to collect proper clinical specimens has passed. an ill person or family member, physician, hospital staff member, or operator of a water utility or recreational site may report suspected cases of waterborne illness. whatever the source of the report, verify the diagnosis by taking a thorough case history and, if possible, by reviewing clinical information and laboratory findings. (this analysis can be further substantiated by detecting suspected etiologic agents in water). verification of the diagnosis is done in consultation with medical professionals. when a complaint involves illness, complete forms c - (case history: clinical data and case history: food/water history and common sources) either at the time of initial notification, during a personal visit, or during a telephone call to the person reported to be ill. use this same detailed interview approach with every person who has been identified in the initial complaint or alert, even though some may not have been ill. be aware that potential cultural and language barriers can make interviews difficult. a different interviewer may be needed to accommodate these barriers. continue this until sufficient information is obtained to decide whether there is, indeed, an outbreak of waterborne illness. from persons who are at risk of illness but who remained well, also obtain water and -hour food histories, inquire about recreational water exposure in past weeks, and information about their activities in common with the ill persons. information from these persons is as important to make epidemiologic associations as it is from the cases. when it is apparent that an outbreak has occurred and a specific event has come under suspicion, substitute forms d - (case history summaries: clinical data and case history summaries: water/laboratory data) for form c. form d can be used initially in many routine waterborne illness outbreak investigations where it is obvious that a common-source outbreak has occurred or when all of the ill persons consumed water together (e.g., drank from the same public system, consumed ice at an event) or recreated at the same place (e.g., swam in the same lake or used the same hot tubs). this will simplify recording, because most affected persons will give similar information. at this time, notify the district, state, or provincial epidemiologist about the outbreak. if a specific pathogen (e.g., norovirus, e. coli o :h , cryptosporidium spp.) has been identified as the etiologic agent, consider developing a form for recording relevant information. many state/provincial or national public health agencies have standard forms tailored to specific pathogens. include signs and symptoms of the illness and other clinical information, the etiology of the agent, and usual methods of transmission. computer programs (e.g., epi info™) can aid in the design of such standard forms. upon contact with the affected person, identify yourself and your agency and explain the purpose of the visit or call. a professional attitude, appropriate attire, friendly manner, and confidence in discussing epidemiology and control of waterborne illnesses are essential for developing rapport with affected persons or their families and in projecting a good image of the investigating agency. keep in mind that you are not interviewing someone you inspect or regulate, but that you are providing a service to the affected person. exhibit genuine concern for persons affected and be sincere when requesting personal and confidential information. communicate a sense of the urgency of the investigation, and emphasize that their participation will make a positive contribution for the control and prevention of waterborne illness. parental consent must be obtained before interviewing children under years of age. in some locations, consent from the affected person's physician may also be required. after asking open-ended questions about the person's food exposures and illness history, follow up with more specific questions to fill in the details and better ensure a thorough recall. base your level of communication on a general impression of the person being interviewed, considering information about age, occupation, education, or socioeconomic status. tact is essential. use either form c or form d, as appropriate, as a guide. state questions so that the persons who are being interviewed will describe their illnesses and associated events in their own words. try not to suggest answers by the way you phrase questions. fill in form c - (if appropriate) and take additional notes during the interview. ask specific questions to clarify the patient's comments. think questions through before conducting the interview. realize that people are sometimes sensitive to questions about age, sex, special dietary habits, ethnic group, excreta disposal, and housing conditions. nevertheless, any or all information of this type can be relevant. word questions thoughtfully when discussing these characteristics and habits. such information can often be deduced from observations. if doubt remains, confirm your guesses by asking indirect questions. information on recent travel, gatherings, or visitors may provide a clue to common sources or events that would otherwise be difficult to pinpoint. review known allergies, recent immunizations, recent changes in the patient's medical status, and similar information. remember that the agents associated with waterborne disease can also be spread by other means such as consuming food, person-to-person, visiting child care centers, animal-to-person in petting zoos, through walk-in-spray fountains, and pools for young children. as persons describe their illnesses, check boxes next to appropriate symptoms or signs on form c . do not ask about all symptoms or signs listed; however, ask about those marked with an asterisk if the ill person does not mention them. if there are questions, explain symptoms to the patient in understandable terms. the symptoms and signs in the first two columns of form c are usually associated with poisoning or intoxication, although some occur during infections. those in the third, fourth, and fifth columns are usually associated with enteric infections, generalized infections, and localized infections, respectively. those in the last column are usually associated with disturbance of the central nervous system. diseases in any category will sometimes be characterized by a few symptoms and signs listed in the other columns, and not all signs and symptoms occur for any one ailment or for all persons reporting illness. if an illness seems to fall into one of these categories, mention other symptoms in the category and record the patient's response. whenever possible, use physician and hospital records to verify signs and symptoms reported by patients. clinical data may strengthen or dismiss the possibility of waterborne illness. before contacting a physician or a hospital, become familiar with laws and codes relating to medical records to ensure that you have legal access to these records. legal release forms may be necessary to obtain some records. do not distribute names of patients, their other personal identities (e.g., address, phone number), or their clinical information to unauthorized persons. the entries begin with the day of illness, followed by the previous days. if the illness, however, began early in the day or before any of the listed meals, modify the entries on the form so that the -hour history can be completed in the space pro-vided on the form. if the incubation period is days to a week in duration, use additional copies of form c and modify day or day before subtitles. signs and symptoms will sometimes give clues to the transmission route by indicating the organ systems affected. if the early and predominant symptoms are nausea and vomiting, ask about the most recently ingested water or beverage within the past h. in these situations, suspect high-acid water supplies, carbonated beverages and fruit drinks, because these tend to leach metallic ions from water pipes and containers. if diarrhea, chills, and fever predominate, be suspicious of water and beverages ingested - hours before onset of illness for salmonellosis, shigellosis, and norovirus related gastroenteritis. if the incubation period averages - weeks, consider typhoid fever, cryptosporidiosis or giardiasis. diseases with incubation periods exceeding weeks (e.g., hepatitis a and e, amebic dysentery, or schistosomiasis) can be handled as special cases for which longer histories would be sought. others, such as chronic lead and arsenic poisoning, have incubation periods of variable durations and onsets so gradual as to be indeterminable. see table b (illness acquired by ingestion of contaminated water: a condensed classification by symptoms, incubation periods, and types of agents) for details on specific pathogens, table c (illnesses acquired by contact with water: a condensed classification by, symptoms, incubation period, and types of agents), and table d (illnesses acquired by inhalation of microorganisms aerosolized from water. a classification by symptoms, incubation period, and type of agent). other microorganisms not listed in tables b, c, and d that can be potentially spread by water include the bacteria klebsiella pneumoniae, mycobacterium avium complex, acinetobacter calcoaceticus, elizabethkingia meningoseptica, stenotrophomonas maltophilia, pseudomonas putida, serratia marcescens, protozoa isospora, microsporidium, algae schizothrix calcicola. these microorganisms are less frequently identified with waterborne illness, but they may become opportunistic pathogens, particularly for highly susceptible and immunosuppressed persons. further investigation is needed to confirm their role in the spread of waterborne diseases. gather information about all sources of water to which the patient(s) may have been exposed weeks before onset of illness. the water supply and the event that precipitated the illness might not be obvious. persons often have difficulty recalling exposure to all water sources including; ice or water ingested; aerosols and recreational water contact. therefore, if the person does not remember specific exposures to water, ask about the water consumed in usual or routine daily habits and the amounts ingested; exposure to recreational waters; and unusual exposures or events attended during this interval. this may stimulate recall of away-from-home water consumption or contact that was unusual. ask about other risk factors for enteric illness, such as contact with young children and child care centers, animal contact, ingestion of raw foods of animal origin, and usual food preference habits. for persons who have been traveling, ask them where (both cities and rural areas) they have traveled during the incubation period of suspected agents. determine if they drank water from any taps or pumps in rural areas they visited. ask whether unheated (or untreated) tap water or beverages containing unheated (or untreated) water or ice was ingested at restaurants, in hotels or at events in the places they visited. also, ask whether they ingested bottled water and, if so, the brand name. find out whether they drank water from streams, ponds, springs, or other natural water sources. if they did, ask if they observed any abnormal condition of the water such as algal growth, high turbidity or discoloration. ask if domestic or wild animals had access to the water. if they have skin or eye infections or generalized infections, ask them to name all swimming pools, water slides, beaches, lakes, ponds, or other chlorinated and nonchlorinated water courses where they swam, waded or bathed during their trip. also ask them whether they used any hot tubs, spas, whirlpools, or similar devices. this information sometimes provides clues to common sources or to events that otherwise would be difficult to discover. record the information on form c . in a protracted outbreak, or when investigating an outbreak of a disease with a long incubation period, expect recall to be poor. in this situation, obtain from ill persons and others at risk a listing of their water, ice, and beverage preferences and amounts usually ingested, or their purchases of these items within the range of the incubation period of the suspected disease. as a guide, draw up a list of either water, ice, and beverages that are commonly consumed by the affected group or those waters, ice, and beverages previously identified as vehicles of the suspected disease under investigation. summarize data from all copies of forms c - on form d. form d allows rapid review of all exposed persons (ill or not ill) and serves as a basis for analyzing the data. diagnosis of most diseases can be confirmed only if etiologic agents are isolated and identified from specimens obtained from ill persons. get specimens from the ill persons to confirm an etiologic agent. • in large outbreaks, obtain fecal specimens from at least ten persons who manifest illness typical of the outbreak • in smaller outbreaks, obtain specimens from as many of those ill and those at risk as practicable, but from at least two, and preferably ten, ill persons • try to collect specimens before the patient takes any medication. if medication has already been taken, collect specimens anyway, and find out the kinds and amounts of medicine taken and the time that each dose was taken • also get control specimens from persons with similar exposure histories that did not become ill obtain clinical specimens at the time of the initial interview during acute illness or as soon as practicable thereafter. even though this is not always possible, take specimens even after recovery because etiologic agents may remain in low populations or concentrations. if a disease has already been diagnosed, collect specimens as listed in table b . if a disease has not yet been diagnosed, choose kinds of speci-mens that are appropriate to the clinical features. laboratory information obtained from the first patients may be useful to physicians in the treatment of cases detected later. apart from the fact that people are more likely to cooperate while they are ill, some pathogens or poisonous substances remain in the intestinal tract for only a day or so after onset of illness. if the patient is reluctant to provide a fecal specimen explain that the specimen will be tested to identify the causative agent and compare it to any agent recovered from the water. if a disease has not yet been diagnosed, choose specimens that are appropriate to the clinical features. laboratory information obtained from the first patients may be useful to physicians in treating cases detected later. some pathogens (e.g., salmonella, parasites) may be recovered for weeks after symptoms have abated. if applicable for the disease under investigation, take specimens even after recovery because some etiologic agents may remain in low numbers, and changes in serologic titers can be detected. before collecting specimens, review table e (guidelines for specimen collection) and, if necessary, get additional instructions from laboratory personnel and seek their advice on how to preserve the stool specimens if you cannot deliver them to the laboratory immediately. many public health agencies have special fecal specimen kits. demonstrate to the patient how to use the materials in the kit, how to complete the form in the kit and how to mail it if you are not going to pick it up. if mailing specimens, make sure that you are aware of the regulatory requirements that may apply to the transport of infectious material. stool specimen containers for intestinal parasite examination are not suitable for bacterial or viral examinations because they ordinarily contain a preservative, such as formalin or polyvinyl alcohol. if an inappropriate transport medium is used, a specimen can be rendered unsuitable for laboratory examination. feces. if the patient has diarrhea or is suspected of having had an enteric disease, obtain a stool specimen (preferred specimen) or a rectal swab. instruct patients to provide you with their own specimens by one of the following means. . if practicable, give the patient a stool specimen container with a wooden or plastic spoon or a tongue depressor. a clean container available in the home (e.g., a jar, or disposable container that can be sealed) and a clean plastic spoon or similar utensil can be used if laboratory containers are not available. . label the specimen container with the patient's name age/date of birth and date of collection. . collect the stool specimen by one of the following methods: (a) put sheets of plastic wrap or aluminum foil under the toilet seat and push them down slightly in the center, but not so far as to touch the water in the bowl. sheets of paper can be tacked on the rise of a latrine and pushed down to form a depression in which to catch feces. take care to ensure that toilet cleaning chemicals and other microorganisms in the toilet bowl do not contaminate the fecal specimen. after defecating, use a clean spoon or other utensil to transfer about g of feces into a specimen container or other clean container. (b) defecate directly into a large clean dry container or bedpan. use a clean spoon or other utensil to transfer about g or the size of a walnut of feces into a specimen container or other clean container. (c) scrape feces off a diaper with a clean spoon or other utensil to transfer about g of feces into a specimen container or other clean container. . collect fecal swabs by twisting the cotton-wrapped end of the swab into the stool obtained in one of the ways described above. follow instructions given in table e . if necessary, use fecal-soiled toilet paper or cloth diaper and twist a swab into the top of feces. take care to ensure that there is no carryover of toilet paper as they are impregnated with barium salts which are inhibitory to some fecal pathogens. dispose of excess fecal material into the toilet and carefully wrap all soiled articles (e.g., by placing them inside two plastic bags) and dispose of in domestic waste. check that the specimen container is tightly sealed and properly labeled and place into a clean outer plastic bag (special zip lock bags for clinical specimens, if available). store the specimen in a cool place, preferably at °c to await pick-up or despatch. do not freeze. feces from rectal swabs. collect rectal swabs by carefully inserting the swab approximately . cm ( in) beyond the anal sphincter. gently rotate the swab. fecal matter should be evident on the swab. vomitus. if the person is vomiting or subsequently does so, arrange to collect vomitus. tell the patient to vomit directly into a sterile specimen container or a plastic bag. otherwise, transfer some vomitus from a clean receptacle into the container with a clean spoon. refrigerate, but do not freeze, this specimen until it can be picked up or delivered to the laboratory. blood. take blood if a patient has a febrile infection or when infectious agents are suspected (see tables b, c, and d) . blood specimens are collected for: • bacterial culture • detection of antibodies to specific agents • detection of certain toxins before collecting specimens, get additional instructions from laboratory personnel and seek their advice. blood should be obtained by an appropriately trained and accredited person (check appropriate laws). collect blood during the acute phase of illness, as soon as the febrile patient is seen (within a week after onset of illness) and, if comparing of serologic titers, again within weeks (usually - weeks later) during the convalescent phase. draw ml of blood (from an adult) or ml (from a child) or - ml (from an infant). if possible, collect the blood from the same patients from which stool specimens were obtained if both specimens are to be examined. label tubes and vials at every step of serum transfer. do not freeze whole blood because the resultant hemolysis interferes with serologic reactions. collect into a sterile syringe or evacuated sterile tube that does not contain anticoagulants. if practicable, centrifuge the blood at , rpm for min; pour off the serum into small screw-cap vials and store at approximately − °c. if the serum cannot be separated immediately, rim the clot with a sterile applicator stick and refrigerate approximately °c to get maximum clot retraction if the specimen is to be stored unfrozen overnight. if centrifugation cannot be done, store the blood specimens in a refrigerator until a clot has formed, then remove the serum and transfer it with a pasteur pipette into an empty sterile tube. send only the serum for analysis urine. instruct patients to collect urine in the following manner. clean the area immediately around the urethral orifice with a paper pad that has been pre-moistened with % tincture of iodine or other appropriate antiseptic. then begin to urinate into a toilet and collect ml (about oz) of midstream urine into a sterile bottle. use either a second antiseptic-moistened pad or an alcohol-moistened cotton ball or tissue to clean any drops from the top or side of the bottle. other instructions. follow applicable instructions given in table e . before or immediately after collecting clinical specimens, use waterproof permanent markers to label each container with the patients name, complaint number, case identification number, specimen number, date and time of collection, tests requested, and other appropriate information. tightly seal all containers. clinical specimen collection report for each specimen. complete form e (clinical specimen collection report). the complaint number, case identification (id) number, and specimen number must be entered on each report so that laboratory results can later be correlated with other data. on form c record the type of specimen collected, and submit both the specimen and a copy of form e to the laboratory. send a copy of the laboratory report to the patient's physician or call if urgent. if the patient/case or other household member collected any water, ice, or beverage as instructed during initial contact, label containers with the complaint/outbreak and sample numbers. proceed as instructed in table f (general instructions for collecting water samples for microbiological analysis) and complete form f (water/ice collection report) and/or forms g -g as applicable. record conditions of collection as called for on the forms. if a hypothesis associates the illness with water, caution these persons not to use the water source unless the water is first boiled and to discard all previously prepared ice and water-containing beverages until notified otherwise. develop a working case definition to classify exposed persons as either cases or non-cases. start with the most specific symptoms (such as diarrhea and vomiting) rather than broader symptoms such as nausea or malaise. for example in an outbreak of gastroenteritis, a case might be defined as a person from whose stool a specific pathogen was isolated. it may be a person who was at risk and developed diarrhea within a specified period of time. diarrhea will have to be defined, perhaps as three or more loose, watery stools during a -hour period. in some cases, a particular pathogen responsible for the outbreak might have been identified from clinical specimens. a case definition, which is developed later in the investigation, might include either a person having specific signs and/or symptoms within a period of time or a person from whom a specific pathogen was isolated. the ultimate case definition has a tremendous impact on the investigator's ability to make illness and exposure associations and to calculate probability of these associations. sometimes the first symptom or sign provides a clue to developing a case definition. information in tables b, c, d, g, and h can be useful in making case definitions. compare newly identified cases with the definition to see whether each is part of the outbreak. classify cases into categories: • a confirmed case is a person with signs and symptoms that are clinically compatible with the disease under consideration and for which there is either (a) isolation of an etiologic agent from (or otherwise identified in) an appropriate specimen from the patient, or (b) serologic evidence of a fourfold or greater rise in convalescent antibody titer. a confirmed case must also have possible exposure to the etiologic agent within the incubation period of disease. see table e . criteria for confirmation of etiologic agent responsible for outbreaks of waterborne illnesses for definitions of confirmed cases for specific waterborne diseases: • a presumptive case is a person with signs and symptoms that are clinically compatible with the disease under consideration, and for which there is laboratory evidence of infection (e.g., an elevated antibody titer but less than a fourfold increase), but the etiologic agent was not found in specimens from patients or no specimens were collected. a presumptive case must also have possible exposure to the etiologic agent within the incubation period of disease. • a suspected case is a person with signs and symptoms that are clinically compatible with the disease under consideration and history of possible exposure, but laboratory evidence is absent, inconclusive or incomplete. • a secondary case is a person who became infected from contact with a primary (outbreak-associated) case or from a vehicle contaminated by a primary case. onset of illness for secondary cases typically is one or more incubation periods after the outbreak-associated cases. it is not essential, however, to classify cases into these categories. do so only if it aids in developing a final case definition or in making comparative analyses of data. consider doing analyses using case definitions of both confirmed and combined confirmed, presumptive, and highly suspect cases, and compare the results. make a preliminary evaluation of the data collected as soon as possible. if you decide that there is an outbreak, use the information you have to develop a hypothesis about the causal factors. an outbreak is an incident in which two or more persons have the same disease, have similar clinical features, or have the same pathogen (thus meeting the case definition), and there is a time, place, or person association among these persons. a waterborne outbreak is traceable to ingestion of contaminated water or ice or to contact with contaminated water. a single case of either chemical poisoning or a disease that can be definitely related to ingestion of drinking water or contact with water can be considered an incident of waterborne illness and warrants further investigation. waterborne methemoglobinemia in an infant who resides in a rural area having a high concentration of nitrates in well water is an example of a single case of waterborne illness due to ingestion. a rare diagnosis such as primary amebic meningoencephalitis in a person who swam in a body of freshwater and inadvertently ingested the ameba, naegleria fowleri, through the nose is an example of a single incident related to water contact. sometimes it will be obvious from an initial report that an outbreak of waterborne disease has occurred simply because of the number of persons displaying certain signs and symptoms at or near the same time. many complaints, however, involve illness in only one or a few persons. it is often difficult to decide whether ingestion or contact with a particular water source and onset of illness was associated or coincidental. certain diseases that are highly communicable (e.g., shigellosis and epidemic viral gastroenteritis) may result in secondary infections from person-to-person spread or from subsequently contaminated food or water. however, if complaints are received from several persons who are associated with ingesting water or contact with water at the same place, water is likely to be involved. routine review of the log pertaining to potential waterborne illnesses for similar complaints can often be useful in detecting time, place or person associations. an investigation may also proceed based upon the suspicion of an intentional contamination of a water source. a time association exists if the time of onset of similar illnesses is within a few hours or days of each other. place associations exist when persons have ingested water from a particular single source, have swum in, worked in or otherwise been exposed to the same water, have attended the same event, or reside in an area common to all. person associations indicate a shared personal characteristic, such as being of the same age group, sex, ethnic group, occupation, social group, or religion. waterborne illnesses transmitted by a community water supply usually afflict persons of both sexes and all ages throughout the community. non-community water sources, such as bottled water, ice, water from individual wells, or water from areas of recreation should also be considered when making associations. keep in mind that water can contaminate foods during washing or freshening, and it can contaminate utensils and vessels that are used to handle or store foods. water may therefore be a source of contamination of another vehicle. also, water can be ingested as aerosols generated by shower heads, whirlpools, hot tubs, fountains, cooling towers, and irrigation devices. once some of these associations become obvious, question other persons who could be at risk because of their time, place, or person associations with the ill persons. from time, place, or person associations that have been established or suggested by the investigation, formulate hypotheses to explain (a) the most likely type of illness, (b) the most likely vehicle involved, (c) where and the manner by which the vehicle became contaminated, and (d) other possible causal relationships. the section "collection and analysis of data" describes calculations that can aid in the formation of these hypotheses. test hypotheses by obtaining additional information to support or reject them. if the hypothesis includes food contamination, the instructions given in the manual, procedures to investigate foodborne illness, might be useful. guidelines for confirmation of waterborne outbreaks are presented in table g and guidelines for confirmation that water is responsible for illness are presented in table h . if there is strong evidence to support a hypothesis that the outbreak is waterborne, take precautionary actions. the choice of action is dictated by the (a) suspected causal agent, (b) size of the water source, (c) availability of alternate water sources, and (d) expected use of the water. on the basis of available information, estimate the population at risk and engage any public relations staff with your organization to help inform all persons potentially impacted. when dealing with a microbiological contaminant or agent, consider issuing a boil-water advisory with water treatment guidelines (e.g., heating water in a covered container to a rolling boil for at least min and keeping it covered until use). other options that can be explored include chlorinators that can be installed in individual and non-community systems. for community and non-community supplies in which chlorine is already used, increasing the chlorine dosage and opening hydrants and taps to draw the super-chlorinated water through the whole system might be an option. increasing chlorine is sometimes not effective because the chlorine contact time is too short or super-chlorinated water does not reach some parts of the system. furthermore, chlorination is ineffective against cryptosporidium oocysts and requires a long contact time to kill other human pathogens like hepatitis a virus and giardia. for suspected chemical contamination contact a specialist for further assessment and remedial strategies, such as activated charcoal filters. as a last resort, shut off the contaminated system until the source of contamination is found and controlled. be cautious when you take this drastic measure, because it may do greater harm than good by causing lack of water for hospitals, nursing homes, or for firefighters to extinguish fires. if the water is shut off or the treatment facility or distribution system disrupted (as in the case of floods or other disasters), consider means to distribute water from an alternative source to healthcare facilities and homes. if an illness could have resulted from water contact, close the offending water source, post warning signs around it, and patrol the area. where there is a swimming pool, hot tub, spa, fountain, or whirlpool, evaluate the recirculation system and its operation. it may be that increasing disinfectant concentration by super-disinfection could resolve the problem. where there may be chronic operational problems, evaluate ph, disinfectant concentration, and bacteriological laboratory records. choose your course of action, including consultation with appropriate professional experts, depending on the contributing factors existing at the time of investigation. verify the effectiveness of these actions (e.g., boil-water advisory, superchlorination, provision of alternate water source) to protect public health by monitoring illness levels in the population to determine if the outbreak terminates. if the outbreak continues unabated, consider the possibility of other transmission routes. also, verify the effectiveness of repairs to the water system, super-disinfection, and other actions by closely monitoring the quality of the water supply or recreational water to determine if laboratory reports indicate that the water is now safe for consumption or contact. if there is a public health threat, work with any available public relations staff to announce the outbreak in the mass media so that the public who consumed or was otherwise exposed to the implicated water can be alerted to take appropriate action including seeking medical consultation or treatment. provide only objective factual information about the outbreak. coordinate among the investigating agencies to assure that a consistent and accurate message is delivered. it is easy for agencies to miscommunicate before and during a water crisis (see box , false alarm; box , the walkerton outbreak; box , the flint water crisis). it is often preferable to have one spokesperson for all agencies. do not release preliminary information that has not been confirmed. the person giving information about an outbreak should be well informed about the etiologic agent being investigated and prepared to deal with questions. if the health hazard warrants a public warning at the hypothesis stage, tell the public why emergency measures are being invoked and that subsequent information may be cause to modify the action. as the investigation proceeds and the etiologic agent is confirmed and contributory factors are identified, consider terminating emergency measures, and give advice on specific control and preventive measures. attempt to reach all segments of the population at risk; this may require communication in multiple languages. route all news releases or statements to all persons involved in the investigation. in situations involving large outbreaks or highly virulent or toxigenic etiologic agents, set up an emergency hotline for the public to call to ask questions. this is likely to occur if there is an intentional contamination event where there is high publicity and public concern. train staff to handle these calls in a consistent manner so that the advice is the same who gives it. faulty information derived from poorly tested hypotheses can lead to severe political, legal or economic consequences. an example of this occurred in sydney, australia, in when an apparent water contamination event was publicized for the public to take precautionary actions. the false alarm was costly because of rebates to water customers, additional water testing, and for hiring extra staff, as well as a loss of confidence in the facility (see box , false alarm). they may then be disseminated by the mass media with inappropriate interpretations of the public health significance. furthermore, this information may be used as an unrealistic base for water programs or water regulations because of either misinterpretations or pressure from misinformed consumer-advocate groups. all involved parties should follow a written protocol for cross-agency communication and release of information to the public. unreasonable delays are unacceptable. test hypotheses by obtaining additional information to either confirm or refute their validity. do this by case-control or cohort studies, additional laboratory investigations, and on-site investigations (e.g., laboratory reports of water testing). sydney water (a new south wales state-owned corporation) supplies million liters of water each day to . million properties in sydney and its outlying areas. the city has a large and complex catchment with nine major dams and several storage reservoirs. about , km of water main, almost pumping stations and many tunnels deliver water from four main river systems. the water is filtered through eleven treatment plants. seven are owned by sydney water and four are privately owned. these plants provide % of sydney's drinking water and one plant, prospect, provides up to %. in , the quality of sydney's drinking water came under acute review when giardia and cryptosporidium were found in the city's main water supply at the warragamba dam. initially, low levels of these parasites were first detected in the water supply on july, but these were within the acceptable health limits. in days following, much higher levels were recorded, and on july the first "boil water" alert (in which residents were instructed to boil their tap water before use) was declared for the eastern central business district of sydney. however, by late on july high readings were found in samples at the prospect filtration plant, in a reservoir and at a location further down the system, and a "boil water" alert was issued for the south of sydney harbour, and on july a sydney-wide "boil water" alert was issued affecting most of sydney's residents. on august the warning was discontinued. however, high levels were again found on august (the second event), although it was believed that most organisms would likely be dead. more positive readings were found on august , although at lower levels. further contamination was identified on august and an extended boil water alert was again declared. this was progressively lifted suburb by suburb until further contamination was reported on september (the third event). a -week alert was then instituted, which was finally lifted on september . it was determined that the parasitic contamination was caused by low-quality surface water entering the dam. this contaminated source was attributed to moderate rainfall in july, followed by heavy rainfall in august and september which caused intermittent supplies of the raw water to enter the dam. despite high levels of cryptosporidium (up to > , oocysts) and giardia (up to > cysts) being recorded in july and august, , no increase in human cryptosporidiosis or giardiasis was detected in the exposed population. the incident was highly publicized and caused major a public alarm because the number of people affected, the on and off boil water alerts, and the fact that the filtration plant had been advertised as one of the best in the world. the economic and political repercussions were extensive. the cost of the crisis to sydney water was estimated at a$ million which included $ million paid in rebates to customers, $ million in lost revenue, water testing and staff costs and at least $ . million for damages claims. these costs exclude those relating to improvements to the system and infrastructure. the lack of cases of cryptosporidiosis, giardiasis or other water-related health problems led to suggestions that the parasites were either not an infectious type, or not as extensively distributed. an inquiry after the event revealed the publicity as an exaggeration of fact, with australian water technologies, part of sydney water, severely overestimating levels of cryptosporidium and giardia present in the water, with the recorded levels exposed to consumers as not harmful to human health. the handling of the crisis by state-owned sydney water was heavily criticized, causing the resignation of both the chairman and the managing director, and bringing up issues of private vs. public ownership and scientific uncertainty. the eventual consequence of the state inquiry was the establishment of the sydney catchment authority in to assume control of sydney's catchments and dams, while sydney water maintained responsibility for water treatment and distribution and for sewage collection, treatment and disposal. if an outbreak investigation requires resources beyond your agency's capacity, request assistance from other health professionals. it is desirable to have a team including, if feasible, an epidemiologist, an engineer, a microbiologist, a sanitarian/ environmental health office/public health inspector, a chemist, a physician and others, to undertake a detailed waterborne illness investigation. such personnel can usually be provided by local, state/provincial, or national agencies concerned with health, environment, or agriculture, depending on the expertise needed. for events suspected to arise from intentionally contaminated food, contact emergency response or law enforcement agencies. continue to search for and interview both ill persons who have had time, place, or person associations with the identified cases (see the section on "make time, place, and/or person associations"). review recently received complaints in the water-related complaint log (form b). contact other nearby health agencies, hospital emergency rooms, elderly care centers, and local physicians to discover other epidemiologically related cases. call previously contacted persons to see whether they know anyone else who has become ill or had a common association suggested by data in the log. the illness you are investigating may be part of a larger multijurisdictional outbreak, and therefore communicate with adjoining local and state agencies to learn if they are seeing similar illnesses. state or provincial public health agencies can check reportable disease records and state/provincial public health laboratories can start looking for clusters in isolates that they are characterizing. for outbreaks where intentional contamination of water is suspected or confirmed, public health and law enforcement agency officials may conduct the investigation jointly. if it becomes apparent that an outbreak is associated with a specific water supply (source) or recreational water or event, use form d for recording information. at this stage of the investigation, interviews can be expedited by reviewing the event itself to stimulate each person's recall. ask about specific symptoms and signs that are known to be common to the syndrome, as well as, time of ingestion or contact with water and onset of illness. mention each source of water to which the person may have been exposed, and ask each person (whether a case and well persons at risk) which of the water sources had been ingested or contacted. the number of persons to be interviewed depends on the number exposed and the proportion of them who are probably affected; if fewer than persons were at risk, try to interview all of them; if several hundred are involved, interview a representative sample. be sure to obtain clinical specimens from these cases and well persons at risk (controls). it is more difficult to obtain positive results if symptoms from persons have ceased. there may be situations where self-administrated questionnaires are sent to cases and persons at risk. use either form c or form d or modified versions for this purpose. after questionnaires have been completed, summarize the data on form d. also, identify and interview secondary cases if they become apparent. because no two waterborne disease outbreaks are identical, the order of the expanded investigation may not always follow the outlined sequence of procedures. some investigative steps can usually be done simultaneously by different investigators. additional procedures may also be required. the principles and techniques described will suffice for most investigations. modify forms, if necessary, to accommodate the type and amount of information to be collected. make on-site observations. prove or refute hypotheses developed during the epidemiological portion of the investigation. focus on sources and modes of contamination and ways contaminants could survive and pass through water treatment. as applicable, conduct an on-site investigation of source (lakes, streams, areas around groundwater, etc.), treatment facilities, distribution lines, cross connections, water reservoirs, places of recreational water contact and/or sites at which aerosols were generated. such an epidemiologically focused investigation is quite different from sanitary surveys done during routine evaluations of water source sites, treatment plants or recreational water facilities. not all drinking water (even municipal and bottled water) is disinfected; so, it is important to identify whether the water source is treated and if so, how. some treatments (filtration, reverse osmosis, membrane treatments, riverbank filtration, and others) may not be complemented with a disinfection step. sanitary survey information can provide information about potential sources of contamination in the area of a usually pristine water source. microbiological records of a water supplier, particularly if any total coliform positive samples were found by the system in the last months, may help identify a contamination pathway. if significant matters relating to water quality are observed or otherwise identified during the investigation, note them and communicate them to those responsible for the water system and to the proper authorities. do not lose the focus and objectivity of the investigation by confusing matters of quality and aesthetics with factors related to contamination by, and survival of, infectious and toxic agents. use the haccp-system, also known as systems analysis, way of thinking in your investigation. contact the person with the highest responsibility for the operation and maintenance for the implicated water source, water treatment facility, and/or distribution lines. identify the types of records that ought to be reviewed during the investigation and their likely source. do not forget that the responsible authorities also can have records (about water quality, if there has been a change of municipal water supply, industrial water pollution, wastewater pollution). they can be good sources of information about recent pipe breaks and other water system issues that could be related. in many cases they will be aware of the potential for contamination upstream of source water intakes. if applicable, obtain water distribution maps and recent water quality reports from appropriate departments. if you are not familiar with the community in which the investigation is to be done, obtain maps of the area to locate streams, lakes, water treatment facilities, and other community features that might have a bearing on the investigation. check if there are water protection areas and their rules. get plans and specifications on design of treatment facilities from consulting engineers or state agencies that approve these facilities. contact weather bureaus, airports, radio/television stations, or newspapers for information on heavy rainfall, flooding, extremely low temperatures, droughts, or other unusual weather conditions that preceded the outbreak, if this information is unknown to investigators. contact police or fire departments about traffic accidents, which can be the source of the outbreak. review all background data pertaining to the suspect water. as information is gathered, record it on applicable parts of form g. discuss with laboratory personnel that a field investigation will be made, and get their suggestions regarding samples and specimens that should be collected (see tables e and f) . confer with them about special analyses, media, and sampling procedures; make arrangements for rapid transport of samples to the laboratory. the samples must maybe be transported at the right temperature. pick up appropriate forms and sample collection equipment (preferably preassembled in a kit-see table a ). the laboratory can probably help assemble this kit. during the investigation, identify factors that contributed to contamination and survival of the etiologic agents and perhaps also to their growth or amplification or another cause of the outbreak. identified factors and situations that have contributed to waterborne disease outbreaks include those listed in table . focus the investigation on the potential situations listed in table , as applicable. remember that other possibilities can occur. describe circumstances that contributed to contamination and that permitted the etiologic agent to survive so that it reached drinking, agricultural, industrial, or recreational water. also describe circumstances that allowed pathogenic bacteria or algae to multiply in the water. write your findings down on the back of form g (illustration of contamination flow) or on a separate sheet. continually update the listing in table with newly available data. introduce yourself (who you are, where you come from, who ordered you there) to the owner, resident, or persons in charge and state your purpose, when you arrive at the place of the suspected contaminated water source. emphasize that your visit is to confirm or eliminate suspicion that this water was a source of illness. tell him or her that a complete epidemiologic study is in progress and that other possible sources (such as food) will be investigated as well as operations of this site. explain that your investigation is not to fix blame but to identify the cause of the outbreak. emphasize that the findings can yield benefits related to the ability to identify needed improvements, to educate staff and to provide public support. try to create an atmosphere of cooperation. maintain an open mind and try to answer all questions. if you can not answer a question, tell the person that you will come back with an answer. come back to the person within or weeks even if you do not have any new information. give the person your phone number and e-mail address and tell the person to contact you if the person has more information later. privately interview key persons responsible for operating or repairing water facilities. do not forget to interview persons from other work shifts. identify persons who were working there at the likely time of contamination and have since left and interview them as well. ask questions to determine the flow of water and operations from intake through distribution through plumbing systems. ask about any changes in operation, unusual events in the watershed or repairs to the water facilities. ask if you can check records, both in paper form and on the computer (monitoring system), analyses of results, and/or incident reports. plant personnel may not describe water treatment or installations exactly as they existed at the time that a mishap occurred. they may fear criticism or punitive action as a result of their possible role in the causation of the outbreak. their descriptions should be plausible and should account for possible sources and modes of contamination and indicate possibilities for survival of pathogens. if a description does not contain all the information desired, reword questions and continue the inquiry. confirm accounts by private interviews with others knowledgeable of water treatment or operation of the facility. be alert for inconsistencies among the accounts told by different persons. seek resolution of discrepancies in accounts by watching actual procedures as they are being carried out, by taking appropriate samples, or by conducting experiments. a communicative working relationship between the plant management and the investigator influences plant workers' attitudes toward the investigative team. consider the position, feelings, and concerns of the manager and staff; defensive reactions are normal on their part. diagram each phase of the water system or situation under study on form g (illustration of contamination flow). insert special symbols and notes for all sites that might be involved in introducing contamination to the water or where contaminants might have survived treatment. record other information gathered on the appropriate parts of forms g - . review and collate appropriate information on quality control and operational records from the water utility and from responsible agencies. as applicable, obtain information on quality of untreated surface or groundwater from a local, state/ provincial, or national pollution control or geological survey agency. also, seek water distribution maps, well logs, descriptions of geological conditions and indices of groundwater quality from them. for surface water supplies, obtain information on upstream discharges and unusual events that may have affected raw water quality. get data on finished water quality in the distribution system from a local, state/ provincial water surveillance or regulatory agency. water suppliers also frequently have records of raw and finished water quality. review data on quality control tests (e.g., ph, chlorine residual, chlorine demand, bacteriological and chemical tests, turbidity, jar test data, incident reports) that are available. obtain data on cross connection control programs and sewer repairs from the water supplier or other local agencies (e.g., building inspectors, sewage departments). review files for data concerning potential sources of contamination for individual or semipublic water supplies (e.g., diagrams of septic tank systems, sewer line locations, well logs, small individual wastewater plants, accidental industrial pollution of water, traffic accidents involving chemicals, salting of roads or sawmills). check if they have any haccp-systems or water safety plan and, if so, how they monitor their ccps (critical control points) and if they are implementing control measures. ask them about haccp, to see if they understand the system and if results are documented. check if the haccp-system is validated (should be documented) and that they are conducting internal audits. get information on all aspects of normal operations as well as unusual events or conditions to determine whether such events were coincidental with the time of suspected contamination as determined from the epidemic curve. also, consider the time it takes for a contaminant in the raw water or treatment plant to reach households in the affected community. ask responsible persons for this information. compare data on heterotrophic plate and total coliform counts of raw and finished water leaving the treatment facility and of water in distribution lines. also, compare data on chlorine residuals within the plant with that in distribution and check, if they have, that the uv-light is functioning. review other test data (e.g., turbidity and chemical analyses) that may indicate a problem situation. identify locations and dates of sample collection. take photos, if it is allowed, of things you suspect are not right. go back more than one incubation period of the disease under investigation. record this information on form g (record review of on-site investigations, and test results prior to and during outbreak). photocopy appropriate records for confirmation and subsequent review and attach them to the record review form. be alert for evidence of falsification of records. while reviewing records, watch for evidence of the following: • potential contamination of groundwater systems because of proximity to septic tank systems, latrines, animals manure or landfills, industrial contamination of the water supply, small sewage plants, especially old and nearly forgotten ones, and recent heavy rain • high heterotrophic plate or coliform counts, or counts that exceeded the average (median) or typical count • sudden changes in water quality or operating practices that suggest the possibility of contamination or treatment failure • high turbidity, unusual odor, color, or taste, or high coliform counts in raw water, which can indicate potential overloading of the normal treatment process • high levels of ammonium, nitrate and nitrite, which can indicate organic and inorganic contaminants • low chlorine residuals in treated water or higher-than-normal amounts of chlorine used, which can indicate either a high chlorine demand or a sudden high level of contamination • a sudden drop in amount of disinfectant used, possibly indicating failure or interruption of a disinfection process. no functioning alarm system • a sudden change in the amount of a chemical (e.g., alum or ferric sulfate) used, suggesting equipment disfunction or inadequate coagulation or flocculation and thus poor filtration • lack of treatment chemicals if a more corrosive water supply is used (see box , the flint water crisis) • pump failures, draining of distribution lines or reservoirs, or massive pumping to fight fires, which can produce low pressures that can cause contamination through cross connections or back siphonage • repairs to water mains, wells or pumps where contamination could have been introduced record this information on form g or other appropriate form in the g series. as applicable, investigate the water source, treatment facility, distribution and plumbing systems, sites where water was contacted, and sites at which microorganisms amplified and aerosols disseminated. use forms in the g series as guides while observing facilities, gathering data, making measurements and collecting samples. google or bing maps or other similar resources' views of the watershed can be very helpful in identifying potential sources of contamination that you will need to investigate further. these maps can also facilitate your own map and diagram making on form g . the water source may be surface or ground or in some cases a combination of the two. verify this by observations at the site and by talking to the property owner or persons responsible for operation or maintenance of water supply or recreational facilities, as applicable. examination of "weather events" such as heavy rainfall may indicate a potential for surface water contamination (see box , the walkerton outbreak). when a surface water is either suspected or implicated as the source of a contaminated supply, get information about the watershed concerning possible sites of contamination of the suspected etiologic agent. this includes, but is not limited to (a) land use, (b) sewage effluent from treatment plants and septic tanks, (c) industrial plants that may be discharging toxic waste, (d) mining wastes, (e) landfill leachates, (f) slaughterhouse discharge wastes, (g) animal feed lots, (h) both domestic and wild animals that use the source water for drinking, (i) sludge disposal from sewage treatment plants or septic tanks (e.g., land spreading or lagoons), (j) storm water discharge. if this information is not available from records or persons familiar with the site, visit the site and observe possible sources of contamination and pollution (e.g., while traveling by foot, vehicle, boat, or helicopter, as applicable). record this information on form g (source and mode of contamination of surface water). diagram the surface water and sites of contamination on form g . note type and location of sources of contamination and their distances from the water. visit groundwater sources. using form g (source and mode of contamination of groundwaters) as a guide, question owner or operator and inspect groundwater installations to ascertain character of the land and surface and subsurface soil and water. when a well or improved spring is under consideration as the source of the contaminated supply, observe its location relative to possible sites of contamination and to whether its construction allows contaminants to reach the water. determine locations of all sewage outflows or disposal sites (e.g., septic tanks and absorption lines, cesspools, privies, and other sewage disposal facilities), gradients, and distances from the well or spring. determine the type of soil at the site. if the soil is limestone or fissured rock or if there is a high ground or perched water table, pollution may travel many miles. in this case, the search for sources of contamination may have to be expanded for a considerable distance from the well or spring. ascertain whether there were heavy rains, heavy snow melts, or sudden discharge in may, , many people in walkerton, a small ontario, canada, community of about , people, began to simultaneously experience bloody diarrhea and other gastrointestinal infections. on may - , torrential rain had unknowingly contaminated the town's water system, but operators failed to check residual levels for a period of several days, allowing unchlorinated water to enter the distribution system. however, the privatelyowned walkerton public utilities commission insisted there was no problem with the water despite other laboratory tests showing evidence of e. coli contamination. illnesses began about may , with the first death occurring on may and the seventh and last on may . by may , however, many more cases had been diagnosed, the infectious agent determined to be e. coli o :h , and contaminated well water was confirmed as the source of the e. coli; all this allowed the region's medical officer of health to issue a boil water advisory, warning residents not to drink the tap water. two days later, laboratory results identified the presence of campylobacter and e. coli o :h and dna testing showed that the contaminating source was a cattle farm a short distance from a well used for the water supply. by the time the outbreak was over, > were ill and had died. the people who died directly from drinking the e. coli-contaminated water might have been saved if the walkerton public utilities commission had admitted to contaminated water sooner. those in charge of the water utilities at the commission had no formal training in their positions, retaining their jobs through three decades of on-the-job experience. they were later found to fail to use adequate doses of chlorine, fail to monitor chlorine residuals daily, make false entries about residuals in daily operating records, and misstate the locations at which microbiological samples were taken. regulations state that water suppliers are required to treat groundwater with chlorine to sufficiently neutralize contaminants and sustain a chlorine residual of . mg/l of water after min of contact. had utility operators adhered to the protocol, the disaster most likely would have been averted. the operators knew that these practices were unacceptable and contrary to ministry of environment guidelines and directives; they eventually admitted falsifying reports and were sentenced to short jail terms. the ontario government was also blamed for not regulating water quality and not enforcing the guidelines that had been in place. the water testing had been privatized in october . an enquiry found that the water supply, drawn from groundwater, became contaminated with the e. coli o :h strain from manure from cattle on a farm washing into a shallow water supply well after heavy rainfall. the risk of contamination from farm runoff into the adjacent water well had been known since . key recommendations from the enquiry included source water protection as part of a comprehensive multibarrier approach, the training and certification of operators, a quality management system for water suppliers, and more competent enforcement, which were incorporated into ontario new legislation. the bottom line of the enquiry was that officials and municipal water facilities operators and managers across north america need to recognize public waters are a most valued but vulnerable public resource. investment in keeping them safe and secure needs to be a community top priority. from dams that could have resulted in flooding within the duration of the incubation period of the disease under investigation. obtain information on the depth of the well in reference to the ground water table from the owner or by referring to any available well logs on public file or from local drillers. observe well construction and get information about depth of casing, depth and method of grouting, and whether there is an underground discharge. observe whether there is an impervious well platform and whether the pump or casing seal was subjected to flooding. illustrate the situation by showing location of the well in this event is considered a disaster, still unfolding, initiated from a political decision to save money, and ending up with acute and chronic illnesses and deaths to residents of a michigan city, as well as high system remediation and health-related costs to the taxpayer. on april , , flint, genesee county, michigan, switched its water supply from detroit's system to the flint river as a cost-saving measure for the struggling, majority-black city on the recommendation of the state-appointed emergency manager. flint agreed to separate from the detroit water and sewerage department and go with the karegnondi water authority, including the decision to pump flint river water. this was to be an interim measure until a new pipeline from lake huron was constructed in to serve the region. soon after the switch, residents begin to complain about the water's color, taste and odor, and to report rashes and concerns about bacteria. in august and september city officials issued boil-water advisories after coliform bacteria were detected in tap water. in october , the michigan department of environmental quality (mdeq) blamed the cold weather, aging pipes and a population decline. in the same month a general motors plant in flint (continued) reference to possible sites of contamination on form g . note distances between the well and contamination sites and elevations. determine whether any pumps were out of order or had been repaired during the interval of concern. if priming of the pump was done, find out the source of the water used. record this information on form g . test hypotheses of modes of contamination by conducting a dye test and/or sampling the water. (see appropriate sections of this manual for directions.) collect samples of water from these sites and submit them for analysis of the suspected etiologic agent or for any physical, bacterial, or chemical tests that will provide evidence of contamination or movement of the contaminants. (see procedures for collecting water samples) record these results on forms g or g and i (laboratory results summary). when appropriate, confirm hypotheses by a dye or other tracer test. (see section on this subject). determine the means by which the etiologic agent survived treatment or was otherwise not eliminated or inactivated. consider the treatment process as a series of barriers placed between contaminants and consumption of the treated water. the operation of each barrier should be optimized. review available data for each step in the treatment process. records of well-maintained and properly calibrated continuous monitoring equipment will be especially valuable. look for failures in the barriers, which could include (a) lack of disinfection, (b) inadequate concentration of disinfectant or contact time, (c) interruption of disinfection, (d) inadequate filtration, (e) lack of corrosion inhibitors, which may follow inadequate pre-filtration treatments. in in flint, michigan excessive levels of lead were found in drinking water from corrosion of water distribution pipes (see box , the flint water crisis). corrosion inhibitor had not been added. also, look for possible introduction of contaminants within the treatment process, such as in treatment chemicals. stopped using municipal water, saying it was rusting car parts. on january , , the city announced that flint's water contained a high level of trihalomethanes, a byproduct from increased disinfection by the city. though this is in violation of the safe drinking water act, officials told residents with normal immune systems that they have nothing to worry about. in january , detroit's water system offered to reconnect to flint, waiving a $ million connection fee but the offer was declined by the emergency manager. by february, state officials continued to play down any water problems saying that the water was not an imminent "threat to public health." on february , parts per billion (ppb) of lead were detected in drinking water at a flint home and the federal environmental protection agency (epa) was notified. the epa does not require action until levels reach parts per billion, but science indicates that there is no safe level for lead in potable water. officials from epa and mdeq discussed the lead level in the sample, and epa found that the state was testing the water in a way that could profoundly understate the lead levels. on march , , a second testing detected ppb of lead in flint drinking water. a consultant group hired by flint, reported that the city's water met state and federal standards, and it did not specifically report on any lead levels. in may, tests revealed high lead levels in two more homes in flint. in july, an epa administrator told flint's mayor that "it would be premature to draw any conclusions" based on a leaked internal epa memo regarding lead. however, in september, flint was asked to stop using the flint water supply or consider corrosion control for it, because it was causing lead to leach from the water pipes and children had high levels in their blood. state regulators insisted the water was safe. nevertheless, on october , the governor of michigan ordered the distribution of filters, the testing of water in schools, and the expansion of water and blood testing after a briefing on the lead problems with the mdeq and federal officials. at the same time, flint city officials urged residents to stop drinking water. on october , flint reconnected to detroit's water system, and residents were advised not to use unfiltered tap water for drinking, cooking or bathing. on october , the director of mdeq reported that his staff had used inappropriate federal protocol for corrosion control, and soon after, the governor announced that an independent advisory task force would review water use and testing in flint. on december flint added additional corrosion controls, and soon after an emergency was declared. at the end of december, the task force found that the mdeq was accountable for its lack of appropriate action, and the director resigned. on january , , the governor asked the national guard to distribute bottled water and filters in flint, and president obama declared a state of emergency in the city and surrounding county, allowing the federal emergency management agency to provide up to $ million in aid. three days earlier the crisis expanded to include legionnaires' disease, because of a spike in cases, including ten deaths, after the city started using river water. on january , the michigan department of health and human services stated it did not have enough information to conclude that the increase in cases was related to the ongoing flint water crisis, although the. head of michigan's communicable disease division had said three months earlier that the number of legionella cases at that time "likely represents the tip of the iceberg." as of february , the number of reported cases was close to . a flint hospital official was surprised that michigan and local health agencies did not inform the public about the legionnaires' outbreak in genesee county in - until january ; the hospital earlier had spent more than $ , on a water treatment system and bought bottled water for patients. the source of legionella is not known but it was likely in the flint river, and possibly extensive flushing of flint's colored water, which had undesirable odors and tastes, by residents may have caused chlorine residual in the pipes to be washed away, leaving the pipes susceptible to growth of the legionella; in addition, aerosols from the extensive flushing from turned-on faucets might have led to close contact between the residents and the pathogen. the investigation of the cause of the illnesses continues with criminal charges laid against michigan departmental employees. observe treatment processes from the water inlet to the finished water discharge. diagram on form g the treatment process; insert notations of hazardous situations that were observed. collect samples of water at the inlet, after each phase of treatment that may have functioned suboptimally or failed, and at the outlet. test the samples for pathogens that cause a syndrome characteristic of that being investigated, for indicator organisms and for physical and chemical characteristics of the water, as appropriate to the situation. evaluate effectiveness of the disinfection process and resulting residuals. determine the type of disinfectant (e.g., gaseous chlorine, hypochlorite, chlorine dioxide, chloramine, ozone, ultraviolet irradiation) used and whether the disinfection treatment was adequate for the volume of water treated. determine, by talking to water treatment plant employees and reviewing records of the plant or regulatory agency, whether there were any interruptions of disinfection during the two weeks prior to the first onset date. determine contact time between the point of addition of the disinfectant and the first point of use. measure the chlorine residual, ph and temperature of the water just before it leaves the plant. observe the condition, operation, and maintenance of disinfectant dispensing equipment. review plant records to identify any sudden changes in disinfectant demand that causes temporary depletion of disinfectant residuals and allows survival of pathogens. review maintenance records for disinfectant dispensing equipment and quality assurance records for online analyzers. record this information on form g a (disinfection failures that allowed survival of pathogens or toxic substances). calculate disinfectant rate applied and usage (see formulae in form a). for example, to calculate disinfectant rate, if the flow rate is , , gal/day and the dosage is lb/day: the destruction of pathogens is dependent on (a) type and condition of microorganisms present, (b) type of disinfectant used, (c) concentration of available chlorine or other disinfectant, (d) contact time, (e) water temperature, (f) ph, (g) degree of mixing, (h) presence of interfering substances (which may be related to turbidity). utilize treatment records that provide small scale time resolution, such as online monitoring data, to determine whether the process was stable during the time period in question. daily averages may provide evidence of massive failures, but will not provide information about whether consistent treatment was being provided. in general, the relative effectiveness of microorganisms' resistance to free chlorine, from high resistance to low resistance, is as follows: • protozoan oocysts (i.e., cryptosporidium) • protozoan cysts (i.e., giardia, entamoeba histolytica) • viruses (hepatitis a virus, poliovirus) • vegetative bacterial cells (shigella, escherichia coli) protozoan oocysts are highly resistant to chemical disinfectants, but not to physical means such as uv light or ozone (gas). microorganisms within each group and strains among the same species differ somewhat in resistance. the state of injury induced by environmental impacts and selection of resistant strains influence survival. aggregation of microorganisms and/or close association with debris shield them to various degrees from lethal effects of disinfectants and attachment to surfaces such as pipe walls to form biofilms that protect organisms from inactivation by disinfectants. a measurement of microbiological inactivation by disinfectants is the ct value (ct calc ), which is the product of the free residual disinfectant concentration (c) in mg/l that is determined before or at the first user (customer) and the corresponding disinfectant contact time (t) in minutes (i.e., c × t). refer to table i (ct . values for inactivation of giardia cysts at different concentrations of disinfectants, temperatures, and ph values) and table i (ct values for inactivation of viruses at ph - , at different temperatures with different disinfectants for comparing disinfectant efficiencies). make residual measurements during peak hourly flow. for comparisons of ct values between the indicated ph, temperature, and concentration values, use linear interpolation. (for example, for free chlorine, °c, concentration mg/l, ph . = [ − = ; / = ; + ] = ). if no interpolation is done, use the ct . value at the higher temperature, at the higher ph and higher concentration. a simple ct calculation, for example, using a disinfectant concentration (c) at the basin effluent of . mg/l and a detention time (t) of min, is as follows: use this calculation for comparing to values in table i or j. the calculated ct value should be higher than the value stated in the table for specific conditions of disinfection, temperature, ph, and concentration (residual). in this situation, if the temperature of the water was °c, the ph and the concentration of chlorine mg/l, a ct value of would be needed for a . reduction of giardia cysts. the ct value of . would have been inadequate to meet the criteria and could explain the survival of the pathogen under investigation. microbial inactivation efficiencies vary considerably among different disinfectants and are influenced by the characteristics of the water and water temperature. tables i and j show that, in general, ozone is more effective than chlorine dioxide, which is more effective than free chlorine, which is more effective than chloramines. also, in general, longer contact time increases the degree of inactivation, and higher water temperatures as well as lower ph values increase rates of inactivation. rapid mixing of the disinfectant with water increases disinfection efficiencies, whereas dissolved organic matter reacts with and consumes the disinfectant and forms products that have weak or no disinfection activity. certain inorganic compounds and particulate matter also react with disinfectants. the ct value must be determined sequentially whenever a disinfectant is added to water. contact time (t) is the duration in minutes for water to move from the point of application of the disinfectant or the previous point of residual disinfectant measurement to the point where residual disinfectant concentration (c) is measured. it is measured from the first point of disinfectant application and from all subsequent applications until or before the water reaches the first user. determine contact time in pipelines by dividing internal volume of the pipe by the maximal hourly flow rate through the pipe. determine the flow rate from (a) plant records, (b) continuous monitoring device readings, (c) measurements at hourly intervals, or (d) if this sort of information is unavailable, measurements at expected high flow periods. use tracer studies to determine contact time within mixing basins and storage reservoirs. these values represent only % effectiveness because of short circuiting. chlorine, fluoride, and rhodamine wt (but not b) are commonly used tracer chemicals. contact time is usually measured by a step-dose method, but a slug-dose method is used where chemical feed equipment is not available at the designated point of addition or where such equipment does not have the capacity to provide the necessary concentration. (see appropriate epa literature for procedures, and consider getting engineering expertise if these matters are too complex.) estimate whether pathogens had been inactivated. to do this, divide the ct calc value by a value (ct x% ) resulting in a certain percentage inactivation (e.g., . % [ -log] or ct . for giardia cysts and . % [ -log] or ct . for viruses). this gives an inactivation ratio. see table i for ct . values for giardia and table j for ct . values for viruses. following is a sample calculation for data in table i when water temperature is °c, ph in a clearwell (reservoir for storing filtered water) is . , time (t) (either calculated or measured by dye test) is min, and the disinfectant used is chlorine: the desired ct value for . % inactivation of giardia for ph at °c is between and depending on concentration of disinfectant. in this case, the disinfectant measured at the clearwell outlet is . mg/l. therefore, the result, , is larger than the value, , required in the table; hence, these disinfection concentration (c) and time (t) conditions should result in a . % or greater inactivation of giardia cysts. for free chlorine, a -log inactivation of giardia cysts provides greater than a -log inactivation of viruses. the following example, using the data in table i , demonstrates a means to calculate the increased disinfectant dosage needed for a plant during the transition from summer to winter, when the water temperature fell from to °c, chlorine dioxide was the disinfectant used and the t value (calculated or measured) is min. using table i in this situation, the plant should have increased the chlorine dioxide concentration from . mg/l to . mg/l to maintain the same efficiency of disinfection. if this had not been done, it may explain the survival of pathogens in the water supply. the sum of these ratios gives the total inactivation ratio, which should equal or more to provide effective disinfection. make calculations and record information on form g a. the following example shows the way this is done. chlorine is added to three basins. chlorine concentration, contact time, temperature and ph are measured at these locations and recorded as shown in table . data from table i is combined to do the calculation. the resulting sum exceeds . . this ensures that the plant met the recommended or required ct. regulations may require that community and non-community public water systems that use surface water or water under direct influence of surface water meet a criterion (e.g., minimum of . % [ -log] removal and/or inactivation of giardia cysts and a minimum of . % [ -log] removal and/or inactivation of viruses of fecal origin that are infectious to humans). removal and/or inactivation of microorganisms may be accomplished by either filtration plus disinfection or disinfection alone, depending on the water source. water systems using chlorine with ct values that attain minimal level or inactivation of giardia cysts will result in inactivation of . % ( -log) of viruses. evaluate the prefiltration processes (e.g., coagulation, flocculation and sedimentation). coagulation is a process that uses coagulant chemicals and mixing, by which colloidal and suspended materials are destabilized and aggregated into flocs. flocculation is the process that enhances agglutination of smaller floc particles into larger ones by stirring. sedimentation is the process by which solids are removed by gravity separation before filtration. observe whether these processes reduce turbidity. calculate detention (transit) time within the settling tank and seek information about frequency and method of cleaning the tank. for example, if an -ft-deep sedimentation basin has a volume of million gal, and the plant flow rate is million gal/day, detention time in the basin is: (in your country you may want to calculate rates based on metric measurements) several different types of filtration may be used in water treatment facilities. these are conventional, direct (both conventional and direct are referred to as "rapid" filtration), slow sand filtration, and diatomaceous earth filtration. conventional filtration consists of a series of processes including coagulation, flocculation, sedimentation, and filtration. direct filtration consists of a series of processes including coagulation and filtration but excluding sedimentation. slow sand filtration is a process involving passage of raw water through a bed of sand at low velocity (usually less than . m/h), utilizing both physical and biological means to remove particles and microorganisms. in diatomaceous earth filtration, water is passed through a precoat cake of diatomaceous earth filter medium while additional filter medium is continuously added to the feed water to maintain the permeability of the filter cake. if done properly, each filtration method results in substantial particulate removal. when rapid sand filters have a head loss of about - ft, they require back washing. filters are backwashed by reversing the flow of the filtered water back through the filter at a rate between and gal/min/ft of sand-bed area. sometimes water jets at the surface aid in loosening and removing deposited material on the sand. observe an actual backwash and look for indications of short-circuiting or areas of the filter material that seem agglomerated or resist being cleaned by the flowing water. if backwash water is not discharged to waste, evaluate where it is released. slow sand filters eventually become clogged. when this occurs, a scraper or flat shovel is used to remove the top layer of clogged sand, and new sand (equivalent to the depth removed by scraping) replaces the old. test the effectiveness of filtration for each filter unit by observing capacity and filtering area relative to volume and turbidity of the filtered water. also, review turbidity, headloss, and filter rate record. look for anomalies, especially in the few hours after a filter is returned to service, and before the filter is backwashed. review criteria that cause a backwash to be initiated, and establish if these criteria were followed during the time preceeding the outbreak. determine the source of backwash water and the frequency of back washing of filters from records and head gauge readings. check whether the water used to back wash or clean filters came from an untreated source and determine the fate of the backwash water. in the case of illness due to chemical substances, evaluate types of chemicals used and condition, operation and maintenance of chemical feeding equipment. consider sampling backwash water for pathogens under investigation. review plant records for results of monitoring and be alert for changes that suggest treatment failure. record this information on form g b (source of contamination and treatment failures that allowed survival of pathogens or toxic substances.) data in table k (estimated removal of giardia and viruses by various methods of filtration), give a summary of expected minimal removal of giardia and viruses in well operated filtration systems. values can be subtracted from ct values required for disinfection. although contamination is likely to be associated with raw incoming surface water, look for bypass connections where raw or partly treated water can get into treated water. also look for common walls that separate treated and untreated water. consider the possibility that a contaminant was introduced in any of the treatment chemicals themselves, or as an act of sabotage. determine whether any flooding has occurred during the interval of concern. check absentee records for possible enteric illness of the water treatment plant staff. such illness may reflect either sources of contamination or victims. record this information on form g b. at domestic locations, evaluate treatment devices (such as chlorinators, filtration units, softening equipment) as described above, but modified to fit the situation under investigation. record observations and measurements on forms g a and g b, as applicable. the water distribution system can be complex, with multiple entrance points for treated water and different pressure zones in which water can enter but not leave. water flows in the direction in which it is being "requested," so can flow in different directions in the same pipes from one hour to the next. contaminated water can enter a potable water supply from a non-potable water supply when the two are directly connected. such interconnections are referred to as cross connections. to evaluate such situations, trace lines of the treated supply from the point of treatment or entrance into a building to points of use and associated plumbing. look for any interconnections of other water supplies, such as wells, waste lines or holding tanks for water intended for fire control. if cross connections are found, look to see whether backflow prevention devices are inserted between the lines and, if so, whether they are functioning properly. also, look to see whether there is an air gap between the water inlet and vessel or tank. evaluate the arrangement and operation of check valves on connections between the two water systems. review inspection report for backflow prevention devices. contaminated water can also enter a treated supply by siphonage from a contaminated vessel or sewerage to the potable water line having negative pressure. this is referred to as back siphonage. examine all water vessels to see whether they contain submerged inlets or hoses connected to water faucets, and if so, whether properly functioning vacuum breakers are in place. without proper air gaps or properly functioning vacuum breakers, there is a possibility of siphonage of water from plumbing fixtures in upper stories to lower stories when line pressure is negative. this may occur when faucets on lower floors are opened after the water supply valve has been turned off for repairs or when the supply line has had a sudden loss of pressure, as can happen with nearby heavy use of water (e.g., to fight fires or irrigate) or when pressure lines are broken. measure water pressure on upper stories of buildings to determine whether negative pressure occurs. (pressure losses may be transient and of very short duration.) interview building managers and residents about whether there were (a) any repairs of water service during the past month, (b) fires that occurred nearby, or (c) other situations that could have caused negative pressure in the water line. also, if appropriate, review fire and utility department records for information about these situations. get dates of line repairs to see whether they correlate with the time of incubation periods of early cases. measure chlorine residual (of chlorinated water systems) and take samples for microbiological tests at several strategic locations in the distribution systems. perform calculation on comparison of disinfectant residual. if a toxic chemical poisoning is under investigation, talk to home owner, building manager or maintenance staff about whether pesticides or other toxic compounds were sprayed with equipment connected to a hose or a sprinkler system. furthermore, interview building managers and residents about whether there are persons residing there who either are or recently were ill with diarrhea. they may represent sources of the etiologic agent or may identify victims. interview those identified about the onset of their illness and symptoms and examine their plumbing systems. record information obtained during the investigation of distribution and plumbing systems, and record related calculations on form g (source and mode of contamination during distribution and at point-of-use). evaluate implicated waters used for swimming, water skiing, bathing, clothes washing by hand, or agricultural activities, in a manner similar to that described under the section on investigation of surface water source. if the potential site of contact was natural surface water, determine whether the water is likely to be infested by parasites and look for the presence of snails (swimmer's itch). for swimming pools, measure the water's ph, chlorine residual, water temperature, and turbidity, if applicable. also, review pool records for previous information on these characteristics. high turbidity in pools, hot tubs, and spas is a sign of either poor filtration or inadequate disinfection. evaluate whether the resulting water would adequately protect those who swam or waded in it or had any physical contact with it. evaluate filter and chlorination equipment as described for water treatment. backwash filters and collect a sample to get an indication of microorganisms present on the filter (thus obtaining historical information). this approach has been useful for identification of pseudomonas aeruginosa. look for the presence of slime on tub, whirlpool, slide and pool surfaces, and collect some of this material for analysis for p. aeruginosa. if the answer is not obvious, ask ill persons whether they had puncture injuries or wounds or scrapes while immersed in water. record this information on appropriate parts of form g (contamination source and survival of pathogens or toxic substances for recreational waters). collect samples of the water (see section on "collect water samples"), and test them for pathogens and/or indicator organisms, as applicable. the agents listed in table d can multiply in water and if such water is aerosolized, they can be transmitted to human beings via the respiratory route. highly susceptible persons (e.g., the elderly, smokers, immunosuppressed individuals) are the usual victims. look for possible sites where water may have been or is being disseminated as aerosols. consider (a) air conditioning cooling towers and evaporative towers, (b) hot water systems (heaters and tanks), (c) shower heads, (d) faucets with aerators, (e) mist machines used to freshen fruits and vegetables in markets, (f) humidifiers, (g) nebulizers/respiratory therapy equipment, (h) whirlpools and spas, (i) dental drills and cleaners, (j) cooling water apparatus for grinders, (k) splash from hoses, (l) water pressure line breaks, (m) decorative water features, (n) outside misters, (o) other aerosol-producing devices. sample water from all suspect sites for legionella or other waterborne agents that may cause illness when inhaled. it is not possible to recognize by visual inspection the potential for water to be contaminated with legionellae. warm temperatures, especially those between °c ( °f) and °c ( °f), are conducive to growth of legionellae. additionally, stagnant water allows time for legionellae to multiply, especially in dead-end lines, reservoirs and hot water tanks, and in water trapped in shower heads and faucet aerators. if it is deemed appropriate or necessary to sample for detection of legionella in the environment, collect water samples from suspect sources. it is important to use a lab with proven expertise in isolating and characterizing legionella, such as those labs in the u.s. certified under the environmental legionella isolation techniques evaluation (elite) program. the centers for disease control (cdc) have a convenient form for recording case histories (http:// www.cdc.gov/legionella/downloads/case-report-form.pdf). it is not appropriate to sample air for detection of legionella hazards. it may, however, be appropriate to use micromanometers or smoke to trace direction of air flow to determine route of dissemination. micromanometers measure pressure differences, and flow can be assumed to travel from high to low pressure areas. smoke moves from areas of higher pressure to areas of lower pressure and is extremely sensitive to air currents. observe direction and spread of smoke movement. record this information on form g (contamination source and sites of amplification and aerosolization of pathogens). prior to the collection of samples, investigators should consult with the testing laboratory that will be used, to receive specific laboratory sampling instructions and sampling kits. sampling protocols for potable and non-potable sources are dependent on the specific etiological agent and the related analytical procedures performed by the testing laboratory. collect samples promptly to test for possible etiologic agents and for microorganisms indicative of fecal contamination. contaminants in water are in a dynamic state; their presence and quantity differ with time and place. see table f (general instructions for collecting drinking water samples) for guidance on collecting and shipping samples for viral, bacterial, and parasitic analyses. samples for bacteriological tests can be collected in one of three ways: (a) by letting a stream of water flow into a container or by submersing a container into a volume of water, (b) by passing a large volume of water through a filter, (c) by putting moore swabs (see table a for description) or similar absorbent materials in surface water or drains for a few days (see table f ). use bottles that have been cleaned, rinsed, and sterilized, or use sterile plastic bags to collect and store samples for bacteriological examination. for a chlorinated water supply, or when in doubt about the presence of residual chlorine, use bottles containing mg/l sodium thiosulfate to combine with any free chlorine in the sample and prevent lethal effects of chlorine on microorganisms in the sample. this compound will not interfere if used for non-chlorinated water. when collecting water samples, first try to get "historical" samples that might give an indication of the condition of the water at the time it was ingested by those who became ill. obtain historical samples from water in bottles in refrigerators, toilet tanks, hot water tanks (for chemical analyses only), fire truck reservoirs, storage tanks, and taps at seldom-used and dead-end locations, and from ice in refrigerators and commercial ice plants. direct the laboratory to test historical samples for pathogenic organisms or toxic chemicals, as well as indicator organisms, because these samples have a chance of still containing the etiologic agent, whereas samples collected during the investigation several days or weeks after the event may be of water that has been flushed free of contamination or has been significantly diluted. take samples from to points throughout the distribution system. sample dead-end locations if they are found. do not neglect to obtain raw water samples even though treatment is provided. this is important, as it suggests possible sources of contamination and reflects the effectiveness of treatment. compare these test results with records of results on previous samples of raw or treated water. before drawing a sample from a water tap, make sure the tap is connected to the supply to be tested. do not collect samples (other than for legionella) from hose connections, sprays, or swivel faucets; uncouple these connections or choose different outlets. it is unnecessary to flame outlets, as this does not improve the quality of the sample. first, ensure your hands have been thoroughly washed then take a line sample by allowing the water to run to waste for - min. adjust the flow of water so that the thiosulfate will not wash out of the bottle or bag (do not overfill-most laboratory bottles indicate a maximum fill line). keep sample containers closed until the moment they are to be filled. hold the bottle near the base, fill to the "fill line" or within an inch of the top without rinsing, and immediately replace the stopper or cap and secure the hood, if attached. if a whirl-pak™-type plastic bag is used instead of a bottle, hold the base, rip off the perforated top, open the bag by pulling the side tabs apart, grasp the end wires, and place the bag under the flowing water. remove the bag before it is completely filled and squeeze most of the air out; fold over the top of the bag several times and secure by twisting the end wires. take a source or a distribution line sample by opening the tap fully and letting the water run to waste for sufficient time to empty the service line (or if in doubt, for min) and proceed as above. collect samples from open shallow wells and step wells by dropping a clean wide mouth container on a string or rope into the well. allow the container to sink below the water surface and then pull it out of the well. pour contents into a sample jar or bag. collect samples from rivers, streams, lakes, reservoirs, springs, toilet tanks, and non-pressurized storage tanks by holding a ml sample bottle near the bottom and plunging it neck down to a depth of cm ( in) below the surface; turn it right side up, and allow it to fill. don a plastic disposable glove when small vessels used for drinking are sampled in this manner. when collecting these samples, move the bottle in a sweeping, continuous, arc-shaped motion, counter to stream flow or in a direction away from the hand. collect samples at locations approximately one-quarter, one-half, and three-quarters the width of the stream or water course. special apparatus can be used for sampling at various depths. samples can then be taken by positioning large bottles on a rod or pole at the desired depth and location before pulling their stoppers with a wire, string or thin rod. samples of bottom sediments are sometimes useful for the detection of certain pathogens. collect surface scum or regions containing dense particulate colored material when seeking cyanobacteria (blue-green algae). collect slime, if present, when seeking pseudomonas. if large amounts of water are needed, seek assistance and obtain specialized sampling equipment from agencies responsible for water quality. if possible, avoid wading when sampling bodies of water because wading often stirs up bottom sediments. if this is the only way to get a sample, however, wade against any current (e.g., upstream in creek or river) and keep moving forward until sample taking is completed. piers or similar structures, or the front end of a drifting or slow moving boat, make good sampling stations. concentration of bacteria by the use of swabs, filters, or by absorption, is particularly important when waterborne pathogens are sought. to concentrate bacterial pathogens from flowing water (e.g., streams, lakes, sewer lines, or drains), suspend moore swabs (or non-medicated sanitary napkins or non-medicated tampons if moore swabs are unavailable) for - days. these can be held in place by wire just below the surface or at other depths. if rodents are about, put moore swabs in wire baskets. after the sampling period, either put swabs or pads into a plastic bag and pack in ice, or put the swabs or pads directly into an enrichment broth for the pathogen sought. take or send these to the laboratory promptly. concentration of microorganisms can be increased by filtration with a variety of filters (e.g., membrane filters, cartridge filters, or other filter media). when membrane filters are used for pathogenic bacteria recovery, pass at least l of water (relatively free of turbidity) through a sterile . μm membrane filter. for viral analysis, use virus-absorbing electropositive cartridge filter to concentrate l or more water (see table f ). keep filters cool (but not frozen) and ship to a reference laboratory for further processing. for giardia cysts and cryptosporidium detection, collect samples by passing at least l water through a cartridge filter (see table f ). for inorganic chemical analyses, use l polyethylene containers. these should be new, or acid-washed if previously used. collect the water without flushing the lines, preferably in the early morning before water is used. for trace metal analyses, preserve one sample with ml of high-grade nitric acid to a ph of or less. this is particularly important whenever it is suspected that metals may have leached from water pipes or vessels. for organic chemical analysis, use l glass containers with teflon-lined caps. clean and rinse the containers with a good quality laboratory solvent and heat at °c for min. rinse the cap thoroughly with distilled water. fill the container so that there is a minimum of air space. for physical analyses, collect at least l, or other amounts requested by the laboratory. collect ice aseptically in sterile plastic bags or jars. use sterile tongs to collect cubes; sterile spoons for collecting chipped or crushed ice; and sterile chisel, hammer, or pick to chip block ice. put block ice or large chips into plastic bags. if legionella is sought, sample water at sites of any source that may have been aerosolized and send to a lab with proven expertise in legionella isolation and characterization, such those in the cdc elite program. this includes cooling towers, evaporative condensers, water heaters and holding tanks, humidifiers, nebulizers, decorative fountains and whirlpool baths (see section on investigating sites where aerosols are disseminated for a more complete listing). turn off fans of condensers before sampling; if this is not possible, wear a respirator. use ml to l polyethylene bottles that have had sodium thiosulfate added if the water to be tested has been chlorinated. for each sample, don disposable plastic gloves and collect the sample by inverting the bottle and moving it in a continuous arc away from the hand. measure and record water temperature. handle samples as described in table f . rub swab over faucet aerators and shower heads if these are considered as sources of aerosols. break stick and allow tip to fall in a tube containing - ml sterile water (not saline). investigators are often requested to test air to demonstrate the presence of legionella in aerosols. although legionellosis is an airborne disease, legionellae are susceptible to low humidity and become non-viable on drying. therefore, air sampling is an ineffective and inefficient way of determining whether a legionella hazard exists, and it can thus be misleading. label each container with sample number, date, time of collection, and your name or initials. complete the water/ice sample collection report, form f, for the first sample. list additional samples with sample numbers and other pertinent information on the back of the form. in those situations where the laboratory needs additional information, attach the appropriate g series forms. send the original form f and list with samples to the laboratory; retain a copy for your files. inform the laboratory of the type and number of samples and specimens; also, consult with the laboratory on methods to preserve and transport samples, if necessary, and on time of their arrival. if legal proceedings are anticipated, deliver sample personally to the analyst, or seal the sample container in such a way that it cannot be opened without breaking the seal. note on form f the method by which the bottle was sealed. maintain a chain-of-custody log to document the handling of the sample, and have the log signed and dated each time it changes hands. consult with state/provincial regulatory agency on complying with legal requirements for chain-of-custody procedures. recipient should record on the form whether the sample was sealed when the laboratory received it. if analysis cannot be done on the day of collection, chill water samples rapidly and hold them at temperatures at or below °c ( °f), but do not freeze, because populations of bacteria such as escherichia coli and of parasites decrease during frozen storage. hold ice samples frozen; if this is not possible, keep the temperature below °c h ( °f). investigators should consult with the testing laboratory that will be used to receive specific laboratory sample packaging, labeling, and transportation instructions as protocols are dependent on specific transportation regulations (iafta, tdgr) within each jurisdiction. ensure each sample is uniquely identified and labeled (as per the receiving laboratories requirements). many laboratories include barcode labels along with the sample containers within the sample collection kits. ensure that the correct label is affixed onto the correct sample container and that this information is transferred to the shipping manifest accurately (chain of custody form). specimens should be packed and the packages labeled according to applicable regulations governing transport of hazardous materials. generally, the transport of samples of water and ice intended for laboratory analyses are packed and shipped in a manner to ensure the sample does not change from the time of sampling to the time received by the testing laboratory and shipped using the most expeditious means (e.g., personal delivery or overnight mail). typically samples of water or ice are packed with refrigerant (ice packs, dry ice, etc.) in insulated and sealed containers (see table f ). several measurements are routinely called for during on-site investigations. brief instructions are given for those that are commonly done; nevertheless, follow manufacturer's instructions if these are available. color comparison kits are available for testing for free, combined and total residual chlorine. the diethyl-p-phenylenediamine (dpd) test is an example (see table a ). check instrument calibration regularly. use dry reagents, because the liquid forms are unstable. chlorine comparators can be used to test for bromine by multiplying the result by the factor . and to test for iodine by multiplying the result by the factor . . measure temperature. measure water temperature by immersing the sensing end of either thermocouples, transistors, or thermometers into the water. sometimes measurements need to be made at various depths; use thermocouples with wire leads of sufficient length for this purpose. calibrate temperature measuring devices periodically. measure ph. calibrate the ph meter as recommended by the manufacturer with at least two standard buffers (e.g., ph . or . ) and compensate for temperature, if the meter does not do it automatically, before each series of tests. remove a sample of water to be tested and immerse the ph electrode into the sample; record the reading. ph can also be measured by color comparators that employ color indicator solutions or discs. (ranges of ph color indicator solutions are bromophenol blue, . - . ; bromocresol green, . - . ; methyl red, . - . ; bromocresol purple, . - . ; bromothymol blue, . - . ; phenol red, . - . ; cresol red, . - . ; thymol blue, . - . ; and phenolphthalein, . - . .) in this case, water containing more than mg/l chlorine in any form must be dechlorinated with sodium thiosulfate before the ph indicator solution is added to prevent decolorization of the indicator. always report temperature at which the ph is measured. measure turbidity. nephelometric turbidity unit (ntu) is the usual standard unit, but other turbidity measurements (such as particle counts) are used. the ntu requires a nephelometer, which measures the amount of light scattered predominantly at right angles and absorbed by suspended particles (e.g., clay, silt, finely divided organic matter, inorganic matter, soluble colored organic compounds, and microscopic organisms) in the water sample. calibrate turbidimeters with a standard reference suspension. make turbidity measures on the day samples are taken. vigorously shake samples, wait until all air bubbles have disappeared, and then pour sample into turbidimeter tube. read directly from scale on instrument or from an appropriate calibration scale. pump chemical smoke into the air at the exit of the device suspected of releasing aerosols. observe the direction and spread of the smoke. otherwise, measure pressure differentials with a micromanometer. measure other attributes of water. follow instructions given by manufacturers or in standard reference books (see further reading). use fluorescein dye, lithium or other tracers in appropriate soils to determine the means by which contamination from sewage, industrial wastes, or other sites of pollution reached the water supply. fluorescein dye is particularly helpful in evaluating flow of contamination through fissured rock, limestone, gravel, and certain other soils. this dye is not readily absorbed or discolored by passage through these soils or sand, as are many other dyes, but it is discolored by peaty formations or highly acid (ph < . ) soils. make a concentrated fluorescein dye solution by mixing g of fluorescein powder into a liter of water. usually, / to l of this solution are sufficient for the test for up to , l of water. fluorescein dye is also available in liquid and tablet form. one tablet will dye approximately l (~ us gal). pour the calculated amount of fluorescein solution or put a sufficient number of fluorescein tablets into a receptacle at a point of potential pollution. usually this point will be located within yards and at a higher elevation than the water source under study. cesspools, latrines, distribution boxes, sink holes, borings, septic tanks, drains, manholes, toilets and plumbing fixtures are typical places to introduce the dye. if dye is poured into a plumbing fixture or dry hole or boring, add water to wash it down. the amount of dye to use varies with the distance the dye must travel, the expected time of the journey, the size of the aquifer or water channel, and the nature of the soil. take samples of the water when the dye is introduced into the test hole or fixture and then hourly for up to h to detect arrival and departure of fluorescein. if no dye is observed, repeat the test with twice the amount of dye. whenever possible, use a fluorescent light or fluorometer to analyze water samples for evidence of fluorescein. a fluorometer can be set up and calibrated, and a continuous recording can be made. this meter can detect fluorescein in concentrations of μg/l (ppb). fluorescein dye will temporarily color water, which discourages use of the water until the dye is sufficiently degraded or diluted. alternate tracers can be used if specific ion meters are available. the dye stains all it touches. methanol is a good solvent for the dye, and hypochlorite solutions decolorize it; both can aid in removing stains. abrasive soaps are useful for cleaning stained skin; fluorescein-stained clothing should be washed separately. appearance of dye in a water supply is conclusive evidence of seepage from the site where the dye was introduced. failure to detect dye, however, is not conclusive evidence that seepage did not or would not occur if more dye had been added or if weather conditions or subsurface flow had been different at the time of the test than during the outbreak event. illustrate source and direction of contaminated water flow as indicated by the dye test on form g . take photographs of sources of contamination and evidence of staining of the ground at the site or dye-stained color of the water. in situations where a single source of contamination is obvious or where multiple sources are readily apparent, dye studies serve little purpose. drinking water, however, is not the only source of water that may contribute to outbreaks. other sources of water that can contribute to outbreaks include water not intended for drinking, recreational water and water used in agriculture during harvesting and packaging. legionnaires disease is the pneumonia caused by the inhalation of contaminated water aerosol containing the bacteria legionella, with legionella pneumophila being responsible for % of all infections. it is also a common cause of healthcare associated pneumonia. legionella can replicate within free-living amebae in water, allowing it to resist low levels of chlorine used in water distribution systems. risk of infection is more common in warm and humid weather, when water droplets are able to drift further due to higher absolute humidity. fifty percent of all legionella outbreaks have been traced to cooling towers with l. pneumophila serogroup responsible for all cooling tower outbreaks. all aerosol generating devices, however, can be potential sources of legionella. some other sources of aerosolization that may have contributed to or be associated with outbreaks include: whirlpool displays, building's air conditioning systems, water spray fountains, public bath houses, vegetable misting systems in grocery stores, evaporative condensers, showerheads, humidifiers, air scrubbers, car washes, ornamental and decorative fountains, potting soil, respiratory therapy equipment, dental units, road asphalt paving machines, car windshield washer fluid and car air-conditioning systems. in the investigation of a legionella outbreak, (see box , the flint water crisis, which describes a likely legionella outbreak from a commercial water source) due to the varied sources, there is a need to use a broad investigative questionnaire and the collection of environmental data. environmental factors such as dry bulb temperature, relative humidity and wind rose data can provide information regarding drift evaporation, deposition (settling) and the size of the affected zone. although aerosol drift can carry legionella up to mi ( km), the risk of infection is usually highest within ft ( m) of the source. there are also air dispersion models that can be used to determine drift zone and the use of human activity mapping in the identification of potential sources. in general, e. coli and norovirus are the most common pathogens responsible for recreational waterborne outbreaks associated with non-treated water such as beaches and lakes. cryptosporidium, which is resistant to chlorination, is the most common pathogen resulting in outbreaks in treated water venues such as swimming pools and water spray parks. it should be noted that e. coli, the indicator of choice of recreational water samples, is not indicative for the presence of norovirus and giardia, cryptosporidium. e. coli can also be "naturalized" and have been found to survive and multiply in beach sand. beach water sampling results therefore may provide false positive or false negative results and may not be the best indicator for the presence or absence of pathogens. recreational waterborne outbreaks are not just traced to the ingestion of contaminated water (table c . illnesses acquired by contact with water: a condensed classification by, symptoms, incubation period, and types of agents). hot tub rash, or pseudomonas dermatitis/folliculitis commonly occurs in public hot tubs or spas such as those found in hotels. the rash is often a result of skin infection from the bacteria pseudomonas aeruginosa colonizing in the hair follicles after exposure to contaminated water. pseudomonas aeruginosa is an opportunistic pathogen that can survive within the biofilm on the tub surface or within the piping system. outbreaks can occur when there is a heavy bather load resulting in an increase in chlorine demand, which in turn reduces the effectiveness of the disinfectant to control the population of pseudomonas. blue-green algae or cyanobacteria bloom can occur in warm, slow-moving or still water. when conditions are favorable, mostly during hot summer weather, cyanobacteria populations may increase dramatically, resulting in a "bloom" as they rise to the surfaces of lakes and ponds. they resemble thick pea soup and are often blue-green in color. although blooms can occur naturally, water bodies which have been enriched with plant nutrients from municipal, industrial, and agricultural sources are particularly susceptible. some cyanobacterial species may contain various toxins, some are known to attack the liver (hepatotoxins) or the nervous system (neurotoxins); others simply irritate the skin. health effects from cyanotoxin exposure may include dermatologic, gastrointestinal, respiratory and neurologic signs and symptoms (table b . illness acquired by ingestion of contaminated water: a condensed classification by symptoms, incubation periods, and types of agents). water can also be an indirect cause of foodborne outbreaks by providing a media for the survival, transportation and the introduction of pathogens into food products. water used during production, including irrigation, pesticides and fertilizers application and washing, frost protection, harvesting, has long been recognized by food safety scientists as one of plausible and probable sources of the contamination of fresh fruits and vegetables. there have been many outbreaks from produce traced to pathogens being introduced by contaminated irrigation water. although harvested products are sometimes washed with chlorine solution, pathogens may still survive the process through internalization. e. coli o :h may migrate to internal locations in plant tissue and be protected from the action of sanitizing agents by virtue of its inaccessibility. experiments have also demonstrated that e. coli o :h can enter the lettuce plant through the root system and migrate throughout the edible portion of the plant. however, this claim has been refuted by others. salmonella and e. coli can also adhere to the surface of plants, and enter through stomata, stem and bud scars and breaks in the plant surface caused by harvesting and processing. water containing bacteria can be drawn into the produce if it is immersed in or sprayed with water that is colder than the produce itself. e. coli o :h may also use its flagella to penetrate the plant cell walls and attached to the inside of the plant. once attached, it may be able to grow and colonize the surface of the plant. the concerns are not just with bacteria. the present of norovirus in the hydroponic water can result in internalization via roots and dissemination to the shoots and leaves of the hydroponically grown lettuce. irrigation water may be contaminated from runoff from nearby domesticated animals and their lagoons, feedlots, ranches into rivers; from feral/domestic animals with direct access to creeks, ditches, rivers, ponds; from sewage flows into waterways and contaminated wells. in some parts of the world sewage contaminated water is preferred for irrigation despite a potential risk of transporting enteric pathogens, since it carries nutrients (n and p) for the plants. there is sufficient information to conclude that the application method of irrigation water to fresh produce can have an effect on the microbiological risks associated with the crop. in general, keeping water away from the edible parts of ready-to-eat crops that are consumed without cooking can result in a lowered risk of a foodborne outbreak. the least to more risky methods for irrigations for microbial contamination are: subsurface irrigation (buried soak hoses) < drip irrigation < indoor flood irrigation (hydroponics) < outdoors flood irrigation (water-filled furrows) < overhead irrigation (sprinklers). an outbreak of illness arising from exposure to water demands immediate epidemiological investigation to assess the situation, gather, evaluate, and analyze all relevant information, with the goal of ( ) halting further spread of this illness, and ( ) predicting, preventing, and/or attenuating future outbreaks. this twofold mandate of epidemiology is usually described as "surveillance and containment." at the commencement of an investigation, the unknowns usually outnumber the known facts. there is no substitute for prompt, thorough, and careful collection of interview data from ill and well persons who ingested or contacted the suspect water, attended a common event, or who were part of a group of persons where illness occurred. careful analysis of these data, particularly with reference to common patterns of "time," "place," and the characteristics of the persons involved, can often eliminate many vehicles, agents, and pathways quite early in the investigation, and focus on the remaining possible vehicles, routes, and agents. later, laboratory results may confirm the agent, the specific pathology, the route taken by the infection or toxic agent, and indicate what is needed to stop the spread, but early epidemiology can often be invaluable in predicting the outcome and taking preventive steps to contain the problem before the lab results are available. lessons can be learned from most outbreak investigations and are invaluable for increasing our understanding of these pathologies, and preventing their future occurrence. an outbreak is defined as either an unusually large occurrence of an expected illness at that time of year in that place, or the occurrence of a type of illness that does not usually appear at that season and location. the "time" factor should be studied immediately by plotting the onset time of each case on a time-based grid, to create the epidemic curve. although any number of cases can be involved, the minimum number for an "outbreak" to be declared is two associated cases, with special exceptions such as naegleria fowleri where, because of the severity and the possibility that cases may have been missed, a single case constitutes an "outbreak." although the epidemic curve is usually measured in hours or days, protracted exposure to agents in water may mean apparent sporadic cases linked to a common source over months or years. if an "outbreak" is suspected by a sudden increase of cases, determining who is to be categorized as a "case" is not necessarily a simple process. many people notoriously fail to report enteric illness for many reasons: embarrassment, lack of time, no clear idea which agency should be notified, mild self-treatable symptoms, or simply because they prefer not to make a fuss. they may therefore be incorrectly classified at least initially as "nonill." consider also that - % of the general population will have experienced some form of "upset stomach" in the last hours, regardless of exposure to the suspect item, and they may be incorrectly classified, at least initially, as "ill." to reduce the "false negatives" and "false positives" that are expected with self-reporting, the investigator needs to establish a working case-definition. a careful case definition categorizes people as "case" or "control" with the best accuracy possible within the time constraints and resources available. a case definition could be considered "too sensitive" if it classifies as a "case" a person who experiences: "… at least one episode of stomach cramps, nausea, vomiting, or diarrhea in the last hours." this would confuse subsequent analysis, and produce more false positives. similarly, a case definition could be considered "too specific" if it classifies as "not-ill" a person who had experienced only three episodes of diarrhea or vomiting, because they failed to satisfy a case definition requiring "…at least four episodes of vomiting or diarrhea in the last hours." should this last individual, having been declared as not fitting the case definition, be taken into the "notill" group, the error and subsequent analysis is confounded even further. a reasonable case definition therefore attempts to reduce both types of errors, and will depend upon the early indications of what the etiology may be. in the instance of a suspected salmonellosis, a case could be defined as "a person who was in good health before attending the event on monday may rd, and who experienced two or more of the following symptoms anytime up to midnight, sunday may th.: nausea, vomiting, stomach-cramps, diarrhea, headache, or fever." note that a case definition should include a place of exposure if known, a timeframe during which symptoms may have been experienced (salmonellosis has a range from to h. usually - h), and the additional footnote that the individual was not already symptomatic before the suspected "exposure." calculate the percentage of ill persons who manifest each symptom by dividing the number of persons reporting the given symptom by the number of cases ( for the example, table ) and multiplying the quotient by . the distribution of symptoms can be used to identify the most likely pathogen, and aids in requests to the laboratory for microbiological assays of samples and specimens. other symptoms (e.g., prostration, lethargy, weakness) may be included if deemed appropriate or helpful, but the six symptoms in table should always be included. headache, for instance, is associated with many viral infections (e.g., norovirus, rotavirus), but much less so with bacterial infections. fever is usually associated with an invasive bacterial infection (such as salmonellosis or campylobacteriosis), and is not usually seen in outbreaks of simple enteritis (such as with cholera). this information helps to determine whether the outbreak was caused by an agent that produced intoxication, an enteric infection, or generalized illness. in the example given, a predominantly diarrheal syndrome without much fever or headache tends to eliminate some of the viral infections (norovirus or rotavirus) or the host-adaptive/invasive serotypes of salmonella (e.g., s. dublin or s. choleraesuis). median onset time calculations may further reduce possible candidate etiologies. in historical investigations, or where no laboratory confirmation is possible, the symptom profile and onset times can sometimes predict the etiology of the outbreak within reasonable certainty. an epidemic curve (also called an onset curve or onset distribution) is a graphic illustration called a histogram that shows the distribution of the time of onset of first symptoms for all cases that are associated with the disease outbreak. paper printed with square "grid" lines will allow the investigator while on site to represent each case as a single "block." the horizontal axis is the sequence of intervals of time and date. the unit of time that defines the width of each interval depends on the characteristics of the illness under investigation. for example, intervals of days or weeks are appropriate for diseases with long incubation periods, such as cryptosporidiosis or hepatitis a. intervals of a day or half-day are appropriate for outbreaks of enterohemorrhagic e. coli strains or shigellosis, while single-hour, -h, or -h intervals will be more suitable for illnesses with shorter incubation periods, such as chemical poisonings. the vertical axis is always the actual count, or "frequency" of cases (blocks) stacked at each interval. it is often necessary to redraw the onset curve as more accurate information becomes available. if the illness is known, a rule of thumb is that the time interval used for each "block" on the x-axis should be no more than ¼ the incubation period of the disease under investigation. if the illness is not known, select an interval where the data produces a bell-shaped curve; not too flat and not too tall. construct this graph using time-of-onset data from forms c or d, employing an appropriate time scale. once all the onset times for the cases have been plotted on the histogram, determine the range as the interval between the shortest and longest incubation periods. in fig. a , the range is the day period from the th to th march. the median onset time is preferred to the mean because the latter is vulnerable to a few or even a single very small or very large value. the median on the other hand, is the midvalue of a list of all individual onset times, including duplicate entries, that are ordered in a series, from shortest to longest. if the series comprises an even number of values, the median is the mean of the two middle values. most standard reference texts on communicable diseases give onset times as median values. the mode is simply the interval having the largest number of observations. a distribution with a single "peak" is called a uni-modal distribution, while an outbreak with two peaks is called "bi-modal." subsequent modal peaks following the first may indicate either a "secondary wave" of cases or the exposure of other people at a later time. the shape of the epidemic curve helps to determine whether the initial cases originated from a single point-source exposure (such as water or food available for only part of a day), or from repeated exposures for a longer time, or even more gradual person-to-person spread. a point-source epidemic curve is characterized by a sharp rise to a peak, followed by a fall that is almost as steep ( fig. a ). an "explosive" outbreak of this type is common where a municipal water supply is the vehicle, affecting large numbers of people in a very short period of time, but without secondary cases occurring, or any evidence of onward spread within the community. propagated outbreaks are those in which the initial victims ("primary cases") manage to spread the agent to other people ("secondary cases") such as family members, patients, clients, or other contacts in crowded places through aerosols, personal contact, or contaminated water/food/utensils/surfaces, etc. propagation following a point-source exposure is demonstrated by a second increase in reported cases following the decline of the first cluster. sometimes this takes the form of a second "modal peak" separated by approximately one incubation period, but this distinction is soon lost. figure a shows no evidence of propagation; fig. b suggests that propagation may have taken place, although care must be taken to consider other explanations. in addition to ( ) true propagation, where the secondary wave can be expected to appear one incubation period after the first, secondary waves may be also explained by ( ) exposure to the same point source (e.g., food or water supply) at different, but specific times by other people; this might be a repeated offering of contaminated food or water at two or more mealtimes; ( ) a second pathogen (perhaps from the same unhygienic food or water source) which may have a different symptom profile and a different (incubation) time. slow propagation from the beginning of an outbreak with neither an obvious point-source, nor any distinctive "waves" separated by an incubation period as in fig. c , usually indicates one-at-a-time person-to-person spread through closecontact, poor personal hygiene, aerosol (e.g., influenza, or sars), or sexual transmission (e.g., hiv/aids). it can also be explained by (non-propagated) continuing exposure, for example drinking of contaminated surface water following a conflict, natural disaster or other breakdown of infrastructure. as such it is commonly associated with waterborne cholera, shigellosis, typhoid fever, or e. coli infection, and characterized by scattered cases which continue until the chain of infection is cut. slow, constant and/or intermittent exposure to persons over time to pathogenic microorganisms can also result from sewage run-off after a series of heavy rainfalls. in addition to revealing whether the outbreak was due to a single point-source, or had been spread steadily through the community by propagation in some way, another important objective in constructing the epidemic curve is to estimate the incubation period of the illness if it is not already known. with waterborne illness especially, the time of exposure may be further obscured because people usually drink water several times a day. hence, the incubation period cannot always be determined for each case, but the actual time of onset is usually available. the incubation period is the interval between exposure to food or water that is contaminated (with enough pathogens or with a sufficient concentration of toxic substances to cause illness), and the appearance of the first sign or symptom of the illness. each etiology is characterized by a typical incubation period (tables b, c, d, and g). individual onset times will vary due to immune factors, co-morbidities, the dose ingested, and other ingested materials, but the investigator can often make a rough estimate of the average incubation time by examining the aggregation of all onset times as an epidemic curve. the modal peak of a single "cluster" or distribution is the time interval in which most cases commence symptoms. in fig. a this occurs on march , and in fig. d that occurs at the double interval feb - th. where two separate modal peaks (a "bi-modal distribution") suggests secondary cases ("propagation"), then the distance between the first two modes is a good estimate of the incubation period. figure b shows about days between primary and secondary modal peaks, suggesting that the initial exposure is likely to have been days before the first mode. in fig. b this would be sometime on or near the th of the month. if the exposure point is known but the agent is not, then that estimation of the median incubation period will allow many etiologic agents to be excluded due to date of onset of symptoms: between march and april , count per day onset histogram for cases of shigellosis, march to april , illustrating slow spread through a community through either propagation (person-to-person spread via poor hygiene), or exposure by many people to a small well at different times (a non-propagated route) incubation periods that are clearly outside the range of times observed. the list of possible candidates can be further reduced by examining the symptom profile and other characteristics of the illness and suspect food or water vehicle. as time passes, the onset curve also provides an ongoing measure of the potential for propagation, and the incidence rate. all this information can be useful in deciding whether the illness in question is an infection or intoxication and thereby determining which laboratory tests should be requested (tables b, c, d, and g). note that not all water or foodborne illnesses listed in a standard reference such as the "control of communicable diseases manual" (apha ), are directly communicable person-to-person; many require a suitable substrate (food or drink) and adequate time/temperature combinations to attain sufficient numbers or the production of enough toxin to induce a pathological condition. an exposure time can sometimes be estimated from a clear, point-source, singleexposure onset distribution (fig. d ). it has no solid basis in statistics, but has sometimes been found to be useful in practice. the typical incubation periods for most foodborne and waterborne illnesses are readily available for comparison (e.g., control of communicable diseases manual, apha/cdc, ), and in this manual in tables b, c, d, and g. an incidence rate is the number of new cases of a specified disease reported during a given time period in relation to the size of the population being studied, multiplied by a constant, usually , to give percentages. thus new cases of e. coli o :h infection among the residents of a children's summer camp in july is an incidence rate of ( / ) × or ( . ) × = . % for that month. if several people have left and their state of wellness is not known, their impact should be expressed in the form of the possible range of values around the known incidence rate within the two extremes whereby they may all be well or they may all be ill. thus, where six children who were at the camp had departed around the time of the outbreak and their health is unknown, the range could be from a possible ( / ) × (or . %) if all of the six had been well, up to ( / ) × (or . %) if all had been ill. note that the "missing" six are added to the denominator only when we speculate that none were ill, whereas they are added to the numerator and denominator if we speculate that they might all have been ill. in this example, the overall incidence rate would be reported as " %, with a possible range from . to . %." depending upon the situation, it is often necessary to identify exposures which may be related to the illness, and to calculate an incidence rate for each such exposure. for example, in the summer camp illustration (above) it might be useful to enquire if gender, age, location, or some other attribute or activity increased the risk of becoming ill. this should not be interpreted automatically as implying that a given exposure would be associated with the outcome in any situation. by hypothesizing that gender was linked to the risk of illness, for example, does not imply that males are more vulnerable to the illness (the outcome) than females, but it can indicate that gender may have been related to the exposure, which in turn increased the risk. as an illustration, suppose that boys at the camp had been swimming, while the girls had gone on a nature walk. the boys may subsequently show increased incidence rate for e. coli o infection, not because they are more susceptible, but because of their activity. every proportion or percentage statement should be made with clear reference to the appropriate denominator used. incidence rates of waterborne illnesses are usually similar for both sexes at any given age group in the population, but differences in activities or dietary habits or susceptibility due to age or underlying health status can change the risk. the very young, the elderly and the immunocompromised can be at more susceptible, while in some instances, previously exposed populations may have developed a measure of immunity to an infection that may still cause more serious illness among visitors. a further complication arises where the "at-risk" population (perhaps residents at an institution, summer camp, or on a cruise ship) have generally consumed all the food and water for the extended period. careful interviewing of affected persons often uncovers one or more persons who entered the subject community shortly before becoming ill or who visited the community for a short time and became ill after leaving it. example: the south-west part of the county is served by three semi-private water systems. thirty cases of waterborne illness are being investigated in the area. when the numbers of cases are displayed for each water system, no clear grouping or clustering is evident, although the delta supply appears associated with about % more cases than the other two (table a) . however, when the analysis introduces the total population of persons who depend upon each water system (as denominators), a different scenario emerges. the incidence rates (expressed here as percentages) now allow a meaningful comparison (table b ). we can see that persons using the bravo system have roughly five times the risk of illness compared to people who are served by the other two systems. the use of the denominator is vital for most calculations. caution: numerous other factors may also explain the outbreak and these should be carefully examined. for example, the households using the bravo supply may be closer to an unhygienic corner store, drink from a cross-connected public water fountain, or their children may swim in a more polluted pond than the other communities. potential sources such as these should be eliminated before the water supply is announced as the source of the illness. sometimes a spot map may be useful in showing the location of the residence of each case, while on a larger scale, the rates of illness can be shown using city blocks, census tracts, townships, or other subdivisions. different colors or symbols to indicate cases with different time of onset periods (such as weeks) may help to support a hypothesis as to where contamination was introduced, inasmuch as the earliest cases tend to cluster around the point where contamination first occurred. the weakness of this procedure is that if the exposure had been at a restaurant, workplace, or school, plotting the relationship to the location of the home would not be useful. the investigation of waterborne or foodborne disease outbreaks invariably commences after both exposure and illness have happened. this is the classical "casecontrol" study, where a group of ill people ("cases") and a group of non-ill people ("controls") are compared in terms of their exposures. to measure the association between exposure and illness, the data are typically displayed in a × contingency table. table compares cases and controls in terms of their exposure to a suspected factor "x." the table is ready for analysis using odds ratio, as well as the chi-square or the fisher's exact tests where appropriate. one × table will be used for each possible exposure (e.g., each beverage, food, or other material). as many cases as can be identified and contacted, and as many non-ill people (controls) as can be found, should be interviewed as quickly as possible about their exposures to each suspect item. fading memories, the chance of obtaining stillavailable samples of implicated food or water, and the opportunity to obtain fecal specimens before the patient is started on the ubiquitous broad-spectrum antibiotics are all reasons for rapid response. case and control numbers do not have to be the same; the calculations compare ratios so equal numbers in each group are not needed. generally a : to : ratio of cases to controls is perfectly adequate. as interview data from cases and controls are accumulated, leading to formation of hypotheses about the source of the illness, human resources should be deployed in two additional essential tasks: ( ) tracking down and confirming the hypothesized source of the illness, and ( ) promptly issuing warnings to all affected groups about the possible risks from any source that is still accessible, with assurances that further bulletins will be issued as soon as confirmation is received. this precautionary principle is a vital component of risk management in modern public health. waiting for absolute confirmation before releasing warnings and advisories should not be an option in the twentyfirst century. the principle holds that while false alarms can be quickly forgiven, further illness should be avoided at the highest priority. failure to heed this step has contributed to needless suffering and severe damage to reputation, trust and credibility. a case-control approach is necessary because unlike the data in table b , we rarely have full information about all the attendees, and therefore the true incidence/attack rate is not available. very rarely, when all cases and controls are available for interview, we would have the true incidence rates for ill and for not-ill persons and this would allow a "retrospective cohort study" to be carried out. under such circumstances, and using table as an illustration, we could state that of persons exposed to item x, persons ( . %) had become ill compared to ill of not exposed ( . %). where incubation times are longer than a day, there is increasing likelihood that only a small proportion of the non-ill people will be available for interview, and on many occasions, not even all the ill persons can be contacted. the point here is that the investigator is usually working with sub-sets of the true cases and controls. the controls in table and possibly even the cases may have been drawn from larger groups, and therefore we cannot state the incidence rate, for example, as: "… of exposed were ill," because the " " had been artificially assembled, and may not resemble the true incidence at all. we can, however, use exposure rates, for example: "…of ill persons, ( . %) had been exposed to x," and, "…of who were not-ill, only ( . %) had been exposed to x." the overwhelming majority of waterborne or foodborne illness investigations are run as "case-control" studies (or to be more accurate, "case-comparison" studies, as very little true "controlling" is accomplished during the selection of the comparison group). a broadcasted invitation to all who might have been exposed to come forward, typically results in few non-ill persons volunteering information, because nonaffected individuals believe they have little if anything to contribute. this reduces validity even further, and more active recruitment is often necessary to convince them that their information is just as essential for the investigation as are the contributions from the less-fortunate attendees. let us examine a waterborne illness suspected as being due to the consumption of water bottled from a certain spring. you have found people who meet the case definition of illness, and another non-ill people in same neighborhood who report no symptoms at all, and who will be your controls. in table we display the data and ask the question: "is drinking this water related to the risk of illness?" whenever a × table appears, the first step is to calculate the odds ratio (or). an odds ratio tells us if there is a relationship (where or ≠ ), and the strength of the relationship (the or value itself). it also clearly indicates the direction of the relationship: was drinking or not-drinking the dangerous activity? this is easily determined by finding the dominant pair from (a × d) or (b × c). in the example above, (a × d) is greater, so cell "a" links the row "drank" with the column "ill," while cell "d" links "not drink" with "not-ill." this assumption is not as obvious as it may seem; the cause of the illness may have been whatever "other" thing was drunk by those who avoided spring water! it is important to clarify that the odds ratio yields the strength of the association, not the statistical significance. most or values (where many exposures are being assessed) will be close to . (= "no association"), while an or clearly exceeding . signifies a positive association between this exposure and illness, such that this exposure increased the risk of illness. an or < . is protective, meaning that exposure to this factor reduced the risk of illness compared to the other group. for example, an or of . means that the exposed group had only one-quarter the risk of illness compared to the non-exposed group. the non-exposed group therefore has a greater risk (by a factor of ). while this protective effect can be due to true therapeutic protection (e.g., exposure to antibiotics when you have an infection), it is frequently explained as "statistical" protection. as an example, consider an outbreak where everyone consumed only one of two possible types of bottled water. one source, a, contains a pathogen, and b does not. if the ill people were found to be five times more likely to have consumed type a (odds ratio = . ) then the not-ill would have five times the rate of consuming water b, and only one-fifth of the rate of choosing water a (or = . or %). this can also be read as the risk of illness for the non-exposed group, or as the risk of staying well by the exposed group. an easier way to interpret an or less than is to place over the or to reveal a value greater than , but clearly labeled "protective." the or is a ratio between numbers, and therefore not sensitive to the actual numbers of people in individual cells, an important consideration when the numbers of subjects are relatively small. this is illustrated by the common question: "how large does an odds ratio have to be before it is considered evidence of an association?" a popular response is "at least . ," but this must be considered with extreme caution. for instance, with very large studies, an or of . (barely more than . ) can be shown to be very highly significant statistically (p = . ), whereas in a small-n study, an or of even . may not achieve statistical significance. the odds ratio is certainly a useful measurement, and should always be used when a × table is encountered. it will quickly advise you ( ) that there is an association, ( ) the strength of that association, and ( ) the direction of the association, none of which are specifically measured by a test of statistical significance. unfortunately, it is not reliable with small cell sizes, and is unable to answer the question: "how likely is it that these numbers could happen just due to chance?" for this, we need to test the statistical significance. the best advice is to use the or (or relative risk where appropriate) together with a test of statistical significance. most online statistic calculators or laptop versions of sas, spss, epiinfo, etc. will give a selection of useful statistics (odds ratio, relative risk, several versions of chi-square, and fisher's exact test, both onetailed and two-tailed.) in keeping with all scientific enquiry, we begin by advancing the notion (the "null hypothesis") that there is no association between the exposure and the illness, and attempt to support that notion. if insufficient evidence is found to support the null hypothesis, we reject it and cautiously consider that an association may exist between the two variables. this can be described as a statistically significant association. two methods of testing are presented: the chi-square test (written χ and pronounced "ky"-square) for most × (or larger) tables, and the fisher's exact test (only for × tables) when chi-square is not valid due to the numbers in the cells being too small (the following sections give advice about this decision). the original data value in each cell we call the observed, or "o" value, and these are compared with the numbers that you would expect ("e" values) if there were no relationship at all; that is, if the variables were not related, and the data were arranged purely by chance (as stated by the null hypothesis). the chi-square test measures the difference between the o and e values. if they are close, we have to accept that there may be no real relationship; if far apart, we can reject the null hypothesis and cautiously declare that exposure and illness were probably related. numerous online statistical calculators can be used to yield ors, rrs, and chisquare values. if you prefer to do the calculation by hand, construct a × table as shown, with "observed" data, marginal totals, and the grand total. the expected "e" values are found from: to make sure the chi-square analysis is appropriate for your table, you must be sure that all "e" numbers are more than . the quickest way is to first calculate for the cell with the smallest e value; (this will be the cell with the smaller column total and the smaller row total.) in table , the smallest e value will be cell "d," and this is calculated as ( × )/ = . . as this is > , all other e values will be greater than this, so chi-sq. is valid. (note that the smallest e value did not coincide with the smallest o value). . for all four cells the sum (χ ) is: . + . + . + . = . an online statistical calculator will give you this same chi-square (χ ) value. to verify by hand whether the o vs. e difference is statistically significant, compare your chi-sq. value (for a × table only) with . . if your calculated value exceeds . , then this is unlikely to be due to chance, and thus you can begin to believe that this exposure did influence the risk of illness, and you can reject the null hypothesis. statistical results usually include a probability (p) statement. this is the probability that the null hypothesis ("no association") is correct. the . value is the minimum needed for statistical significance, where the p is less than % (p < . ). recall that the p is the probability that no real association exists between exposure and illness. by convention, if p > . (more than %) then the relationship is declared not statistically significant. where p = . or < . , then the relationship is statistically significant. the smaller the p value, (p < . , p < . , etc.) the more confidence you have that a relationship really exists. other critical values exist for assessing calculated chi-sq. values, from larger tables than × , and at more extreme levels of significance. a further chi-square calculation is shown as an appendix. where a table greater than × is found to have more than % of the cells with an e value less than , chi-square is not valid. the solution is to collapse either columns or rows to allow the e values to increase. for example in table a , two cells out of six ( %) have e values less than , but if "high dose" is merged with "medium dose" the resulting increase in observed (o) cell sizes is also reflected in greater e values, while the table becomes × (table b) . some outcome information has been lost, but the chi-square analysis can proceed. if, after trying to collapse cells and/or rows, a × table is reached still with an e value < , the fisher's test is indicated. this procedure is reserved only for × tables where one or more expected (e) values is less than , making the chi-square test not valid. our example is taken from an investigation into an outbreak of shigellosis presumed to be due to water from a well ( table ). the odds ratio has been calculated as ( × )/( × ) = . , meaning ill persons were six times as likely to have drunk well water compared to non-ill the "!" denotes a factorial, meaning that number multiplied by the next smallest number, and so on down to . (e.g.: ! = ) p persons. an attempt to use chi-square is prevented by at least one e value less than of . (cells c and d both show e values as ( × )/ = . ). the starting null hypothesis is "that no relationship exists." this is not quite the end of the calculation however. the goal is to calculate the probability of the original data occurring plus all more extreme probabilities. the original data have to be adjusted by increasing the "dominant" pair of cells by + and the others by − , while leaving the margin totals the same (table ) . because no zero has yet appeared in the matrix of cells, we continue to increase the "dominant" pair by + and obtain a zero. the next calculation is the last. (by convention, ! and ! = ) (table ) . no reference table is required. the total calculated probability ( . ) is exactly the probability that the null hypothesis ("that there was no relationship"), is correct: . %. by convention, for a result to be significant statistically, that probability (p) must be less than % (< . ), so in this instance we are not able to reject the null hypothesis and must conclude that the relationship could have occurred by chance alone more than % of the time. the odds ratio of . is explained as the number of times more likely it was for a shigellosis victim to have drunk well water than for a non-ill person. this increased risk would normally be impressive, but because of the small number of persons in the study, it has been found not to pass the test of statistical significance. a basic write up of the results might read: "a relationship exists between drinking well water and developing shigellosis. a shigellosis patient is six times more likely to have drunk water from the well compared to a non-ill person. this relationship is not statistically significant, however, and could have occurred by chance alone more than % of the time. the null hypothesis of no-relationship cannot be rejected." [ df, p > . , or: . , not statistically significant.] with the odds ratio (or) calculated for all the suspected exposures, and the chisquare test or fisher's exact test calculated for the strongest of these, all the results can be displayed in a composite table. earlier protocols for the investigation of waterborne and foodborne diseases encouraged the use of the "factor-specific attack rate table" (for example the "foodspecific attack rate table"), but where only a "convenience sample" of controls and cases are available, we are unable to derive valid incidence/attack rates. investigators are discouraged from using it as it may produce misleading results. the exposurerate table for cases and controls is preferred in all case-control studies, and compares the rates of exposure to each factor between both the ill and non-ill people. table displays six exposure factors from a hypothetical outbreak involving water contamination. exposure rates are calculated from both cases and controls. the "spring-water" data that we used for the odds ratio calculation example in table appears as the first exposure in table . the column headed "differences in exposure rates" subtracts the exposure rate among the non-ill from the exposure rate among the ill. [use: exp. rate (cases) minus exp. rate (controls), keeping the signs correct]. you are looking for a large positive difference to indicate the most likely culprit. the spring water shows the largest positive difference at + %. the odds ratio of . supports this, again the largest value, indicating that ill persons were times more likely to have drunk the spring water compared to non-ill persons in this group. hence both the large positive difference in exposure rates and the large odds ratio point to the spring water being the likely source of the illness, and it is certainly the strongest association between illness and any of the exposures shown. the chi-square value has also been added ( . ), as well as the associated p value. taken together, the evidence clearly points to this factor as the culprit. in those less-common circumstances in which all the ill and non-ill persons can be contacted for interview, the table can be rearranged to show attack rates (incidence rates) for each of the suspect factors (table ) . here, the column of "differences" shows the attack rate (exposed) minus the attack rate (non-exposed), (i e − i n ), and again a large positive difference will point to the culprit. this measure is called the attributable risk and for the spring water example we obtain + %, the largest value of all the risk factors. also, because of the availability of valid attack rates (incidence rates), the true relative risk (rr) is available, and can be substituted the p (probability) value is a statement of statistical significance. it indicates the probability that there is no relationship between the factor and the illness. so as the number becomes very small (as shown here) we can be increasingly satisfied that a real relationship does exist. see the statistical significance section for the correct way to calculate this ns = not significant the ("true") relative risk (also called the risk ratio) is only used when we have the true incidence data. it is calculated as the attack rate (exposed) over the attack rate (non-exposed), or i the p (probability) value is a statement of statistical significance. it indicates the probability that there is no relationship between the factor and the illness. so as the number becomes very small (as shown here) we can be increasingly satisfied that a real relationship does exist. see the statistical significance section for the correct way to calculate this ns = not significant for the odds ratio. the data in table shows the same data as table rearranged for easy comparison. values in the column of "differences" are not the same as for table and of course the relative risks are not the same as the odds ratios in table , but both of these results still point clearly to the suspect exposure. in both analyses, spring water is clearly the factor most strongly associated with illness. it is important to note that in both tables a high rate (exposure-or attack-) on the left side taken by itself is meaningless until it is compared with the rate from the right side of the table. this again underscores the importance of gathering complete data from the non-ill as well as the ill. an interesting phenomenon is visible in the second factor listed (soft drink). the or is listed as . , which is "protective," meaning that this factor is strongly associated with not being ill. it is the equivalent of or equal to . ( / . ), and the chi-square is seen as quite large, although not enough for statistical significance. this is sometimes seen where two factors are "in competition" with each other; if everyone had drunk one item, and the spring water was the contaminated source, then those drinking the other item would be strongly "protected" because they did not drink the spring water, and this shows clearly. all other factors have or values very close to . . most attack rate tables record some persons who did not ingest the suspect vehicle but who nevertheless became ill. plausible explanations are that (a) some people forget which beverages or foods they ingested; (b) some might have become ill from other causes; or (c) some may have exhibited symptoms with a psychosomatic rather than a physiological origin. it is also not unusual for the table to include some persons who ingested contaminated water or food but did not become ill. plausible explanations are that (a) organisms or toxins are not always evenly distributed in water or food and consequently some persons ingest small doses or perhaps none at all; (b) some persons eat or drink larger quantities than others; (c) some are more resistant to illness than others, and (d) some will not admit that they became ill, or fail to report it. whichever table is used, the combined totals for cases (ill) and controls (well) are fixed and should not change for each exposure unless there are "missing" responses from interviewees. while some procedure manuals include confidence limits around both rr and or, this may be omitted here as the use of the chi-square test or fishers exact test yield the statistical significance for both tables. illness caused by ingestion of waterborne toxicants and some pathogenic organisms can be dose-related in that the risk of developing symptoms, and their severity varies with the quantity ingested. where the suspect water is no longer available (for example, the well may have been quickly super-chlorinated to break the chain of infection before samples were taken), attack rates can be based on the amount of water usually drunk per day by each person. this is easily extended to other non-treated sources of water such as ice cubes, water-reconstituted fruit juices, and flavored crystals. a comparison of attack rates at various water intake levels may provide valuable evidence that water is, or is not, the vehicle responsible for the outbreak. for an example, see table . here, the entire group was people and we have interviewed them all, so we are justified in calculating the attack/incidence rates: in this example, the attack rate increased as the consumption of water increased, which suggests that the illness was directly related to water and the agent it contained. this is a trend established from the group as a whole, and an individual's experience may vary with factors such as (a) preferences of water ingestion, (b) intermittent contamination, (c) unequal distribution of the contaminant, or (d) varying susceptibility of individuals. these data can be compared with rates from persons who ingested no water, but only hot tea, hot coffee, soups, and/or other safe sources of liquids. if unheated water was indeed the vehicle, and the agent was a living biological agent, these persons should have attack rates showing no increase in risk of illness. (outbreaks from a toxic agent may be unaffected by chlorination, boiling, and some types of filtering.) the data can be displayed in a contingency table as follows for analysis using chi-square procedure (table ) . for this example, chi-square equals . and if calculated by computer or online, p will be shown as p = . . reference to form j confirms that for a × table ( df), the calculated chi-square ( . ) exceeds the critical value for statistical significance at the . level ( . ), allowing us to claim statistical significance at p < . . odds ratios are normally associated only with × tables, but here, the or can usefully be calculated on selective cells or groups of cells as long as you clearly explain the selection process. for instance, persons who were ill were . times more likely to have drunk three or more glasses of water per day compared to those who were well. for this calculation we collapse cells into a × table and crossmultiply: (a + c) × (f + h)/(b + d) × (e + g) = ( ) × ( )/( ) × ( ) = / = . . alternatively, because we have all people involved, we can compare the attack rates (ar) for each intake level, and observe the increasing attack rate as the intake increases: for five or more glasses/day, ar: %, for - /day, ar: %, for - / day, ar: %, and for < /day, ar: %. we might summarize as follows: "there was a relationship observed between the quantity of water consumed each day and the risk of illness. the incidence rate increased with the quantity consumed from % for < glasses/day to % for five or more glasses/day. this relationship is statistically significant. the null hypothesis of no association can be rejected." , df, p < . ] water as a vehicle can deliver pathogenic organisms in many ways beyond simply drinking a glass of water, or using a drinking fountain. investigators should be sure to ask about the preparation of ice-cubes, the mixing of fruit flavored crystal drinks, reconstituting concentrated orange juice, brushing and rinsing teeth, and washing hands, utensils, or containers. swimming or playing in muddy pools or even swimming pools have caused waterborne poliomyelitis, and naegleriasis, while swimming in saltwater inlets have allowed inadvertent infections from vibrio parahaemolyticus and v. vulnificus. unwashed plastic jugs containing poster paint residue have caused rapid illness when drink crystals are reconstituted in them, while refillable plastic containers and bottles have a long history of contamination from biological and chemical agents. in the late s, an increase of viral ear, nose, and throat infections among people who were using parkland next to a river was hypothesized to have been due to people waterskiing on the river and creating an aerosol. the river was the receiving body for effluent from a water treatment plant upstream. record all laboratory results on form i, laboratory results summary. compare epidemiological and statistical results with on-site observations, laboratory results and the information summarized on form i. the agent responsible for the outbreak can be determined by (a) isolating and identifying pathogenic microorganisms from patients, (b) identifying the same strain and/or pfge pattern or genetic sequence of pathogen in specimens from several patients, (c) finding toxic substances or substances indicative of pathological responses in specimens, or (d) demonstrating increased antibody titer in sera from patients whose clinical features are consistent with those known to be produced by the agent. when implicating the water as a likely (or presumptive) vehicle of transmission, ideally identification of a pathogen in samples of suspect water will correspond to the one found in clinical specimens from ill persons or that produces an illness that is compatible with the incubation period and clinical features of the ill who were exposed to the water. for organisms that are common in the gastrointestinal tract or that have multiple strains, compare strains isolated from ill persons with strains isolated from the suspected water. additionally, specific microbial markers (e.g., serotype, phage type, immunoblotting, plasmid analysis, antibiotic resistance patterns, restriction endonuclease analysis, nucleotide sequence analysis) or chemical markers identified by chromatography or spectrophotometry can be used for this purpose. for confirmation of water-related transmission, the same pathogen strains should be found in both the ill persons and the epidemiologically implicated water. however, due to the period of time that may have passed after the outbreak was actually reported, and to methodological issues, such as the need for concentrating pathogens in water samples, it is often unlikely that the outbreak-associated pathogen will be found in the water samples. laboratories frequently test water samples for indicator organisms, such as fecal coliforms, escherichia coli, or enterococci, rather than pathogens. the finding of these bacteria in high densities in the water may indicate contamination (from a fecal source) and implicate the water was a possible vehicle. however, the finding of increased indicators in water samples alone is insufficient evidence to confirm the water as the source of an outbreak. the probable source of contamination or the situation that allowed contamination to reach and survive in a water supply (e.g., water supply not disinfected or inadequately disinfected, inadequately filtered, or upstream to sewage or agricultural discharges; cross connection between sewerage and drinking water pipes; well improperly constructed; nearby septic tank system; or livestock in water supply) can often be identified, but the etiologic agent in the water may never be found. success in finding the etiologic agent is most likely where (a) the incubation period of the illness is short, (b) the agent is stable in water and the system is static, or (c) large amounts of the agent are being continually added to the water supply. try to recover and identify the specific agent whenever a water supply is suspected to be the vehicle of transmission, even if finding the etiologic agent is likely to be difficult and not considered practical for routine monitoring of water supplies. if water samples do not reveal a likely causal agent, clinical data as well as time, place, and person associations can cast strong suspicion on a water supply, particularly if indicator organisms are found in the water. tests other than those for pathogens, however, are frequently used to evaluate water supplies on a routine basis. organoleptic tests attempt to evaluate the total effect of all compounds present in water that can be measured by the senses of taste, smell, or sight. results cannot be expressed in terms of specific compounds present, and the measured qualities are usually a result of a mixture of compounds. these tests are often empirical and arbitrary, but changes in the physical qualities of water (such as ph, turbidity, color, odor, or taste) can indicate abnormalities of the water. outbreaks have occurred, however, when turbidity readings have met present standards and when water appeared and tasted good. chemical examination of water is useful for (a) detecting pollution (especially from industrial wastes and pesticides), (b) determining effectiveness of treatment processes, (c) evaluating the previous history of the water, (d) determining hardness, and (e) detecting the presence of specific toxins. results are usually expressed in milligrams per liter (mg/l = ppm, parts per million), or micrograms per liter (μg/l = ppb, parts per billion). historically, acute water-related outbreaks seldom involve chemical substances, so chemical tests are not requested routinely unless either (a) circumstances indicate possible chemical contamination or (b) clinical symptoms suggest chemical poisoning. flowing water in a distribution system can be monitored to determine chlorine residual. free available residual chlorine refers to that portion of the total residual chlorine remaining in chlorinated water at the end of a specific contact period that will react chemically and biologically as hypochlorous acid or hypochlorite ion. the reaction is influenced by ph and temperature. total or combined residual chlorine refers to chlorine that has reacted with ammonia or other substances and is not available for further reactions, as well as the free available chlorine. a chlorine demand exists in a chlorinated water until a free available residual is produced. a free available chlorine residual, e.g., mg/l ( ppm) or higher, maintained throughout the distribution system of a community supply is an indicator of safety from enteric bacteria but not necessarily from pseudomonads, viruses or parasites. outbreaks have occurred when chlorine residue levels have met present standards. analyses for microbial indicator organisms provide information on the microbiological quality of water and guidance as to its safety for consumption or contact. indicator organisms are easier to test for than pathogenic organisms, and some serve as a surrogate measure of fecal contamination in water. the absence of indicator organisms in the water, however, does not guarantee water safety; numerous outbreaks of water-related disease have occurred from water in which no indicator organisms were detected. evaluation of the safety of water should be based upon a combination of results of (a) an on-site study to identify sources and modes of contamination and means by which contaminants survived treatment and (b) appropriate laboratory analyses. microbiological results should be compatible with observed sources of contamination and/or treatment failures found during the investigation. although all natural waters contain bacteria, the number and kind vary greatly in different places and under different climatic and environmental conditions. the number of bacteria isolated and reported, however, often represents only a fraction of the total number present, for several reasons. colonies seen on agar plates develop from either single organisms or clusters or chains of organisms. heterotrophic bacteria represent only those that can use organic matter and grow at the selected temperature ( - °c) within - hours under aerobic/microaerophilic conditions in/on a defined medium when the standard test (spread plate, membrane filter or pour plate) is used. the hpc may also be done using different media under different incubation times/conditions. (higher counts are usually found when the longer incubation periods are used.) also, certain microorganisms are unable to grow aerobically either in or on the medium used. because of these variables, the terms total plate count (tpc), standard plate count (spc) and aerobic plate counts (apc) should not be used. hpcs serve as an index of changing sanitary conditions. in general, counts of good-quality well water are fewer than - colonies per ml. densities in surface water are higher, but quite variable, depending on water temperature, sources of pollution, amount of organic matter present, and soil that washes into the water. the sources of pathogens, toxic substances, or fecal contamination may not increase the hpc of a surface water sample as much as washings from soil. nevertheless, marked changes in the number or kind of microorganisms should be viewed with concern, at least until the reason for the change is discovered. heterotrophic plate counts greater than /ml and some specific antagonistic species may interfere with the growth or recovery of pathogenic or indicator organisms. some heterotrophic species are opportunistic pathogens that may pose a health threat to immunocompromised persons. the coliform group of bacteria comprises those from non-fecal environmental sources, and those from animal and human intestines, including escherichia coli. the environmental species of non-fecal bacteria are found in soil, on fruits, leaves, and grains, and in run-off water, especially after heavy rains. some of these species are capable of surviving in water longer than e. coli. furthermore, some coliform strains and can multiply on decaying vegetation in water, in biofilms in pipelines, or on pump packings, washers, and similar materials. therefore, finding coliforms may not be indicative of fecal contamination, although most water utilities have standards for coliforms in water. fecal coliforms are present in large densities in all human and animal feces, normally much higher than pathogens which are typically only present in infected persons and normally at lower levels. as such, high populations of fecal coliforms can indicate recent sewage pollution of water, but are not always indicative of pathogens present, particularly viruses and parasites. none of the coliform group, however persists as long as most viral or protozoan pathogens in water, and indicator bacteria described below (fecal streptococci and clostridium perfringens). typical chlorination or ozonation of water inactivates coliform bacteria. presence of the coliform group or even a high population of coliform bacteria is not proof that a treated water supply contains pathogens. however, coliforms can provide a warning that either the water treatment was inadequate or contamination occurred after treatment, and that some pathogens may be present. as mentioned above, under some conditions, pathogens may be present where there are few or no coliforms. furthermore, unlike coliforms, many parasites and viruses are resistant to normal levels of disinfectants. coliforms have little or no correlation with the presence of parasitic protozoa or pathogenic viruses. the standard test for the coliform group may be carried out by a membrane filtration technique, a multiple-tube fermentation technique (presumptive test, confirmed test, or completed test), or a presence-absence test. results of the membrane filtration technique are reported as colony forming units (cfu) per ml of water. results of the multiple-tube fermentation technique are reported as the most probable number (mpn) per ml of water. this is a statistical estimation of the total number present, but the actual number can fall within a considerable range. counts derived from these two methods are not necessarily the same, but they have the same sanitary significance. false-negative or false-positive results can also occur with the membrane filtration technique because of interfering background growth of nonfecal microorganisms. results of the presumptive test of the multiple-tube fermentation technique can be misleading, because other microorganisms frequently found in water also produce gas in laboratory media, and may thereby give false-positive results. also, especially in waters containing a large number of microorganisms, some coliforms present may produce gas slowly, leading to false-negative results. the presence of coliform bacteria is corroborated by means of the second phase of the multiple-tube fermentation technique, known as the confirmed test. positive results are usually considered confirmation of the presence of coliforms. a third phase of this test, known as a completed test, further ensures the correct identification of coliform bacteria. a simple modification of the coliform test is to analyze for the presence or absence of coliforms in a -ml drinking water sample. the "presence-absence (p/a) coliform test" allows for simple examination of a larger number of samples. when a positive sample is detected, it is advisable to measure coliform densities in repeat samples by one of the other methods to determine the magnitude of the contamination. thermotolerant coliform (fecal coliform). coliform bacteria will frequently grow at a relatively high temperature, . °c, unlike species or strains normally encountered in the environment, which usually have an optimal temperature near °c. this thermotolerant characteristic has been used in an attempt to separate coliform bacteria into those of so-called fecal and non-fecal origin. this test may provide better indication of fecal contamination than the coliform test, but it is however, unreliable. positive results are not proof that either organisms of fecal origin or pathogens are present. the number of thermotolerant coliforms is considerably lower than the number of total coliforms in contaminated water; therefore, the test is less sensitive for testing treated drinking water. furthermore, escherichia coli o :h , which has been implicated as causing water-related illness, does not grow well at . °c. escherichia coli. e. coli is common in feces of human beings, other mammals, and birds. it can also be found to grow naturally in the environment, specifically in tropical waters. comprised of the larger coliform group, its detection in water is a more definitive indicator of fecal contamination, compared to total or fecal coliforms. however, a positive test result does not identify if the fecal source is human or nonhuman. rather, the finding of e. coli in water serves as an indicator that fecal matter reached the water and provides a warning, but not proof, that pathogenic organisms may also be present. it should be noted that some strains of e. coli are pathogenic (see table b ). simple commercial p/a and quantitative tests have been developed to detect the presence of total coliforms and e. coli in hours by observing color changes and fluorescence of the media under daylight and uv light. such tests may be useful for field evaluation of microbiological water quality. another group of organisms, collectively known as fecal streptococci, is also used as an indicator of fecal contamination. enterococci (enterococcus faecalis, enterococcus faecium) are particularly used for testing recreational waters. like coliforms, enterococci are normal inhabitants of the intestinal tract of human beings and other animals. in human feces, they occur in considerably lower numbers than e. coli. some members of the group, such as e. faecalis, subsp. liquefaciens, however, have been associated with vegetation, insects, and certain types of soils. enterococci generally survive longer than coliforms in fresh water, and therefore the source of contamination may be distant in either time or place from the site where samples were obtained. their resistance is, however, less than that of clostridium perfringens, enteric viruses, and parasites. like e. coli, simple commercial p/a and quantitative tests have been developed to detect the presence of enterococci in hours by observing color changes under uv light, which may be useful for field evaluation of microbiological water quality. clostridium perfringens (sulfite reducing clostridia). c. perfringens is also of fecal origin, but it occurs in feces in much lower densities than e. coli and can also be found in soils. being a spore-former, it can survive for long durations in soil and water, and persist when all other bacteria of fecal origin have disappeared. therefore, it is a useful indicator of remote or intermittent contamination in wells that are not frequently examined by the coliform test; but, it is not, by itself, evidence of recent contamination. chlorine, in the concentration typically used in water treatment, does not inactivate all spores; and thus c. perfringens is not valuable in assessing the efficiency of chlorination for bacterial vegetative cells. its long persistence and its resistance to chlorine make this organism a potential indicator for viral and parasitic organisms that have similar resistance and disinfectant susceptibility. coliphage. coliphages, which are viruses that infect e. coli, are simpler to detect and enumerate, compared to other viruses, and are generally associated with fecal contamination. they have been considered as possible indicators of treatment effectiveness for human enteric viruses. coliphages are categorized into two groups: the somatic phages, which enter e. coli via the cell wall and the male-specific phages, which enter e. coli through the sex pili. the somatic and male-specific phages are common in sewage and the feces of human beings and other animals, but in lower densities than the common fecal indicator bacteria, fecal coliforms, e. coli, and enterococci. some strains appear to be more resistant to chemical disinfection than water-related pathogens or indicator bacteria. be aware of local standards for water distribution systems, private water systems, and recreational water. although drinking water standards, such as the total number of coliforms allowed in a water sample, vary from jurisdiction-to-jurisdiction, it is generally agreed that any fecal contamination (e.g. fecal coliforms, escherichia coli) render the water unacceptable for human consumption and may close down recreational bathing waters. there are numerous pathogens that can be transmitted by water, many of which are also able to cause respiratory symptoms, in addition to the classical gastrointestinal symptoms. for a comprehensive summary of waterborne pathogens see "american waterworks association manual of water supply practices, m waterborne pathogens, nd edition ( ) ." for several reasons, analyses for pathogens are not usually conducted during routine water testing, or are only conducted by specialized laboratories. first, tests for pathogens are pathogen-specific, expensive, and often difficult to perform because they may require specialized trained personnel. secondly, the etiologic agent of the outbreak is often unknown at the time of analysis; hence, many analyses would have to be done blindly. thirdly, pathogens are not always recovered because they are heterogeneously dispersed and diluted in the environment, and their numbers decline in water over time. as a result, they may be absent or present in low densities by the time samples are collected following an outbreak. fourthly, recovery efficiencies are often poor because microorganisms are stressed by disinfectants or the method is sensitive to interferences from the source waters environment, hence not easily recovered by routine methods. additionally, recovery efficiencies for viruses and protozoa may be poor because of the interferences of substances within the sample matrix with method reagents (concentrating l of water down to μl will also concentrate inhibitory chemicals and substances). finally, the time required for isolation and identification is often long, and the number of samples is usually too small to allow the investigator to have much statistical confidence in the results when pathogens are not found. negative results should be reported as "not detected" because they do not ensure that the water sampled was not the source of the pathogen. procedures used for many bacterial pathogens are qualitative because enrichment procedures are used. quantitative procedures (e.g., mpn) require considerable work and are less reliable than those used for coliforms because small populations may be present, and these may be unevenly distributed. despite these difficulties, pathogens that cause a syndrome similar to the one being investigated should be sought. see tables b, c, and d, for descriptions of the disease syndrome associated with the pathogens described in the following material. finding the same pathogen in specimens from patients and in water samples confirms water as a vehicle. summarize investigative data in a narrative report. describe in this report situations that led to contamination of the water and survival of etiologic agents up to the time of consumption. include all events that contributed to the outbreak to guide control and preventive measures. compare your data with the listings in table g (guidelines for confirmation of waterborne outbreaks) and table h (guidelines for confirmation of water responsible for illness), and criteria for confirmation of vehicle responsible for waterborne illness before assigning the etiologic agent and the vehicle. outbreak confirmation is based on (a) time, place, person associations, (b) recovery of etiologic agents from clinical specimens from cases and samples of water, and (c) identification of sources and modes of contamination and means by which pathogens or toxic substances survived treatment. all three of these, however, might not be found in any one investigation. complete form k (waterborne illness summary report). attach the narrative and the epidemic curve. also attach form d (case history summaries: water/laboratory data), all applicable parts of forms g, forms h, form i, and other data that will provide supplemental information to reviewers. send this report through administrative channels to the appropriate agency responsible for waterborne disease surveillance. make the final report as complete as possible, so that the agency can accurately interpret the results and develop a meaningful waterborne disease data bank. in the interest of continuing cooperation, give all participants in the investigation due credit and send each a copy of the report. also, send copies of the report through administrative channels to agencies (a) that have jurisdiction over the implicated water, (b) that initiated the alert, and (c) that participated in the investigation. those concerned with water sources, treatment and recreation, as well as with public health, should make every effort to ensure the complete investigation and reporting of waterborne diseases. without reliable, complete information, trends in waterborne disease incidence and causal factors of the disease are difficult to determine. good surveillance is essential for detecting and evaluating new waterborne disease hazards. the primary purposes of a waterborne disease investigation are to identify the cause, establish control measures, and take actions to prevent future illness. prudence may require some action before all the hypotheses regarding the water supply involved and the source of contamination are confirmed. frequently the local health authority will issue a boil water advisory if a microorganism is suspected to have contaminated the water. refer to "possible precautionary control actions" section for a discussion of these precautionary control measures. if these measures have not already been considered, consider them now. once control measures have been implemented, continue to monitor for disease to evaluate whether the measures were effective. in a waterborne event in sydney, australia (see box ) sydney water severely overestimated levels of cryptosporidium and giardia present in the water raising public alarm. boil water advisories were announced and rescinded several times. however, it is better to announce boil-water advisories than to have thousands ill, as has happened in the past, such as the cryptosporidium outbreak in milwaukee in . deficiencies in treatment must be corrected and defective parts of distribution systems must be repaired, beginning with those that either contributed to or had a high potential for contributing to the outbreak. the effectiveness of these efforts will be directly related to the thoroughness of the investigation. document the source and the manner of contamination and survival of the etiologic agent through the water treatment process. provide clear documentation of contributory factors, so that preventive measures taken will be specific to the problem. if previous sanitary surveys have revealed, or if subsequent ones reveal, that conditions which contributed to the outbreak are widespread, initiate a training and education program. these programs can be developed for water treatment plant or recreational water operators and employees, engineers, homeowners, or other appropriate groups. impress upon them the importance of proper construction and operation of facilities and proper protection, treatment, storage, and distribution of water. follow up with periodic inspections and surveys and verify by sampling, as appropriate, to determine whether faulty conditions have been corrected or allowed to be reintroduced. legal action may be necessary to ensure compliance with official standards and accepted sanitary practices. formulate solutions to problems found during outbreak investigations, and incorporate these into regulations for drinking, agricultural, industrial, domestic, and recreational waters. inform the public, through mass media and other means available to your agency, of hazardous conditions that can affect their water supply, but do so only after hypotheses are confirmed. the public must be told of any potential or actual harm that may result from ingesting or contacting contaminated water and must also be informed of measures that they can take and that official agencies are taking to correct these conditions. the water supply and recreational water facilities must be verified periodically to determine whether critical processes are being monitored and operated within limits of appropriate public health standards (see box , the walkerton outbreak). most waterborne illnesses are preventable, but prevention requires that those in the water treatment industry and in health and water-protection regulatory agencies be constantly vigilant to ensure that the hazards are understood and that questionable water treatment or delivery system construction or practices are avoided. examples investigation guidelines and investigative forms iafp manual, "procedures to investigate waterborne illness, rd ed"; copies of form c; one dozen copies each of forms e and f; two copies of form d and all parts of form g, epi-info software (cdc, atlanta). water sample bottles (bottles for chlorinated water should contain enough sodium thiosulfate to provide a concentration of mg of this compound per l of sample), plastic bags (whirl-pak ® type), ml, -l and -gal sized jars and jugs. sterile and wrapped sampling implements moore swabs (compact pads of gauze made from strips cm [ ft] by cm [ in.] tied in the center with a long, stout twine or wire-for sewer drain, stream or pipeline samples), fiberglass-epoxy bacterial filter cartridge, . μm; tongs, scoop or similar utensils for collecting ice. specimencollecting equipment (for human specimens from cases and controls) sterile containers (with lids) for stool specimens, bottles containing a bacterial preservative and transport medium, mailer tubes or styrofoam box, sterile swabs, rectal swab units, tubes of bacterial transport medium, stool preservative medium for parasites, phlebotomy supplies for blood specimens. kits for testing chemical disinfectants and ph dpd (n,n-diethyl-p-phenylenediamine) chlorine comparator with color disc for chlorine ( . ppm) and chlorine test papers; field-type ph meter or ph comparator with color disc or ph test papers; applicable ph indicator solutions and dpd reagent solution; dissolved oxygen testing unit. dye tracing study equipment fluorescein (yellow-green fluorescent) dye in powder form ( packages containing g each), in tablet form ( tablets), or in liquid form (prepared by mixing g in l of water); fluorometer; filters (primary and secondary) for use with fluorometer; sample holder for continuous sampling or individual sampling; fluorometer recorder. disinfectant and neutralizer . % w/v solution of calcium hypochlorite or . % household liquid bleach; % w/v sodium thiosulfate. virus filtration equipment for viruses and parasites b large plastic container for storing water sample prior to concentration; portable electric or gasoline powered water pump with quick disconnect brass or stainless steel plumbing adapters or hose couplings; two filter holders for -in. water filter cartridges fitted for adapters or couplings; portable water meter fitted for adapters or couplings; four lengths of fiber-reinforced garden hose fitted with adapters or couplings; one length of a strong-walled supply hose fitted with adapters or couplings; -in. prefilter ( μm nominal porosity wound polypropylene yarn filter with hollow perforated stainless steel core) cartridge filter; -in. virus absorbing filter pleated . μm porosity nylon membrane type (positively charged) for waters of ph values up to . , or pleated . μm porosity glass fiber membrane type (positively charged) for waters of ph value of . or lower (e.g., virosorb, -mds, amf/cuno meriden, pleated, . μm, glass filter); ml sterile, ph , % beef extract solution in gal wide-mouth screw capped autoclavable polypropylene container for each sample to be collected; stands to support filter holders during filtration; for parasites -in. polypropylene yarn-wound cartridge filter, . μm porosity (e.g., micro wynd ii™, amf/cuno; meriden, ct. . μm normal porosity). (continued) laptop or tablet, with software; thermocouples of varying lengths with either recording potentiometer, data logger, or digital indicator; devices to take samples below surface and sediment samples; chemical smoke kit and/ or micromanometer; occupational safety and health administration (osha) or equivalent approved respirator; sterile plastic gloves; plastic container liners for ice; waterproof marking pens; waterproof test tube rack; pencils, note pad; roll of adhesive or masking tape; labels; waterproof cardboard tags with eyelets and wire ties; flashlight; matches; test tube rack to fit tubes used; insulated chest or styrofoam container; packing material; camera with flash; spare batteries for all equipment; % ethyl alcohol; propane torch; refrigerant in plastic bags, liquid in cans, rubber or heavy plastic bags that can be filled with water and frozen; heavy-duty bags for ice, "canned ice," or cold-packs (blue ice). a assemble a kit to be kept in the agency responsible for investigating waterborne illness. it should include at least ten water sample bottles; ten -l, or gal jars or jugs; ten specimen collection containers or devices; and one each of the following supporting equipment and sterilizing equipment. date of sterilization should be marked. periodic resterilization or replacement of sterile supplies, media, or transport media is required to maintain the kit in a ready-to-use condition b similar equipment for sampling for either viruses or parasites may be available from national water, environmental, or health agencies how much to collect two rectal swabs or swabs of fresh stool from ten ill persons; samples from ten controls also can be submitted. whole stool is preferred if nonbacterial stool testing considered a fresh stool sample from ten ill persons; samples from ten controls can also be submitted. to enhanced detection, three stool specimens per patient can be collected > h apart as much stool sample as possible from ten ill persons (a minimum of ml of stool sample from each); samples also can be obtained from ten controls. a fresh urine sample ( ml) from ten ill persons; samples from ten controls also can be submitted. label each specimen in a waterproof manner and put the samples in sealed, waterproof containers (i.e., plastic bags). batch the collection and send in overnight mail to arrive at the testing laboratory on a weekday during business hours unless other arrangements have been made in advance with the testing laboratory. contact the testing laboratory before shipping, and give the testing laboratory as much advance notice as possible so that testing can begin as soon as samples arrive. when etiology is unclear and syndrome is nonspecific, all four types of specimens may be appropriate to collect c for more detailed instructions on how to collect specimens for specific parasites, please go to http://www.cdc.gov and search the website of key words d for more detailed instructions on how to collect specimens for viral testing, please go to http://www.cdc.gov and search the website of key words e the containers have been tested for the presence of the chemical of interest prior to use f unused specimen collection containers that have been brought in to the field and subjected to the same field conditions as the used containers. these containers are then tested for trace amounts of the chemical of interest table e (continued) isolation of agent from ill persons and from water and laboratory criteria for confirming etiologic agent as stated in table g . combination of on-site investigation, statistical evidence and laboratory analysis. (see entries below) presumptive vehicle on-site investigation demonstrating source and mode of contamination of water and survival of etiologic agent in water. also, desirable to have laboratory isolations from water of etiologic agent that causes syndrome similar to that observed during the investigation and other supportive epidemiologic data. if so, this might provide sufficient evidence for confirmation. or p-value for water < . when other epidemiologic data supports water hypothesis. also, desirable to have either laboratory isolations from water or on-site investigation that demonstrates source and mode of contamination and survival of treatment that supports the hypothesis. if so, this might provide sufficient evidence for confirmation. or odds ratio or relative risk for water greater than and the lower limit of the % confidence level greater than when other epidemiologic data supports the water vehicle hypothesis. also, desirable to have either laboratory isolations from water or on-site investigation that demonstrates source and mode of contamination and survival of treatment that supports the hypothesis. if so, this might provide sufficient evidence for confirmation. for calculation of data when all persons who may have been exposed to the suspect vehicle (but not all persons will have ingested every beverage/food) have been identified and interviewed (retrospective cohort) form j : chi-sq. analysis can be easily completed using on-line calculators or statistics programs such as epi-info. however, to confirm the result or to do the whole thing yourself, here are the steps: ill well totals step : create a x table as shown with observed data (o values) and marginal totals step : calculate odds ratio: (axd)/(bxc) = ( x )/( x )= . step . . chi-sq. (all four cells) = . + . + . + . = . step : compare your calculated chi-sq. value with the critical value to determine significance (table ) : begin at column p < . … your calculated chi-square value must meet or exceed the critical value to be considered statistically significant at that level. if you fail to meet or exceed the minimal value for p < . , the result is p > . , and the relationship is declared "not significant". step : summarize: exposure was related to illness. ill persons were eight times more likely to have been exposed to this factor than non-ill persons. this relationship is statistically significant. the probability of these data occurring by chance alone is less than . %. reject the null hypothesis of "no association." [odds ratio: . , % cl: . < or < . , chi-sq.: . , df, p < . ] form j : fisher's exact test can be easily completed using on-line calculators or statistics programs such as epi-info. however, to confirm the result or to do the whole thing yourself, here are the steps. ill well totals step step : calculate the probability directly... here, cell 'a' has smallest e value at . p = ! x ! x ! x ! = . ! x ! x ! x ! x ! step : the final probability (p) is the sum of all probabilities (in this case p + p + p ) or approximately . . step : summarize: exposure was related to illness. ill people were almost times more likely to have been exposed to this factor compared to non-ill people. the relationship is statistically significant. the probability of these data occurring by chance alone is less than . % (< . ). reject null hypothesis of "no association". [odds ratio: . , % cl: . < or < . , p = . ]. . when deciding which cells to increase by + , always multiply (a) × (d) and compare with (b) × (c). increase each cell of the pair with the higher product and decrease each cell of the pair with the smaller product, while keeping all marginal totals unchanged. . the final p is an "exact" p (probability) and may be reported as such (p = . ). in this example, it is also < . of course, and can be reported in this way if preferred. . the fisher's test is used when the chi-square test is invalid due to any "e" values < in a × table. in all other circumstances, chi-sq. is an excellent approximation for the fe test. . if original data include a zero in one of the cells, you will calculate only one p value. (the o.r. will be reported as "undefinable" but the direction of the effect will be very clear). . this p is calculated for a one-tailed fe test. it is adequate for this application. two-tailed fe test will require further calculation. . should a relationship not meet the critical value for significance (that is, p > . ), it is described as "not statistically significant". note that a relationship may be observed, but this result is telling you that it could have occurred by chance alone more than % of time if you were to repeat the analysis. that may still require further investigation, but from a statistical standpoint, it cannot be claimed as a statistically significant relationship. water treatment plant design, fifth edition american waterworks association. manual of water supply practices, m waterborne pathogens, second edition the flint water crisis confirms that u.s. drinking water needs improved risk management produce safety-what's going on here? national environmental health association neha-cert ep global health -division of parasitic diseases and malaria page last reviewed surveillance reports for recreational water-associated disease & outbreaks. page last reviewed on internalization and dissemination of human norovirus and animal caliciviruses in hydroponically grown romaine lettuce environmental protection agency technical guidance manual lt eswtr disinfection profiling and benchmarking environmental protection agency guidance manual for the compliance with filtration and disinfection requirements public water systems using surface water sources environmental protection agency. manual of individual and non-public water supply systems. epa no. epa no. water treatment manual: disinfection. environmental protection agency health canada risk analysis of the walkerton drinking water crisis algal bloom-associated disease outbreaks among users of freshwater lakes-us microbial resistance to disinfectants: mechanisms and significance. environ health perspect safe drinking water: lessons from recent outbreaks in affluent nations risk management for assuring safe drinking water ensuring safe drinking water: learning from frontline experience with contamination. american water works association cyanotoxin management and human health risk mitigation in recreational waters a massive outbreak in milwaukee of cryptosporidium infection transmitted through the public water supply private water supplies: technical manual good practice guide to the operation of drinking water supply systems for the management of microbial risk: research project two cases of keratosis follicularis squamosa (dohi) caused by swimsuit friction part two report of the walkerton inquiry: a strategy for safe drinking water public health inspector's guide to the principles and practices of environmental microbiology acute otitis externa: an update collect representative distribution system samples guidance on water supply and sanitation in extreme weather events. who regional office for europe effect of irrigation method on transmission to and persistence of escherichia coli o :h on lettuce transmission of escherichia coli o :h from contaminated manure and irrigation water to lettuce plant tissue and its subsequent internalization acknowledgments the committee and association thank and cite the following persons for chloramines refer to all forms of chloramine. the ct values may be assumed to achieve greater than . % inactivation of viruses only if chlorine is added and mixed in the water before addition of ammonia. if this condition is not met, the system must demonstrate by on-site studies or other information that it is achieving at least this much inactivation of viruses key: cord- -vuupgg i authors: robinson, esther r; walker, timothy m; pallen, mark j title: genomics and outbreak investigation: from sequence to consequence date: - - journal: genome med doi: . /gm sha: doc_id: cord_uid: vuupgg i outbreaks of infection can be devastating for individuals and societies. in this review, we examine the applications of new high-throughput sequencing approaches to the identification and characterization of outbreaks, focusing on the application of whole-genome sequencing (wgs) to outbreaks of bacterial infection. we describe traditional epidemiological analysis and show how wgs can be informative at multiple steps in outbreak investigation, as evidenced by many recent studies. we conclude that high-throughput sequencing approaches can make a significant contribution to the investigation of outbreaks of bacterial infection and that the integration of wgs with epidemiological investigation, diagnostic assays and antimicrobial susceptibility testing will precipitate radical changes in clinical microbiology and infectious disease epidemiology in the near future. however, several challenges remain before wgs can be routinely used in outbreak investigation and clinical practice. which can occur in response to local, societal or environmental changes: for example, one might see an increase in the prevalence of staphylococcal wound infections when hospital ward or operating theatre cleaning procedures change, or when there are changes in the use of antibiotics. however, in the strictest sense (which we adopt here), the term implies a series of infections caused by indistinguishable or closely linked isolates, which are suffi ciently similar to justify talking about 'an outbreak strain' . such outbreaks can range in size from a few individuals, for instance in a family outbreak or an outbreak on a hospital ward, to epidemics that rage across countries or continents. investigation of a suspected outbreak has two aims: termination of the cluster of disease and prevention of similar occurrences by understanding how such outbreaks originate. a key question surfaces at the start of any such investigation: is one really seeing an outbreak in the strictest sense, caused by a single strain, or is one merely seeing an increased incidence of infection, involving multiple unrelated strains? th e answer to this question is of more than academic interest, as it dictates how the fi nite resources available for infection control are best deployed. for example, evidence of cross infection with a single methicillin-resistant staphylococcus aureus (mrsa) strain on a ward might prompt an aggressive strategy of patient isolation and decolonization, whereas an increase in infections caused by diverse staphylococcal strains (presumably each derived from the patient's own microbiota) might prompt a look at policies for wound care or antibiotic usage. similarly, identifi cation and charac terization of an outbreak strain or the discovery of its source or mode of transmission infl uences the behavior of the infection control team -potential responses include removal of the source, interruption of transmission or strengthening of host defenses. in the past decade, many diff erent kinds of outbreaks have hit the headlines (table ) , with concern focused on the spread of multi-drug-resistant strains in hospitals (such as mrsa) [ ] or in the community (such as multidrug-resistant tuberculosis [ ] ); the threat of bioterrorism [ ] ; and 'emerging infections' , caused by newly discovered pathogens, such as severe acute respiratory syndrome (sars) or infection with the novel coronavirus (hcov-emc/ ) [ , ] , or by novel variants of previously recognized species or strains, such as stec o :h [ , ] . outbreaks are often linked to social factors, including mass travel, migration, conflict or societal break down, or to environmental threats, such as earthquakes or floods. they can arise from exposure to a common source in the environment (for example, legionellosis arising from a water source); when the period of exposure is brief, these events are termed 'point-source outbreaks' . alternatively, outbreaks can be propagated by human-to-human spread or, in the case of zoonoses, such as swine or bird flu, can result from the spread to humans from animal reservoirs. outbreaks can also be classified according to context, for example whether they occur in the community or in healthcare settings, or according to the mode of transmission, for example food-borne, waterborne, airborne or vector-borne. here, we examine the applications of new highthroughput sequencing approaches to the identification and characterization of outbreaks, focusing on the application of whole-genome sequencing (wgs) to outbreaks of bacterial infection. we describe how traditional epidemiological analysis works and show how wgs can be informative at multiple steps in outbreak investigation. although traditional epidemiology can often track down the source of an outbreak (for example, a case-control study can identify the foodstuff responsible for a foodpoisoning outbreak [ , ] ), for several decades laboratory investigations have also had an important role in outbreak investigation and management [ ] . thus, when suspicion of an outbreak has been raised on clinical or epidemiological grounds, the laboratory can provide evidence to confirm or dismiss a common microbial cause. alternatively, an increase in laboratory reports of a given pathogen may provide the first evidence that an outbreak is under way. however, in addition to providing diagnostic information, the laboratory also offers epidemiological typing, which provides an assessment of how closely cases are related to each other. in broad terms, this means classifying isolates as unrelated (not part of an outbreak) or sufficiently closely related (in extremis, indistinguishable) to represent epidemic transmission. epidemiological typing requires the identification of stable distinguishing characteristics. initially, this relied on analyses of useful phenotypic features (such as serological profiles, growth characteristics or susceptibili ties to bacteriophage or antimicrobial agents) [ ] . however, the arrival of molecular biology in general and specifically of the polymerase chain reaction (pcr) led to a profusion of genotypic approaches, largely docu menting differences in patterns of bands seen on gels: examples include pulsed-field gel electrophoresis, ribotyping, variable number-tandem repeat typing, random amplification of polymorphic dna, arbitrarily primed pcr and repetitive-element pcr [ ] . this riotous proliferation of genotypic typing methods, often with complex and non-standardized workflows, led achtman in the late s to coin the phrase yatm for 'yet another typing method' [ ] and to pioneer, with others, the adoption of sequence-based approaches, notably multilocus sequence typing (mlst) [ ] . in this approach, differences in stretches of dna sequence from conserved housekeeping genes are used to assign bacterial isolates to sequence types, which, in turn, often fall into larger clonal complexes. sequence-based approaches bring the advantage of portability; in other words, results from one laboratory can be easily com pared with those from others around the world. in addition, archiving of information in national or inter national datasets allows isolates and outbreaks to be placed in the wider context of pathogen population structure. yet, despite the advantages of sequence-based typing, drawbacks remain. for example, there is a lack of standardization, as evidenced by the existence of multiple mlst databases and even multiple competing mlst schemes for the same species [ , ] . in addition, costs and complex workflows mean that most pathogen typing is performed in batch mode, retrospectively, in reference laboratories that struggle to provide data with real-time impact -one possible exception is the near-real-time typing of mycobacterium tuberculosis isolates in the uk [ ] . approaches such as mlst also lack the resolution needed to reconstruct chains of transmission within outbreaks, tending instead to lump together all isolates from an outbreak together as 'indistinguishable' members of the same sequence type. wgs promises to deliver the ultimate high-resolution genotypic typing method [ ] [ ] [ ] [ ] . although we recognize that virologists pioneered the use of wgs for pathogen typing, targeting genomes small enough for wgs with traditional sanger sequencing [ ] , here we will concentrate on the application of wgs to outbreaks of bacterial infection, catalyzed by the recent arrival in the marketplace of a range of technologies that fall under the umbrella term 'high-throughput sequencing' (sometimes called 'next-generation sequencing') [ , ] . high-throughput sequencing, especially with the arrival of bench-top sequencers [ , ] , brings methodolo gies for bacterial wgs that are simple, quick and cheap enough to fall within the remit of an average-sized clinical or research laboratory. through a single unified workflow, it becomes possible to identify all the features of interest of a bacterial isolate, speeding up the detection and investigation of outbreaks and delivering data in a portable digital format that can be shared internationally. by delivering a definitive catalog of genetic polymorphisms (especially single-nucleotide polymorphisms or snps), wgs delivers far greater resolution than traditional methods. for instance, whereas mlst identified only a single sequence type for a collection of mrsa isolates, wgs identified several distinct clusters [ ] . two recent studies of tuberculosis transmission have shown that the resolution of wgs with snp typing is much higher than that provided by the previous 'gold standard' typing method, mycobacterial interspersed repeti tive unit variable number tandem repeat (miru-vntr) typing [ , ] . wgs also links epidemiology to pathogen biology, delivering unprecedented insights into genome evolution, genome structure and gene content, including information on clinically important markers, such as resistance and virulence genes [ ] (figure ). traditional outbreak investigation can be divided into discrete steps, although these often overlap. wgs has the potential to contribute to each of these steps ( table ). when pathogens are endemic, for example, mrsa or clostridium difficile in healthcare facilities, it can be difficult to decide whether one or more outbreaks are under way or whether there has simply been a general rise in the incidence of infection. eyre and colleagues [ ] showed that bench-top sequencing of whole bacterial genomes could be used in near real time to confirm or refute the existence of outbreaks of mrsa or c. difficile in an acute hospital setting. in particular, they found that the genome sequences from an apparent cluster of c. difficile infections turned out to be unrelated and so did not represent an outbreak sensu stricto [ ] . metagenomics, that is, wholesale sequencing of dna extracted from complex microbial communities without culture, capture or enrichment of pathogens or their sequences, provides an exciting new approach to the identification and characterization of outbreak strains that does away with the need for laboratory culture or target-specific amplification or enrichment. this approach has been used to identify the causes of outbreaks of viral infection [ ] . most recently, diagnostic metagenomics has been applied to stool samples collected during the german outbreak of stec o :h , allowing recovery of draft genomes from the outbreak strain and several other pathogens and showing the applicability of diagnostic metagenomics to bacterial infections [ ] . case definition within an outbreak usually involves a combination of clinical and laboratory criteria; for instance, a complex of symptoms and an associated organism. this definition can then be used for active case finding to identify additional patients in the cluster. during the german stec outbreak, rapid genome sequen cing together with crowd-sourced bioinformatics analyses led to the development of a set of diagnostic reagents that could then be used in defining cases within the outbreak [ ] . similarly, during new outbreaks of viral infection, genome-scale sequencing can act as a precursor to the development of simpler specific tests that can be used in case definition [ , ] . during this phase of outbreak investigation, inferences from sequence data (such as on phylogeny, transmissibility, virulence or resistance) can be integrated with clinical and environmental metadata (such as geographical, temporal or anatomical data) to generate hypotheses and build and test models. for example, in a landmark study, baker and colleagues [ ] combined high-resolution genotyping and geospatial analysis to uncover the modes of transmission of endemic typhoid fever in an urban setting in nepal. during this phase of hypothesis generation, it may be possible to infer hidden transmission events. for instance, when faced with the recurrence of a strain of c. difficile in a hospital after more than years of absence, eyre and colleagues [ ] concluded that unsuspected community transmission of c. difficile was the most likely explanation for their observations. they also noted that most of their c. difficile cases were unrelated to other recent cases in the hospital, from which they concluded that their hospital infection control policies were working as well as they could and that further reductions in the incidence of c. difficile infections would have to rely on additional and different interventions. in some cases, it may be possible to hypothesize what determinants underlie the success of an outbreak strain. for example, the sasx gene (a mobile genetic elementencoded gene involved in nasal colonization and pathogenesis) appeared to be a key determinant of the successful spread of mrsa in china [ ] , and genes for the panton-valentine toxin were hypothesized to contribute to the spread of a novel mrsa genotype that caused an outbreak in a british special care baby unit [ ] . prediction of resistance phenotype from genotype has been applied routinely for years to viral pathogens such as human immunodeficiency virus, for which the cataloguing of resistance mutations in a publicly accessible database has greatly strengthened the utility of the approach [ ] . data are accumulating from s. aureus [ ] and from e. coli strains that produce extended-spectrum beta-lactamases showing that wgs can be used to predict the resistance phenotype in bacteria (nicole stoesser, department of microbiology, john radcliffe figure . whole-genome sequencing delivers high-resolution typing and insights into pathogen biology. in this hypothetical example, the two large ovals represent sets of isolates (small ovals) that have been assigned to genotypes using conventional laboratory typing. clouds indicate clusters within those genotypes built using epidemiological data. whole-genome sequencing provides a more detailed view of pathogen epidemiology, revealing previously unseen links (red lines) between genome-sequenced isolates (filled small ovals) within and between genotypes. whole-genome sequencing also provides insights into pathogen biology, including the factors associated with virulence (represented here by toxin gene x) and drug resistance (represented here by resistance gene y). host factors associated with disease may also be identified during data collection. increasingly, wholegenome sequences of humans are available and being used to study population genetic risks for diseases, as reviewed recently by chapman and hill [ ] . during this stage, there is often a series of iterative refinements to assumptions and models. for example, in a detailed retrospective analysis of tuberculosis cases in the english midlands, walker and colleagues [ ] first documented the diversity of m. tuberculosis genotypes in their collection and then explored how the patterns of genome diversity were reflected in contemporaneous and serial isolates from individual patients and among isolates from household outbreaks. this allowed them to define cut-offs in the number of snps that could be used to rule isolates in or out of a recent transmission event. in some instances, they could then allocate cases to clusters in which a link had been suspected, but had not been proven, by conventional epidemiological methods. in other cases, where a link had been suspected on grounds of ethnicity, they were able to exclude recent transmission within the west midlands region. outbreaks of meningococcal disease caused by serogroup c have largely been eradicated in the uk by vaccination. however, a retrospective genomic analysis of strains from a meningococcal outbreak allowed chains of transmission to be identified [ ] . this study pioneered the automated comparison of wgs data using a new public database, the bacterial isolate genome sequence database (bigsdb) [ ] ; the development of this kind of user-friendly, open-access tool is likely to underpin the adoption of wgs in epidemiological investigations in a clinical and public health environment. relatedness between isolates within an outbreak (and more widely) is often assessed by the construction of a phylogenetic tree [ ] . such phylogenetic inferences can enable the identification of sources or reservoirs of infection: examples include the acquisition of leprosy by humans from wild armadillos and the acquisition of mycobacterium bovis in cattle from sympatric badger populations [ , ] . integration of phylogeny with geography has allowed the origins and spread of pandemics and epidemics to be traced, including the yersinia pestis pandemic [ ] and, controversially, the cholera outbreak in haiti, which has been traced to nepalese peacekeepers [ ] . molecular phylogenies also make it possible to look back over years, decades, even centuries. for example, he and colleagues [ ] showed that two distinct strains of fluoroquinolone-resistant c. difficile emerged in the usa in to , and that these showed different patterns of global spread. genomic information, together with estimates from the sequence data of the time since isolates had diverged ('molecular clock' estimates) allowed them to reconstruct detailed routes of transmission within the uk. similar studies have revealed patterns of the global spread of cholera, shigella sonnei and mrsa [ , , ] . vaccination provides a means of disrupting transmission by removing susceptible hosts from the population. for example, immunity to specific capsule types responsible for pneumococcal infection is targeted by their inclusion table step confirming the existence of an outbreak bench-top sequencing of whole bacterial genomes in near real time to confirm or refute the existence of outbreaks of mrsa or c. difficile [ ] open-ended diagnostic metagenomics to identify and characterize outbreak strain [ ] case definition wgs and/or metagenomics leads to the development of diagnostic reagents then used in defining cases within an outbreak [ , , ] descriptive study: collecting data and generating hypotheses integration of wgs with geographical data to uncover modes of spread of typhoid [ ] reconstruction of routes of transmission, including hidden transmission events [ , , , ] identification of virulence factors and antimicrobial resistance [ , , ] analysis and hypothesis testing iterative refinements to assumptions and models [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] institution and verification of control measures documenting effects of vaccination on pathogen populations [ , ] confirmation that infections are imported rather than locally transmitted [ , , ] communication need for user-friendly digital output easily transferred between laboratories and expert advice of clinical academics at home in research and clinical environments in a multivalent vaccine. high-throughput sequencing studies provide clear evidence that capsule switching is occurring in pneumococcal populations in response to vaccination, which has implications for disease control and vaccine design [ , ] . viral illnesses have long been the target of successful vaccination programs. wgs analysis of rubella virus cases from the usa has confirmed that indigenous disease has been eradicated and that all the cases there are imported, with virus sequences matching those found elsewhere in the world [ ] . to be useful to clinicians, whole-genome sequence data must be readily accessible in a portable, easily stored and searched, user-friendly format. however, data sharing even through established hospital informatics systems is a non-trivial task, particularly given the current diversity in sequencing platforms and analytical pipelines. perhaps the answer here is to ensure the involvement of clinical academics with the relevant research credentials and accre ditation to make clinical decisions, who might be best placed to pioneer the use of wgs data to manage outbreaks. as we have seen, there is now ample evidence that wgs can make a significant contribution to the investigation of outbreaks of bacterial infection. it is therefore safe to conclude that once wgs has been integrated with epidemiological investigation, diagnostic assays and antimicrobial susceptibility testing, we will soon see large changes in the practice of clinical microbiology and infec tious disease epidemiology. nonetheless, several challenges remain before wgs can be routinely used in clinical practice (table ) . there is still a need for improved speed, ease of use, accuracy and longer read lengths. however, given the ongoing, relentless improvements in performance and cost-effectiveness of high-throughput sequencing, it is likely that these financial and technical challenges will be met relatively easily over the coming years [ ] . nonetheless, improvements in the analysis, archiving and sharing of wgs data need to occur before sequencing results can become trustworthy enough to guide clinical decision-making. significant investment in establishing standards, databases and communication tools will be required to maximize the opportunities provided by wgs in epidemiology. there may also be organizational and ethical issues with data ownership and access [ ] . careful contextualization of wgs data will be needed before robust conclusions can be drawn, ideally within an agreed framework of standard operating procedures. interpretation of genomic data requires a detailed knowledge of within-host and between-host genotypic diversity, whether defined at a single time point or longitudinally. readings from the molecular clock provide the temporal information needed to reconstruct the emergence and evolution of lineages and transmission events within an outbreak. this means that extensive benchmarking will be needed to determine the rates of genomic change, which are likely to be species-and even lineagespecific. only when wgs data have been obtained from a large number of epidemiologically linked and unlinked cases in a given lineage will it be possible to define cutoffs for the genomic differences that allow linked and unlinked cases to be accurately defined. this may also rely on comparisons with an 'outgroup' , that is, a group of cases that clearly fall outside the outbreak cluster. estimates of rates of genetic change have been published for some organisms: for example, s. aureus mutates relatively rapidly, with × - mutations per year, corresponding to . snps per genome per year [ , ] , whereas m. tuberculosis evolves slowly, acquiring only . snps per genome per year [ , [ ] [ ] [ ] . however, such data are available for only a very limited number of other pathogens. this will need to be expanded significantly before routine use of wgs data becomes a reality. we suspect that there may be consistent differ ences in the mode and rate of genotypic change between organ isms for which an asymptomatic carrier state (for example c. difficile) or a latent period (m. tuberculosis) exists and those, such as measles, for which there is no carrier state. in conclusion, it is clear that wgs is already transforming the practice of outbreak investigation. however, the dizzyingly fast pace of change in this field, with steady improvements in high-throughput sequencing, make predictions about the future difficult, particularly now that nanopore sequencing technologies are poised to deliver a revolution in our ability to sequence macromolecules in clinical samples (not just dna, but also rna and even proteins) [ , ] . portable nanopore technologies might provide a route to real-time near-patient testing and environmental sampling, as well as delivering a combined read-out of genotype and phenotype in bacterial cells (perhaps even allowing direct detection of the expression of resistance determinants). it also seems likely that clinical diagnostic metagenomics [ ] , perhaps equipped with target-specific enhancements such as sorting or capture of cells or dna, will deliver improved genomic epidemiological information, including insights into within-patient pathogen population genetics and identification and typing of non-culturable or difficult-toculture organisms. one thing is certain: the future of bacterial outbreak investigation will rely on a new paradigm of genomics and metagenomics. therefore, it is up to all clinical and epidemiological researchers to embrace the opportunities and meet the challenges of this new way of working london: penguin hus investigation team: epidemic profile of shiga-toxin-producing escherichia coli o :h outbreak in germany -preliminary report open-source genomic analysis of shiga-toxin-producing e. coli o :h meticillin-resistant staphylococcus aureus (mrsa): global epidemiology and harmonisation of typing methods drug-resistant tuberculosis issues in biosecurity and biosafety severe acute respiratory syndrome (sars) genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans outbreak of escherichia coli o :h associated with sprouts outbreak of shiga toxin-producing escherichia coli o :h associated with organic fenugreek sprouts overview of molecular typing methods for outbreak detection and epidemiological surveillance a surfeit of yatms? multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms pathogen typing in the genomics era: mlst and the future of molecular epidemiology the evolution of the escherichia coli phylogeny mycobacterial interspersed repetitive unit typing of mycobacterium tuberculosis compared to is -based restriction fragment length polymorphism analysis for investigation of apparently clustered cases of tuberculosis genome sequencing in clinical microbiology high-throughput bacterial genome sequencing: an embarrassment of choice, a world of opportunity high-throughput sequencing and clinical microbiology: progress, opportunities and challenges are diagnostic and public health bacteriology ready to become branches of genomic medicine methods for subtyping and molecular comparison of human viral genomes sequencing technologies -the next generation stepping stones in dna sequencing performance comparison of benchtop high-throughput sequencing platforms dw: a pilot study of rapid benchtop sequencing of staphylococcus aureus and clostridium difficile for outbreak detection and surveillance whole-genome sequencing for analysis of an outbreak of meticillin-resistant staphylococcus aureus: a descriptive study whole-genome sequencing to delineate mycobacterium tuberculosis outbreaks: a retrospective observational study whole-genome sequencing and socialnetwork analysis of a tuberculosis outbreak next-generation sequencing technology in clinical virology a culture-independent sequence-based metagenomics approach to the investigation of an outbreak of shiga-toxigenic escherichia coli {o :h } a new arenavirus in a cluster of fatal transplantassociated diseases newly discovered ebola virus associated with hemorrhagic fever outbreak in uganda combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission mrsa epidemic linked to a quickly spreading colonization and virulence determinant rationale and uses of a public hiv drug-resistance database a genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant staphylococcus aureus pandemic human genetic susceptibility to infectious disease resolution of a meningococcal disease outbreak from whole-genome sequence data with rapid web-based analysis methods bigsdb: scalable analysis of bacterial genome variation at the population level molecular phylogenetics: principles and practice probable zoonotic leprosy in the southern united states whole genome sequencing reveals local transmission patterns of mycobacterium bovis in sympatric cattle and badger populations yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity aarestrup fm: population genetics of vibrio cholerae from nepal in : evidence on the origin of the haitian outbreak emergence and global spread of epidemic healthcare-associated clostridium difficile shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from europe evidence for several waves of global transmission in the seventh cholera pandemic rapid pneumococcal evolution in response to clinical interventions in vivo capsular switch in streptococcus pneumoniaeanalysis by whole genome sequencing analysis of whole genome sequences of strains of rubella virus from the united states generations of sequencing technologies the need for ethical reflection on the use of molecular microbial characterisation in outbreak management with bacterial genome sequencing evolutionary dynamics of staphylococcus aureus during progression from carriage to disease use of whole genome sequencing to estimate the mutation rate of mycobacterium tuberculosis during latent infection recent advances in nanopore sequencing unfoldase-mediated protein translocation through an alpha-hemolysin nanopore microevolutionary analysis of clostridium difficile genomes to investigate transmission high-throughput whole-genome sequencing to dissect the epidemiology of acinetobacter baumannii isolates from a hospital outbreak genomics and outbreak investigation: from sequence to consequence tmw is an mrc research training fellow. the authors declare that they have no competing interests. mlst, multilocus sequence typing; mrsa, methicillin-resistant staphylococcus aureus; snp, single-nucleotide polymorphism; stec, shiga-toxin-producing escherichia coli; wgs, whole-genome sequencing. key: cord- - lf cp authors: timen, aura; hulscher, marlies e.j.l.; vos, dieuwke; van de laar, marita j.w.; fenton, kevin a.; van steenbergen, jim e.; van der meer, jos w.m.; grol, richard p.t.m. title: control measures used during lymphogranuloma venereum outbreak, europe date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: lf cp to assess the response to the reemergence of lymphogranuloma venereum, we conducted a cross-sectional survey by administering a structured questionnaire to representatives from european countries. responses were received from countries. the ability to respond quickly and the measures used for outbreak detection and control varied. evidence-based criteria were not consistently used to develop recommendations. we did not develop criteria to determine the effectiveness of the recommendations. the degree of preparedness for an unexpected outbreak, as well as the ability of countries to respond quickly to alerts, varied, which indicates weaknesses in the ability to control an outbreak. more guidance is needed to implement and evaluate control measures used during international outbreaks. to assess the response to the reemergence of lymphogranuloma venereum, we conducted a cross-sectional survey by administering a structured questionnaire to representatives from european countries. responses were received from countries. the ability to respond quickly and the measures used for outbreak detection and control varied. evidence-based criteria were not consistently used to develop recommendations. we did not develop criteria to determine the effectiveness of the recommendations. the degree of preparedness for an unexpected outbreak, as well as the ability of countries to respond quickly to alerts, varied, which indicated weaknesses in the ability to control an outbreak. more guidance is needed to implement and evaluate control measures used during international outbreaks. r esponding effectively to international communicable disease emergencies is a complex process that involves national and international cooperation. efforts should be aimed at managing patient care and containing the disease by interrupting the chain of transmission ( , ) . the severe acute respiratory syndrome outbreak has shown the need for being prepared and being able to deal with international emergencies in a consistent way; all countries need to be prepared and able to respond to an outbreak. countries throughout europe have developed preparedness plans to face a possible pandemic caused by a new infl uenza virus. but even with a well-acknowledged threat like an infl uenza pandemic, differences in preparedness between countries exist ( , ) . the differences might be even greater when timely control measures are needed for outbreaks that remain unnoticed for a long time. systems for surveillance and outbreak management among european countries differ, as do their health policies and guidelines. we wondered whether these differences could lead to different outbreak control measures and therefore to differences in the effectiveness of these control measures. we studied the quality and timeliness of public health actions during the reemergence of lymphogranuloma venereum (lgv) among men who have sex with men (msm) in europe from january to february . in january , the european surveillance of sexually transmitted infections network (essti) issued an international alert. this action was considered a trigger for countries to identify possible cases; defi ne, inform, and investigate the population at risk; and to implement control measures. the resurgence of lgv in europe contained many features similar to an infectious disease emergency: it occurred unexpectedly; there was delay in the recognition of cases, which allowed the disease to spread within the risk group; and there was no preconceived outbreak control plan. moreover, in many countries, lgv is not reportable and surveillance is voluntary. our study of the response to this lgv outbreak demonstrates the need for a unifi ed response to new, unexpected, infectious diseases. we assessed the similarities and differences in how various countries managed the lgv outbreak to identify common practices and to formulate criteria for improving the response to international outbreaks. the items on the questionnaire were based on a framework derived from the literature about outbreak management ( , ( ) ( ) ( ) . in addition, to assess the quality of the development and implementation of key recommendations for controlling the outbreak, we used parts of the international agree instrument (www.agreecollaboration.org) for appraising guidelines and guideline development programs. the questionnaire was divided into sections. the fi rst section was dedicated to the alert and initial response to lgv and included questions about actions taken after the essti alert, risk assessment, and occurrence of cases. the second section included questions about the development of outbreak control measures and gathered information about how evidence was collected and analyzed, how measures were formulated, when experts were consulted, and how recommendations were updated. the third section included questions about the content of outbreak control measures (i.e., case identifi cation, case defi nitions, laboratory confi rmation, treatment, reporting, and interventions for health professionals and the groups at risk). the fourth section addressed implementing outbreak control measures (i.e., strategies, dissemination of information, targets for monitoring effectiveness, and additional resources). questionnaires were completed electronically or on paper, and data were analyzed by spss . (chicago, il, usa). lgv is a sexually transmitted infection (sti) caused by chlamydia trachomatis serovars l , l , and l . contrary to infection with other serovars, infections with c. trachomatis l - are not limited to the mucosa but rather are often invasive and can spread to the lymph nodes, which results in a more severe clinical outlook. in industrialized countries, cases are incidentally imported from tropical and subtropical areas where the disease is endemic ( ) . public health measures are usually restricted to contact tracing and adequate management of sex partners in individual cases; outbreak management is not needed. by the end of , cases had been reported to the public health authorities in the netherlands, followed by a substantial increase in cases in subsequent months. the cases were seen among msm. clinical signs were mostly gastrointestinal and included proctitis, purulent or mucous anal discharge, and constipation ( ) . in the early days of the outbreak, the potential for international spread was recognized because patients reported having had sexual contacts in other countries such as belgium, the united kingdom, and france ( ) . to create awareness, a message was sent through the early warning and reporting system of the european union and through the essti. since then, lgv cases have been identifi ed in several european countries, the united states ( ) , and canada ( ) . most patients were hiv positive ( ) , and some were hepatitis c positive ( ) . the questionnaire was sent to countries; of these countries had reported outbreaks of lgv in the past. completed questionnaires were received from countries (austria, belgium, denmark, finland, france, germany, ireland, italy, the netherlands, norway, portugal, scotland, slovenia, spain, sweden, switzerland, united kingdom, and turkey). of the questionnaires, were completed by medical doctors, by medical epidemiologists, and by researchers/microbiologists. in countries (belgium, ireland, portugal, slovenia, and sweden), the questionnaire was fi lled in by or more experts from different areas of expertise. the countries that did not respond to either the questionnaire or the electronic reminders (slovak republic, poland, malta, latvia, iceland, cyprus, estonia, and greece) were excluded from the analysis. a complete overview of the activities reported for controlling lgv and their development and implementation is given in the tables and . after the essti alert in january , timely national alert and response systems were set up by of the responding countries. these systems included provisional control guidelines ( countries), voluntary reporting ( countries), and tools for disseminating information to health professionals ( countries). of the countries who undertook early alert and response activities, also reported cases. the main objectives of the alert were active case fi nding ( countries), assessing the size and nature of the outbreak ( countries), and providing appropriate clinical care ( countries). in countries, the initial alert and response were undertaken by professionals from the sti surveillance system in collaboration with specialists in outbreak control. in the other countries, only surveillance specialists were involved. five countries had a national outbreak management team or advisory committee that provided scientifi c advice on surveillance and outbreak management. the multidisciplinary outbreak management teams always included epidemiologists and microbiologists; less frequently included were molecular biologists, dermatovenereologists, genitourinary specialists, and communicable disease control specialists. in country, communication experts and social scientists also participated in the outbreak management teams. no general practitioners, nurses, patients, or policymakers were involved in outbreak management teams. of the countries, control measures were aimed primarily at identifying new cases ( countries) and promoting awareness among the risk group ( countries) and sti clinics ( countries). a risk assessment was performed by countries. when developing recommendations for outbreak control, criteria varied with the countries (tables and ) . evidence was systematically collected by literature ( countries) and electronic database searches ( countries). informal consensus procedures were mostly used to formulate recommendations ( countries) based on experiencebased analysis of evidence ( countries). procedures for updating control measures were available in countries. a total of countries developed national, multidisciplinary guidelines for lgv control, of which issued authorization procedures for the guidelines. active case fi nding was initiated by countries and contact tracing by . five countries implemented both. information activities for the group at risk were performed by countries and countries alerted their sti clinics. an overview of all the control measures is given in the tables and . a total of respondents (denmark, germany, norway, sweden, spain, united kingdom, scotland, austria, the netherlands, ireland, and belgium) used an identical case defi nition for confi rmed cases: msm or sexual contacts of patients with lgv, who had anorectal or inguinal syndrome and positive nucleic acid amplifi cation tests (naat) for chlamydia trachomatis genotype l , l , or l . from these countries, case defi nitions were also issued for probable and possible cases and differed widely according to laboratory criteria. laboratory diagnosis of c. trachomatis was performed by naat on the following samples: rectal swabs ( countries), biopsy material from lesions ( countries), urethral swabs ( countries), and urine ( countries). genotyping to confi rm the presence of serovars l -l was also available from countries. supplementary testing of patients for concurrent stis was recommended as follows: hiv ( countries), syphilis ( countries), hepatitis c ( countries), hepatitis b ( countries), and neisseria gonorrhoeae ( countries). with respect to antimicrobial therapy, various regimens and different doses were used. for countries doxycycline ( mg ×/day for days) was the fi rst choice of treatment. alternatives mentioned were tetracycline ( g/ day), minocycline ( mg loading dose followed by mg ×/day), and erythromycin ( mg ×/day). clinical and laboratory follow-up of the patients was performed by countries. the control measures were implemented by disseminating educational materials in countries, disseminating national bulletins in , and holding meetings and conferences for professionals in countries. most countries ( / ) had the risk group help disseminate information. targets to monitor the effectiveness of recommendations were not formulated by any country. this outbreak of lgv had special features with high clinical and public health signifi cance. first, recognition of cases was diffi cult due to the unusual clinical presentation that mimics infl ammatory bowel disease. second, the diagnosis of lgv involved invasive procedures for collecting samples and required naat, which were not licensed for rectal specimens. furthermore, patients mostly belonged to sex networks of msm in large cities with numerous anonymous partners from different countries ( ) and where (international) contact tracing was diffi cult. in most european countries, lgv is not notifi able by law so cases are likely to be dealt with outside the public health domain. the potential of unnoticed further spread and the risk for simultaneous transmission of other infections, such as hiv and syphilis, increased the public health importance of this outbreak. differences were seen between countries with respect to ability to rapidly respond and implement measures that are needed to detect or to control a possible outbreak. countries that reported cases of lgv were more likely to recommend control measures although measures were also needed to detect possible cases. to identify and diagnose cases, clinical specialists and public health physicians, as well as the risk group, must be aware of the outbreak, particularly for an lgv outbreak. lgv is a rare disease in europe, and often healthcare workers are not aware of the clinical features of the disease. outbreak control measures require collaboration between persons in multiple specialties, such as specialists in surveillance, communicable disease control, health promotion, and physicians involved in the direct patient care (venereologists, genitourinary medicine specialists, gastroenterologists, microbiologists) that do not necessarily work together in other circumstances. in this outbreak, information from the surveillance systems was as important for health providers as for policymakers; this information had to lead to immediate recognition of a public health threat and direct action. emerging infectious diseases • www.cdc.gov/eid • vol. , no. , april however, in the management of lgv patients, differences were seen between countries with respect to case defi nitions, laboratory testing, and antimicrobial drug treatment. with most patients belonging to international sex networks, uniform diagnostic procedures and treatment protocols would have been helpful for ensuring a uniform approach to outbreak control. furthermore, control measures were impaired because in many countries lgv is not a notifi able disease; therefore, there is no legal basis for disclosing names of sexual contacts to facilitate contact tracing and prevent further spread. contact tracing was made even more diffi cult because of the numerous anonymous sexual contacts in various european cities. criteria for evidence-based development of recommendations were not always consistently used to extract and analyze evidence for best practices during the lgv outbreak, which led to differences in outbreak management. specifi c targets for monitoring the effectiveness of recommendations were not formulated by any country. one strong point was the acknowledgment by many countries of the importance of having the risk group, msm, disseminate alerts and advocate awareness. until now, the reemergence of lgv has affected msm in european countries. the essti alert prompted these countries to take action to identify cases early, improve the management of cases, and assess the size of the outbreak. of the respondents, stated that they had not taken any action at this stage for various reasons: they did not receive the alert (turkey, slovenia) or they did not participate in the essti (switzerland). coordination at the european level should encourage and monitor the response of all countries to alerts. our study has some limitations. we assumed that all countries that were participating in the essti network in had also been informed about the lgv outbreak. later, it became clear that the countries that had joined the european union on may , , did not receive the es-sti alert. because only of these new european union member countries completed the questionnaire, it was also impossible to assess how outbreak control measures were developed and implemented. another limitation inherent to the method used was that not all key persons involved in the control of lgv were able to fi ll out the questionnaire. as the questionnaire was sent to the country representatives in the essti, it is possible that not all relevant information was available on the control measures and activities that had taken place at regional or local levels. furthermore, the quality of the outbreak management process and the development of outbreak measures could only be assessed indirectly on the basis of the answers to the questionnaire because only a few countries provided more detailed documents like guidelines or articles. the lgv outbreak is still ongoing in europe, and since the completion of this study more countries may have undertaken measures to identify and treat cases and to prevent further transmission. our fi ndings are helpful for understanding the responses to unexpected disease outbreaks. however, we do acknowledge that lgv is an sti (rather than a quickspreading communicable, airborne disease) and therefore, affects a minority of sexually active citizens (msm) in the country. communicable diseases differ from other health threats or crises because they spread from person to person. therefore, problems are often not restricted to country. various specifi c interventions are therefore justifi ed by the difference in local systems, cultures, and situations. however, the principles of outbreak response are general, and countries can learn from each other. this study shows that countries have varying degrees of ability to respond quickly to an unexpected outbreak; these fi ndings expose weaknesses in the outbreak control capacity in europe. although important steps have been taken for improvement ( ) , the quality of lgv outbreak control in europe could benefi t from uniform approaches in controlling other infectious diseases with potential for international spread and from exchanging information between countries. the challenge for the future will be to coordinate outbreak management in various countries for which continuity and coherence are essential. this study shows that coordination should at least aim to provide guidance as to when and how alerts should be implemented by various countries as well as to establish uniform case defi nitions and ensure the availability of optimal diagnostic facilities. we also show a lack of common strategies and that these should be developed with respect to treatment algorithms and contact tracing. furthermore, quality systems following the whole chain of outbreak management (alert, outbreak control measures, implementation, and evaluation) are needed. these systems should be based on standard approaches to outbreak management followed by external review of implemented measures. more international collaboration is needed to improve response and to ensure high standards of practice in managing international outbreaks and threats caused by emerging or reemerging stis. crisis situations increase the chance of overlooking essential steps in outbreak management because of time constraints, uncertainty, and the lack of substantial evidence in effective approaches to controlling new diseases. furthermore, during outbreaks, key recommendations involve quick decision-making by professionals who often have no time for reevaluation. although this need for quick decisions has been acknowledged for other threats like avian fl u, sars, or bioterrorism, little experience has been acquired with managing outbreaks of stis. our systematic approach could be helpful in preparing for or assessing the response to all kinds of public health emergencies. communicable disease outbreaks involving more than one country: systems approach to evaluating the response control of communicable disease manual world health organization. checklist for infl uenza epidemic preparedness. who/cds/csr/gip/ . . geneva: the organization how prepared is europe for pandemic infl uenza? analysis of national plans world health organization. revision of the international health regulations lymphogranuloma venereum preliminary report of an outbreak of lymphogranuloma venereum in homosexual men in the netherlands, with implications for other countries in western europe resurgence of lymphogranuloma venereum in western europe: an outbreak of chlamydia trachomatis serovar l proctitis in the netherlands among men who have sex with men increasing rates of sexual transmitted diseases in homosexual men in western europe and the united states: why? canadian lgv working group. emergence of lymphogranuloma venereum in canada lymphogranuloma venereum among men who have sex with men-the netherlands a cluster of acute hepatitis c virus infection among men who have sex with men-results from contact tracing and public health implications first case of lgv confi rmed in barcelona update on the european lymphogranuloma venereum epidemic among men who have sex with men address for correspondence: aura timen email: aura.timen@rivm.nl emerging infectious diseases • www.cdc.gov/eid • llc is pleased to provide online continuing medical education (cme) for this journal article, allowing clinicians the opportunity to earn cme credit. medscape, llc is accredited by the accreditation council for continuing medical education (accme) to provide cme for physicians ama pra category credits™. physicians should only claim credit commensurate with the extent of their participation in the activity. all other clinicians completing this activity will be issued a certifi cate of participation. to participate in this journal cme activity: ( ) review the learning objectives and author disclosures; ( ) study the education content md, has disclosed no relevant fi nancial relationships. cme author charles p we thank the members of the essti steering group and representatives from the countries who participated in the survey. this research was supported by a grant from the netherlands organization for health research and development (zonmw).mrs timen is a senior consultant on communicable disease control at the centre for infectious diseases of the national institute of public health and the environment (rivm), the netherlands. her main interest is the quality of outbreak management. key: cord- -ze hnddp authors: georgiou, harris v title: covid- outbreak in greece has passed its rising inflection point and stepping into its peak date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ze hnddp since the beginning of , covid- is the most urgent and challenging task for the international scientific community, in order to identify its behaviour, track its progress and plan effective mitigation policies. in this study, greece is the main focus for assessing the national outbreak and estimating the general trends and outlook of it. multiple data analytics procedures, spectral decomposition and curve-fitting formulations are developed based on the data available at hand. standard sieqrdp epidemic modelling is applied for greece and for the general region around it, providing hints for the outbreak progression in the mid- and long-term, for various infections under-reporting rates. the overall short-term outlook for greece seems to be towards positive, with a downward trend in infections rate daily increase (i.e., now beyond the exponential growth rate), a possible peak within a few days beyond april th, as well as the high availability level of icu w.r.t. expected demand at peak. on the negative side, the fade-out period seems to be in the order of several months, with high probability of recurrent surges of the outbreak. the mitigation policies for the `next day' should be focused on close tracking of the epidemic via large-scale tests, strict border checking in international travelling and an adaptive plan for selective activation of mitigation measures when deemed necessary. b acktrace of events and the availability of reliable data have enabled the construction of the timeline of events leading to the sars-cov- epidemic in china that has now turned into a world-wide pandemic within a few months. based on data-driven modelling of the outbreak in various countries and cross-country regions, along with 'synchronization' to imposed policies and mitigation measures, it is possible to formulate a realistic outline of events, effects on the outbreak, as well as hints on how the situation will evolve in the next few weeks. this paper is focused primarily on characterizing the sars-cov- outbreak in greece, based on data as they become available on a daily basis from national and international sources. a short review of the timeline and the pathology of the virus are presented briefly; next, data analytics on the outbreak on the national level are providing hints and baseline parameters of the epidemic in greece; the seir-like approach is introduced as a standard tool for modelling and predicting the outlook and the general outline of the next-day mitigation strategies; finally, a general discussion is made on how the pandemic evolves and how to address the challenges that lie ahead. on december st , when the western world was celebrating the new year's eve, china officially reported a cluster of cases of pneumonia-like illness of unknown cause in wuhan, hubei province. the next day officials close the huanan seafood market, suspected to be the source. a week later china identified a novel coronavirus as the cause of disease, which by then was already spreading in the local population. the first death by the disease, originally called 'wuhan pneumonia' and officially labeled by who as 'covid- ', was reported in wuhan on january th . although the genome of the virus was readily available since january th, the virus continued to spread across the region and by january th its was already infecting people in thailand, japan and south korea. the next day who confirmed human-to-human transmission of the virus, unofficially tagged as ' -ncov' at that moment, while china was already reporting confirmed cases. beginning on january rd, the cities of wuhan, ezhou and huanggang announce a general lockdown regarding public transportations, events and public gatherings. by the end of january the virus had already reached europe (germany) and australia, while china was reporting hundreds of new cases with a doubling rate of almost one day. since most of non-asian countries were still imposing no restrictions to international flights, it was clear by then that this was going to be a world-wide pandemic of unknown proportions. indeed, by february th the international death toll of victims of the new virus was more than , surpassing the fatalities of the sars epidemic in and that claimed people. on february th egypt reported its first confirmed case, the first african country in the recent days, and on th france reported its first fatality from the virus, the first outside asia. two days later a paper from chinese researchers provided some preliminary details about the virus, showing that covid- is not as deadly as other types of coronaviruses, with about % this study focuses on the covid- outbreak in greece and provides data-driven epidemic modelling and experimental results regarding the current state. based on these results, the overall short-term outlook for greece seems to be towards positive, having recently passed the rising inflection point and approaching the peak of the infections, and most probably capable of covering the projected icu demand peak by a large margin. on the downside, the fade-out period seems to be in the order of several months, with high probability of recurrent surges of the outbreak. the 'next day' mitigation policies need to be carefully planned, highly adaptive and based on close tracking of the outbreak via large-scale testing in the general population. of patients having mild disease, % severe disease including pneumonia, about % critical diseases including respiratory failure, septic shock and multi-organ failure and about % leading to death. these numbers were to be revised later on, but provided the general profile and pathology of the virus. on february th the world-wide death toll from covid- surpassed , including cases from more than countries besides china. who continued to point out the severity of the spread and the lack of will and funding from the international community to address it properly and promptly. israel and other countries in the region were already reporting confirmed cases by february st, a significant event for tracing the initialization of the epidemic in greece about a week later on february th. additionally, group of several dozens of people in total, tourists returning from israel & egypt and their close contacts, were quarantined after the first confirmed case was reported in northern greece. about the same time, another group of greek travellers had already returned back home from a business conference in northern italy, while the border checks for the virus in the airports were still relatively relaxed (only some fever checking or none at all). this was the kick-off moment for greece and at the time of new cases reporting being larger outside china than inside it. the who officials had not yet declared a pandemic, but on february th raised the risk from 'high' to 'very high', stating that in such a case global travel restrictions would have a 'significant economic and social impact'. in the following week the world-wide number of confirmed cases surpassed , and almost every country in europe was now starting to deal with national outbreaks. on march th the who officially declared the global covid- outbreak as 'pandemic' and greece goes into lockdown on schools, social events and public gatherings, following a few days of escalation towards measures of social distancing and self-isolation recommendations. on march th the international toll of covid- fatalities outside china surpass those of inside china, the source of the outbreak. from there on, the exponential growth of the spread is ravaging europe and the rest of the world, especially italy, spain, france and the usa, with no solid signs of slowing down, although some countries with containment measures (see: figure ) set early on seem to be in control and at the brink of a downward trend in newly reported cases. a. outbreak onset and timeline in greece. greece seemed to have a slow start regarding its internal sars-cov- outbreak. by early february it was clear that the virus is going to land inside the borders at some point after a few days of a couple of weeks at most. additionally, reports coming from other european countries already affected, as well as from china which still is the main source of information regarding the pandemic and the virus itself, gave time to the authorities to plan a gradual escalation of measures. the timeline of the main events in greece, followed by quick escalation of restrictive measures towards the final lockdown (mar, ) is as follows: • feb, : a few suspected cases reported in patras, travellers on a ship from italy. • feb, : st confirmed case reported, a woman who returned from northern italy. • mar, : reports of increased traffic away from large cities. • mar, : country-wide lockdown in effect. besides the first confirmed case on february th, the first important milestone in this timeline is the hours between march th- th, when the entire group of tourists who returned from israel and egypt (both already in national outbreak since february st and th, respectively) was tested and most of them were confirmed as infected. the next milestone is on march th, when the first confirmed case of unknown origin was reported. the next day this number was four and four days later it was , which translates to a spreading rate of . < r < for these cases of 'unknown origin'. from there on, it was almost certain that it was now infeasible anymore to contain them in time with backtracing and targeted isolation. the third and most vivid milestone, i.e., the country-wide lockdown measures, was an already expected outcome by the public since the - previous days, as the outbreak in italy was starting to explode. figure illustrates the confirmed cases of infections in greece per region on march th, a week before the countrywide lockdown went into effect and while the outbreak was starting to significantly increase speed. it is worth noting that, although since march rd greece is in lockdown, some businesses are still allowed to operate; these are primarily pharmacies, supermarkets, banks, groceries, bakeries, etc (food, medicines, basic needs). movements of individuals is allowed only to/from work and to/from home for limited trips of shopping, pet walking, athletics (single). no public venues or events are allowed at least up to the middle of may. there are strict checks at the tolls and penalties for travellers and even individuals without carrying proper paperwork. for still-working persons, driving in a personal car is encouraged and public transport, although still functioning, has severely limited the scheduled trips per route. coronaviruses constitute a large family of viruses that can cause a wide range of disease cases, ranging from common colds to severe pneumonia and fatalities, usually from secondary cases and other underlying pathologies. they are usually found in animals and some are transmittable to humans, which may later mutate and become transmittable between humans too. sars and mers diseases are caused by a corresponding coronavirus and their pathological characteristics are wellstudied in the last two decades. early in the epidemic in china, the sars-cov- virus was isolated and its genome analyzed. figures and illustrate two of the very first pictures of the virus via electron-microscope. it was quickly identified as a sars-like in type, pathology and estimated epidemic characteristics. soon after the first few hundred of confirmed cases in china were treated in hospitals, a general profile of its symptoms started to emerge and the doctors throughout the world could immediately identify a 'possibly positive', as figure shows. according to the currently available world-wide data, the virus' reproduction and contagious characteristics place it somewhere between sars and ebola (see: figure ). its fatality rate is somewhat more difficult to estimate, as this depends largely on each country's health infrastructure and capacity, the stage of the outbreak, if these facilities and saturated or not, other underlying pathological issues in the general population, etc. on april th ( ) the top who official tedros adhanom ghebreyesus stated * that covid- is 'ten times deadlier' than the h n strain ('swine flue'), which evolved world-wide between january and august , with more than . million confirmed cases and , deaths. he also added that in some countries the doubling period is 'three to four days' and that this virus 'accelerates very fast it decelerates much more slowly'. * v. wood, 'coronavirus times more deadly than swine flu, says who', the independent (uk), -apr- . a first estimation places its fatality rate in china (early outbreak) at least above . % of confirmed cases; however, post-analysis with extensive cases analysis, as well as results from countries with a very large rate of randomized tests (including south korea, iceland, germany) lower the actual fatality rate to % or less (see: figure ). taking into account the epidemic data from several countries within this first threemonth window, figure shows the real range of the fatality rate, ranging from . % to % or more, depending on the circumstances and phase of the epidemic. overall, the world-wide pandemic seems to be evolving in exponential or sub-exponential rate depending on the country, time since the first (or first th) confirmed case and, primarily, the time of the onset of strict lockdown measures. figure presents the progress of the covid- pandemic in various countries and continents, with higher curvature towards the right associated to slower spreading rates. a virus outbreak in the general population of a town, a region or an entire country is a very dynamic and usually a rapidly evolving natural phenomenon. depending on the speed of infections spread, the severity of the resulting diseases and the capacity of the local/national health system, this can be categorized as a natural disaster that may be very difficult to contain and mitigate. there are several phases in a sars-like virus epidemic, as figure illustrates. phases - are mostly 'dormant', when the virus is mutated and begins to transmit form animals to humans, but remained undetected until the number of infections becomes significant. in phase the virus is spreading freely in human populations, with the authorities not yet knowing how/where to address it and not yet having strict measures in effect to mitigate it. during this phase, the infections increase at a high exponential rate and a large portion of them is usually undetected and, thus, under-reported. phase may be split into two sub-phases: the first (phase a) begins at the moment the quarantine measures are in effect and start to gradually slow down the exponential growth to a peak (maximum number of active infections); the second (phase b) begins at the peak and continues to the point when the active infections decrease and the evolution is becoming a curve that asymptotically approaches zero. then, phase is the period of this asymptotically decreasing active infections, where usually the quarantine measures are gradually deactivated; this is the phase when most recurrent events occur, as some still-infected and unregistered cases can move freely again in the general population. without prompt and effective vaccination procedures and large-scale tests in place for the general population, these events are almost certain to happen with flu-like viruses. after any such recurrent events fade out, the final phase is in effect and the virus spread can be tracked on a seasonal level, taking into account natural immunization (recovered patients) and vaccination that make a new large-scale outbreak very unlikely. since early detection and stopping is only rarely a realistic option, in most cases the most critical phase in terms of mitigation is the middle or 'peak' of active infections (phase ). previous experience has proved that the most crucial factor there is the capacity of the health system that handles the concurrent active infections and most importantly: (a) the number of icu available for critical cases, (b) the number of health workers that get infected or quarantined themselves, i.e., out of the 'battle', and (c) the availability of targeted tests and other resources, e.g., personal protection gear, spare parts for medical equipment, consumables in hospitals, etc. in order to keep the infection rate within the capacity of the health system, i.e., below a critical threshold, it is imperative that social distancing and protective measures are early in phase -this causes the infection rate to slow down and the peak to become lower, an effect that is often referred to as 'flattening the curve' (see: figure ). on the other hand, slowing down the infection rate results in much longer 'tails' in phase , i.e., a similarly slower rate of the asymptotically fading-out of the outbreak. additionally, if no vaccination is available in phase , any deactivation of the quarantine measures re-exposes the general population to undetected infections and the probability of a recurrent outbreak becomes higher. in other words, the more 'flat' the curve is at the peak of the outbreak, the longer is the fade-out period is and with higher possibility of another outbreak. additionally, since the infection-to-recovery cycle usually produces natural immunization (depending on the virus type), having a 'flat' curve also translates to lower levels of natural protection for the general public and usually stronger subsequent waves of the same outbreak. figure in the end, if the complete wipe-out of the virus cannot be guaranteed in the long term, the only stable outcome is when the general population has been immunized, naturally (infected/recovered) or artificially (vaccination), at a minimum proportion usually much higher that - %, depending on the type of the virus -but still, % is not required, due to the 'herd immunity' phenomenon ( , ) . hence, 'flattening the curve' is a measure of securing more time for the health system to cope with the highest infection rate or 'peak' and for the community to improve intermediate treatments and . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint the mathematical modelling of epidemics has been a very active research field for decades, even before sources with detailed data were available. as explained in section , it is important to be able to estimate the progress of the outbreak and its phase, in order to properly and promptly plan the mitigation measures. by far, the most popular and well-established approach is the family of compartmental epidemic models, originally developed as far back as s. their common characteristic is the base assumption of having a target population partitioned in compartments that are homogeneous in all relevant properties (e.g., sex, age, underlying pathologies, etc) and there are direct interactions between them. the three basic compartments are s='susceptible', i='infectious' and r='recovered', assuming insignificant rate of deaths and permanent immunity after recovery. variants of this sir base model include a d='deaths' compartment (sird), e='exposed' compartment (seir, seird) for introducing an incubation period, q='quarantined' compartment (seiqrd, seiqrdp) for separating the already isolated confirmed/possible carriers, etc. the sir-like models, along with more recent seir-like variants, are still used as the baseline for comparing other approaches to epidemic modelling. these are usually based on sequential monte carlo ( , ) , markov chain monte carlo (mcmc) or markov chain quasi-monte carlo (mcqmc) ( - ), hidden markov models (hmm) ( ) ( ) ( ) ( ) , etc, each posing other assumptions, advantages and drawbacks -most commonly the availability or not of a significant amount of epidemic data upon which they are to be trained. the sir-like epidemic modelling is closely related to the lotka-volterra system of equations ( ) , developed in the s to describe the evolution of dynamic systems via differential equations. they constitute an example of the more generic kolmogorov model ( , ) which can describe the dynamics of ecological systems with predator-prey interactions, competition, disease, etc. based on recent models that are already being tested with covid- data from china and other countries, the current work explored the (still scarce) epidemic data for greece via the generic framework of a seiqrdp model setup ( , ) . the additional p='insusceptible' corresponds to a fraction of the general population (if any) that, even when exposed to the virus, cannot become 'infected' and, thus, does not enter the e compartments and stays outside the 'pipeline' of the epidemic. each interaction between the seiqrdp compartments is governed by an scalar parameter that governs the way fractions of each subset is 'transferred' to another, e.g., from 'infected' to 'recovered'. figure illustrates the seiqrdp model and the meaning of each parameter. the internal structure of the model, i.e., the interactions that describe the dynamics of the system, is formulated by eq. through eq. . the system of seiqrdp model are typical first-order linear differential equations ( ) in the form of dy /dx + p (x)y = q(x), which can be solved analytically according to eq. : [ ] however, these analytical solutions are useful mostly for estimating the asymptotic steady-state outcomes and only when the equations are fully defined, i.e., when all the function parameters are already known ( ) . for example, eq. in seiqrdp can be analytically solved according to eq. and eq. , i.e., by substituting x = i(t), y = s(t), where α, β, n are the seiqrdp model parameters in eq. , c is a constant and ∆t is the integration range. for the entire time series from start t = to a current point t = τ , eq. is simplified to eq. : [ ] and for τ = the c constant is defined as s( ) e ξ( )dt = s( ) = c . according to the seiqrdp formulation in figure , the ατ (independent of i(t)) term means that asymptotically all 'susceptible' s(t) will be transferred to 'insusceptible' p (t) compartment regardless of the convergence of 'infections' i(t) asymptotically to zero. this is not realistic for fixedsized populations, since the infection will probably fade out before everyone gets immunized (or dead), i.e., with some still remaining in s(t), due to the 'herd immunity' phenomenon ( , ) . each of the parameters of seiqrdp model in the block diagram of figure and the corresponding system of differential equations provide very important hints regarding the dynamics of the underlying system, i.e., the evolution of the epidemic that the model describes, given enough data are available as ground truth. since the seiqrdp system of differential equations described by eq. through eq. indicate a specific underlying 'structure' for the systems' dynamics, i.e., solutions to interconnected differential equations, arithmetic euler-like solution approaches can be used very early on, when the epidemic data are just beginning to accumulate on a day-to-day basis. this is perhaps the main advantage over other approaches that require a statistically significant pool of epidemic data as ground truth from the beginning, e.g., in order to estimate posterior probabilities, etc. the application of a seiqrdp model for greece is presented in section .d, while evaluation of a similar model for the entire region is presented in section .d. in order to analyze the progress of the outbreak in greece, a detailed dataset of daily reports must be used. more specifically, the base dataset used in this study is the one provided for open-access † and updated on a daily bases by john hopkins csse ( ) , which is the most popular and reliable source at the moment. it includes confirmed cases of infected i(t), deaths d(t) and recovered r(t), registered per-country and in some cases per-province/region/state, collected by the official sources from who, cdc (us), european cdc, state authorities in each country, as well as other open-access sources. the basic curves for greece from the beginning of the national epidemic are presented in figures and , in linear and logarithmic scale, respectively. from the basic curves, especially the i(t), it is clear that the progress of the outbreak in greece is exponential, as expected, but with a relatively slow rate. in the first two weeks there are several step-wise 'pauses' and 'bursts', as it is usually observed in the early stages of a fast-growing epidemic. this is due to the fact that the set sizes are still relatively small and statistics still unstable, as well as the lack of strict mitigation measures that are usually activated with some delay. the critical 'necks' before large increases in new infections seem to be around day and day since the start of the time series, i.e., march th and march th, respectively. as presented previously in section a, these dates coincide with two important events in the greek timeline: (a) the st confirmed case in the group of tourists who returned from israel & egypt and (b) new confirmed cases of unknown origin and the st virus-associated death. for (a) it was understood that this group of tourists were asymptomatic for a few days and, thus, have been spreading the virus in the general population in the meantime, as the data proved subsequently. for (b) it was clear that the new confirmed cases of unknown origin, i.e., unrelated to both the group of tourists from israel & egypt as well as the other group that returned from northern italy a few days earlier, were to increase rapidly, as was indeed the case. this is particularly important, because at this point † https: . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint it is understood that the virus has escaped the strict and detailed backtracing of infections and their close encounters, in order to impose targeted isolations. thus, the operational plan should change to wide-range mitigation measures, as quickly as possible. fortunately, this is what happened in the following days and, given that the outbreak continued to spread at a fast rate, greece went into a nation-wide lockdown days later. a. comparison to other countries. taking into account the progress of the pandemic world-wide since early january , the curves in figures and reveal that greece had a slow start. however, it is not sufficient to simply align the offset of each country's specific event to the others', e.g., the first reported death or the th confirmed case of covid- . the entire curve has to be compared and 'aligned' to others for a more realistic match. for this reason, dynamic time warping ( , ) was used for comparing greece's infections i(t) curve to countries in the general region of europe and central/eastern mediterranean sea, especially those in direct 'contact' with greece via international flights. figure illustrates the original and the dtw-matched curves of greece (blue) versus switzerland (red). the dtw matching provides two important parameters for further study: (a) a more realistic estimate of the time offset for temporal alignment and (b) a dtw-based euclidean distance that can be used as a similarity measure. using these two parameters, figure illustrates the relative temporal difference (offset) and figure the dtw-based similarity of greece-versusothers regarding the confirmed cases of infections i(t). as the comparative plots in figures and show, the outbreak in greece seems more 'aligned' with uk, estonia, and north macedonia and more 'similar' to croatia, egypt, algeria, finland, etc. it should be noted that at the beginning of the outbreak in greece the temporal lag offset w.r.t. the group of countries presented here was more than days 'behind'. during the last two weeks it seems that the outbreak in greece gets gradually 'synchronized' with what is happening with the rest of the countries in this region and now the lag seems to be less than two days (t = − . ). this is particularly important in terms of a similar alignment of the timeline of gradual . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint deactivation of mitigation measures: if a country is still far 'behind' in the progress of the epidemic, then re-establishing international flights increases the risk of having another wave of the outbreak inside this country, as discussed earlier in section . b. data-driven analytics. using the daily time series for confirmed cases of infected i(t), deaths d(t) and recovered r(t) in greece, appropriate approximations can be developed in order to estimate important parameters of the outbreak in greece. specifically, using the i(t) data series the following exponential formulation can be designed according to eq. : where a, b, c are the function parameters. their best-fit optimal values in the least-squares (lse) sense ( ) and the % confidence intervals for greece are presented in table . figure presents the difference between a 'naive' exponential y(t) = e cx(t) (red) with only one parameter and the good fit (r = . , rmse= . ) of eq. (magenta). in the second case it is clear that the function design, i.e., an exponentially saturating formula, as well as a linear error weighting that is applied towards the more recent date range, provides the very robust set of optimized parameters that table presents. it should also be noted that, as the i(t) becomes more linear due to the gradual slow-down of the national outbreak, the exponential factor c in eq. and table converges to zero and factors a and b increase, i.e., the value of i(t) asymptotically approaches its upper threshold as it crossed well inside phase a of the epidemic and moves towards its 'peak' (see: section ). it should be noted that the approximation of eq. is valid only for epidemic phases and most of phase a as explained in section , because after the curvature sign change or 'inflection point' ‡ ( , ) of i(t) at the start of phase ( d i(t) /dt = ) and especially when closing towards the peak between subphases a and b, the curvature d i(t) /dt becomes negative and the slope di(t) /dt of i(t) begins to decrease, i.e., the saturation point of eq. is no longer an asymptotic limit as it 'leaves behind' the actual i(t) peak. using the approximation of eq. and table , the basic reproduction number r can be approximated by an analytical formulation too, taking the limit of the mean ratio of the marginal increase of i(t), as described in eq. . figure illustrates the progress of the (estimated) r for greece from the beginning of the national epidemic, according to eq. . ‡ an inflection point of a function is where its concavity changes from upwards to downwards ('falling') or vice versa ('rising'); more formally, the points where its curvature or second derivative changes sign, passing through zero-value in between. technical report | april , | ref: hg-tr a -cov gr | . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint the estimate of r in figure at the current state (far right) can be confirmed by taking a sliding-window linear regression (lr) ( , ) on the most recent temporal window on the actual i(t) data series, using the standard lr formulation as described in eq. , eq. and eq. . additionally, the corresponding doubling rate dd can be estimated from r by eq. .ŷ i =b xi +b [ ] b b =ȳ −β x [ ] wherex according to the r approximation of eq. and using a marginal step of τ = day, the current eight-day lr approximations of r = . ( . , . ) and dd = ( , ) in figure confirm the corresponding estimations calculated by eq. and eq. . the value of r seems to have reached the critical low threshold of . briefly on - th of april, followed by consecutive days of stable value of . until today. it is worth noting that the greece's team of experts on the official daily briefing of april th stated for the first time that 'r is now falling below '. two other important parameters that can be estimated by taking a sliding-window lr on the most recent temporal frame on the actual i(t) data series, using the formulation as described in eq. , eq. and eq. , are the ratio of icu to i(t) and the ratio of deaths d(t) to i(t). the first is a good indicator of whether there is a trend towards possible saturation of the health system in treating severe cases of infection. the second can be used to compare the national fatality rate with the global statistics estimated internationally, in order to see if the under-reporting of i(t) is much more significant than in other countries and, hence, verify the inherent risk of all the infections-related assumptions in the target country. fortunately, the icu trend in greece seems to be steadily decreasing during the last ten days, after a sharp rise the days before. given the fact that greece entered this crisis with only and still with less than icu currently available throughout the country, keeping this number down is crucial in the quality of treatment of severe cases and of course avoiding the saturation of the health system if it comes close to its maximum capacity. as figure shows, the current estimation of the icu-to-i(t) ratio has dropped from - % and is now at about . % ( in ) and with steady -day lr slope (- . ). the current d(t)/i(t) ratio for greece is also providing a good lr fit, presented in figure , with a value fluctuating slightly between % and %, currently at . % ( in ) and with relatively steady -day lr slope (+ . ). this is generally inside the 'global' region of % to % that is estimated internationally for covid- , as presented previously in figure . it has been accepted by state officials that the underreporting of i(t) in greece may be up to : (only in infections registered) or more, given the numbers from other countries and the targeted-only tests in greece. a recent study § ( ) estimates the true number of i(t) for greece between , and , in the general population ¶ rather than , officially documented by april th, i.e., an underreporting rate of . : in currently active infections. nevertheless, the d(t)/i(t) fatality ratio is still within the expected zone, indicating that the overall tracking of i(t), d(t) and r(t) data series are reliable enough to track the general progress of the national outbreak, at least as much as in any other country still behind or just entering phase of its national epidemic. § https://imperialcollegelondon.github.io/covid estimates/ ¶ estimated true infected epidemic in greece and in any other country, the corresponding time series have to be investigated in terms of linear and periodic trends, i.e., analyze them into their primary frequency components. in signal processing this is normally done via time-domain filtering or a fourier transformation for frequencydomain filtering ( ) . in case of non-stationary signals, filters can be formulated via adaptive algorithms in order to track the stationarity shifts of the underlying event ( ) . a more generic alternative that is usually applied in complex systems where the input/output association is governed by multiple 'internal' parameters is via state-space representation, where the input and output are connected through an internal 'state vector'. in this case, the model is trained so that for specific inputs produces specific outputs based on functional dependencies between each of them and the state vector. if the training data are saturated with noise or if the system itself is non-stationary, this formulation can be generalized in a probabilistic way -this is the core idea behind kalman filtering ( ) . in almost all cases of analytical formulations for signal processing the basic assumption is that the underlying system is a linear model or can be closely approximated within a useful range by 'linearization' ( ) . unfortunately, these methods are not easily applicable per-se in long-term epidemic modelling, since the underlying system in governed by a system of differential equations that describe the dynamics of the phenomenon, which in epidemic outbreaks is the non-trivial interactions between groups of populations including the susceptible, the exposed, the infected, the fatalities, the recovered, etc. more on this approach is presented later on in section . one important factor that can be investigated regardless of the long-term approximation of the underlying system is analyzing the step-wise dependencies between successive data points, especially the confirmed cases i(t). in statistical terms, this is done by estimating the auto-correlation in the time series for various lags, which produces a quantitative description of dependencies between dates, i.e., separated by a specific number of days. a more descriptive analysis is the fourier figure presents the normalized auto-correlation plot of ∆i(t) (blue); it is evident that the two sides of the lobe are almost entirely linear and the lr lines (red) in each side are almost parallel to the reference line (green) that corresponds to the case of ∆i(t) = c, i.e., for constant daily increase of i(t + τ ) = cτ + i(t). this proves that, at least in asymptotic behaviour towards the current state, i(t) increase in greece is gradually becoming linear. additionally, using fft for spectral decomposition, figure presents the spectrum (normalized, abs.value, half-width) of ∆i(t) (blue). from left to right, the x-axis corresponds to temporal window size of the corresponding component. in practice, this means that the left-most points in the plot correspond to spectral components spanning to a temporal window of half the entire time series, i.e., periodic trends of three weeks or more. on the opposite side, the right-most points in the plot correspond to spectral components spanning to a temporal window of , , days, etc. from this plot it is clear that there are indeed two groups of significant spectral components: (a) short-term in the span of and days and (b) long-term in the span of days. this is observation coincides with two very important periodic trends of the covid- outbreak, already documented empirically throughout the world ( , ) : (a) the incubation period of the virus, mostly asymptomatic and thus highly contagious, is estimated at . - . days; and (b) the suggested quarantine safe period for the onset of symptoms in asymptomatic carriers or after their recovery is at least two weeks, i.e., associated with the long-term spectral component if incubation period is included (infection just before quarantine ends). observation (a) can probably be associated with the short-term spectral component of days - , i.e., the window between the onset of an infection and the manifestation of disease symptoms. observation (b) may be associated with the long-term spectral component around day , given that the additional week can be attributed to infections set right at the end of a two-week it should be noted that spectral components describe both increasing and decreasing trends, i.e., either sudden increases and decreases of ∆i(t). thus, first observation suggests that large changes of ∆i(t) w.r.t the mean are expected with a frequency of about the - th day, as well as the th day. data are still limited for a long-term (statistically significant) validation per-component, but observed fluctuations of these primary spectral components are limited and, hence, these numbers can indicate valid hints regarding the effectiveness of specific mitigation measures activated during that time. another way to track the periodic 'bursts' of newly reported infections as the are reported on a daily basis is to track the changes in the short-term slope of ∆i(t). instead of approximating the entire i(t) curve as in eq. and figure for estimating the long-term behaviour, a short-term temporal window can be used to approximate the lr slope of i(t) as it progresses, i.e., the amplitude and sign of ∆i(t) changes over few subsequent days. figure illustrates such a short-term tracking of ∆i(t) via the st-order differential d logb (t) /dt of lr slope of i(t) withb as defined in eq. , or in other words the ∆ i(t), over a short-term sliding window of four days. the main curve (magenta) in figure is the short-term lr slopeb value for i(t) as it evolves; the arrow annotations indicate decreasing (green) or increasing (red) trends; the asterisks (blue) on the x-axis indicate the major events regarding the activation of mitigation measures in greece as described in the timeline in section a. finally, the asymptotically fading sinusoid (black) is a lse-fitted approximation of g ( t) byĝ(t), as defined by eq. , eq. and eq. , with their lse-optimal parameters presented in table . [ ] z(t) = α sin(α t − α ) + (β t + β ) [ ] from the approximation curve in figure there is clear indication of three major factors: (a) periodic trend, captured by the first part of eq. with αi parameters, (b) linear decreasing trend, captured by the second part of eq. with βj parameters, and (c) asymptotically fading trend, captured by the rd-degree polynomial of eq. with p k parameters. the periodic trend parameters, more specifically the α = . , can be translated from radians to daily temporal range via α / π = t /t where t = d is the current length of the data series for greece (april th) since the first confirmed infection case (february th), hence yielding a period tp = α t / π ≈ . t ≈ . d. again, this number almost coincides with the empirical data regarding the incubation (asymptomatic) period of covid- , estimated at . - . days ( , ) . additionally, the linear trend with marginally downward slope (β < ) shows a gradual slowdown of the 'force' of the outbreak in greece, while the asymptotically fading trend captured by the rd-degree polynomial (p k ) shows that the 'bursts' or 'waves' of the newly reported infections (∆i(t)) are also fading out after less than t /tp ≈ . periods ( - in practice, according to figure ). taking into consideration that the main mitigation measures (blue asterisks in x-axis) in greece were activated just before each major 'peak' in (∆i(t)), it can be stated that they were imposed in a timely manner and, thus, they were appropriate and effective in containing the 'force' of the national outbreak until today. based on the compartmentalized sir/seir epidemic modelling described in section , in this study a seiqrdp model was designed and trained using the i(t), d(t) and r(t) data series for greece, from -feb- to -apr- . the purpose of this work was to re-estimate the general properties of sars-cov- virus and the covid- outbreak on the national level, in order to: (a) confirm that the available data series are adequate and their evolution in accordance to the research outcomes from other countries and on world-wide level; and (b) to estimate the progress of the outbreak on the mid-/long-term level, specifically for the epidemic phases, the expected peak date and magnitude, etc. the solution of the seiqrdp system of differential equations defined in eq. through eq. was estimated by a standard lse solver ( ) for iterative matching of the predicted trajectories to the real data. for inclusion of a minimal underreporting of infections, i(t) data series was amplified by an additional + % upon its recorded values. the lse solver used centralized differential estimators, e- time step size ( . ms) and e- error tolerance for stopping criterion. in all cases, the process converged to a solution within less than iterations, which hints that the actual epidemic data for greece are well-described by the seiqrdp model. figures and present the best-fit solution of the seiqrdp model (points) and its projection (lines) until august ( ), in linear and logarithmic scale, respectively. the dotted line in figure illustrates the onset of a subsequent surge of the outbreak if all the mitigation measures (quarantine) was to be deactivated immediately (april th). table presents the values for all the seiqrdp parameters for the best-fit solution. given the estimated under-reporting of confirmed cases i(t) as explained earlier in section .b, two additional scenarios were tested: one for the low estimation of . : ( , / , ) and one for the high estimation of . : ( , / , ) . similarly to the previous, figures and present the bestfit solution of the seiqrdp model (points) and its projection (lines) until august ( ), in linear and logarithmic scale, respectively, for the 'low' scenario of . : under-reporting of i(t). the dotted line in figure illustrates the onset of a subsequent surge of the outbreak if all the mitigation measures (quarantine) was to be deactivated immediately (april th). table presents the corresponding values for all the seiqrdp parameters for the best-fit solution. . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint finally, figures and present the best-fit solution of the seiqrdp model (points) and its projection (lines) until august ( ), in linear and logarithmic scale, respectively, for the 'high' scenario of . : under-reporting of i(t). the dotted line in figure illustrates the onset of a subsequent surge of the outbreak if all the mitigation measures (quarantine) was to be deactivated immediately (april th). table presents the corresponding values for all the seiqrdp parameters for the best-fit solution. in tables and , parameter λ is highlighted as the only one with significant variation between the three under-reporting scenarios for i(t). more specifically, the marginal . : and the 'high' . : solutions are compatible, but the 'low' . : is not, since its λ value is almost six-fold smaller than the other two, despite the fact that in all cases the lse best-fit solutions are of good quality (see comments). the lambda parameter in seqrdp is associated to the rate of transfers between 'quarantined' q(t) and 'recovered' r(t) compartments (see: figure ). this is an interesting issue for further investigation at a later time, when more data will be available through post-analysis after the resolution of the national outbreak, in relation to a more realistic estimation of the actual underreporting of i(t) during the crisis. summarizing the seiqrdp best-fit solutions for the various scenarios of infections under-reporting, estimations of peak . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint i(t) dates for greece are presented in table . note that, given the epidemic phase uncertainty due to the still limited data series, no value estimations are presented for i(t). nevertheless, the goodness-of-fit of the seiqrdp solutions provides a valid 'explanation' for the dynamics of the national epidemic, i.e., the interaction between the compartments. thus, the overall shape and scale of the corresponding curves can be considered as safe for general assessments, including peak i(t) dates. the data analytics, best-fit model parameters and projected outcomes for greece, as presented in the previous sections, provide solid evidence that the covid- outbreak at the national level can be tracked with adequate accuracy for the general assessment of the situation, including the transition through the phases of the epidemic. additionally, it can be compared to the corresponding world-wide analytics and epidemic parameters for validation. a. outlook for greece. officially, the sars-cov- spread in greece begun with the first confirmed case of infection on february th. from there on, both the infections are rising monotonically, i.e., the national epidemic is still prior to its peak, where the infections are expected to be stabilized. additionally, the rate of increase in the confirmed infections has been rising too, thus yielding an exponential growth, up to a point somewhere between days - past january nd, i.e., somewhere in april nd- th (see: figure . taking into account the evolution of the outbreak and the progress of the estimated epidemic parameters beyond this point, it seems that the rate of increase has been gradually slowing down until today. in fact, there have been three consecutive days in offset + past january nd of decreasing slope in the rate of confirmed infections (april th- th: ). this is evidence that, indeed, a rising inflection point was passed around april nd- th and, the rate of infections increase is slowing down and greece is nearing its peak. in other words, it is now beyond phase and well inside phase a, according to the descriptions in section . based on this evidence and the fact that icu needs (recently at − and steady) are still well inside the currently available capacity of the country's health system (≈ ), icu availability can be safely considered as guaranteed with a very high probability through the outbreak peak and beyond that. in the long-term, the seiqrdp projection estimates the total number of fatalities directly related to covid- at a few hundreds at most up to and including the entire summer, provided that the national epidemic will be tracked continuously and accurately, as well as an effective plan for adapting the mitigation measures appropriately in the next several months. on the opposite side, high-impact mitigation measures and prompt containment of an epidemic most commonly translates to a low immunization / high residual susceptibility level for the general population after the outbreak, provided that no large-scale artificial immunization (vaccination) will be available soon and re-introduction of the virus in greece is almost a certainty after the international travelling restrictions are gradually deactivated. hence, additionally one or more outbreak surges are expected in the national level within the year, always in correlation to what is happening to neighbouring countries and international travelling, as well as the speed of deactivation of national mitigation measures (lift of quarantine). in the end, a high proportion of the general population in greece has to get immunized through recovery or vaccination, in order to establish an evolutionary stable 'herd immunity' state. an additional negative factor is the expected slow fadeout period, i.e., longer phase in the epidemic, due to the estimated high rate of under-reported infections. results from the corresponding seiqrdp best-fit projections of peak dates in table show that the higher the under-reporting rate, the slower the progress of the outbreak is through its peak and fade-out period. this is a very important aspect of planning the deactivation of mitigation measures at the national level, as well as the need to very strict border checking regarding international travelling and large-scale covid- testing in the general population for accurate tracking of the residual or new spread. b. supporting evidence. in more technical terms, the evidence that leads to the outlook for greece can be seen in the results presented in previous sections. more specifically, the close inspection of figures and , as well as the details in the plot of 'status tracking' in figure , reveal that the national epidemic is indeed slowing down. additionally, the epidemic parameters estimated from the related data for greece are within the expected ranges w.r.t. the international experience with covid- since the start of the pandemic. this is also true for the periodic trends of the national outbreak, based on the main spectral components (see: figure ). the overall 'positioning' of greece in terms of the onset, phase difference and infections curve similarity towards the countries in the greater area (europe, north africa, near middle-east), according to figures and , reveal that the national outbreak is a rather average-case rather than an outlier. the values of parameters in the seiqrdp best-fit solutions seem to behave as expected (except perhaps λ) and the value of its most important 'exponential spread' parameter is reliably at β = . , regardless of the under-reporting ratio in infections. in general, during the last - days all the data analytics and modelling parameters seem to be 'smoothing out' gradually towards a more steady state, i.e., approaching the peak of confirmed infections, thus ending phase a and beginning phase b (downwards slopes). . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint tigation, perhaps in a post-analysis level after the resolution of the current crisis, when more data will be available. one such factor of uncertainty is the presence of a significant data shift or 'step' in the time series, observed visually on day past january nd, i.e., april th. this 'step' constitutes a very low + newly reported infections i(t) between two days of + and + , while at the same time having a very large daily increase in recoveries r(t) (see: figures and ). this may be attributed to late confirmation or official reporting of clinical tests for patients prior to their release from hospital, but this is only an assumption. another uncertainty factor is the actual rate of underreported infections at the national level, mostly due to targetedonly covid- tests instead of wide-range tests in the general population as in other countries. although several epidemic parameters are not affected by this (e.g., seiqrdp b = . ), there are other important aspects that require this clarification (e.g., estimation of peak date), even in terms of post-analysis after the resolution of the current crisis, in order to assess the effectiveness of the policies taken. finally, the sub-optimal behaviour of the seiqrdp modelling w.r.t. the general region around greece is a prohibiting factor in assessing the 'next day' on the international level. although the national epidemic in greece is steadily 'synchronizing' with that in the rest of the countries, no safe conclusions can be stated for the situation and possible recurrent surges of the outbreak when travelling restrictions will gradually get deactivated. similarly to the results presented earlier for the national epidemic in greece, figures and present the best-fit solution of the seiqrdp model (points) and its projection (lines) until august ( ), in linear and logarithmic scale, respectively, assuming no under-reporting of i(t), for the greater region around greece. the dotted line in figure illustrates the onset of a subsequent surge of the outbreak if all the mitigation measures (quarantine) was to be deactivated immediately (april th). table presents the corresponding values for all the seiqrdp parameters for the best-fit solution, which seem to deviate significantly from the corresponding solutions for greece, except β ≈ . which is close to β = . as in tables through . table . lse-optimal seiqrdp model parameters in eq. through eq. for the greater region around greece ( -jan- to -apr- ), no under-reporting of infections. as presented previously for greece, the seiqrdp bestfit solution for the greater region around greece provides an estimation of the peak i(t) date, which seems to be around the th of april. note that, given the epidemic phase uncertainty due to the still limited data series, as well as the moderateonly convergence of the lse solution process, no reliable value estimation can be provided for i(t). nevertheless, figures and seem to provide a valid 'explanation' for the dynamics of the greater-region epidemic, i.e., the interaction between the compartments. thus, the overall shape and scale of the corresponding curves can be considered as safe for general assessments, including the peak i(t) date at some point closely after the mid-april. additionally, the start of phase for the greater-region epidemic, i.e., the inflection point for i(t), seems to have already happened some time within the last - days (april - th). overall, it seems that greece is a few days 'behind' the progress of the covid- outbreak in the greater region around it, with some countries being 'ahead' and others lagging 'behind' the average. it is extremely important to track these phase differences in the national epidemics, especially for countries that are closely interconnected via adjacent land borders, tourist shipping routes or direct flights. without very | doi: (preprint) h. v. georgiou . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint strict border checking, large phase differences may translate to introduction of undetected infectious 'seeds' to a still nonimmunized population, at least until an effective large-scale vaccination against covid- becomes readily available in all countries. covid- constitutes a fast-pacing, world-wide pandemic that has evolved quickly into a multi-aspect international crisis. even with proper policies and mitigation measures properly and promptly in place, tracking the outbreak even at the national level is an extremely challenging data analytics & modelling task as the event itself is still active, thus only limited and perhaps unreliable data are currently available. in this study, greece is the main focus for assessing the national outbreak and estimating the general trends and outlook of it. multiple data analytics procedures, spectral decomposition and curve-fitting formulations are developed based on the data available at hand. standard sieqrdp epidemic modelling is applied for greece and for the general region around it, providing hints for the outbreak progression in the midand long-term, for various infections under-reporting rates. the overall short-term outlook for greece seems to be towards positive, given the start of a downward trend in infections rate daily increase, a possible peak within a few days beyond april th, as well as the high availability level of icu w.r.t. expected demand at peak. on the negative side, the fadeout period seems to be in the order of several months, with high probability of recurrent surges of the outbreak. the mitigation policies for the 'next day' should be focused on close tracking of the epidemic via large-scale tests, strict border checking in international travelling and an adaptive plan for selective activation of mitigation measures when deemed necessary. herd immunity: a rough guide sequential monte carlo filtering estimation of ebola progression in west africa sequential monte carlo methods for epidemic data (phd thesis). (dept. of mathematics and statistics markov chain monte carlo algorithms using completely uniformly distributed driving sequences consistency of markov chain quasi-monte carlo on continuous state spaces markov chain monte carlo and sequential monte carlo methods in dynamic models and stochastic volatility models conditional markov processes statistical inference for probabilistic functions of finite state markov chains. the annals math an inequality with applications to statistical estimation for probabilistic functions of markov processes and to a model for ecology error bounds for convolutional codes and an asymptotically optimum decoding algorithm contribution to the theory of periodic reactions deterministic mathematical models in population ecology preliminary analysis of covid- spread in italy with an adaptive seird model epidemic analysis of covid- in china by dynamical modeling mathematical handbook of formulas and a contribution to the mathematical theory of epidemics in proceedings of the an interactive web-based dashboard to track covid- in real time exact indexing of dynamic time warping addressing big data time series: mining trillions of time series subsequences under dynamic time warping pattern recognition encyclopedia of mathematics estimating the number of infections and the impact of nonpharmaceutical interventions on covid- in european countries digital processing of random signals: theory and methods adaptive filter theory the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application early dynamics of transmission and control of covid- : a mathematical modelling study acknowledgments. the author wishes to thank every team and researcher that is currently working towards scientific works of high quality, readily accessible to the community, including technical papers, research papers and datasets. this is the only viable way to address such fast-pacing events of major world-wide impact collectively and effectively, as quickly and reliably as possible, while the crisis is still evolving. key: cord- -h w jsyd authors: cheshmehzangi, ali title: introduction: the city during outbreak events date: - - journal: the city in need doi: . / - - - - _ sha: doc_id: cord_uid: h w jsyd as the largest quarantine in human history, the city of wuhan, china, with more than million people went under a complete lockdown situation on jan . an unprecedented situation that lasted longer than ever imagined. this occurred solely due to the spread of the novel coronavirus disease (later renamed as “covid- ”), just one day before the celebration of the chinese new year. events. from the beginning, as the cities prepared themselves to control the spread of the disease, their resilience for other aspects became more vulnerable. hence, the city authorities needed to pay more attention and have better preparedness in place, as it is only a matter of days or weeks before a city could literally collapse. in their report on 'health emergency and disaster risk management framework', the world health organisation (who) ( ) announced that from to , a total number of , outbreaks were recorded across countries. this was later increased with a further cases in before we experienced the newest outbreaks in china and nigeria in late and early . the numbers are not something that we see in our daily news reports but are certainly very alarming in many ways. it also proves how frequent we face outbreak events, and how important it is for us to study various methods of tackling the outbreak impacts on our cities and communities. in an outbreak event, whether we deal with epidemic and pandemic events, cities suffer tremendously, societies can become extremely vulnerable, and economies can fail. till the time normalisation can happen, there may be a lot of losses-from human life losses to impactful economic losses. globally, there is no single city with an adequate healthcare capacity that can accommodate thousands of infected patients, set aside a scenario in which millions of people are infected in relatively small proximity of the city level. it has been proven that even the least deadly disease can spread at a gradual pace and have a gradual increase in mortality rates. this can occur mainly due to a lack of healthcare infrastructure (comprised of both capacity and provision) to accommodate larger groups of patients at the same time. in a similar situation, the city of wuhan struggled to maintain the needs of patients in a timely manner. an example of which was the attempt to build a hospital in less than a week, indicating the importance of disaster management strategies and the need for urgently increasing the capacity of the healthcare infrastructure and facilities. in such events, time is exceptionally scarce and responses need to be fast. unfortunately, not all responses will be accurate in this process and not all can respond effectively. nevertheless, the process needs to happen at a large scale, and covering a range of factors; particularly if there were no or little preparedness in place. in this process, decisions are made rapidly but carefully. they are often short-lived or temporary, while the situation remains uncertain during multiple phases of the outbreak event. these phases will be discussed more thoroughly in the next chapter. in general, the second generation of human-to-human cases in an outbreak event may raise new concerns about the handling of the situation. as such, containing the disease is no longer the only priority. more than ever, the city would then need to focus on enhancing the resilience of multiple aspects and manage the situation promptly. hence, urban resilience and city management measures are highly important, as they can essentially save 'the city in need'. such an approach requires holistic planning with its three primary characteristics of ( ) predictive, ( ) prescriptive, and ( ) preventive. in an attempt to strengthen urban health resilience, such outbreaks require urgent attention to maintain and support the needs of residents, visitors, and those who are directly and indirectly affected. this requires the city's preparedness to maintain and manage multiple and essential city systems, such as health, food and clean water (including both supply and delivery), assets, medical support, safety and security, and social stability. most importantly, this requires people's resilience and how society can handle the situation effectively. through many global examples of outbreak events, we verify that (urban) resilience should be strongly backed up by regional management and national strategies. it requires support both internally and externally. this needs to be planned and implemented in a network of multiple stakeholders, enabling the resilience to be at multiple levels and considering multiple health aspects. throughout the whole process of an outbreak, we need to have careful measures for urban resilience; and these should be holistic and inclusive to better contain people, health, infrastructure, and management of the situation. this book is an immediate response to a major pandemic outbreak event at the dawn of this new decade. it started as an outbreak in the central part of china. it did not take long for it to be an epidemic event. it remained as a case of the epidemic for about two months, before it was characterised and declared a pandemic. it took more than two months for the infected cases to reach , cases globally. but then it took less than two weeks to double the number of cases, and only a few days till it passed , cases. the numbers were then much higher than initially expected. this declaration of change from epidemic to pandemic was due to deep concerns about the irrepressible spread of the disease and its severity, lack of resilience, and alarming levels of inaction at the global level (who b). this decision was believed to be delayed already (announced on th of march ), which marks a difference between reality and realisation. however, we are rest assured that there are lessons to be learned from what has been done in the past, what has been experienced, and what can be done in the future. in all cases, cities play a major part in managing the situation as well as to avoid the widespread disease, and to contain the situation as promptly as possible. all these require careful planning. but before we delve into the details, this chapter will serve as an introduction to first explain what is 'outbreak event'? and how it differs from other events and patterns of large scale outbreaks, such as an epidemic, pandemic, and endemic? afterward, the following sub-sections will explain the issues associated with city vulnerability and urban resilience. this is narrated through a broader understanding of theories, literature review, and current practices. this chapter will conclude with an overview of three r's in the practice of urban resilience, namely 'reflections', 'readiness', and 'responses'. the eventual discussions of this chapter will set a good foundation for the following chapters in order to assess the multiple stages of outbreak events and provide a range of theoretical and practical suggestions. the later suggestions are shaped around the idea of a comprehensive urban resilience framework in outbreak events, which is novel in the field of resilient cities and health-related city management scenarios (e.g. health emergency and health crisis). but before we do so, it is important to understand the definition of outbreak event and how it differs from other definitions in the field. there are common misinterpretations between different health-oriented and disease events. in the field of epidemiology, a typical outbreak event is defined as the sudden spread of a contagious disease that occurs at a particular spatial scale in a certain period. epidemiology itself is an interdisciplinary field, bridging between scientific disciplines like biology, statistics for investigation and analysis, social sciences for multiple uses, and engineering for exposure assessment. it is a discipline that is now commonly used in research and practices of biological sciences, public health, and clinical research (porta ) . in epidemiology, there are a variety of research studies that stretch from outbreak investigation to clinical trials, covering a range of analytical, scientific, and comparative studies that investigate the cause and spread of disease, analyse the pattern and progress, as well as control and guidelines to support information dissemination, knowledge share, and decision making processes. the world health organisation (who) (who webpage, on environmental health in emergencies, sub-section 'disease outbreaks' a) define outbreak diseases as the ones usually: "…causes by an infection, transmitted through person-to-person contact, animal-to-person contact, or from the environment or other media. outbreaks may also occur following exposure to chemicals or to radioactive materials". while there is an immediate need to investigate the actual cause or source of an outbreak, the investigation can take a long time, and often result in the development of potential scenarios, hypothesis, or continuing scientific research. who (ibid) also categorises the outbreak events into three distinct categories of: ( ) communicable disease outbreaks, ( ) disease outbreak events caused by chemicals, and ( ) disease outbreaks of unknown etiology. the first category generally includes particular environmental factors as the main source of the outbreak, this can be caused by humans, but the source itself comes from the environmental factors influencing the spread of disease; such as from air quality, food, water, and sanitation as four common examples. the second category occurs less frequently and is mostly due to exposure to chemicals or toxins in a particular area. the third category occurs more regularly around the globe, and usually the cause if not clear from inception and it may remain undetected for a while. this category is the focus of this book, through which we try to address resilience and management measures to overcome the urban challenges and diverse disruptions of disease outbreak events. one factor to note is that there are different ways of dealing with different outbreak events, e.g. there are differences between different categories (i.e. shown in the above three categories) and our responses to them, clear differences between natural disasters and disease outbreaks (alwidyan et al. ) , as well as differences between different stages of a particular event (see chap. ). some studies refer to disease outbreaks as disaster scenarios (sandi and kangbai ) or include them in the same category ). however, even though there are some overlapping factors and measures between the two, the author suggests refraining from categorising outbreak events as disaster events or scenarios. the rationale behind this is due to the apparent differences in the nature, progression, and multi-stage characteristics of outbreak events. also, not only that disease outbreak events are different themselves, but some of them may be defined differently at different times and in different contexts, such as the reoccurring case of dengue disease outbreak (brady et al. ) . nevertheless, the stages of disease outbreaks are very similar in how they develop over a period, and only differ in terms of how they can progress, spread, and eventually become contained. in each event, the city resilience and management measures and methods are not the same, but they are generally similar in terms of how we should respond to the impacts and vulnerabilities caused by the situation. in addition, disease outbreaks are different in scale and have patterns of occurrence, recognised as 'epidemic', 'pandemic', and 'endemic' situations. these are different to the general outbreak categories of 'common source' (both continuous source and point source), 'propagated' that is generally transmitted between person to person, 'behavioural risk related', and 'zoonotic' that is normally transmitted from animals to humans (extracted from 'glossary of epidemiology terms'). there are common misunderstandings between these patterns of occurrence, and some research studies confuse one with another. each of these categories represents a different stage at different scales of a disease spread. in most cases of outbreak events, there exists a later or immediate epidemic situation; hence, it is usually regarded as an 'epidemic disease outbreak'. if the spread is contained in just one location, then it can be regarded as just a disease outbreak. however, as this is generally unlikely, it is often regarded as an 'epidemic outbreak'. this is a common case as the spread can occur only in a few days and can easily go beyond the boundaries of a particular region. in most cases, this is almost inevitable as we frequently commute and mobilise, and as we are constantly in contact with multiple groups of people who do the same, too. this cycle of mobility provides an opportunity to increase the probabilities of disease spread or transmission and helps to transfer it from one location to another in a blink of an eye. on the other hand, green et al. ( ) acknowledge the distinction between the two terms, namely "outbreak" and "epidemic", and argue that the difference is indeed related to the size of the event, referring in particular to the scale a disease eventually spreads. in this regard, an epidemic situation is defined as the further expansion of the outbreak event, normally including a larger number of cities and communities, beyond just a particular contained region. this is very common for novel diseases. also as brady et al. ( ) conclude in their studies, there is still scope to understand a practical definition of an outbreak event; one that is unconventional, holistic, and clear. the case of pandemic becomes more momentous as the spread becomes a nearglobal or global situation, meaning that it includes not only multiple regions but also multiple countries across the globe. the actual occurrence of a pandemic event mainly depends on how fast and how efficient an epidemic event is managed. in some cases, a pandemic can last for a much longer period (such as hiv aids pandemic, recognised from onwards). in reality, it can last until it is completely cured. finally, endemic is defined as an infection spread that is "constantly maintained at a baseline level in a particular geographic area without external inputs" (extracted from 'centre of disease control and prevention (cdc)' webpage, division of scientific education and professional development (dsepd) ). this is not necessarily defined as an event but is recognised as a continuing situation of the disease spread. henceforth, we mainly use the terms 'outbreak' or 'outbreak event', as we focus mostly on the defined scale of the city. this book addresses this scale as it requires further attention from the perspective of resilience and management, two factors that will be assessed and discussed throughout. however, the suggestions are common for both epidemic and pandemic situations, but more closely to a more common case of 'epidemic'; an outbreak event that we can say is not completely disastrous but is exceedingly impactful on the societies. before reaching the "vaccine effectiveness period" (pezzoti et al. ) , the city and its communities suffer from the invasive disease outbreak. in a situation like this, cities are more vulnerable. in a common scenario, the situation is always unexpected; hence, preparedness is not exactly adequate to respond to earlier stages of the outbreak and is not as prompt as it should be. in the first few days, or even in the first few weeks of the outbreak, the situation appears to be uncertain and difficult to handle. this is mainly because of the outbreak changes drastically, the broad-spectrum life patterns change in a sudden, and our daily routines and operations become completely disrupted. the multiplicity of impacts is sensed across multiple sectors, affecting the most: our society. while the long term vulnerabilities can be reduced in a more progressive way (lim et al. ) , the short term treatments may take longer than initially expected. as suggested by brady et al. ( ) with appropriate and timely control, the disease outbreak burden can be minimised. yet, this requires preparedness as early as possible and it requires ready-made planning to reduce the city's vulnerability in crucial areas/factors, wherein need the most. as addressed by other studies, fluctuations in case numbers and regular surges can frequently disrupt and slow down the progress of treatment and containment (ibid), which can drive "already-stretched healthcare resources to breaking point" (also see hay et al. a; hay et al. b , garg et al. , cotter et al. brady et al. ) . more importantly, the city's vulnerability increases as the spread continue to affect the primary services and systems of the city, such as healthcare, food systems, transportation services, etc. in general, disease outbreaks are usually fast-developing situations with indeterminate progress and constantly changing updates. these effects or factors put pressure on the society as much as they cause an excessively "high burden due to the lack of response capabilities" (garg et al. , grais et al. , najera , who ebola response team brady et al. ) . also, there is an urgent need to reduce vulnerabilities, by enhancing emergency risk management for health, which is believed to be multi-sectoral (emergency risk management for health fact sheets , p. ), including: this includes a range of factors for individuals, larger groups of people populations, infrastructure, services, and other community factors. in this regard, the need for primary health care at multiple levels is essential to reduce any "underlying vulnerability, protect health facilities and services, and scale-up the response to meet the wide-ranging health needs" (ibid). hence, during an outbreak event, as the city becomes more vulnerable, we should ensure that supporting measures and the role of urban resilience is not reduced. to name a few, for instance, we have patients with other health issues who require attention, we have the elderly whom are more vulnerable than the others, we consistently need essential daily supplies and services, such as food, water, energy, etc., as well as other factors that should be taken into full consideration. therefore, we cannot just avoid all those dynamism or else it cannot last long for a city to fall apart. in the outbreak events, the vulnerability of the city goes beyond just vulnerable communities. the situation is dissimilar to those examples that only target a particular group. hence, outbreak events are usually widespread. this is also one of the reasons why outbreaks are different from those examples of disasters and are instead more related to health emergency conditions (examples by who ). generally, in the outbreak events, cities and communities with weak(er) or no institutional structure suffer the most. for the case of the covid- pandemic, this was evident from inception. this was tracked from the earlier records and updates from who ( b): "the international community has asked for us$ million to help protect states with weaker health systems as part of its strategic preparedness and response plan". the numbers were later increased and included more countries and regions. two months after, the united nations requested for a total of us$ billion cash contributions for nations that will struggle to contain the outbreak. those countries/regions that are not well prepared are likely to experience a shock before they could cope with the unexpected situation. municipal actions, from managerial and decision-making bodies, try to assess the situation as any response is sensitive and require careful processing and monitory. society gets the biggest hit as they experience panic attacks, anxiety, and uncertain conditions. in such events, our voracious nature vivacities as we are alarmed to prepare for survival. in general, people often rush to store more necessary food and supplies, and create a self-imbalance in the equilibrium of regular production and production trends. we do not buy what we need; but instead, we buy what we need and what we think we may need. this is caused by the uncertain circumstances that can change in any direction at any time. the vulnerability does not end there, and becomes more severe if the society is not reassured (schoch-spana et al. ) , and if immediate measures are not in place. hence, there are major debates around society management challenges during outbreak events, such as community/public engagement processes (biehler et al. ; jamrozik et al. ) , public information policies (maxwell ) , health and risk communication (miller ) , community values (schoch-spana et al. ), public health ethics (kenny et al. ; lee ; marckmann et al. , spike , etc. in addition, an extended communication plan is required to effectively respond to those societal needs to ensure vulnerabilities are minimised at multiple stages and throughout the outbreak event. furthermore, the contagious disease could affect many people directly and indirectly, and this potentially increases the vulnerability of society from multiple dimensions (american psychological association ), more than just the disease itself: "the threats to psychological well-being that outbreak pose often can be overcome with the skills of resilience, which can serve as a kind of emotional vaccine. we all can develop resilience. it involves behaviours, thoughts, and actions that can be learned over time". therefore, as a response to vulnerability increase, there is a major need to increase and maintain the urban resilience measures; those interventions that boost the city's management, and those strategies that eventually save the city from a looming disaster. there is more to urban resilience in the disease outbreak events than just a typical example of a resilient city strategic plan. as discussed earlier, outbreak events are inimitable situations; and indeed, they require exclusive responses, too. this was evident from the time when we developed the first resilient city toolkit several years ago (siemens, arup, and rpa ) . through a variety of studies on resilient cities and urban resilience measures, we can verify a range of direct impacts on health, emergency medical services, communities, infrastructure, economy and businesses, profitability, production systems, social well-being, and quality of life. as many foundations of the city deteriorate at a rapid pace, we have to ensure the city is prepared enough to handle the situation before making progress. more recent published books on urban resilience planning are mostly related to natural disasters (to name a few: clarke and dercon ; sanderson et al. ; lamond et al. ; baldwin and king ; miyata et al. ) that address factors of preparedness, resilience, responses, and action plans; those that then respond to immediate, gradual, and long-term transformations. there are fewer examples that include disease and contagion as part of those resilience planning (rodin ; jones ; yang ; singh et al. ; yang chan and shaw ) , which include a range of measures for risk management or bring together related reflections and initiatives (burayidi et al. ) . hence, in order to be effective in practice, urban resilience needs pioneering state-of-the-art thinking. in addition to this, the need for supporting guidelines (ihekweazu, et al. ) and frameworks are certainly essential, too. as our cities grow more in numbers and size, and as they face more adversities and challenges (from the webpage of resilient cities ), we may not always be ready to mitigate particular events; sometimes, we have to adapt, and often we have to enhance what we may have or develop what we may not have (cheshmehzangi ; cheshmehzangi and dawodu ) . in this regard, we need to develop a set of strategies to combat those particular events that can cause significant disruptions or could progressively jeopardise our cities and societies. urban resilience measures are ever needed to respond to those adversities and challenges, those we foresee and not foresee. an outbreak event is one of those examples of specific events, which can be damaging in multiple ways and can increase the burden on the overall city management. in such incidences, the vulnerabilities are extensive and affect the multiple operations of cities. the situation of an outbreak event of any kind suggests an insalubrious city status; it is unhealthy for the government, governance, institutions, economy, health, and on top of all, the society. to date, there is little literature or specific research associated with urban resilience in outbreak events. on the other hand, there are generic examples of practical measures, frameworks, tools, and guidelines that enable us to support those cities in need. yet, in real practice, the city authorities often require to make decisions fast and precisely. those decisions need to be context-specific and should address cultural factors, social needs, and economic concerns of that specific place/city. the process is so fierce that it can cause significant disruptions in any direction. any decision needs to be carefully crafted before it is released to the public, or else it can turn into playful games of multiple means of the media, from social media to a more monstrous international media. they can generate false news, increase anxiety and fear, and they can simply make a pandemonium. in the outbreak events, there are many issues associated with the overarching public health factors that require a new (or revised) perspective; hence, vulnerabilities are at a much higher rate when outbreak events hit the city and its communities. undoubtedly, resilience is needed for any occasion for any community. more importantly, we also need to acquire those resilience skills, both individually and collectively as part of society. the probabilities of failures or failed occasions are high, and reversing them can take longer and interrupt the progress of containment and recovery at any time. any minimal disruption is perceived as a major issue, and the impacts are felt event much greater. many sectors come into an absolute halt, even if temporary, but they suffer significantly. they usually look forward to novel solutions, innovations, and findings in medical research-in other words, something that can save the situation sooner than later. in general, urban resilience must be realised as the backbone of how cities can be managed, both effectively and efficiently, especially during the outbreak events. there are only a handful of preparedness (i.e. including but not limited to services, supplies, and facilities) that can be in place before the actual start of the outbreak; hence, the majority of the work is not necessarily related to preparedness but is indeed the immediate and strategic responses that should develop, shape and get implemented during the event itself. this is exactly why, similar to some of those disaster events, vulnerabilities are high and cities and communities are at a highrisk level. in their report, who ( , p. ) suggest that while the "leadership in managing infectious risks and responding to outbreaks is clear, the health sector also has a critical role in preventing and minimizing the health consequences of emergencies due to natural, technological and societal hazards". in addition to this statement, it is important to note that from the city management perspective, multiple sectors must experience similar-if not the same-situation. other sectors associated with such incidents aim to promptly deal with emergencies and meritoriously cope with the disruptions caused by the event. in other words, the city as a whole becomes a new entity that requires to deal with emergencies at multiple levels and in multiple sectors. by having a resilience plan (i.e. in any practice-based or practical form), the city can work more effectively in managing the event and its negative impacts on the society. hence, it is suggested to enhance the city's resilience where we can and where it seems feasible to do so in the specific context (i.e. in terms of capacity, capabilities, economic background, social issues, etc.). with such a planning approach, we can speed up the containment and recovery processes of the outbreak-i.e. to better contain the spread of disease, and avoid the event to evolve from an emergency status into a disaster situation. finally, what has to be addressed is the way we prepare and respond in a process. this requires a framework that could reflect on the ever-changing situation(s) of outbreak events, which will be addressed in later chapters in more detail (see chaps. and ). therefore, there is an essential need to act reflectively and responsibly by multiple actors of the government (of multiple departments), emergency units and emergency medical and health services, and other associated stakeholders of the public sector, private organsiations, non-governmental organisations (ngos), community organisation groups, and the general public. in reality, the situation creates a new ecosystem of management and operations, one that requires to have resilience measures and adaptive capabilities. in their report on 'communicable diseases following natural disasters', who ( ) proposed a set of risk assessment and priority interventions, to ensure the needs of the society are addressed promptly throughout the events and adequate planning is operational for both therapeutic and preventive interventions. these factors, apart from having adequate planning measures, requires a tangible resilience capacity in order to reflect quickly, be ready, and respond to those situations in the best possible way. these would be the concluding remarks of this introduction chapter in the following section. as an introduction to the book, this chapter has summarised a general overview of outbreak events, and how they are progressively more important in the fields of 'urban resilience' and 'city management'. the aim of this book is then to see how we can save the city before it becomes too vulnerable, and how we can respond to those unexpected and unfortunate events that could cost us many human lives and many other pressures. in a way, the analysis so far indicates that the extent to which we see outbreak events in a city boundary needs more scholarly attention. as mentioned earlier, there are many cases of outbreak events that we do not even hear about; as we only learn about the ones of the global importance or higher contagious nature. some are only become more visible because of their political importance, or the economic impacts they may have at the much larger global scale (such as the recent covid- outbreak). yet, as it appears from the recorded data of global outbreak events (who ), it is indicated that we constantly deal with various outbreak events in communities all around the globe. how we may reflect on those events are something that we should take into full consideration for better future preparedness and a much-enhanced resilience ( fig. . ) . it only makes a logical sense that we should plan this ahead and not wait for the unforeseen impacts. as we continue to neglect the importance of outbreak events, we may continue to neglect the importance of resilience measures we should develop for our cities and communities around the world. this is not a simple task, but without a doubt, it is one very important task that can save the lives of many people who could live if we take action either in advance or as early as possible. so far, we highlighted the basic knowledge, the existing literature on outbreak events, and the perspectives that refer to the situation of a typical outbreak event. we learned outbreak events are not universal; as they differ from one disease to another, and from one context to another. we realised the same disease can also be different fig. . the three primary r's in the practice of urban resilience. source the author's own from one location to another. our cities are also very different, with primary differences in how they operate, their size, infrastructure, capabilities, economic conditions, social values, services, networks, etc. therefore, our cities and communities would certainly reflect on outbreak events very differently, too. this means their readiness will be different, and how they may respond will ultimately be different. however, certain commonalities cannot be simply avoided in case of an outbreak event. for instance, the commonalities are mostly related to those institutional and societal needs, meaning how we plan to keep up the operations of our systems and services, how we may provide access to clean water, daily food supplies, energy, hygiene, amenities, and how our emergency units are supported and enhanced, as well as many other factors. in sum, cities, although different in many ways, will face similar difficulties/challenges in the case of outbreak events. careful and comprehensive planning cannot be anything less than an assurance to overcome those difficulties that can simply threaten any community that exists in our world. in reality, we have to understand there is no immune community; at least, there is none that we know about. the next few chapters of the book focus purely on key factors of urban resilience and city management to address their practicalities in a probable case of an outbreak event. henceforth, the book addresses methods and strategies to enhance urban resilience during outbreak events. these ideas are generated through existing literature, practices, available tools and frameworks, dialogues with multiple experts of different disciplines, continuous discussions with local governmental authorities and global organisations, and the invaluable experience gained from standing with the community in a particular pandemic outbreak event. resilient cities webpage responding to natural disasters 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disasters, promoting resilience (high reliability and crisis management) ebola virus disease in west africa-the first months of the epidemic and forward projections communicable diseases following natural disasters: risk assessment and priority interventions health emergency and disaster risk management framework webpage source on the category of 'environmental health in emergencies', sub-section 'disease outbreaks rolling updates on coronavirus disease (covid- ), as part of updates on march : who characterizes covid- as a pandemic public health and disasters: health emergency and disaster risk management in asia (disaster risk reduction) early warning for infectious disease outbreak: theory and practice key: cord- - hpfw jk authors: chen, simiao; chen, qiushi; yang, weizhong; xue, lan; liu, yuanli; yang, juntao; wang, chen; bärnighausen, till title: buying time for an effective epidemic response: the impact of a public holiday for outbreak control on covid- epidemic spread date: - - journal: engineering (beijing) doi: . /j.eng. . . sha: doc_id: cord_uid: hpfw jk rapid responses in the early stage of a new epidemic are crucial in outbreak control. public holidays for outbreak control could provide a critical time window for a rapid rollout of social distancing and other control measures at a large population scale. the objective of our study was to explore the impact of the timing and duration of outbreak-control holidays on the coronavirus disease (covid- ) epidemic spread during the early stage in china. we developed a compartment model to simulate the dynamic transmission of covid- in china starting from january . we projected and compared epidemic trajectories with and without an outbreak-control holiday that started during the chinese lunar new year. we considered multiple scenarios of the outbreak-control holiday with different durations and starting times, and under different assumptions about viral transmission rates. we estimated the delays in days to reach certain thresholds of infections under different scenarios. our results show that the outbreak-control holiday in china likely stalled the spread of covid- for several days. the base case outbreak-control holiday ( d for hubei province and days for all other provinces) delayed the time to reach confirmed infections by . d. a longer outbreak-control holiday would have had stronger effects. a nationwide outbreak-control holiday of d would have delayed the time to confirmed infections by nearly d. furthermore, we find that outbreak-control holidays that start earlier in the course of a new epidemic are more effective in stalling epidemic spread than later holidays and that additional control measures during the holidays can boost the holiday effect. in conclusion, an outbreak-control holiday can likely effectively delay the transmission of epidemics that spread through social contacts. the temporary delay in the epidemic trajectory buys time, which scientists can use to discover transmission routes and identify effective public health interventions and which governments can use to build physical infrastructure, organize medical supplies, and deploy human resources for long-term epidemic mitigation and control efforts. the coronavirus disease (covid- ) pandemic is spreading rapidly. the city of wuhan in hubei province, china, was at the epicenter of this epidemic [ ] . studies have estimated that the basic reproductive number of covid- is higher than that of severe acute respiratory syndrome (sars) coronavirus [ ] . covid- has posed major challenges for epidemic control because its routes of transmission are not fully understood, and prevention and screening, diagnosis, and treatment approaches still need to be developed and tested. public health authorities initially lacked evidence-based approaches and protocols to contain the epidemic, and the rapid spread of the virus required new physical infrastructure, medical supplies, and human resources for an effective epidemic response. in the initial response to the epidemic of a new virus, social policies to change people's behaviors are potentially powerful in reducing and slowing down the spread of the disease. during the early stage of the covid- outbreak in china, the holiday during the chinese lunar new year, was a public holiday for outbreak control, which began during the same time period as the chinese lunar new year, was utilized as a social policy that enabled fast responses at national scale [ , ] . during this time period, the chinese government initiated emergency responses to the epidemic, and enacted a series of non-pharmaceutical interventions such as travel restrictions, social distancing, active contact tracing, isolation, and quarantine, as well as public information and education campaigns [ ] . for example, the chinese government encouraged people to stay at home, discouraged mass gatherings, and closed schools, government offices, factories, libraries, and museums [ ] [ ] [ ] [ ] [ ] [ ] [ ] . a public holiday for outbreak control-hereinafter referred to as an outbreak-control holiday-has been used as a public health policy in the past. for example, mexico launched an outbreak-control holiday to contain the spread of h n in , during which schools and workplaces were closed and people were encouraged to stay at home [ ] . during such an outbreak-control holiday people do not go to work and tend to stay at home, limiting social contacts to family members and close friends. as a result, these holidays can slow down the spread of epidemics that are transmitted via social contacts [ ] [ ] [ ] [ ] [ ] . as an epidemic response strategy, an outbreak-control holiday can interrupt a wide variety of transmission routes, including direct and indirect physical contact, droplet contact, and airborne transmission. outbreak-holidays can thus be particularly useful when a new pathogen's precise transmission routes are not yet known [ ] [ ] [ ] [ ] [ ] . while several studies have investigated the effectiveness of travel restrictions and social distancing measures in preventing the spread of covid- in china, it is still generally unclear how the trend of an epidemic changes according to different characteristics of an outbreak-control holiday [ , ] . taking china's outbreak-control holiday as an example, this paper aims to contribute to future policy decisions by answering the following questions: what was the likely impact of the outbreak-control holiday in china on the early covid- epidemic? how would this impact have varied if the following parameters of the outbreak-control holiday had been different: the duration, implementation timing, and the effectiveness of accompanying policies? our results provide important insights for policy makers charged with designing public health interventions to control the present covid- pandemic, as well as epidemics that will emerge in the future. we used a compartment model (fig. s in appendix a)-a commonly used modeling approach to estimate the impact of interventions on infectious disease transmission [ , ] -to simulate covid- spread in china. our model divided the population into subgroups according to the status of covid- infection, including susceptible, latent infection, active infection, confirmed diagnosis, followed by treatment and recovery. in order to capture how the disease spread across provinces, we further separated the population into two regions: hubei province, which was the center of the epidemic, and the rest of china. to capture the transmission due to travel across hubei's borders, our model allowed transition of the susceptible and latent infected population between hubei and the rest of china. the infection force was proportional to the prevalence of untreated infections, including people in both latent and symptomatic infection stages. we made the following assumptions: first, we assumed that the population under treatment, although still infected, did not cause more infections because they were receiving treatment in isolated settings. second, we did not consider reinfection among the recovered population, due to likely immunity and the relatively small size of this group. model development and statistical analysis were performed in r(verson . . , austria). our model accounted for several events that could potentially affect transmission dynamics. the model simulated the disease transmission since january , when the diagnosis of covid- was formally established. we assumed that there were persons traveling through hubei province based on the pastyear daily travel volume during the chinese lunar new year travel season, or chunyun. since many cities in hubei were locked down since january [ ] , we assumed no transitions between hubei and other provinces since that time. we calibrated transmission rates before and during the outbreak-control holiday to estimate its impact on epidemic dynamics. we assumed that the disease transmission rate after the outbreakcontrol holiday returned to the level before the holiday (see section s in appendix a for further model details). our primary data sources were the daily updates of the covid- epidemic published by china's national and provincial health commissions, including the cumulative number of confirmed cases, deaths, and recoveries, for both china as a whole and hubei province [ , ] . we used the average incubation period for the duration of the latent infection period in our model [ ] . we estimated the values of other model parameters and the initial epidemic conditions using model calibration [ , ] . calibration targets included daily increments of confirmed cases, cumulative number of deaths, and cumulative number of recoveries from january to january , separately for hubei province and the combined total of the other provinces in china. we used a direct search algorithm [ ] to identify the model parameter values that resulted in the closest match between the projected outcomes and the calibration targets. to account for uncertainties in the model parameters, we repeated the calibration process for replications and collected the set of calibrated parameters with a total calibration error no larger than % above the minimum error. further details of the model parameter description can be found in section s in appendix a. our calibrated model performed well in capturing the overall trend of the reported numbers of confirmed cases, deaths, and recoveries during the calibration period ( fig. s in appendix a). the calibration results suggest that the transmission rate during the outbreak-control holiday was % of the rate before the holiday in hubei province and % of the rate before the holiday in all other provinces of china. we estimated the cumulative numbers of confirmed infections and all infections for the following outbreakcontrol holiday scenarios: ① base case: an outbreak-control holiday for d in hubei province and d in all other provinces of china, both starting on january [ , ] ; ② no outbreak-control holiday; ③ -day holiday: an outbreak-control holiday for d starting on january , with the same length as the chinese lunar new year holiday; ④ -day holiday: an outbreak-control holiday for d starting on january ; and ⑤ -day holiday: an outbreak-control holiday for d starting on january . in addition, we estimated the cumulative numbers of confirmed infections and all infections for variations in starting time for the base case outbreak-control holiday: ① a -day earlier start and ② a -day later start. we also estimated the cumulative numbers of confirmed infections and all infections for variations in the effectiveness of other epidemic control policies during the outbreak-control holiday: ① a further % reduction of the transmission rate during the outbreak-control holiday compared with the base case scenario; and ② a further % reduction of the transmission rate. we further estimated the number of days until specific levels of covid- epidemic spread were reached under the different policy scenarios: ① the number of days until , , and confirmed infections were reached; and ② the number of days until and cases of all infections (including confirmed/diagnosed, undiagnosed, and latent infections) were reached. we compared these numbers under the different outbreak-control holiday scenarios against the comparator scenario of "no outbreak-control holiday" to quantify the reductions in epidemic spread caused by the base case outbreak holiday and its variants. the funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. fig. shows the epidemic impact of the outbreak-control holiday with different durations for mainland china. the vertical dashed lines indicate the starting time of the outbreak-control holiday in the base case scenariothat is, january . the dots represent daily cumulative confirmed infections [ ] . the outbreak-control holiday significantly reduced infections in comparison with the "no outbreak-control holiday" scenario. the impact of the outbreak-control holiday increased with increasing duration of the holiday. the outbreak-control holiday did not immediately reduce the confirmed infections following the start of the holiday (as shown in fig. (a) ) because the covid- incubation period is relatively long and because the holiday started during the early stage of epidemic control. the outbreak-control holiday immediately reduced all infections (as shown in fig. (b) ) and delayed epidemic spread in the long run. in section s (in appendix a), we show the impact of the outbreak-control holiday separately for hubei province; in section s (in appendix a), we show the impact of the outbreak-control holiday for all other provinces in china. compared with the "no outbreak-control holiday" scenario, the base case outbreak-control holiday delayed the time to confirmed infections by . d and the time to confirmed cases by . d. the delay in the time to reach total infections was of similar magnitude ( table ). the delay in the time to specific epidemic spread levels increased with the duration of the holiday. for example, a nationwide outbreak-control holiday with a -day duration would have increased the time to confirmed infections by . d, while a nationwide outbreak-control holiday with a -day duration would have delayed the same number of infections by nearly d. the values in the cells represent the differences in days to reach the specified epidemic levels between a policy scenario and the comparator. c the base case scenario represents an outbreak-control holiday with a -day duration in hubei province and a -day duration in all other provinces in china [ , ] . fig. shows the epidemic impact of the outbreak-control holiday with different starting times. the policy impact increases with earlier starting times. this impact, however, diminishes as the epidemic progresses. if the base case outbreak-control holiday had been implemented d earlier, the time to confirmed infections would have been delayed by an additional . d. however, the earlier implementation would only have caused an additional . -day delay in the time to reach confirmed infections. if the base case outbreak-control holiday had been implemented d later than in reality, the impact of the outbreak-control holiday would have been substantially weakened (fig. ) . fig. shows the epidemic impact of the base case outbreak-control holiday in the presence of additional interventions with further effects on the transmission rate. such interventions could substantially boost the impact of the policy. compared with the base case outbreak-control holiday with the current calibrated reduction in the transmission rate, reducing the transmission rate by % or % results in an additional . and . d, respectively, to reach confirmed infections. , and dashed lines represent the outbreak-control holiday scenarios with transmission rates further reduced by % and %, respectively, during the holiday period. the shaded bands represent % uncertainty intervals of model outputs. china's outbreak-control holiday in the early stages of the covid- epidemic bought a substantial amount of time to prepare for an effective epidemic response. our model shows that the epidemic spread was substantially dampened by the chinese lunar new year holiday and its subsequent extension by d. the outbreak-control holiday rapidly and significantly reduced the covid- transmission rate-according to our calibration results, to % of the pre-holiday rate in hubei province and to % of the pre-holiday rate in all other provinces of china. the core strategy of the outbreak-control holiday was to substantially reduce social contacts in the population and thus prevent covid- transmission from patients in pre-symptomatic phases. in contrast, without an outbreak-control strategy social contacts may actually intensify during a holiday, because people often meet during holidays and engage in social activities together, potentially exacerbating the spread of an epidemic. during the outbreak-control holiday, the chinese government people to stay at home and limit social contacts-both directly (e.g., through public information and education campaigns) and indirectly (e.g., by closing public buildings and transport systems) [ ] . the outbreak-control holiday further delayed the mass movement of people across china and reduced the contacts that people from hubei province had with community members in their lunar new year holiday destinations in other provinces of china. the base case scenario in our analysis was the outbreak-control holiday issued by china's state council during the early stage of the epidemic-a -day holiday for hubei province and a -day holiday for all other provinces in china. in addition, we separately quantified several important components of this overall impact: the nationwide lunar new year holiday, which lasted d; the nationwide extension of the lunar new year holiday by days; and the additional -day holiday extension in hubei province, which brought the total holiday duration in hubei province to d. the lunar new year holiday induced about half the impact of the overall outbreak-control holiday; the additional extension of the outbreak-control holiday in hubei province induced about one fifth of the overall policy impact. as such, the lunar new year holiday, whose start incidentally coincided with the emergence of the covid- epidemic, was a major driver of the overall outbreak-control holiday impact. we included the lunar new year holiday in the estimate of overall policy impact, because it is likely that the chinese government would have adopted an outbreak-control holiday around a similar time as the start of the lunar new year holiday, if this traditional holiday had not coincided with the early phase of the epidemic. moreover, the chinese government already started encouraging people to stay at home and limit social contacts during the traditional holiday [ ] , effectively changing it into an outbreak-control holiday. finally, future epidemic outbreaks-which outbreak-control holidays could help contain-are unlikely to coincide again with national public holidays. the overall impact of the entire holiday time, including the lunar new year holiday, is thus the most policy-relevant estimate. our second key finding is that an outbreak-control holiday is more efficient in delaying epidemic spread the earlier it is implemented and the longer it lasts. while the traditional lunar new year holiday coincided with the early stage of the covid- epidemic, the chinese government acted quickly in using and extending it for outbreak control. it also extended it for a longer time in hubei province, the original epicenter of the epidemic. our findings here should motivate governments facing future epidemics to consider adopting extended outbreakcontrol holidays in the earliest stages of an emerging epidemic. in considering such decisions, governments need to weigh the epidemic impact of outbreak-control holidays against other social outcomes, which were not measured in this study. for instance, outbreak-control holidayseven those that are expected-can reduce economic growth [ ] . future research should extend our work to include multiple outcomes of outbreak-control holidays, and to quantify the differential impacts of policy variants, such as implementing outbreak-control holidays at different times in different places. our third key finding is that the impact of outbreak-control holidays in delaying epidemic spread will be substantially enhanced if other interventions further reduce transmission rates during the holidays. such interventions could include contact tracing, community-based management of close contacts of infected people, and environmental disinfection and ventilation. the goal of our study was not to replicate the entire epidemic trajectory and the control efforts during the covid- epidemic in china, but rather to explore the impact of an outbreak-control holiday that primarily focused on social distancing during the early period of the epidemic and to understand how its duration and starting time would affect the pace of disease transmission in general. governments can start outbreak-control holidays nearly immediately, because this policy does not require new infrastructures or systems: governments merely need to announce and publicize the holiday. in contrast, other outbreak-control policies and approaches take longer to plan and implement, because they require new infrastructures or systems. we used the epidemiological data from the early stage of the epidemic (i.e., during the normal chinese lunar new year holiday before january) to calibrate our model of the covid- transmission dynamic. this selection allows us to isolate the impact of the outbreak-control holiday from the policies and approaches that were implemented later. such later policies and approaches included the "leave no patient unattended or untreated" strategy, which comprised of mass testing for covid- and facilitybased isolation and treatment of patients with both severe and mild covid- [ ] . this strategy required new infrastructure. for instance, in february the chinese government opened new hospitals for treatment and isolation of covid- patients in wuhan, hubei province, (the huoshenshan and leishenshan hospitals) and implemented facility isolation for patients with mild-to-moderate covid- in so-called fangcang shelter hospitals [ ] . this strategy also required time to build broad social support for mass testing and facility-based isolation [ ] . the combined impact of the early outbreak-control holiday and the later policies was that by march the covid- epidemic was brought under control in the city of wuhan and in the rest of china [ ] . our results show that if no other measures had been implemented after the outbreak-control holiday, as we assumed in this study, the epidemic spread after the holiday could have returned to the trajectories of nearly exponential growth that were observed before the holiday. that is, an outbreak-control holiday, which mainly enhances social distancing for a finite period of time, should not be expected to be sufficient for epidemic control. rather, it can merely serve to slow down transmission for some time. this finding indicates that, once an outbreak-control holiday ends and the economy reopens, second-waves are likely-unless people continue preventive measures, such as working from home and maintaining physical distance and wearing masks when outside the home [ ] . the main benefit of a public holiday for outbreak control in and of itself is thus that it buys time to develop effective responses that are not immediately available. first, a country can use the time of halted epidemic spread during an outbreak-control holiday to build critical infrastructure for further epidemic control measures, such as emergency field hospitals. second, the time allows a country to organize medical supplies for the screening, diagnosis, and treatment of covid- patients and to train and deploy specialized human resources for the longterm epidemic response, including hospitalists and infection-control specialists. finally, the time can be used for scientific discovery and knowledge gain, which is important for designing the most effective and efficient epidemic response for the longer term [ ] [ ] [ ] [ ] [ ] [ ] . during the outbreak-control holiday in china, substantial progress was made toward the characterization and identification of covid- [ , ] , the origin and transmission routes of the virus [ , , ] , the epidemiological pattern of the epidemic [ , , ] , and potential treatment approaches [ ] [ ] [ ] . at the same time, however, our knowledge of covid- transmission routes remains imperfect, and specific antiviral treatment and vaccines are not yet available [ , ] . our study has several limitations. first, we modeled the impact of the outbreak-control holiday policy in china, which included not only time off work but also particular measures to encourage social distancing, such information and education campaigns and the closing of public buildings, spaces, and transport systems. replication of the impact a public holiday for outbreak control, which we estimated, will thus depend on the precise policy design, even for a very similar future epidemic. future empirical research should identify the individual impacts of each of the key components of the outbreak-control holiday policy used in china. second, we did not explicitly capture changing capacity for covid- testing and diagnosis in our model. for the simplicity of model structure, we instead assumed an overall delay in diagnosis after the infected individuals showed symptoms, which was calibrated to the reported confirmed cases. future modeling work should explore how the impact of outbreak-control holidays changes with growing capacity to test and diagnose covid- and similar diseases as an epidemic progresses. third, we only estimated the epidemic impact of the outbreak-control holiday, and did not quantify the impact on social and economic outcomes. future research should identify the impact of the outbreak-control holiday on a range of outcomes and weigh them against each other in a principled way, such as through a cost-benefit analysis. taking china as an example, we show that an outbreak-control holiday can substantially dampen covid- epidemic spread. yet, if the epidemic is not fully contained during the outbreak-control holiday (i.e., there are still undetected cases in the community), cases will surge and eventually return to the trajectories observed before the holiday. our findings thus emphasize that long-term preventive strategies are needed, which are effective even as people return to work after the holiday. the major benefit of an outbreak-control holiday thus does not lie in long-term epidemic control but in a short-term delay of epidemic spread. this delay can buy time for governments to build infrastructure for prevention and treatment and prepare processes for public health interventions. it can also buy time for scientists to generate the knowledge that can guide policy to increasingly higher levels of impact in controlling covid- and similar epidemics. covid- control in china during mass population movements at new year the reproductive number 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china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding a novel coronavirus from patients with pneumonia in china a pneumonia outbreak associated with a new coronavirus of probable bat origin epidemiology working group for ncip epidemic response of the chinese center for disease control and prevention. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) in china clinical characteristics of coronavirus disease in china baricitinib as potential treatment for -ncov acute respiratory disease a trial of lopinavir-ritonavir in adults hospitalized with severe covid remdesivir in adults with severe covid- : a randomised, doubleblind, placebo-controlled, multicentre trial what to do next to control the -ncov epidemic? this research was supported by the alexander von humboldt foundation, through the alexander von humboldt professor award, funded by the federal ministry of education and research, germany. all authors declare no competing interests. key: cord- -pv ijdnx authors: perakslis, eric title: a primer on biodefense data science for pandemic preparedness date: - - journal: patterns doi: . /j.patter. . sha: doc_id: cord_uid: pv ijdnx the coronavirus outbreak is sweeping the globe with outbreaks reported on every continent except antarctica as of march . data scientists are uniquely and diversely skilled in ways that can be highly effective in minimizing, combatting, and recovering from the impacts of the covid- outbreak. in this opinion, the basics of biodefense as well as specific opportunities for the data science community to contribute are discussed. the coronavirus outbreak is sweeping the globe with outbreaks reported on every continent except antarctica as of march . data scientists are uniquely and diversely skilled in ways that can be highly effective in minimizing, combatting, and recovering from the impacts of the covid- outbreak. in this opinion, the basics of biodefense as well as specific opportunities for the data science community to contribute are discussed. there is no doubt that covid- is an unprecedented challenge for humanity, and one where data scientists can play an active and useful role. in an earlier piece, i provided a brief overview of the field of biodefense with a focus on the importance of risk assessment and resilience, the ability to maintain operations during disasters or other unanticipated crises. this piece will dig deeper into biodefense policy as well as suggest specific actions that the data science community can take to contribute to covid- resilience, response, and recovery efforts. starting at the top and looking more deeply into risk and resilience in the united states, much of the policy stems from the homeland security presidential directive , which outlines the policy and strategy for public health and medical preparedness. based upon hspd , the biodefense for the st century directive, signed into law by george w. bush in , the critical components of the plan are biosurveillance, countermeasure distribution, mass casualty care, and community resilience. an excellent source for understanding these initiatives is the biodefense policy landscape analysis tool, which provides significant detail on these policies, including the complex web of relationships of roles and responsibilities between and across federal agencies. one criticism of these policies that is highly relevant to the current outbreak is that they are far too broad and that the original focus, protection from biological weapons, is not aligned with threats such as the current coronavirus outbreak and that an information-driven biosafety strategy that focuses on all threats during peacetime would serve the public better. to me, these criticisms are highly valid, especially when considering the fractured appearance of the us government responses to covid- to date. what is less clear is whether the government response is fractured due to poor execution or because the plan is indeed a poor fit for peacetime public health threats. much of the current peer-reviewed literature on minimizing disruption and ensuring business operations during a crisis and most comprehensive toolkits focus upon ensuring biosafety, which refers to the safe handling of biological agents, or on traditional biodefense, tactics against manmade biothreats. traditional approaches to disaster preparedness often focus upon institutional business continuity plans (bcps). as covid- continues to spread through undocumented community transmission, many have turned to social distancing as their primary prevention and resilience strategy. globally, organizations are limiting travel, having employees work from home, distributing personal protective equipment, and taking other measures that focus upon containment. these measures are helpful and important, but as we are seeing significant community spread, public health officials are blending their focus from containment only to containment and mitigation, and businesses must look ahead in this manner as well. this outbreak is past the point of prevention, and the response must now focus on minimizing the effects as people get sick. one of the most effective ways to think about resilience is to recall every cliché you have ever heard about weak links and apply systems thinking. what happens if your child's school closes and you are forced to quarantine at home with them? do you have backup, and can you work remotely? what about vendors, contractors, and suppliers that you depend on-is there adequate redundancy in your supply chain? does your organization already have an experienced virtual meetings culture? are people used to video conferencing? are the necessary technology toolsets already in their hands? have the newest, least experienced, and/or most struggling colleagues been given what they need to do their part? an addictive quality of humanitarian response actions is the clarity of purpose. there are no endless meetings discussing long-term strategies, and every decision is not accompanied by weeks of handwringing. priorities are often set on a daily basis. everyone knows their tasks and where they fit in. extraneous activity is eliminated as a necessity. think through priorities with a clear mindset and eliminate the nonessential to free resources for the things that must happen and that need the most help. in biodefense strategies, the shift from containment to mitigation initiates the direct-response phase, a shift from prevention to action. just as the airlines ll open access always instruct passengers to place the oxygen mask on themselves before helping others, people must ensure that they themselves and their organizations are secure before attempting to help others. there are many ways that data scientists can be of significant help, and their own communities may be the best place to start. for data scientists who can code, look for opportunities to do that. the same is true for analysts; statisticians; high-content data experts; data policy, governance and regulatory experts; payor and reimbursement policy experts; and all other domains. people looking to help should lead with their strengths but also remember that each of us is more than just the sum of our parts. during the ebola outbreak of - , i was setting up technology at a remote clinic in sierra leone. the clinic had not been opened for patients as the water supply had not been inspected or certified. my undergraduate degree happens to be chemical engineering, and i was happy i could help. be imaginative. with respect to matching specific expertise and problems, telehealth has great promise and is being touted as a solution, but the current availability is spotty geographically, and rapid implementation will need expert guidance. specifically, regulatory, geolocation, and reimbursement expertise are needed for telehealth to reach its full potential during this outbreak. for those with expertise in research and epidemiology, you are likely already in high-demand and activated. if not, as the response to coronavirus will be managed primarily within communities, contacting your state, town, county, district board of health, or equivalent may yield instant opportunity to be of assistance. if you work in biomedical product research and development, your company is likely concerned and developing plans to ensure the resilience of clinical trial sites and participants. by definition, patients in clinical trials all have underlying health conditions, and many have health conditions that will put them at high risk of serious effects if infected with the coronavirus. shortages of drugs and drug manufacture ingredients are already putting the clinical supply chain at risk. trial deviations and the need to adapt trial designs are all possibilities that will require biostatistical and data science support. the list goes on and on. communications strategies must be resilient, and facts must be clear and substantiated. synthetic and in silico modeling of response, outbreaks, supply chain, transmission, and almost every other aspect must be available when and where needed. the tools of digital disease detection are reasonably strong, but if you have ideas that will make them stronger, contact groups such as healthmap (https://healthmap.org/en/) and share your ideas. misinformation campaigns must be countered. campaigns such as ''flatten the curve'' that are making the rounds on social media are based upon solid facts and can be very useful in educating all of us in the importance of slowing the transmission of the virus regardless of how far it has already gone. further, anything that can be done to educate patients and caregivers in ways that preserve precious resources such as coronavirus test kits is important. cyberchondria is a real thing, and many people will be seeking care with minor symptoms and low risk of actual infection. for coders and epidemiologists, there are already very strong and dedicated platforms for building, modifying, and deploying mobile applications for coronavirus tracking and response use cases. a toolset that i have personally used over the years for rapid development and deployment is commcare by dimagi, and they have already built a toolkit and guide specifically for covid- outbreak response. another excellent toolset that has been crowdsourced specifically for coronavirus response is the coronavirus tech handbook. these are not the only toolsets; there are others. pick the one that fits your immediate needs best and get to work. the important thing is not to waste precious time building things from scratch in outbreak settings when time is of the essence. reach for something that works and get it into the hands of those that need it. of course, these are just examples, and the actual opportunities are countless. use your professional and social networks to find the right opportunity to help. if you are not the best fit, use your network to matchmake between people and problems. every solution counts. one fascinating attribute of infectiousdisease outbreaks is that it can be chal-lenging to determine when or how they will end. in the - ebola outbreak in west africa, the epidemic ended quite abruptly and somewhat unexpectedly, and the response went rapidly from start-up mode to shut-down mode. my last trip during that outbreak focused upon rebuilding local infrastructure to enable the local health systems to get back to full operation, including the possibility of an ebola-infected patient presenting and seeking care. health systems being overrun by infectious-disease outbreaks is not limited to lowand middle-income countries (lmics). in the us, we have seen seasonal flu outbreaks severe enough that hospitals have had to erect tents to manage the overflow of patients. unavoidably, healthcare workers will be infected. clinics will be low on staff and supplies, and some clinics will be forced to close and transfer their burden elsewhere. re-establishing services and adequate staffing levels and helping institutions through the fragile state of re-opening and expansion is the third domain of necessity and opportunity. after truly catastrophic events, communications must be re-established and be clear and authoritative. schools and places of business will need to be ready to be re-opened. travel and transportation infrastructure must be re-established, and all of these activities must be supported through fragile initial states. this may require new data systems. during the rebuilding period after ebola, we were tasked with readying clinics for traditional services but also to be prepared for the possibility of an ebola-infected person to show up seeking care. specially designed triage applications that walked newly trained health workers through algorithmically guided case definition steps were an essential element of rebuilding the healthcare system. another essential element of active response is following through on projects that are likely to be needed during the next outbreak or pandemic. in the modern world, it is amazing how fast priorities change and people move on. following the rapid shutdown of the ebola response in west africa, many loose ends were dropped only to be resurrected years later for the ebola response in the democratic republic of congo (drc). had teams been given the resourcing to finish, package, and archive complete solutions, months could have been saved at the beginning of the drc outbreak. just as the strategic national stockpile in the us ensures the supply of potentially lifesaving drugs and medical supplies, we need a technology and data stockpile equivalent that is properly maintained and ready to go when the next outbreak strikes. too much time is wasted in the earliest parts of an outbreak when the curve is furthest from being flat. this is also a good time to simply ''show up'' physically to lend whatever type of assistance your local clinic or public health service needs. at this point, the risks of infection should be greatly decreased, and many hands make light work. whether it is coding, data analysis, swinging a hammer or paintbrush, doing a supply run, or helping document and publish data and/or care and research findings, this should be a time of not just recovery but of improvement. it is well known that strong, resilient health systems are and will always be the first line of defense against epidemics. the goal of this reconstruction pause should not be to return them to prior capability but to make them stronger and ready for the next outbreak. it may be here soon enough. lastly, first and foremost before considering or acting on anything suggested above, take care of yourself, your family, your livelihood, and your community first. the fewer of us who get sick, the more of us who are available to help others before, during, and after the acute phases of this outbreak and the essential rebuilding phases that follow. a primer on biodefense data science and technology for pandemic preparedness, duke university's forge https:// forge homeland security presidential directive/hspd- about the biodefense policy landscape analysis toll v we don't need another national biodefense strategy. modern war institute at west point frequently asked questions about biosafety and covid- commcare for covid- outbreak response about the author eric perakslis is a research, informatics, technology, and r&d leader with more than years of direct experience in information technology, informatics, research, healthcare, government regulation, biotechnology, and pharmaceuticals discovery and development. he received his phd in chemical and biochemical engineering from drexel university. he became cio and chief scientist (informatics) at the fda in before moving to harvard medical school to serve as executive director at the center for biomedical informatics. he currently is senior vp key: cord- - csl md authors: li, shuai; xu, yifang; cai, jiannan; hu, da; he, qiang title: integrated environment-occupant-pathogen information modeling to assess and communicate room-level outbreak risks of infectious diseases date: - - journal: build environ doi: . /j.buildenv. . sha: doc_id: cord_uid: csl md microbial pathogen transmission within built environments is a main public health concern. the pandemic of coronavirus disease (covid- ) adds to the urgency of developing effective means to reduce pathogen transmission in mass-gathering public buildings such as schools, hospitals, and airports. to inform occupants and guide facility managers to prevent and respond to infectious disease outbreaks, this study proposed a framework to assess room-level outbreak risks in buildings by modeling built environment characteristics, occupancy information, and pathogen transmission. building information modeling (bim) is exploited to automatically retrieve building parameters and possible occupant interactions that are relevant to pathogen transmission. the extracted information is fed into an environment pathogen transmission model to derive the basic reproduction numbers for different pathogens, which serve as proxies of outbreak potentials in rooms. a web-based system is developed to provide timely information regarding outbreak risks to occupants and facility managers. the efficacy of the proposed method was demonstrated by a case study, in which building characteristics, occupancy schedules, pathogen parameters, as well as hygiene and cleaning practices are considered for outbreak risk assessment. this study contributes to the body of knowledge by computationally integrating building, occupant, and pathogen information modeling for infectious disease outbreak assessment, and communicating actionable information for built environment management. this study aims to develop a framework for room-level outbreak risk assessment based on integrated building-occupancy-pathogen modeling to mitigate the spread of infectious disease in buildings. the rationale is twofold. first, buildings are highly heterogeneous with a variety of compartments of distinctive functionalities and characteristics, providing diverse habitats for humans and various pathogens [ , ] . modeling the pathogen transmission and exposure within a building at the room level will provide useful information at an unprecedented resolution to implement appropriate disease control strategies. second, the spread of infectious diseases can be mitigated if occupants and facility managers have adequate and timely information regarding the outbreak risks within their buildings. communicating actionable information to occupants and facility managers through an easily accessible interface will help occupants to follow hygiene and social distancing practice, and help facility managers to schedule disinfection for rooms with high outbreak risks. to address the knowledge gaps, a novel environment-occupant-pathogen modeling framework and a web-based information visualization system are developed to assess the outbreak risks and mitigate the spread of infectious diseases in buildings ( fig. ) . first, to assess the outbreak risks, the fomite-based pathogen transmission model proposed in [ ] is adopted in this study. the limitation of the model is that the environmental parameters and occupant characteristics are not automatically extracted and incorporated in the model, hindering the computation of the spatially-varying environmental infection risks in buildings. to overcome this limitation, bim is exploited to automatically retrieve venue-specific parameters including building characteristics and occupancy information that are relevant to pathogen transmission and exposure. then, the extracted building and occupant parameters are used with pathogen-specific parameters in a human-building-pathogen transmission model to compute the basic reproduction number r for each room in a building. r is used as a proxy to assess the outbreak risks of different infectious diseases. second, a web-based system is developed to enable information visualization and communication in an interactive manner to provide guidance for occupants and facility managers. this study innovatively establishes the computational links among building, occupant, and pathogen modeling to predict outbreak risks. the risk prediction for spatially and functionally distributed rooms in a building provides useful information for end-users to combat and respond to the spread of infectious diseases, including the seasonal flu and covid- . the developed method and system add a health dimension to transform the current building management to a user-centric and bio-informed paradigm. fig. in this study, a computational tool is developed based on dynamo [ ] to extract the geometry and properties of each room in a building, and to compute the corresponding venue-specific parameters. fig. shows the workflow of the information retrieval process. lines in fig the workflow for information retrieval is detailed as follows. the steps for extracting room parameters are: thereafter, the total furniture area in each room (named ) is calculated by summing up the surface area of all furniture inside the room. in epidemiology literature, r is one of the most widely used indicators of transmission intensity to demonstrate the outbreak potential of an infectious disease in a population. commonly, r > means the epidemic begins to spread in the population, r < means the disease will gradually disappear, and r = means the disease will stay alive and reach a balance in the population. with the increase of r , the outbreak risk will increase, and more severe control measures and policies will be needed [ ] . in this study, we categorize the level of outbreak risk into low, mild, moderate, and severe based on the range of r . specifically, the risk is low when r < ; the risk is mild when ≤ r < . because there is a fair chance that the transmission will fade out as , is not much larger than [ ]; the risk is moderate when . ≤ r < , indicating an epidemic can occur and is likely to do so [ , ] ; and the risk is severe when r > and immediate actions should be taken by facility managers, such as cleaning the surfaces, to reduce the risk. to better communicate the infection risk to occupants and facility managers, a web-based system was developed to visualize the outbreak risk of different pathogens in each room within a building. fig. illustrates the architecture of the web-based system, which consists of four modules, i.e., data management, model derivative, web application, and user. three add-in functions were developed to help users visualize the interior layout of the building and color-coded rooms with their corresponding risk levels, as well as search specific room- related disease outbreak risk information. the first add-in function is "vertical explode", which is used to view each level of the building. this function can help the user visualize the interior and room layout. the facility users can also use this function to visualize the outbreak risk of rooms on each floor and take appropriate practices. for facility managers, the "vertical explode" function enables them to obtain a holistic view of risk distribution at each level and take informed actions, such as limiting the number of occupants and implementing cleaning and disinfection protocols, to control the spread of the disease. this function is integrated with the web-based system, and clicking buttons were created to activate and deactivate it. the second function is "room filtering", which is used to highlight rooms at different risk levels for a specific pathogen. the user needs to first select one of the three pathogens from the dropdown menu: sars-cov- , influenza, and norovirus. thereafter, the user can set a risk threshold to highlight rooms with r greater than a specific value. in addition, different highlighting colors are used to represent different infection risk levels. low, mild, moderate, and severe risks are represented by color green, blue, celery, and red, respectively. the third function is "room query", which enables the user to search for a specific room and retrieve infection risk for the three pathogens. the "room query" function is displayed as a search box on the web-based system. the users can easily find the potential risk of a specific room using this function. finally, end users can access the web-based information communication system and obtain information about outbreak risk in each room of the building through various channels, including laptops, smartphones, and tablets. a hypothetical case study is used as an example to demonstrate the efficacy of the proposed framework and the newly developed web-based system. the building information model of a six-floor school building with , square feet is used. the building contains classrooms and faculty and graduate assistant offices. the room types considered in the case study include offices and classrooms. five offices and five classrooms were selected. the venue-specific parameters of the rooms are extracted and listed in table , and the computed r values of the three diseases are listed in table . table venue-specific parameters in representative rooms from table , the values of r vary across different rooms and different diseases. r values in offices are smaller than the values in classrooms, which stems from the small occupancy and the low rate of fomite touching in offices compared to those in classrooms. for influenza, the r values in all the rooms are less than , indicating that influenza is unlikely to outbreak in the building through the fomite-mediated transmission. this could be partially explained by the relatively short infectious period, high inactivation rate in hands, low hand-to-fomite pathogen transmission efficiency, and relatively low infectiousness with the same amount of pathogens. for covid- , the r values in all rooms are higher than those of influenza, and the risk in classroom reaches a moderate level, indicating that covid- has the potential to outbreak in the classroom. covid- has a relatively high outbreak risk in most cases because it has a high shedding rate, small surface inactivation rate, and high transfer efficiency from fomites to hands. for norovirus, the r values are high in most classrooms, which might be because of its high infectivity, long infection period, and high hand-to-fomite transmission efficiency compared to the other two diseases. this finding also aligns with the trend obtained in [ ]. the above results prove that the outbreak risk of an infectious disease is influenced by both venue-specific and pathogen-specific parameters, which highlights the significance of integrating bim and the pathogen transmission model in assessing spatial-varying disease outbreak risk. sensitivity analysis was further conducted to evaluate the influence of the rate of fomite touching (+ e ) and the shedding rate (%) of sars-cov- on r based on the estimated ranges of the two parameters (listed in table ). fig. illustrates the changes in r with the increase of + e for all three diseases in both classrooms and offices. from fig. , the disease outbreak risk increases as the increase of + e . the values of r for norovirus and covid- in classroom , , and may exceed with the increase of + e . on the other hand, the infection risk in offices and that for influenza in classrooms will remain low even occupants touch objects in the rooms more frequently. therefore, it is particularly important to educate students in classrooms with relatively high occupancy to not touch the common areas frequently. fig. illustrates the changes in r of covid- with varying shedding rates. from the figure, % has a significant impact on the outbreak risk of covid- in classroom , , and . therefore, for classrooms with relatively large occupancy, control strategies should be taken to reduce pathogen shedding from the occupants, such as using face masks, and covering the mouth when coughing. applied to different rooms to reduce the risks to an acceptable low level. cleaning the surface five times per day will decrease r by over %, compared to no surface cleaning. considering the ongoing outbreak of covid- , classrooms with high occupancy (e.g., classroom ) should be given particular attention on surface cleaning. cleaning surfaces at least two times per day is needed to achieve a low risk level. for norovirus, classrooms with relatively large occupancy (e.g., classroom , , and ) will require more frequent surface cleaning to reduce the outbreak risk to the low level. other complementary strategies, such as increasing hand washing and limiting occupancy, should be adopted to maintain a low level of outbreak risks. as shown in fig. , room filtering and room query functions can help the user easily locate rooms with high risk and query risk information for a specific room. specifically, fig. (a) shows an exemplary output of the room filtering function that highlights the rooms with r value greater than for covid- . fig. (b) displays an example of the room query function in the web system. the pathogen risk information for influenza, norovirus, and covid- is retrieved with corresponding recommendations. with the web-based information communication system, facility managers can take important measures to control the spread of diseases, such as designing appropriate cleaning and disinfection strategies, promoting hand hygiene, reducing maximum occupancy, and accommodating facility usage schedule based on risk distribution across rooms within the building. for instance, deep cleaning and disinfection are required for rooms with severe outbreak risk. in addition, facility managers can post signs at these high-risk areas to remind occupants to take essential practices such as social distancing and hand hygiene. the web-based system will also keep facility users, including teachers, students, and other staff, aware of up-to-date outbreak risk information within the building, and thus taking informed actions to avoid further spread of diseases. for example, facility users can avoid entering rooms with high outbreak risk. . discussion the results and insights derived from the analysis have important implications on adaptive built environment management to prevent infectious disease outbreak and respond to on-going pandemic. due to varying building characteristics, occupancy levels, and pathogen parameters, the microbial burdens and outbreak risks differ significantly even in the same building, highlighting the need for spatially-adaptive management of the built environment. the proposed method automates the batch process for simulation and prediction of outbreak risks for different pathogens at the room level, and visualizes the risks for adaptive management. the results on outbreak risks at room level enables the paradigm for spatially-adaptive management of the built environment. with the new streams of risk information, customizable interventions can be designed. for instance, in consistent with the practice during the covid- pandemic, reducing the accessible surfaces in rooms and restricting the occupancy in the room are some of the effective strategies to reduce the outbreak risks. the spatially-varying risk information can also guide the facility managers to pay close attention to high-risk areas by adopting more frequent disinfection practices. a bim-based information system is developed to extract the necessary information for modeling infection within buildings, and to visualize the derived information in an easy-to-understand and convenient way through web pages. as such, the information-driven interventions could alleviate the pathogenic burdens in the buildings to prevent the spread of infectious diseases. providing information to end-users is critically important for them to change behaviors. human behavior plays an important role in the transmission of pathogens such as the sars-cov- . changing behaviors is critical to preventing transmission. providing timely and contextual information can be a promising option to motive the change of human behaviors. with the room- level outbreak risk information, the users could be motivated or persuaded by the visualized risks to practice appropriate behaviors such as wearing a mask, social distancing, and hand- washing. the facility managers can use the information to conduct knowledge-based management, such as limiting the occupancy in the room, managing crowd traffic, and rearranging room layout. this study has some limitations that deserve future research. first, the model does not consider factors such as sunlight exposure, humidity, and airflow that may impact the persistence and transmission of pathogens in built environments. this is mainly because the quantitative impacts of these factors on pathogen persistence and transmission are largely ambiguous, if not unknown. if these impacts can be quantified and the environmental parameters can be monitored and modeled in bim, our proposed framework can be extended to incorporate these factors. second, the computation of r only considers the fomite-mediated transmission, and does not consider the airborne and close contact transmission. microbial pathogens may have different transmission routes, including airborne, close-contact, and fomite-based transmission. this study focused on fomite-based transmission to illustrate the modeling approach for assessing the outbreak risks, and demonstrate the efficacy of the developed information system to guide infection control practices and building operations. to fully assess the exposure risks and outbreak potentials, all important routes need to be considered. in addition, the outbreak potentials of a variety of pathogens can be considered together to develop an aggregate index, which could be more intuitive for occupants and facility managers who are not public health experts. third, the system mainly relies on static models and does not make full use of dynamic and real-time data regarding built environments and occupant behaviors such as presence and interactions with objects. in future studies, the internet of things sensors can be installed in the buildings and algorithms can be developed to retrieve dynamic data for integration with the models for accurate and robust risk estimation. fourth, the web-based system can be further improved by connecting it with smart devices such as robots for automated cleaning and disinfection and smartphones for precision notifications. this study creates and tests a computational framework and tools to explore the connections among built environment, occupant behavior, and pathogen transmission. using bim-based simulations, building-occupant characteristics, such as occupancy and accessible surface, are extracted as venue-specific parameters. the fomite-mediated transmission model is used to predict the contamination risks in the built environment by calculating a room-by-room basic reproductive number r , based on which the level of infection risk at each room is characterized into low, mild, moderate, and severe. a web-based system is then created to communicate the infection risk and outbreak potential information within buildings to occupants and facility managers. the case study demonstrated the efficacy of the proposed methods and developed systems. practically, the method and system can be used in a variety of built environments, especially, schools, hospitals, and airports, where transmission of infectious pathogens is of particular concern. the outbreak risks predicted at room resolutions can inform the facility managers to determine room disinfection and cleaning frequency, schedule, and standard. in addition, appropriate operational interventions including access control, occupancy limits, social distancing, and room arrangement (e.g. reducing the number of tables and chairs) can be designed based on the derived information. the occupants can access the useful information via 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walther, bruno a. title: the accelerated infectious disease risk in the anthropocene: more outbreaks and wider global spread date: - - journal: biorxiv doi: . / . . . sha: doc_id: cord_uid: gyk cwx the greatly accelerated economic growth during the anthropocene has resulted in astonishing improvements in many aspects of human well-being, but has also caused the acceleration of risks, such as the interlinked biodiversity and climate crisis. here, we report on another risk: the accelerated infectious disease risk associated with the number and geographic spread of human infectious disease outbreaks. using the most complete, reliable, and up-to-date database on human infectious disease outbreaks (gideon), we show that the number of disease outbreaks, the number of diseases involved in these outbreaks, and the number of countries affected have increased during the entire anthropocene. furthermore, the spatial distribution of these outbreaks is becoming more globalized in the sense that the overall modularity of the disease networks across the globe has decreased, meaning disease outbreaks have become increasingly pandemic in their nature. this decrease in modularity is correlated with the increase in air traffic. we finally show that those countries and regions which are most central within these disease networks tend to be countries with higher gdps. therefore, one cost of increased global mobility and greater economic growth is the increased risk of disease outbreaks and their faster and wider spread. we briefly discuss three different scenarios which decision-makers might follow in light of our results. the anthropocene has also been nicknamed the 'great acceleration' because various socioeconomic and earth-system related indicators experienced a continuous and often exponential growth after the second world war (steffen et al., a; mcneill and engelke, ; steffen et al., ) . while this relentless growth of the human enterprise improved human well-being around the world in many aspects (waage et al., ; barrett, ; permanyer and scholl, ; zheng and qian, ) , negative impacts have likewise increased (ipcc, ; ipbes, ) . in tandem, warnings about a climate emergency (lenton et al., ; ripple et al., ) , a sixth mass extinction (pereira et al., ; barnosky et al., ; ceballos et al., ) , increasing ocean acidification and dead zones (hoegh-guldberg et al., ; diaz and rosenberg, ; branch et al., ) , and even widespread ecosystem collapse (jackson, ; barnosky et al., ; unep, ) and transgression of safe planetary boundaries (steffen et al., b) have grown increasingly urgent. to avoid or at least dampen the anticipated or already realized changes, scientists and many others have called out for radical changes to how human economies operate and relate to human societies and their environments (unmüßig, ; simms, ; walther, ; ripple et al., ) . we here want to draw attention to another important and noteworthy feature of the anthropocene which greatly affects public health, human well-being, and economic performance. these findings are especially pertinent as the world reels from the health, social and economic impact of the current sars-cov- pandemic (el zowalaty and järhult, ; ghebreyesus and swaminathan, ; lorusso et al., ) . the increasing connectivity of human populations due to international trade and travel (guimerà et al., ; colizza et al., ; brockmann and helbing, ; gabrielli et al., ) , the rapid growth of the transport of wild and domesticated animals worldwide (rosen and smith, ; schneider, ; rohr et al., ; levitt, ) , and other factors such as the increasing encroachment of human populations on hitherto isolated wild animal populations through loss and fragmentation of wild habitats (patz et al., ; despommier et al., ; pongsiri et al., ; myers et al., ) have led to a great acceleration of infectious disease risks, e.g., the increase in emerging infectious diseases and drug-resistant microbes since (jones et al., ) and the increase in the number of disease outbreaks since (smith et al., ) . to expand the previous analysis (smith et al., ) to the beginning of the anthropocene, we investigated whether the number of disease outbreaks has increased since the second world war. in addition, we examined whether the global pattern of infectious disease outbreaks changed possibly due the increasing connectivity of human populations. in other words, have the disease outbreaks become more globalized in the sense that these outbreaks are increasingly shared by countries worldwide? to investigate these questions, we used a the most complete, reliable, and up-to-date global dataset (gideon informatics, ) which had already been used in the previous analysis (smith et al., ) . this dataset can be used to enumerated the recorded annual number of disease outbreaks. to investigate the changing global patterns of disease outbreaks, we used this dataset to calculate two measures which have been recently introduced into ecological and parasitological studies. these two measures, namely modularity and centrality, quantify the connectivity of bipartite networks. modularity is defined as the extent to which nodes (specifically, sites and species for presenceabsence matrices) in a compartment are more likely to be connected to each other than to other nodes of the network (thébault, ) . the calculation of a modularity measure is useful for global phenomena because it allows the overall level of compartmentalization (or fragmentation) into compartments (or clusters, modules, subgroups, or subsets) of an entire dataset to be quantified. high modularity in a global network means that subgroups of countries and disease outbreaks interact more strongly among themselves (that is, within a compartment) than with the other subgroups (that is, among compartments) (bordes et al., ) . centrality is defined as the degree of the connectedness of a node (e.g., a keystone species in ecological studies; jordán, ; gonzález et al., ) . in the context of our study, centrality is the degree of the connectedness of a country and those countries connected to it. we estimated the countries which are the potential centres of disease outbreaks by investigating the eigenvector centrality of a given country in a network of countries which share disease outbreaks among each other. eigenvector centrality is a generalization of degree centrality, which is the number of connections a country has to other countries in terms of sharing disease outbreaks. eigenvector centrality considers countries to be highly central if the connected countries to them through shared outbreaks are connected to many other well-connected countries (bonacich and lloyd, ; wells et al., ) . modularity and centrality analyses have been used to investigate various ecological, parasitological and epidemiological questions (e.g., tylianakis et al., ; jordán, ; gonzález et al., ; anderson and sukhdeo, ; bascompte and jordano, ; poisot et al., ; bordes et al., ; genrich et al., ) . using a widely used world dataset on infectious disease outbreaks, we here present results which demonstrate that the accelerated number of disease outbreaks and their increased global spread are two further threatening aspects of the accelerated infectious disease risk associated with the globalization process which characterizes the anthropocene. to collate the total number of infectious disease outbreaks over the years - , we extracted the relevant data from the medical database called gideon (gideon informatics, ) which contains information on the presence and occurrence of epidemics of human infectious diseases in each country as well as the number of surveys conducted in each country. the gideon data are curated as records of confirmed outbreaks, are continually updated using various sources such as who and promed, and are accessible via subscription. this dataset is generally considered to be the most complete, reliable, and up-to-date in the world and has been regularly used in previous macro-scale studies of infectious disease, epidemics, and pathogen diversity (e.g., smith et al., ; dunn et al., ; morand et al., ; morand et al., ; poisot et al., ; smith et al., ; morand, ; morand and walther, ) . each row in the gideon dataset specifies the disease 'species', the year and the country of the outbreak. the 'annual total outbreak number' is simply the annual total number of outbreaks regardless of the disease designation and including all countries. the 'annual total disease number' uses the same data for each year as the 'annual total outbreak number' but then counts only the different infectious diseases which had at least one outbreak in that respective year. the 'annual total country number' uses the same data for each year as the 'annual total outbreak number' but then counts only the different countries which had at least one outbreak in that respective year. our entire - dataset contains outbreaks of human infectious diseases in nations. in our case, we built yearly bipartite networks of presence-absence matrices which link countries with all the recorded epidemic outbreaks. we then transformed these bipartite networks where separate nodes from countries were connected with nodes of epidemic outbreaks into unipartite networks using the tnet package (opsahl, ) the calculation of modularity of bipartite networks of shared epidemic outbreaks among countries allowed us to identify modules of countries that share common epidemic outbreaks in each respective year (see introduction) (blondel et al., ; bordes et al., ) . we calculated our modularity measure of unipartite network for each year using igraph (lehoucq et al., ) . high modularity calculated in this context means that an epidemic remains relatively constrained within a few countries while low modularity means that an epidemic has spread across relatively more countries. the calculation of the eigenvector centrality of the unipartite network of each respective year allowed us to determine the number of connections a country has to other countries in terms of epidemic outbreak sharing. eigenvector centrality is a measure of the degree of the connectedness of a country and those countries connected to it. high centrality calculated in this context means that a country is connected to many countries which are also well-connected (bonacich and lloyd, ; wells et al., ) . a visual examination of the time trend of the annual modularity measure suggested a discontinuous trend over time. to detect such a discontinuity (or breakpoint) in the trend over time, we used the r package segmented (muggeo, ; muggeo, ) . this package allows the identification of one or more discontinuities using the bootstrap method; in other words, the decomposition of a relationship into one of more piece-wise linear relationships and the identification of breaking point(s). the standard errors of the breakpoint estimates were computed with the procedure of clegg et al. ( ) which is implemented in the r package segmented. finally, we used a smooth regression to visualize the patterns of changes over time (harrell, ) (e.g., for air transport, modularity, etc.). increase in global measures of mobility and gdp. the increase in measures of mobility during the anthropocene has been staggering, with growth percentages of up to % (table ) . many more impressive local and regional examples exist, see, e.g., (wilson, ; wilson, ) . for further analyses below, we only used the world bank data on flight passengers and air freight; therefore, we detail them here. since the s, the total global number of flight passengers ( increase in the number of outbreaks. since the s, the annual total outbreak number ( fig. d ), the annual total disease number (fig. e) , and the annual total country number ( fig. f ) have increased exponentially. however, for the annual total disease number, this increase has slowed since the s. while there is some annual up-and-down variation, the overall trends are well demonstrated by the smooth line regressions. furthermore, around , the trends for the three variables began a decrease or stagnation in the actual data, but not in the smooth line regressions. we also plotted all the annual centrality values for each nation within six regions. despite a large amount of variation over the investigated time period, the three north american countries had the highest mean of centrality values, followed by the three pacific countries and then the european, south american, asian and african countries (fig. ). these differences in centrality between the six regions are statistically significant (kruskal-wallis χ = . , df = , p = . e- ). our results further support the hypothesis that the anthropocene is associated with to a great acceleration of infectious disease risks. first, we showed that the number of disease outbreaks, the number of diseases involved in these outbreaks, and the number of countries affected have increased during the entire anthropocene (thus expanding on the results of previous studies which were more limited in time or space, e.g., morand et al., ; morand et al., ; smith et al., ; morand, ) . furthermore, these increases have mostly been exponential, although with some recent slowdowns (see discussion below). second, we demonstrated that the spatial distribution of these outbreaks has become more globalized in the sense that the overall modularity of the disease networks across the globe has decreased since around . in other words, clusters of disease outbreaks began to increasingly become connected with other clusters so that the fragmented nature of outbreak clusters diminished over time. before , a disease outbreak usually remained confined to one or a few closely connected countries; thereafter, disease outbreaks have become increasingly pandemic in their nature. we thus revealed a long-term, worldwide change in the biogeographic structure of human infectious diseases associated with outbreaks. we further found that this decrease in modularity is correlated with the increase in air traffic. the increase in global mobility and especially in air traffic (table ) allows an outbreak to rapidly spread across several national and continental borders within a short period of time (see also results from modelling and real-world data below). third, we demonstrated which countries and regions are most central within these disease networks. countries which are more centrally located within these disease networks tend to be also the more developed and emerging countries with significantly higher gdps. therefore, one cost of increased global mobility (which is currently tightly linked to economic growth and globalization, see discussion below) is the increased risk of disease outbreaks and their faster and wider spread (although we note that the risk per capita may be decreasing, smith et al., ) . before we discuss the implications of our results, we address possible limitations and biases. while gideon is generally acknowledged to be the most complete, reliable, and up-to-date global dataset on infectious disease outbreaks, we nevertheless should consider that ( ) there may have been some underreporting in the early part of the anthropocene, and ( ) recent outbreaks may not have been entered into gideon yet. ( ) there may have been some underreporting of infectious disease outbreaks during the early parts of the anthropocene in developing countries. however, the imposition in the s of the so- while we cannot exclude the possibility of some underreporting of disease outbreaks during the early part of the anthropocene, it is rather unlikely that the large increases of several hundreds of percent which we documented in figures d-f are entirely due to underreporting. since the overall trends are so consistent and so large over a relatively long period of time, we argue that these trends are real even if the actual numbers may be off by a few percentage points. ( ) the recent slowdowns shown in figures d-f could be real or due to the most recent outbreaks not having been entered into gideon yet. if they are real, they are not really influencing the overall decade-long trends documented here. however, if they are due to underreporting, then the documented trends would be even stronger. although it is generally acknowledged that correlation does not prove causation, the correlation between air travel and modularity specifically (fig. ) , and the relationship between increased mobility and the faster and wider spread of disease outbreaks (table , figures and ) in general make sense given theoretical models and real-world evidence (see discussion below). however, we acknowledge that other factors may be responsible, especially variables which may covary with mobility measures. further causal analyses are therefore required, but these are beyond the scope of this study. the starting point of a disease outbreak is due to a variety of local conditions or factors (morand and lajaunie, ; morand and figuié, ) . however, after emergence, the local, regional, or global spread of a disease is of course dependent on many other factors of which host mobility is usually one of the most important ones. this is of course especially true for directly transmitted human pathogens (walther and ewald, , and studies cited below), although mobility of humans as well as vectors are also important for the global spread of vector-borne diseases (tatem et al., ; brown et al., ; eritja et al., ; golnar et al., ; oliveira et al., ) . theoretical models predict that increased mobility leads to a faster and more wide-ranging spread of a disease outbreak, and, vice versa, decreased mobility slows and contains the spread of an outbreak. modelling the spread of the sars-cov- pandemic, hufnagel et al. ( ) demonstrated that two control strategies, shutting down airport connections and isolating cities, reduced the spread of the virus. drastic travel limitations also delayed a pandemic by a few weeks in a model of the global spread of influenza (colizza et al., ) . similarly, increasing levels of ( ) isolation of infectious hosts, household quarantine and related behavioral changes which reduce transmission rates and ( ) air traffic reduction increasingly slowed the global spread of influenza, although the latter control strategy required the almost complete halt of global air traffic (cooper et al., ; ferguson et al., ; flahault et al., ; hollingsworth et al., ; epstein et al., ; bajardi et al., ) . epstein et al. ( ) emphasized that a combination of both control strategies would be even more effective, a result mirrored by mao ( ) for a model at the city scale. crucially, hollingsworth et al. ( ) also showed a significant decrease in the number of countries affected if travel reductions are combined with other control strategies to reduce transmission rates. this result was confirmed by cooper et al. ( ) and flahault et al. ( ) who found that fewer cities (distributed around the world) were affected by major outbreaks if sufficiently early and significant travel and transmission reductions were implemented. in a simulated smallpox attack, even gradual and mild behavioral changes had a dramatic impact in slowing the epidemic (del valle et al., ) . another model suggested that public health policies that encourage self-quarantine by infected people can lower disease prevalence (chen et al., ) . real-world examples also demonstrate the link between increased mobility and faster disease outbreaks. real data on influenza in the usa showed that a reduction in air travel resulted in a delayed and prolonged influenza season (brownstein et al., a; brownstein et al., b) . similarly, the presence of airports and railway stations significantly advanced the arrival of influenza during the pandemic in china (cai et al., ) . global connectivity due to air traffic allows an outbreak to rapidly spread across several national and continental borders within a short period of time. for example, the ebola virus outbreak was brought into the continental usa onboard a commercial flight from liberia because the host was asymptomatic during the flight (cdc, ) . sevilla ( ) reviewed and modelled how air travel can aid the global spread of ebola, h n influenza, sars-cov- , and pneumonic plague. a systematic review of the effectiveness of travel reductions concluded that internal travel restrictions as well as international border restrictions both delay the spread of influenza epidemics (mateus et al., ) . therefore, given the staggering global increase in global mobility during the anthropocene documented in table , the increase of the number of disease outbreaks, of diseases involved in these outbreaks, and of countries affected, as well as the decrease of modularity of these disease outbreaks make sense because the mobility of humans, other living beings, and goods (which can act as carriers or vectors) all facilitate the spread of disease and species (e.g., smith and guégan, ; findlater and bogoch, ; sardain et al., ) . given the lack of any antiviral or vaccine treatment, the current sars-cov- pandemic has forced governments to drastically curtail people's mobility and introduce continent-wide social distancing and lockdowns in order to at least slow its spread by lowering transmission rates. thus, the governments' responses to this acute global health emergency actually mirror many of the recommendations which were given by the various modelling studies cited above. it should also be noted that the restriction of people's mobility (and its most extreme form, quarantine) and social distancing were already used before the advent of the germ theory of disease and are even used to some extent by other species (hart, ; tognotti, ; bashford, ) . given the link between mobility and disease outbreaks documented by our study, the key question which decision-makers and society at large should ask are which of the following three scenarios (which we outline in very broad terms only) should we aim for in the coming decades. ( ) once the current sars-cov- pandemic is over, we continue on our path of ever increasing mobility without regard to the costs in terms of the accelerated infectious disease risk. ( ) we attempt to slow down or even reverse mobility rates of infected hosts and vectors. ( ) we attempt to slow down or even reverse mobility rates of humans and other carriers and vectors (in other words, decrease many or all of the mobility measures in table ). we briefly discuss the implications of each scenario. however, this discussion is by no means exhaustive, but meant to stimulate further discussion and study which are urgently needed to come to terms with the accelerated infectious disease risk of the anthropocene. ( ) most likely, at least in the short-term, economic and political decision-makers will return to 'business-as-usual' which means increasing mobility rates even further. after all, various projections predict more immense increases of mobility within the next few decades. for example, international tourist arrivals worldwide are expected to increase by . % a year between and to reach . billion by (unwto, ) from the . billion recorded in (table ) in addition to the environmental and social costs and risks of this scenario (e.g., increasing landuse change, greenhouse gas emissions, resource use and waste production, etc.), including the risk of widespread ecosystem collapse (see introduction), we can now add the cost of an increasing infectious disease risk. while our study only focused on human infectious diseases, this cost related to increased mobility is also increasing for animal and plant disease outbreaks as well as alien species introductions (e.g., anderson et al., ; fisher et al., ; bélanger and pilling, ; sardain et al., ) . while outbreaks of animal and plant diseases may be amenable to a cost- benefit analysis (tildesley et al., ) , the current sars-cov- pandemic has clearly shown that simple cost-benefit analyses cannot be applied when the lives of millions of people are at stake (note that another emerging infectious disease, the global hiv pandemic, has claimed million lives so far). given that another pandemic becomes more likely with increasing rates of emergence and increasing global mobility, a 'business-as-usual' scenario is automatically associated with further epidemics and pandemics, possibly killing further millions of humans and devastating local and regional economies or even the global economy. if a 'business-as-usual' scenario is followed with regards to global mobility, countries and the world community should at least invest in better detection and surveillance methods to catch and contain the next pandemic as early as possible, and in better preparedness of public health facilities in case the next pandemic nevertheless gets out of hand (jain et al., ; bedford et al., ; di marco et al., ) . however, this scenario nevertheless will likely be associated with an increased number of epidemic outbreaks (some of which may become devastating pandemics), given the results of our study. ( ) consequently, the most realistic and agreeable scenario may be to slow down or even reverse the mobility rates of infected hosts and vectors. again, the current sars-cov- pandemic has demonstrated that identifying infected hosts and reducing secondary infection rates caused by these infected hosts appear to be the most successful strategies to achieve elimination of the outbreak (e.g., . the required measures, such as mass home quarantine, restrictions on travel, expanded testing and contact tracing, and additional surveillance measures, are thus mostly focused on ( ) identifying and isolating infected hosts (which means to drastically restrict their mobility) and ( ) drastic restrictions of mobility for uninfected hosts. while the latter is possible in crisis situations, it cannot be a long-term solution to the quandary of the increased infectious disease risk of the anthropocene unless we want to decrease our total global mobility (see scenario below). therefore, much improved identification and isolation infected hosts may be the way forward. already, such measures have been adopted during the current sars-cov- pandemic, e.g., body temperature checks for every air travel passenger even though they appear to be ineffective (cohen and bonifield, ) . however, if efficient and reliable health checks which can identify various diseases and which can be administered relatively timeand cost-efficiently to large numbers of passengers could be implemented, we may be able to significantly restrict the mobility of infected hosts. while such a proposal may sound like "pie in the sky" at the moment, rapid advances in diagnostic techniques, such as translational proteomics, may soon allow us to identify infected hosts using simple breathalyzer, saliva, or urine tests (athlin et al., ; nakhleh et al., ; tao et al., ; zainabadi et al., ) . furthermore, hygienic measures, such as the enforcement of handwashing and the wearing of facemasks in public transport hubs, complete and regular disinfection of important traffic hubs and vehicles (including the air and all surfaces), and much better vector control should become mandatory global standards of public health (e.g., grout and speakman, ; nicolaides et al., , reviewed in huizer et al., , especially in the most central of traffic hubs, such as the world's most connected airports (guimerà et al., ; bajardi et al., ) . such measures would certainly help to decrease the mobility of infected hosts and thus the transmission and global spread of diseases. ( ) the most sustainable scenario is, however, to decrease or even reverse global mobility rates of humans and other carriers and vectors, especially if it is part and parcel of a much larger movement towards global sustainability by reducing humanity's environmental footprint and replacing unsustainable economic growth with sustainable economic degrowth (schneider et al., ; daly and farley, ; alexander, ; czech, ; galaz, ; cosme et al., ; weiss and cattaneo, ; chiengkul, ; sandberg et al., ; schmid, ) . such a general, comprehensive and global slowdown of mobility of both uninfected and infected people and vectors would be opposed for many reasons and by many interest groups, mainly based on economic arguments based around the need for continuous economic growth which has so far almost always been positively linked with increased mobility (e.g., arvin et al., ; hakim and merkert, ; unwto, ; saidi et al., ; nasreen et al., ) . it is to some extent possible to decouple mobility from economic growth (loo and banister, ; lane, ) , but even if such a decoupling was achieved, it would not sufficiently reduce mobility to significantly decrease infectious disease risks. as the modelling results cited above and the experience with the current sars-cov- pandemic clearly show, only a huge reduction in mobility and contact rates is sufficient to achieve a slowdown or halt of a highly contagious disease outbreak which is already under way. yet, a decrease in global levels of mobility should also decrease the overall number of disease outbreaks, according to our results (which is different to just slowing and containing the spread of an outbreak, see discussion above). therefore, the many environmental benefits of economic degrowth and deglobalization would be augmented by a global health benefit, the almost certain decrease of infectious disease outbreaks. since economic degrowth and deglobalization have been advocated by many sustainability experts to deal with the currently converging environmental crises (climate change, ocean acidification, biodiversity, etc., see references above), our results further strengthen the argument for such a 'not-business-as-usual' scenario. moreover, the economic degrowth scenario would also ameliorate many of the local conditions or factors associated with the emergence of outbreaks (such as increased livestock production and contact rates with wildlife, climate change, loss and fragmentation of natural habitats caused by urbanization and agricultural intensification, etc.) thus further decreasing the likelihood of disease outbreaks. in addition, we have a growing understanding that the presence of abundant biodiversity and healthy ecosystems has an overall positive effect on human well-being and health (chivian and bernstein, ; wood et al., ; sandifer et al., ; walther et al., ; morand and lajaunie, ; mcmahon et al., ) which should count as an additional health benefit of the economic degrowth scenario. naturally, decreasing mobility is a moral and political choice which can be informed by science, but not answered by science. however, given all the current negative impacts of high mobility (greenhouse gas emissions, land-use and land-cover change and the resulting habitat loss and fragmentation due to transportation infrastructure and energy production, transport of alien species, etc.), maybe it is time to ask whether it is morally justified, for example, to move the equivalent of all the inhabitants of a small town across a continent so that a football team can be supported by its fans during an away game? is it necessary to fly halfway around the world for a weekend shopping trip? is it really most cost-efficient for supply chains to cover the entire globe when all the externalities are included? is long-term sustainability achievable with ever higher rates of mobility? the demand for ever-increasing mobility is putting many stresses on the earth system and therefore also on many aspects of human well-being and health. in this study, we documented another one: the public health risks of an increasing number of disease outbreaks and their increasingly global spread. even without the devastating current impacts of the sars-cov- pandemic, the additional disease outbreak burden associated with our highly mobile and migratory human societies is a definite cost which must be considered in its moral and ethical implications as we consider the future trajectory of the anthropocene (ehrlich and ehrlich, ; steffen et al., ; schill et al., ) . the medicine that might kill the patient: structural adjustment and its impacts on health care in bangladesh planned economic contraction: the emerging case for degrowth emerging infectious diseases of plants: pathogen pollution, climate change and agrotechnology drivers host centrality in food web networks determines parasite diversity transportation intensity, urbanization, economic growth, and co emissions in the g- countries comparison of the immuview and the binaxnow antigen tests in detection of streptococcus pneumoniae and legionella pneumophila in urine human mobility networks, travel restrictions, and the global spread of h n pandemic elimination: what new zealand's coronavirus response can teach the world. the guardian new zealand's elimination strategy for the covid- pandemic and what is required to make it work approaching a state shift in earth's biosphere food security and sociopolitical stability mutualistic networks quarantine: local and global histories a new twenty-first century science for effective epidemic response the state of the world's biodiversity for food and agriculture. fao commission on genetic resources for food and agriculture assessments fast unfolding of community hierarchies in large network eigenvector-like measures of centrality for asymmetric relations forecasting potential emergence of zoonotic diseases in south-east asia: network analysis identifies key rodent hosts habitat fragmentation alters the properties of a host-parasite network: rodents and their helminths in south-east asia impacts of ocean acidification on marine seafood the hidden geometry of complex, network-driven contagion phenomena assessing the risks of west nile virus-infected mosquitoes from transatlantic aircraft: implications for disease emergence in the united kingdom. vector-borne zoonotic dis air travel and the spread of influenza: authors' reply empirical evidence for the effect of airline travel on inter-regional influenza spread in the united states roles of different transport modes in the spatial spread of the influenza a(h n ) pandemic in mainland china cdc and texas health department confirm first ebola case diagnosed in the u accelerated modern human-induced species losses: entering the sixth mass extinction public avoidance and epidemics: insights from an economic model the degrowth movement: alternative economic practices and relevance to developing countries sustaining life: how human health depends on biodiversity estimating average annual per cent change in trend analysis no us coronavirus cases were caught by airport temperature checks. here's what has worked modeling the worldwide spread of pandemic influenza: baseline case and containment intervention the role of the airline transportation network in the prediction and predictability of global epidemics delaying the international spread of pandemic influenza assessing the degrowth discourse: a review and analysis of academic degrowth policy proposals supply shock: economic growth at the crossroads and the steady state solution ecological economics: principles and applications effects of behavioral changes in a smallpox attack model the role of ecotones in emerging infectious diseases sustainable development must account for pandemic risk spreading dead zones and consequences for marine ecosystems global drivers of human pathogen richness and prevalence can a collapse of global civilization be avoided? 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air transport, freight (million ton-km) air transport maritime highways of global trade maritime logistics: a complete guide to effective shipping and port management an efficient and costeffective method for purification of small sized dnas and rnas from human urine development and poverty reduction: a global comparative perspective a pneumonia outbreak associated with a new coronavirus of probable bat origin this work was part of thefuturehealthsea project funded by the french anr (anr- -ce - - ). s.m. is supported by the thailand international cooperation agency (tica) "animal innovative health". we sincerely thank dieter stockmann from the institute of shipping economics and logistics (isl) and claire thackeray from container trades statistics (cts) for providing data about container movements, jean tournadre for providing data about ship numbers, and ting-wu chuang for providing references. traffic vehicles for transportation < to > million motor vehicles (> %) (steffen et al., a) - international tourism < to > million arrivals (> %) (steffen et al., a) table are approximations whenever numbers are given with a ~, < or > sign because these numbers were taken from graphs in steffen et al. ( a) and isl ( ). abbreviations: dwt = deadweight tonnage is a measure of how much weight a ship can carry; mt = metric ton; teu = twenty-foot equivalent unit, a standard size for . m long containers. key: cord- -u vihq u authors: allam, zaheer title: the rise of machine intelligence in the covid- pandemic and its impact on health policy date: - - journal: surveying the covid- pandemic and its implications doi: . /b - - - - . - sha: doc_id: cord_uid: u vihq u the use of advanced technologies, especially predictive computing in the health sector, is on the rise in this era, and they have successfully transformed the sector with quality insights, better decision-making, and quality policies. even though notable benefits have been achieved through the uptake of the technologies, adoption is still slow, as most of them are still new, hence facing some hurdles in their applications especially in national and international policy levels. but the recent case of covid- outbreak has given an opportunity to showcase that these technologies, especially artificial intelligence (ai), have the capacity to produce accurate, real-time, and reliable predictions on issues as serious as pandemic outbreak. a case in point is how companies such as bluedot and metabiota managed to correctly predict the spread route of the virus days before such events happened and officially announced by the world health organization. in this chapter, an increase in the use of ai-based technologies to detect infectious diseases is underlined and how such uses have led to early detections of infectious diseases. nevertheless, there is evidence that there is need to enhance data sharing activities, especially by rethinking how to improve the efficiency of data protocols. the chapter further proposes the need for enhanced use of technologies and data sharing to ensure that future outbreaks are detected even earlier, thus accelerating early preventive measures. the fourth industrial revolution has brought numerous transformations in the world, catalyzed by the advent and rapid adoption of digital tools. one notable disruption that this revolution has brought is the advent of novel computing methodologies and technologies, which are seen to be transforming all spheres of the global economies. these are observed to be the basis for the unquestionable improvements and quality risk assessments that each sector within the global fabric is experiencing. on this note, one sector that has truly been transformed is the medical sphere, which now prides itself of enriched databases following novel application of different technologies such as artificial intelligence (ai), machine learning, natural language processing, big data, and internet of things (iot) and others. with the increased data, and the technology, those working in the sector have access to advanced predictive modeling and computing tools that have transformed areas such as personal medicine and epidemiology, medical operations, diagnosis, and drug manufacturing . in addition, as noted by watson ( ) , the technologies are helping the medical fraternity to draw variable predictions by comparing historical and present medical data. for instance, it is now possible to use such predictions to assess the healthcare labor force and subsequently use the results to initiate recruitment processes in areas that are most deserving in a meritocratic way. even if ai tools are observed to sometimes extend biases, those are being addressed, a hiring authority can manage to effect the concept of inclusivity and streamline some lingering workforce challenges among other things. while these computing technologies and tools have already given a glimpse of how they can transform the health sector, it is worth appreciating that most of them are still a "work-in-progress" in the medical field and hence need to continue evolving and streamlined. therefore, in that regard, it is understandable that some teething problems and challenges are inevitable, but such need to be addressed with time. additionally, it has been found that some medical professionals and stakeholders in this field are yet to fully embrace the computing tools as part of the advancement in the medical realm; hence, they continue to rely on human-based interpretation, including in life-threatening situations. and, from records, such decisions sometimes tend to be time-consuming and are at times, far from being correct. therefore, to ensure that such scenarios are minimized, there is a need for frameworks to guide the usage of those technologies so that they can be widely accepted and ultimately lead to saving more lives. in particular, the issues of data collection, storage, management, and sharing require to be urgently addressed, as it is seen as the primary source of the apprehension that some in the health community have against them. on this, for a start, the challenge of standardization of protocols needs to be sorted as this hosts issues such as limiting the scope of data, is associated with incompatibility of devices and networks, and exposes the field to extra costs to name a few. addressing such challenges would be key, especially in a period of emergencies like now, when the entire world is hurting from the impacts of covid- pandemic. for instance, despite the challenges raised earlier, some startup companies were able to use the available data from social media, airline ticketing, and medical institutions to identify that the world is experiencing a new virus outbreak days before those in medical fraternity had made similar findings (gaille, ) . with these technologies, it also took less time to identify the outbreak, unlike in other previous outbreaks like in the case of the severe acute respiratory syndrome (sars) outbreak in that took relatively months to identify (qiu et al., ) . in the case of covid- , initially known as -ncov, it only took days (who, b) . these breakthroughs in the medical field, therefore, need to be encouraged, and one way of doing this is the streamlining all available obstacles. in support of this, this chapter surveys how ai processes, aided by availability of data managed to allow for early detection of the coronavirus outbreak, and through the findings, showcase that enhanced data sharing protocols hold the key to improved future urban health policies. the first official confirmation of novel coronavirus (now known as the covid- ) was made public by the world health organization (who) on january , , after its officials based in china received reports from the chinese health official of a new type of infectious virus (who, a). but from records, before this actual confirmation, there were reports that some people had started to show signs like those of the virus as early as december , , in wuhan. of these, six had presented themselves to the hospital in where they were treated and later discharged. but, the cases of similar symptoms continued, and this raised an alarm among health officials who embarked on a fact-finding mission to establish whether they were dealing with a commonly known virus outbreak or a new type altogether. it was after this that, on december , , chinese officials liaised with the who officials to establish that this was truly a new strait of coronavirus. this prompted concerted efforts that lead to the official confirmation of the virus on january , , which later became widespread worldwide (fig. . ) and classified as a pandemic. in view of this historical perceptive, it is true that there was a time lag between when the first symptoms were reported and when the confirmation was done (who, b); thus, since it is now clearly known how the virus is transmitted (from person-to-person), there must have been a sizable number of people contracted the virus. this prompted chinese health officials to place the entire region of wuhan city under a total lockdown as from january , , to prevent further spread (li et al., ) . but, unfortunately, noting that this is a busy city, people from other regions, and countries, as was later established by bluedot, who may have contracted the virus had already traveled back to their countries, and this opened the door for further spread across regions and finally into the breadth and length of the world. in respect to the actual origin of the virus, for now, only theories have been advanced. but, reports to date (retamal, ) support that the first victims of this virus contracted it from the huanan seafood wholesale market in wuhan city. and as noted earlier, being a new virus, the tests were initially being conducted only in china, specifically in wuhan, with the health officials suspecting it to be sars virus, but this was ruled out on january , . this raised alarms, and when it was officially identified and provisionally named " -ncov" on january , , and the data subsequently shared to public, an australian virus identification laboratory based at the peter doherty institute for infection and immunity immediately embarked on its research and by january , , it was able to clone the virus (nature, ). but this is not the only institution that took the virus outbreak seriously. according to niiler ( ) , bluedot, whose profile is shared in the following, was able to employ the services of aidriven algorithms, to analyze data gathered from sources such as new reports, air ticketing, and animal disease outbreaks to predict that the world is facing a new type of virus outbreak. besides the prediction of the new virus outbreak, this startup and another called metabiota (both profiles shared in the following) were able to predict (independently) correctly some of the areas that would experience the virus spread next. among regions and countries predicted by each of these startups that turned to be true include japan, taiwan, south korea, singapore, thailand, and hong kong (heilweil, ) . such predictions came days earlier before any of the said country reported their first case. the information from these different quarters became instrumental in combating the virus. it was through the spread prediction mapped by bluedot and metabiota that the rest of the world and concerned institutions and agencies came to learn that the world is confronting a highly infectious virus that was spreading at alarming rates. on the same, after successfully cloning the virus, the virus identification laboratory shared the data in an open database where authorized researchers and labs can access and conduct further research on cures and vaccines (nature, ). all these efforts prove that with technologies, it is now possible to confront pandemics of global magnitude. but such drive needs to be backed by concerted efforts aimed at eliminating data sharing obstacles associated with different advanced computing technologies and tools. the current case of covid- is not the most devastating nor the only virus that the world has had to struggle with. indeed, looking at the historical fact, there have had some more contagious, devastating, and widespread pandemics experienced before. in the early th century, it is documented that a deadly plague dubbed the black death (bubonic plague) struck the world and killed approximately million people in a span of years (duncan and scott, ) . fast forward, in , another deadly pandemic was the spanish flu (h n influenza virus) struck. this is a type of influenza that is believed to have originated in Étaples, france, and it went on to infect over million people, killing around million of these globally (martini et al., ) . between and , another type of influenza (a subtype h n ) also known as asian flu broke in china, and by the time it was contained, it had claimed the lives of . million people. ten years later ( ), the world suffered another outbreak; this time influenza a (h n ) first reported in hong kong, killing over million people. later on, in , the swine flu (h n influenza virus) killed , people in the united states alone (cdc, ). before this, in , there was an outbreak of sars in china that killed people (song et al., ) . there was also ebola (zaire ebola virus) that was first reported in democratic republic of congo that claimed approximately , people, followed by the zika virus in that infected approximately , people, killing people. in , the world is now confronting the coronavirus, which has spread to over countries, and the end to it is not predictable at the time of writing of this chapter. in all the examples cited earlier, the common denominator is that the success of containing any of these viruses depends on detection and identification. that said, it is worth noting that these pandemics were caused by different types of viruses. these include the influenza virus, henipavirus (nipah virus), filoviruses like those responsible for ebola, and flavivirus that is responsible for zika (aris-brosou et al., ; madhav et al., ) to name a few. this process usually equates to extensive laboratory testing, as illustrated in fig. . . regarding their detection, it is dependent on the type of technology use; hence, from the emergence of the digital revolution, things are seen to be changing in respect to amount of time taken for detection. however, here too, other factors such as the availability of data, quality of the same, and sharing methods are critical. for instance, despite having some levels of modern technology, it took approximately months to identify the sars virus. such delays, however, are credited to the action or inaction of the chinese health officials to withhold information concerning the virus outbreak. in cases where there were concerted efforts between different players, like in the case of ebola outbreak in west africa, it is reported that the virus was identified in a record time, and this prevented its spread beyond the three countries (liberia, sierra leone, and guinea) that it was first reported (wojda et al., ) . in the current case of covid- , as noted earlier, it only took only days to detect and identify the virus and to also predict how it would spread from the original epicenter (wuhan). this was possible due to availability of technologies such as ai (bini, ) , machine learning, and natural language processing; the aforementioned startups were able to use to gather and analyze the data. in particular, the advancement in ai-based infectious disease-surveillance algorithms is understood to reduce the amount taken to detect a virus outbreak. it is evident that since the emergence of the ai-based surveillance, there is a notable level of improvement and efficiency. this is particularly important noting that technological advancements in other sectors such as transport have made movement of people relatively cheaper, quicker, and comfortable; thus, importation of virus and diseases from regions of high concentration to those with little or no virus or disease has become relatively high. this is the reality with the covid- , which was first imported from china and then later from some european countries such as italy to the rest of the world. in this regard, it is true that there are ongoing works and discussion aimed at revising existing policies to ensure the loopholes that have existed, thus allowing that spread of diseases and other outbreaks to nonendemic regions have been sealed. but, with the current happening, it is true that much effort is still needed. the amount of emerging computing literature on infectious diseases demonstrates that substantial research, supported by development of ai-based algorithms, has been increasing exponentially supporting an incline in use of ai technologies involved in diseases and virus surveillance. the increased use of ai-based tools to monitor and survey outbreaks in different regions, through a forward step toward early prevention, needs to be complimented by the availability of substantial data. therefore, as has been stamped in this chapter, it is paramount to have a framework that clearly outlines how specific data need to be shared with the public. in particular, this would help to overcome challenges of insufficient data that are instigated by the act of withholding information by some entities or countries surfing on private interest. on this, a positive step toward its actualization was made in by the who after the zika virus outbreak where through unfettered sharing of data, different agencies and stakeholders were able to utilize advanced technologies to prevent the spread of the virus. and, as noted earlier, such efforts were fruitful in that, unlike other previous virus outbreaks, this had the least number of casualties ( ). henceforth, the use of technologies is seen to be gaining traction with use of analytical tools such as ai algorithms becoming popular as it allows for data scouring from diverse targets (lau et al., ) and it is also compatible with other technologies such as machine learning and natural language processing. such technologies, as noted earlier, are what allowed bluedot and metabiota to obtain the correct predictions they made about the outbreak and spread of covid- to different regions. the use of these modern tools is also hailed for they have the potential to lead to quick diagnosis, help in development of vaccines and cures of outbreaks, and also would prompt development of raft of preventive strategies in areas that would be predicted to be of high risk of experience an outbreak (martins, ) . this is what the two aforementioned companies, whose description is given in the next section, achieved in the current case of covid- . this section highlights some briefs on how bluedot and metabiota were able to utilize modern computing technologies to accurately, and in record time predict coronavirus outbreak, and the target countries that were at risk of experiencing the outbreak. bluedot is a web-based startup that was pioneered in by dr. kamran khan after the sars outbreak. initially, it was known by the trade name of bio-diaspora, but in , it seeded round with a sri lankan private venture (horizons ventures) prompting its renaming to bluedot. the startup came into limelight in when the h n influenza pandemic broke, where it was able to correctly predict that global pathway of the virus by relying on worldwide air travel data. it cemented its authority in the use of modern computing technologies in , where it developed risk assessment models that allowed it to predict the spread of ebola virus outbreak that struck three west africa countries (allen, ). in the current predicament of covid- pandemic, bluedot was among the first to predict ( days before official announcement) that the world was experiencing a new outbreak and also correctly identified countries that were at high risk of being next target of the outbreak (bowles, ). the answer to the success of this startup in making correct predictions lies on their reliance on modern, advanced, computing technologies and availability of data from different spheres. in respect to technologies, the company is observed to heavily rely on ai-based tools, machine learning technology, and natural language processing technologies. using different models and algorithms, the company managed to scour valuable data from different sources such as diverse, global news outlets, global airline ticketing data (heaven, ) , population density data, global infectious disease alert, climate report, and insect vectors and animal diseases reservoirs. in its website ( b), it is clearly noted that it relies on over , official and media sources drawn from over languages each day. it also queries reputable databases such as world factbook and national statistics reports from different regions. with the available technologies, the company is able to employ filters on information from the different sources to narrow the results to the issue at hand (blue-dot, a). on the same, the technologies also allow the use of modern clustering tools that allow it to quickly, and in real time, identify areas or regions with the potential to become hot spots, cold spots, and/or spatial outliers. it also relies on the power of machine learning to train its system using the assorted dataset, and in turn, the systems are able to generate real-time and regular alerts on issues of interest to the company's clients. it is through this that it was able to flag out coronavirus as an outbreak that had potential to spread to other regions quickly. the history of metabiota takes us back to when it was initiated. during those early days, its main engagements were in research focusing on how human and animal health were linked, especially in the african context. in , when the ebola virus broke in west africa, the company was already active, and through its work attracted the attention of the us government, which at the time was actively involved in combating this outbreak (rossi, ) . having experience on the african context, metabiota was requested to assist, and it did a remarkable job, but after the ebola situation was contained, the us government withdrew the funding to the company. the reduction of the funds took a toll on the company, hence prompting a paradigm shift, which entailed the company expanding its operation scope to enable it to serve more clients. in this regard, its target market was insurance companies, who would benefit from information concerning disease outbreaks. henceforth, the company embarked on enriching its disease database, which today is among the most comprehensive ones (rossi, ) . to achieve this, the company embarked on investing and utilizing advanced computation and predictive technologies, and such included ai, machine learning, big data, and natural language processing (nlp) algorithms. through this, the san franciscoebased company serves a wide range of clients including government agencies, insurance companies, contractors, diverse noneprofitmaking organizations, ngos, and others that, in one way or the other, depends on information of infectious diseases outbreaks to enhance their decision-making. with these technologies, it has become among the leading startups in rendering predictions about infectious diseases outbreaks, spread, interventions, and event severity (heaven, ) . it uses nlp algorithms to scour data from diverse sources (both official and unofficial sources). from its website (metaboita, ) , it sources range from biological, political, socioeconomic, environmental, and social media among others. the data gathered from these are analyzed and categorized using reputable analytical and visualization technologies into clusters such as frequencies, severity, and time (duration of outbreaks), and these are shared with its clients depending on information being sought. in the recent case of covid- , metabiota was in the forefront to analyze the outbreak, and during the analysis of the data, some even sourced from social media, the company was able to predict which neighboring countries were at high risk of being the next target of the virus spread, more so because the panic in wuhan had stated to trigger some fear, forcing people to flee. by relying on ai, machine learning, and nlp, the company analyzed human predictive behaviors and scare levels, thus managing to correctly make the predictions a week earlier before any of the said countries (japan, thailand, hong kong, and others) had reported any case of the virus (tong, ) . when it comes to pandemics, one sure way of protecting the masses and averting related negative impacts on the social fabric, the economy and human lives to name a few are providing early detection. today where there are enough digital tools and technologies with capacity to allow for real-time data collection, fast and comprehensive computation, and prediction, early detection ought to be emphasized. but even with these technologies, any lapses, especially in data sharing, are bound to delay the detection and identification of the outbreak and that can prove to be fatal. for instance, in , when sars (sars-cov) broke in guangdong local market in china, health officials and chinese authorities withheld information on the outbreak, and this prompted the identification of the virus to drag for around months. while the fatalities from this virus outbreak were only reported across countries where the virus had spread, such could have been avoided. by the time the virus was contained, it had already spread to countries. in a totally different case, as reported earlier, due to collaborative measures taken in when ebola virus broke in west africa, the virus was identified in a reasonable time, and this prevented further spread of the virus beyond liberia, guinea, and sierra leone. though this virus is very infectious and tends to have high casualties, it leads to the unfortunate death of , people. if the outbreak here was to take the same route that sars, it could have been disastrous and would have spread to numerous countries. in the present case of coronavirus (c vid- ) pandemic that originated in wuhan city, china, the response was totally different from the sars incident. this time round, the chinese authorities were quicker and forthright in their reporting, and also in sharing subsequent information and data. nevertheless, some quarters continue to accuse the chinese authorities for the global spread of the virus. but while mistrust exists, the steps taken by chinese authorities have been lauded. additionally, as noted earlier, when the who officials were notified of this outbreak, they were also quick to identify the virus and to take decisive measures in ensuring that the spread was contained. it only took days for the identification, but as noted earlier, it had taken approximately days (from december , e december ) to detect that the world was confronting a new type of coronavirus. the breakthrough in the early detection being witnessed in these recent years can be credited to several factors. first, the reasons learnt from previous occurrences may have prompted some changes on how governments and stakeholders perceive the issue of pandemic outbreak. secondly, and more importantly, the emergence and subsequent acceptability of a wide range of computational technologies has made it possible for faster data collection, data sharing, and advanced computation and analysis. the availability of data from different sources, including smart devices and healthwearable devices, social media, and existing health database, has also been handy and influential in determining the detection period and tracking of outbreaks. for this reason, gaille ( ) notes that besides technologies, availability of data in large quantities is now seen as the world's new "gold rush" of this century. the availability of these not only influences health outcomes but is also seen to determine geopolitical standing, with those in position to collect, store, and control most of the data seen to be positioned as a global power house and, hence, the push and pull on the g internet between power economies (allam, a; allam and dhunny, ; allam and jones, ; allam and newman, ; kharpal, ) . in addition, even in lower levels of governance, the control of data is seen to be raising heat with large ict corporations competing to control the market share such that they can have exclusive control of data, thus increasing their profit standing (allam and jones, ) . but, beyond selfish interests, it is possible for corporations and governments and organisations with capacity to manage large quantities of data to work together for the sake of the economic landscape, the welfare of the social fabric, and the improvement in the health sector (allam, b; allam, c; allam, d) . such calls are valid in a time like now when the entire global economy, the health sector, and societies are in limbo due to the impacts of covid- . to achieve such noble goals, however, as noted in the previous sections, there are several things that need to be addressed to streamline the data usage landscape. among these include addressing some notable challenges with computing technologies used in analyzing big data. first, there needs to be a framework that guides how data have for long been highly guarded, collected, shared, and accessed in such a way that it does deem to be compromising the security and privacy of individuals. by doing this, it would be possible to increase personal data even further as the ethical and moral issues associated with data sharing would be lifted (allam, a; allam, b) . in particular, this would be important when it comes to accessing and using data comprising personal genome, personal demographic information, and other personal identifying details (vayena and blasimme, ) . in cases where such must be accessed, the use of strategies like k-anonymity (i.e ensuring that datasets have no combination of user identifying attribute) (sweeney, ) to anonymise data, or the use of technologies such as blockchain or quantum cryptography must be made to ensure total anonymization of data. the framework should also address issues to do with standardization of protocols and networks, which have for long been seen to reduce communication of systems, especially in urban areas. on this, as shared by allam and jones ( ) , standardization would then support seamless flow at an urban, regional, and international scale. besides streamlining on the use of technologies, and data-related issues, as has comprehensively been shared earlier, the war against covid- , as has been done already in different countries, needs to be supported by strengthening instituted quarantines, self-isolation, and lockdowns. these actions are in their part enough in enriching health databases, as it is from these that data on people contracting, recovering, and succumbing from the virus are being collected, in addition to those already sourced in medical facilities. this work has candidly explored the role of various technologies, especially ai, machine learning, and nlp and big data in early detection of covid- , especially by exploring how such were instrumental in assisting blue-dot and metabiota companies make their groundbreaking predictions for rendering early detection of the coronavirus. the exploration has demonstrated that the future of the health sector, among others, is promising, if such predictive achievements are to continue. to make this even better, it is the position in this paper that data sharing practices need to be encouraged by adopting best practices such as standardization of protocols, enhancing anonymization, and employing modern technologies such as blockchain and quantum cryptography, which have proven to be novel in such fields. there is also needed to emphasize cooperation between different agencies, institutions, and corporations to ensure that corporate monetary interest on data does not overshadow work aimed toward improving global health, economic equity, and social welfare. urban resilience and economic equity in an era of global climate crisis the emergence of anti-privacy and control at the nexus between the concepts of safe city and smart city cities and the digital revolution: aligning technology and humanity data as the new driving gears of urbanization privatization and privacy in the digital city theology, sustainability and big data on big data, artificial intelligence and smart cities the potential of blockchain within air rights development as a prevention measure against urban sprawl on the coronavirus (covid- ) outbreak and the smart city network: universal data sharing standards coupled with artificial intelligence (ai) to benefit urban health monitoring and management redefining the smart city: culture redefining the use of big data in urban health for increased liveability in smart cities how a toronto company used big data to predict the spread of zika viral outbreaks involve destabilized evolutionary networks: evidence from ebola what do these terms mean and how will they impact health care? better public health surveillance for infectious diseases bluedot protects people around the world from infectious diseases with human and artificial intelligence how canadian ai start-up bluedot spotted coronavirus before anyone else had a clue influenza (flu) what caused the black death? ai could help with the next pandemic-but not with this one how ai is battling the coronavirus outbreak china 'has the edge' in the war for g and the us and europe could fall behind artificial intelligence in health: new opportunities, challenges, and practical implications china locks down city at center of coronavirus outbreak risks, impacts, and mitigation the spanish influenza pandemic: a lesson from history years after how healthcare is using big data and ai to cure disease confronting the risk you can't see coronavirus latest: australian lab first to grow virus outside china an ai epidemiologist sent the first warnings of the wuhan virus the impacts on health, society, and economy of sars and h n outbreaks in china: a case comparison study where it all began: wuhan's virus ground-zero 'wet market' hides in plain sight the metaboita story from sars to mers, thrusting coronaviruses into the spotlight ) k-anonynity: a model for protecting privacy big data predicted the coronavirus outbrea and where it would spread health research with big data: time for systemic oversight predictive analytics in health care: emerging value and risks emergencies preparedness novel coranvirus ( -ncov) situation report. world health organisation the ebola outbreak of - : from coordinated multilateral action to effective disease containment, vaccine development, and beyond key: cord- -hjxph jm authors: petrović, t.; d'agostino, m. title: viral contamination of food date: - - journal: antimicrobial food packaging doi: . /b - - - - . -x sha: doc_id: cord_uid: hjxph jm a review of the relevant foodborne viruses is presented. published data from scientific journals as well as the data presented in official reports and published on the internet were used for this review. in the review, information is given for the main foodborne viruses, implicated virus species, and food matrices involved, some history data are given, as well as modes of transmission, and sources of the virus presence in food. results of surveys on the presence of viruses in different kind of foods commodities (fresh produces and shellfish) and in some cases connections to caused outbreaks are presented. also, possible zoonotic infection and implicated viruses that could be transmitted through food are given. human norovirus followed by hepatitis a virus are the most common foodborne viruses, which are transmitted by food consumed raw, such as shellfish, fresh vegetables, and berry fruit. in developed countries, hepatitis e virus is increasingly being recognized as an emerging viral foodborne pathogen that includes zoonotic transmission via pork products. the existing knowledge gaps and the major future expectations in the detection and surveillance of foodborne viruses are mentioned. , and over persons in japan contracted foodborne gastroenteritis due to astv (oishi et al., ) . more recently, there was an outbreak in germany, predominantly in schools and childcare settings, linked to nov in frozen strawberries that were imported from china (mäde et al., ) . outbreaks have been documented to be caused by different kind of food items (e.g., deli meat, vegetables, berries, shellfish, and a great variety of rte foods like sandwiches, bread rolls, bakery products, cold meat, pastries, and ice cubes) (efsa, ) . the food types that are at highest risk of contamination are foods requiring either intensive manual handling, including manual handling under poor hygienic conditions, or close-to-fork and final-product manual handling. dishes containing fresh (or freshly frozen) fruits and vegetables have been the source of numerous outbreaks of foodborne illness (koopmans and duizer, ; efsa, ) . filter-feeding shellfish are a particular risk, as they concentrate viruses present in water during their growth, and numerous outbreaks linked to the consumption of shellfish have been reported (koopmans and duizer, ; efsa, ) . foods at greatest risk of virus contamination at the preharvest stage are shellfish, soft berry fruits, herbs, and salad vegetables. preharvest contamination of fruits and vegetables, including strawberries (niu et al., ) , raspberries (reid and robinson, ; ramsay and upton, ) , blueberries (calder et al., ) , lettuce (pebody et al., ) , and green onions (cdc, ) were reported and have resulted in outbreaks of disease in countries such as finland and new zealand, where populations have low or no immunity to the disease (pebody et al., ; calder et al., ) . the source of contamination in these outbreaks was reported to be either infected fruitpickers or contaminated irrigation waters (greening, ) . postharvest contamination of raw food may occur as a result of human handling by workers and consumers, contaminated harvesting equipment, transport boxes, contaminated aerosols, wash and rinsing water, or cross-contamination during transportation and storage (harris et al., ) . recontamination after cooking or processing and inadequate sanitation has also been associated with outbreaks of enteric virus infections (richards, ) . foods at risk from contamination by food handlers include a wide range of foods that are subjected to too much handling and are subsequently consumed cold or uncooked. these include bread and bakery goods (kuritsky et al., ) , lightly cooked or raw shellfish, delicatessen meats, sandwiches (parashar et al., ; daniels et al., ) , salads, herbs, fresh fruits, and cold desserts. poor food handling was shown to be a key risk factor in the transmission of noroviruses and rotaviruses in the netherlands (de wit et al., ) . an expert meeting convened under the auspices of the food and agriculture organization (fao) of the united nations and the world health organization (who) reviewed available evidence and grouped viruses according to their ability to cause high morbidity, severe disease, or a significant ability to cause foodborne outbreaks (fao/who, ) . in the fao/who document, the common pathogens such as nov, group a hrv, and hav were ranked as priority hazards. in the category of emerging hazards, hev, nipah viruses, h n avian influenza viruses, and sars coronavirus were considered to be of greatest concern. the meeting discussion resulted in several virus-commodity combinations for which prevention and control measures should be considered. those combinations are: for nov and hav in bivalve molluscan shellfish; for nov and hav in fresh produce; for nov and hav in prepared foods; for rotaviruses in water for food preparation; and emerging viruses in selected commodities. nov is one of the most widely recognized viral agents associated with foodborne outbreaks of nonbacterial and often epidemic gastroenteritis and is considered to be the most common cause of foodborne disease worldwide (greening, ; efsa, ) . nov is shed in huge quantities in the stool and vomit of infected persons, and it has been estimated that the infectious dose may be as few as virus particles (teunis et al., ) . novs are primarily transmitted through the fecaloral route, by consumption of fecally contaminated food or water, or by direct person-to-person spread that is still the major mode for nov transmission. secondary spread is person-to-person spread, but may also occur by airborne transmission. according to efsa ( ) caliciviruses (including nov) cause approximately % of epidemic nonbacterial outbreaks of gastroenteritis around the world and are responsible for many foodborne outbreaks of gastroenteritis. the majority of viral gastroenteritis outbreaks in europe have been attributed to novs, where they were reported to be responsible for more than % of nonbacterial gastroenteritis outbreaks between and koopmans et al., ) . estimations based upon analysis of questionnaire data suggested that in the netherlands approximately - % of community cases of nov gastroenteritis were attributed to foodborne consumption (efsa, ) . also, european data from the beginning of this century show that about % of the nov outbreaks are foodborne (ecdc, ) . this makes nov as common a cause of foodborne gastroenteritis as campylobacter and a more common cause than salmonella (de wit et al., ) . a european-wide surveillance network for nov outbreaks, divine-net, has noted that europe has been faced with an increased nov activity during the second half of the first decade of the twenty-first century. the new nov variants of gii. - had most likely been the dominating circulating strains. the role of foods, such as oysters and imported raspberries, as vectors for nov transmission, had been stressed, because both food commodities have been associated in several nov outbreaks in many countries (petrović, ) . hav is the etiological agent of one of the most common types of hepatitis worldwide, and hav as a serious foodborne infection is a notifiable disease in most developed countries. approximately . million people worldwide become infected with hav annually (issa and mourad, ) . the incidence of infection varies among regions of the world, with the highest rate in developing countries where sewage treatment and hygiene practices are poor and where more than % of children have been reported to be infected, usually asymptomatically, by years of age (cliver, ; greening, ) . conversely, the number of reported cases of hav infection has declined substantially in countries with effective vaccination. the major mode of transmission for hav is directly or indirectly from the human reservoir, mainly as a consequence of traveling to endemic regions, engaging in risky sexual practices, or consuming contaminated water or food (efsa, ). food (pebody et al., ; lees, ; greening, ) and drinking water (tallon et al., ) are considered major vehicles of hav transmission to humans. hav can, via sewage discharge, contaminate watercourses, soil, and consequently food crops (bosch, ; cook and rzeźutka, ) . the other main source of produce-associated hav infection is from food handlers and food processors. hav is distinguished from other viral agents by its prolonged ( - -week) incubation period. since hav is shed before symptoms become apparent and there are often more than infectious virus particles excreted per gram of feces, hav-infected produce harvesters and food handlers can become a source of contamination without their knowledge. in areas with poor hygiene practices, this can present a high risk to human health. foodborne outbreaks of hav are relatively uncommon in developing countries where there are high levels of immunity in the local population, but foreigners in these regions can be susceptible if they are not vaccinated (greening, ) . hev is usually the result of a waterborne infection in developing countries and is suspected to be spread zoonotically in industrialized countries (bosch et al., ) . the disease is endemic in many parts of the world, mostly in the indian subcontinent, northwest china, and central asia. in these regions, hev is transmitted mainly through the fecal-oral route, especially by the consumption of fecally contaminated drinking water, and sewage is a major source for contamination of surface water (greening, ; fao/who, ) . foodborne outbreaks of hev are most common in developing countries as a consequence of inadequate environmental sanitation (greening, ) . hev is unusually reported in industrialized countries and when it is reported, it is mostly as sporadic cases in humans who have traveled to endemic countries. recently, some human hev infection in nonendemic countries could not be explained by the contact of those patients with the virus in the endemic regions. although originally it was believed that hev did not occur in industrialized countries, in recent years it has been identified in europe, asia, australia, and the united states; however, it rarely is a cause of overt disease in these countries (clemente-casares et al., ; emerson and purcell, ) . in contrast to nov and hav, hev has been identified also as a zoonosis (efsa, ) . hev has been detected in the feces of a wide range of domestic animals (meng et al., ; vasickova et al., ; greening, ; petrović et al., ) . it has been found to be highly prevalent in pigs in several countries where hev in humans is rare, including spain, new zealand, the netherlands, serbia, japan, and canada (emerson and purcell, ; lupulović et al., ; petrović et al., ) . also, recent studies have revealed quite variable seroprevalence rates among europe's population and a possible porcine zoonotic transmission has been postulated (meng, ; petrović et al., ) . moreover, the human hev strains described in industrialized countries appear to be closely related to the swine hev strains found in the same countries. although rare, the importance of hev transmission via food is increasingly being recognized in the european union (eu) (efsa, ) . hrv is the leading cause of severe diarrhea among infants and young children. in adults, the disease caused by hrv is considered to be mild (greening, ) . it is estimated that hrv causes more than million cases of diarrhea in children less than years of age annually worldwide (glass and kilgore, ) . hrv infection is a particularly serious problem in developing countries where up to , deaths occur annually among children. in the united states, hrv had been estimated to cause about four million infections per year, resulting in almost , hospitalizations and more than deaths annually . it was estimated that only % of hrv cases was foodborne (mead et al., ) . hrv causes disease in both humans and animals, especially domestic animals (greening, ) . outbreaks associated with food and water have been reported in a number of countries . in countries with a seasonal climate change, hrv is more common during the winter months. in tropical regions, outbreaks can occur both in the cooler and drier months and throughout the year, especially where transmission is related to contaminated water supplies and where no sewage treatment systems exist (ansari et al., ) . hrv is stable in the environment, so infection can occur through consumption of contaminated water or food and contact with contaminated surfaces (greening, ) . evs of concern for water and foodborne spread include polioviruses, coxsackie a and b viruses, and echo (enteric cytopathic human orphan) viruses. they are transmitted by the fecal-oral route and are excreted in feces, but generally do not cause gastroenteritis. they can cause a range of other diseases, including viral meningitis, myocarditis and poliomyelitis (greening, ) . polioviruses were the first viruses that have been confirmed to be foodborne (jubb, ; , but virulent wild-type strains are now very rare because of global immunization campaigns. outbreaks of foodborne illness associated with coxsackie viruses and echo viruses have been reported (cliver, ; . enteroviral infection is most common in summer and early autumn, and many infections are asymptomatic. although evs are regularly detected in the environment, there have been very few recorded foodborne outbreaks associated with these viruses. evs, including echo viruses and coxsackie a and b viruses, have been isolated from shellfish, but no outbreaks associated with the consumption of shellfish have been reported (greening, ) . astvs are distributed worldwide and they have been isolated from different animal species like cats, dogs, pigs, sheep, cattle, and birds, as well as from humans. the main feature of astv infection in both humans and animals is a self-limiting gastroenteritis (greening, ) . astvs are a common cause of human gastroenteritis, with most cases of infection detected in young children less than year of age . although astvs cause a mild infection in adults, they have been associated with gastroenteritis in immunocompromised persons. transmission is through the fecal-oral route via water, food, and person-to-person contact . hadvs are widespread within nature, infecting birds and mammals, including humans. they commonly cause respiratory disease but may also cause other illnesses such as gastroenteritis and conjunctivitis. in children under years of age, the enteric hadvs are the second most prevalent cause of gastroenteritis (after hrv) (allard et al., ) . hadvs can be transmitted from person to person by direct contact, or via fecal-oral, respiratory, or environmental routes. most hadv infections in normally healthy individuals are mild or subclinical, but can be associated with respiratory, ocular, and gastrointestinal disease. all virus serotypes are shed enterically in feces, but of the many types of hadvs, only hadv serotypes and are generally associated with fecal-oral spread and cause gastroenteritis (greening, ) . the virus is shed in large numbers in feces and respiratory secretions for long period, even for months or years after the infection. enteric hadv infections are common all year round. these viruses have been identified in a variety of environmental samples, including wastewater, sludge, in marine, surface, and drinking waters, and shellfish, but no foodborne or waterborne outbreaks associated with the enteric hadv have been reported (greening, ) . food may be contaminated by viruses during all stages of the food supply chain. the presence of viruses in food can be the result and consequence of the environmental contamination during primary production-contaminated irrigation waters by sewage as well as manure, which in turn contaminate produce on the field, during the processing and storage phases-by water contaminated with viruses, and from contact virus transmission from humans, such as infected food handlers (involving fecal-oral and aerosol spread of fecal material and vomit). transmission of zoonotic viruses (e.g., hev) can also occur by consumption of products of animal origin (efsa, ). the relative contribution of different sources (shellfish, fresh produce, food handler including asymptomatic shedders, food-handling environment) to foodborne illness has not yet been determined (efsa, ) . food handlers are very often the reason for virus transmission. transmission could occur via infected food handlers with clinical symptoms, but also from infected food handlers who have recovered from illness and no longer display any symptoms, but may still be shedding high numbers of nov. in addition, transmission could occur via infected food handlers with asymptomatic infections and food handlers who come in contact with sick people (koopmans and duizer, ) . although most outbreaks can be traced to infected food handlers at the end of the food chain, the food contamination could occur anywhere (e.g., seasonal workers during berry harvesting or people on recreational boats near shellfish harvesting areas). fresh fruits and vegetables can become contaminated by enteric viruses, possibly through the use of contaminated fertilizers or irrigation water supplies (grohmann and lee, ) . an increased number of foodborne viral outbreaks are being recorded in several countries. reasons for this include the improved diagnostic methods for virus detection and the increased marketing of fresh and frozen foods that have led to a worldwide availability of high-risk foods (efsa, ) . in , a total of foodborne outbreaks were reported in the eu, and it was at the same level as in . overall, , human cases, hospitalizations, and deaths were recorded. the largest number of reported foodborne outbreaks was caused by salmonella ( . % of all outbreaks), followed by viruses ( . %), bacterial toxins ( . %), and campylobacter ( . %). during , eu member states reported a total of foodborne outbreaks caused by viruses (efsa and ecdc, ) . overall, the number of reported viral foodborne outbreaks increased by more than % compared to and . only a few ( . %) reported viral outbreaks were verified (efsa and ecdc, ); however, the number of verified viral outbreaks also increased by . %, from outbreaks in to in . for out of the total of verified foodborne virus outbreaks, the implicated foods were fruit/berries and juices, and products thereof. these outbreaks were reported by finland and sweden and involved human cases (efsa and ecdc, ) . the panel on biological hazards (biohaz) identified nov, hav, and hev as viruses of significance for foodborne transmission (efsa, ) . data from systemic virus surveillance in foods are missing mainly because there are no systemic surveillances on national or wider levels, and the existing data were collected partly from research projectbased studies and mainly from studies after the outbreak occasions. in the european rapid alert system for food and feed (rasff) online database (http://ec.europa.eu/food/food/rapidalert/rasff_portal_database_en.htm) up to december , , presence of enteric viruses in fruit and vegetables were found in a total of cases (alerts). mostly nov was detected ( / ; . %) in fruit ( / ), most often frozen raspberries ( / ), and just in one case in lettuce (from france). out of alerts of hav presence in different kind of fruits, hav-positive fruit (dates) cases from to originated from algeria, and hav fruit (different kinds of berries) alert cases from until april originated from different, mostly european countries. nov-positive raspberries originated from serbia ( / ), poland ( / ), china ( / ), and chile ( / ). nov outbreaks linked to fresh soft red fruits and leafy greens have been reported. between and , foodborne outbreaks of infectious enteric disease were reported in england and wales. from that number, ( . %) were associated with the consumption of salad vegetables or fruit. the pathogens most frequently reported were salmonellas ( . %) and nov ( . %) (long et al., ) . in denmark, at least linked outbreaks of gastroenteritis with a total of cases were reported in january . lettuce of the lollo bionda type grown in france was found to be the vehicle of virus transmission (ethelberg et al., ) . baert et al. ( ) reported that during from a total of reported foodborne outbreaks in belgium, were caused by nov, affecting persons. the major implicated foods were sandwiches ( / ). furthermore, baert et al. ( ) summarized the data collected from international outbreaks between and reported by eurosurveillance, morbidity and mortality weekly reports and from internationally available peer-reviewed scientific journals. as a result, foodborne and waterborne outbreak events due to nov, epidemiological and/or laboratory confirmed, from to have been reported. further analysis revealed that in . % of the cases, the food handler was responsible for the outbreak, followed by water ( . %), bivalve shellfish ( . %), and raspberries ( . %). maunula et al. ( ) the nov detected in patients' stool samples from six outbreaks were sequenced and epidemiologically linked to the single batch of frozen raspberries originating from serbia. these molecular investigations showed that the apparently independent outbreaks were the result of one contamination event of frozen raspberries (müller et al., ) . out of examined fruit products, despite a good bacteriological quality, stals et al. ( ) found nov gi and/or gii in / , / , / , and / of the tested raspberries, cherry tomatoes, strawberries, and fruit salad samples, respectively. the level of detected nov genomic copies ranged between . and . log per g. baert et al. ( ) reported the results of the study where in total, samples of leafy greens, samples of fresh soft red fruits, and samples of other types of fresh produce (tomatoes, cucumber, and fruit salads) were analyzed in those three countries. nov was detected in . % (n = ), . % (n = ), and % (n = ) of leafy greens tested in canada, belgium, and france, respectively. soft red fruits were found positive in . % (n = ) of the samples tested in belgium and in . % (n = ) of the samples tested in france. also, . % (n = ) of the other fresh produce types, analyzed in belgium, were found to be nov-positive. hav has often been associated with the consumption of contaminated fresh-cut vegetables and fruit (efsa, ). at the beginning of , cases of hav were reported in and around jefferson county, kentucky (rosenblum et al., ) . a case-control study found that eating green salad was strongly associated with acquiring hepatitis. rosenblum et al. ( ) concluded that this outbreak of hav was the first recorded outbreak in the united states apparently associated with fresh produce contaminated before distribution to restaurants. in , a total of cases of hav were reported from schools in michigan and cases from schools in maine. most of the patients ate lunch in schools, and preliminary analysis established a strong association between illness and consumption of food items containing frozen strawberries originating from mexico (hutin et al., ) . forty-three cases of serologically confirmed hav occurred among individuals who ate at a restaurant in ohio in . a case-control study was conducted that determined foods containing green onions, which were eaten by ( %) of case patients were associated with illness (dentinger et al., ) . in , a large hav outbreak connected to one restaurant in pennsylvania was described by wheeler et al. ( ) . out of identified patients, died and at least were hospitalized. identical sequences of hav strains from all tested patients were identified. mild salsa, which contained green onions grown in mexico, was identified as the source of the hav (wheeler et al., ) . petrignani et al. ( ) reported the connection between hav infection with cases in the netherlands at the beginning of , and that semi-dried tomatoes in oil was the source of the outbreak. all the examined patients were infected by an identical hav strain not previously detected in the netherlands. in october , semi-dried tomatoes originating from turkey were identified as the source of several hav outbreaks in australia (more than cases) and france ( cases) (efsa, ). gillesberg lassen et al. ( ) described a foodborne outbreak of hav in denmark from october to april . a case-control study identified frozen berries eaten in smoothies as the potential vehicle. in the following weeks, finland, norway, and sweden also identified an increased number of hav patients without travel history. most cases reported having eaten frozen berries at the time of exposure. in total, cases were notified in the four countries. according to information obtained in the case-control study, different kinds of berries were suspected to be the source of hav, but no specific type of berry, brand, or origin of berries was identified. during , more than cases of hav were reported by eu member states as potentially linked to an ongoing outbreak (wenzel et al., ; ecdc, ) . epidemiological, microbiological, and environmental investigations indicate frozen berries as the vehicle of infection for this outbreak and suggested that it could be linked to a single source (ecdc, ) . frequent zoonotic transmission of hev has been suspected. norder et al. ( ) sequenced the orf genome region of hev strains originating from human blood sera collected between and and found that patients infected in europe were infected by genotype . in order to find the connection between human and swine hev, norder et al. ( ) additionally sequenced the hev strains originating from piglets from herds in sweden and denmark. phylogenetic analyses of the genotype strains showed geographical clades and high similarity between strains from patients and pigs from the same area, so the authors concluded that autochthonous hev cases are present in scandinavia. also, bouquet et al. ( ) assessed the genetic identity of hev strains found in humans and pigs in france. hev sequences identified in patients with autochthonous hev infection were compared with sequences amplified from pig livers collected in slaughterhouses. a similarity of > % was found between hev sequences of human and swine origins, indicating that consumption of some pork products, such as raw liver, is a major source of exposure for autochthonous hev infection (bouquet et al., ) . recently, there has been increasing evidence of foodborne transmission of hev. tei et al. ( ) concluded that consumption of uncooked deer meat was a major epidemiological risk factor for hev infection in the city of kasai in japan. in their study, from the total of examined volunteer subjects with experience of eating raw deer meat, ( . %) of the subjects and only ( . %) of the controls had measurable serum anti-hev igg levels. in addition, the studies of yazaki et al. ( ) and tamada et al. ( ) suggest that consumption of undercooked pig liver and undercooked wild boar meat may have been the cause of some cases of hev in japan. wild boar liver is often eaten raw in japan, and this has also been linked to some hev cases (matsuda et al., ) . numerous survey studies have estimated the prevalence of hev rna in marketed livers. hev rna was detected in . % of livers from supermarkets in japan (yazaki et al., ) , and in % of packages in the netherlands (bouwknegt et al., ) . feagins et al. ( ) examined packages of commercial pig liver sold in local grocery stores in the united states for the presence of hev rna, and found ( %) positive for hev rna. subsequent experimental infection of pigs inoculated with positive pig livers homogenates demonstrated that hev in pig livers was infective. leblanc et al. ( ) examined the presence of hev in the tissues of adult pigs, randomly selected from an experimental herd at slaughter in canada. hev rna was detected in out of the animals tested. even although no hev rna was detected in any of the muscle tested, . % of liver samples obtained at the slaughterhouse tested positive for hev rna. in a chinese abattoir, li et al. ( ) found that . % of liver samples tested were positive for hev rna. during , the centre for food safety in honk kong obtained a total of fresh pig liver samples from pigs slaughtered in a local slaughterhouse. among the collected samples, out of ( %) roaster liver samples were found positive for hev, while none of the pork liver samples were found positive. partial orf sequences of some hev isolates from roaster pigs were found to be the same as those from seven local human cases from , as well as local cases recorded in the past. this study suggests the possibility that, apart from contaminated water or food such as raw or undercooked shellfish, pigs also could be one of the sources of human hev in endemic regions (anon, ) . available data suggests that the consumption of raw/undercooked sausage meat is a potential route of hev transmission. in the united kingdom, grierson et al. ( ) detected hev in out of ( . %) tested sausages, and the presence of hev was found at all three points of the pork food supply chain: production, processing, and point of sale. in another study in the united kingdom, berto et al. ( ) detected hev in out of ( . %) and in ( %) of tested sausages and livers. hev rna was also detected at each of three sites (production, processing, and point of sale) in the pork food supply chain. an autochthonous hev infection was recently described in portugal in a patient who recalled eating traditional homemade pork sausages made of raw meat about weeks prior to the development of the clinical manifestations of acute hepatitis (duque et al., ) . renou et al. ( ) presented the case of the direct evidence of foodborne transmission of hev after consumption of uncooked "figatellu" sausage in france, with % identity between the sequences from the patient and the food product. di evaluated the prevalence of hev in the pork production chain in the czech republic, italy, and spain during . hev rna was detected in at least one of the samples (feces, liver, or meat) from ( %) out of examined slaughtered pigs at slaughterhouses. pig feces showed highest hev rna presence ( %), followed by liver ( %) and meat ( %). out of sausages sampled at the processing and point of sale (supermarkets) stages, hev was detected only in spain ( %, / ). hev sequencing confirmed only g hev strains. the efsa biohaz has published a scientific opinion urging for measures to prevent hev from entering the food chain (efsa, ). the biohaz opinion states that in contrast to nov and hav, hev has been identified as a zoonotic virus that can be very effectively transmitted between pigs, and can be transmitted to humans through consumption of products of animal origin, especially through consumption of meat; however, there are no measures in place to control the spread of the virus (efsa, ). eleven foodborne outbreaks consisting of cases of rotaviral gastroenteritis were reported in new york between and (greening, ) . from that number, seven outbreaks have been associated with food-service premises, and the foods included salad, cold foods, shepherd's pie, and water or ice . large-scale outbreaks of rotaviral gastroenteritis have been reported in japanese primary schools with more than cases recorded for one outbreak (matsumoto et al., ) . school lunches prepared at a central facility were suspected as the vehicle of infection, but no hrv was isolated from food or water. lettuce at a market was found to be contaminated with hrv and hav at a time when there was a high incidence of rotaviral diarrhea in the costa rican community (hernandez et al., ) . recently, mayr et al. ( ) described an hrv outbreak in a mother-and-child sanatorium. in total, food samples from the sanatorium kitchen were taken and tested for hrv. hrv particles were isolated from potato stew. out of samples of packaged leafy greens, tested by mattison et al. ( ) , ( %) were found and confirmed to be positive for nov, and only ( . %) was found positive for hrv group a. additionally, brassard et al. ( ) described the presence of hrv as one of the detected pathogenic human and zoonotic viruses on strawberries. probably one of the most recognized routes of foodborne transmission of enteric viral infections is through the consumption of shellfish grown in sewage-polluted marine environments (okoh et al., ) . the most common route for transmission is accidental contamination after heavy rainfall, when extra loads cause an overflow and there is a release of untreated sewage into the aquatic environment. current water treatment practices are unable to provide virus-free wastewater effluents. consequently, human pathogenic viruses are routinely introduced into marine and estuarine waters (bosch and le guyader, ) . shellfish, which includes mollusks such as oysters, mussels, cockles, clams, and crustaceans such as crabs, shrimps, and prawns are filter-feeders that result in the bioconcentration of environmentally stable, positive-stranded rna viruses, such as nov, hav, and ev in their edible tissues, digestive glands, and gills . shellfish can filter some - l of water per hour and in that process, they concentrate infectious agents that are present in the marine environment (grohmann and lee, ) . by this process, oysters can concentrate viruses up to times compared to the surrounding water (burkhardt and calci, ) . a major public health concern posed by virus-contaminated bivalves is that shellfish are often eaten raw, like oysters and clams, or lightly cooked, like most other molluscan shellfish, just steamed for a few minutes (bosch and le guyader, ) . hav has contributed to numerous foodborne outbreaks that are often associated with raw or lightly cooked shellfish (richards, ) . contamination generally occurs either preharvest or during food handling. the first recorded outbreak of shellfish-associated viral disease resulted from storing clean oysters in a fecally contaminated harbor while awaiting sale (gard, ) . that hav outbreak resulted in more than cases. the largest foodborne outbreak of hav occurred in china in when approximately , people were infected during a -month period after consumption of partially cooked, hav-contaminated clams harvested from a growing area contaminated by raw sewage (halliday et al., ) . a few of the documented shellfish-associated outbreaks include oysters in australia (conaty et al., ) , oysters in brazil (coelho et al., ) , mussels in italy (croci et al., ) , and clams in spain (bosch et al., ) . sewage was generally the source of pollution in most of these outbreaks. contamination of shellfish with hav is still common in italy, spain, and other european countries (greening, ) . foodborne nov outbreaks often result from preharvest contamination of foods such as shellfish (christensen et al., ) . berg et al. ( ) described three oyster-related gastroenteritis outbreaks attributed to nov that occurred in louisiana between and . traceback and environmental investigations revealed that the overboard disposal of sewage by oyster harvesters into oysterbed waters was the most likely source of contamination in at least two of the outbreaks. christensen et al. ( ) described the outbreak in which more than people in denmark became ill from consumption of imported oysters during the new year of / . nov and ev were identified from both oyster and patients' fecal samples. bosch et al. ( ) provide examples of large outbreaks (with more than cases) described in literature connected to the viruses in shellfish. in presented outbreaks from to , mostly nov in oysters, cockles, and clams ( / ) was the causative agent followed by hav in cockles and clams ( / ). in recently conducted studies, nov has been detected in - % of oyster samples collected from europe and the united states by random sampling at market places and oyster farms (boxman et al., ; costantini et al., ) . boxman ( ) published a detailed review about human enteric virus presence and prevalence in bivalve mollusks that were collected from european waters or markets from to . rna of enteric viruses have been detected in shellfish from commercial and noncommercial harvesting areas, as well as in products available on the market for direct consumption and in shellfish associated with disease outbreaks. the presented data suggest a high prevalence of different human enteric viruses, but mostly nov, hav, ev, hadv, and hrv were found in shellfish samples collected from growing areas, as well as from the market in different countries. the viruses were present in shellfish from polluted areas, in depurated shellfish and even in shellfish classified in category class a, as well as those ready for human consumption. the relation with the e. coli most probable number (mpn) that is in use for classification of growing areas and to determine whether shellfish products can be presented for human consumption could not be confirmed in this study. up to february , , in rasff online database notifications of enteric viruses in shellfish on the european market (http://ec.europa.eu/food/food/rapidalert/rasff_portal_database_en.htm), boxman ( ) found alerts on the (suspected) presence of viruses. twenty-eight alerts have been reported on nov in food notified by different eu countries between and , and alerts have been reported on the (suspected) presence of hav in food between and . the majority of these alerts on nov in food concerned oysters ( times), followed by scallops (one report). half of the notified batches of oysters were of french origin, followed by oysters derived from the united kingdom, and ireland. all alerts on the (suspected) presence of hav in food were reported by italy and spain and were only involving shellfish: oysters (five reports), small bivalve animals (four reports), and scallops (one report). half these products were of french origin, whereas the other half was shellfish from peru (boxman, ) . after this period and the data described by boxman ( ) until december , , new nov-positive shellfish alerts were published in the rasff online database. analyzing the alert reports on shellfish, nov presence was mostly connected to oysters ( / ; . % cases) from france ( / ), ireland ( / ), the netherlands ( / ), and spain ( / ); in three cases connected to mussels from the netherlands ( / ) and spain ( / ); in three cases connected to clams from portugal, united kingdom, and vietnam; and in one case connected to raw shell scallops from chile. in the efsa report ( ), from a total of foodborne outbreaks reported in eu member states during , crustaceans, shellfish, mollusks, and products thereof were the most frequently implicated food items. for those outbreaks that were verified, nov was the most frequent cause, followed by hav (efsa, ). in the recent united kingdom food safety authority project-based study, nov was detected in . % oyster samples ( / ), with similar prevalence in the two species of oysters tested ( . % ( / ) for crassostrea gigas and . % ( / ) for ostrea edulis). clear seasonality was observed with a positivity rate of . % ( / ) for samples taken between october and march compared with . % ( / ) for samples taken between april and september (anon, ) . in the first report on the presence of human enteric viruses in shellfish from portugal, approximately different kinds of shellfish, organized in batches, were collected between march and february (mesquita et al., ) . viral contamination was detected throughout the year in all shellfish species and in all collection areas, independently of classification of their harvesting areas. nov was detected in % of the batches, followed by ev in %, and hav in %. overall, % of all analyzed batches were found to be contaminated by at least one of the studied viruses, while the simultaneous presence of two and three viruses was detected in % and % batches, respectively. the special problem was the fact that viruses were detected in six of the eight shellfish batches from the a-class harvesting areas (one nov, three ev, and two hav) (mesquita et al., examined the prevalence of different enteric viruses in commercial mussels at the retail level in three european countries (finland, greece, and spain). a total of mussel samples from different origins were analyzed for virus presence. samples were positive in % of cases. hadv was found to be the most prevalent virus detected ( %), and the prevalence of nov gg ii, hev, and nov gg i were %, %, and . %, respectively. presence of hav was not detected. epidemiological evidence of astv transmission by foods is limited, but infections via contaminated seafood like shellfish and water have been reported (oishi et al., ; . one large outbreak of acute gastroenteritis was reported in japan involving thousands of children and adults from different schools in (oishi et al., ) . the outbreak was traced to food prepared by a common supplier for school lunches and astv type was identified as causative agent. there are several japanese reports of astv genomes identified in shellfish with the evidence of their contribution in foodborne outbreaks of gastroenteritis, mainly after the consumption of contaminated oysters (kitahashi et al., ) . hadvs have been identified in a variety of environmental samples, including wastewater, sludge, and in marine, surface, and drinking waters, as well as in shellfish, but no foodborne nor waterborne outbreaks associated with the enteric hadvs have been reported (greening, ) . swine manure could be a source of hev contamination of coastal waters with subsequent contamination of shellfish (smith, ) . said et al. ( ) reported that the small genotype hev outbreak on a cruise ship returning to the united kingdom in was connected to the consumed shellfish. zoonotic viral infections are generally not transmitted by food; however, there are a few reports on transmission of some emerging viruses via food. this transmission is likely to be rare, relative to other transmission routes, and will probably be restricted to a few food products or items and occasions. for example, highly pathogenic avian influenza (hpai) virus in undercooked poultry or eggs, hev in porcine organs, or muscle tissue and nipah virus in date palm sap are postulated to be foodborne. another emerging virus for which this mode of transmission may be relevant is severe acute respiratory syndrome coronavirus (sars-cov) (fao/who, ; newell et al., ) . all mentioned viruses are zoonotic, and limited epidemiological data exist that support their transmission by the consumption of contaminated foods. each of these viruses is capable of causing significant illness and mortality in humans. they are present in the intestinal tracts of infected humans and animals, and are shed into the environment through feces that can contain high levels of virus (newell et al., ) . sars-cov was spread into the human population through the preparation and consumption of food animals that appear to be infected from another reservoir, probably bats (lau et al., ) . infectious h n avian influenza virus has been found in duck meat, and the consumption of duck blood has resulted in the infection of humans (tumpe et al., ) . almost all reported cases of avian influenza (ai) virus infection in humans that have been recently caused by hpai viruses belonging to the h or h subtypes were transmitted directly from infected birds to humans. other routes of infection, such as consumption of edible tissues from infected avian species or contact with contaminated water, have been suggested as possible sources of infection, but have not yet been proven (efsa, ). transmission of hev through food of animal origin is already documented (yazaki et al., ; tei et al., ; li et al., ; meng, ; said et al., ) and explained in detail previously. nipah virus was shown to affect people slaughtering pigs. whether eating produce from infected pigs can transmit the nipah virus is not known (fao/who, ) . nipah virus was shown to affect children eating fruits contaminated with urine from bats shedding the virus, and three outbreaks in bangladesh have been linked to consumption of fresh local sweet delicacy, which had been contaminated by bats (luby et al., ) . besides those mentioned, there is evidence of transmission of the ebola virus through bushmeat mainly by ingesting the meat of fruit bats. this mode of ebola virus transmission has been found as a route of virus transmission from wildlife to human population (leroy et al., ) . it is important to stress that, for most of the aforementioned emerging foodborne pathogens, contaminated foods is not a usual or even a likely vehicle of transmission, but the potential for foodborne transmission should be considered in epidemiological studies (fao/who, ; newell et al., ) . recently, the european food safety authority (efsa) biohaz stressed that except for tick-borne encephalitis virus, which can be shed by infected dairy animals and subsequently infect humans via milk; and hev, which can be transmitted through consumption of undercooked meat, viral foodborne infections are limited to the recycling of human viruses back to humans (efsa, ). food and environmental virology is a relatively young scientific discipline and consequently there is little published data on virus presence and prevalence in different matrices. there are just a few existing data on virus presence and prevalence in different foods. the data available originates mainly from research project-based studies, and in most cases were from studies conducted after the outbreak occurred. data from systemic virus surveillance in foods are missing mainly because there is no systemic surveillance either on a national or wider level (petrović, ) . another important data gap relates to the lack of knowledge regarding the prevalence of disease caused by viruses in foods in comparison with other possible transmission routes. also, the relative contribution of different sources (shellfish, fresh produce, food handler including asymptomatic shedders, and food handling environment) to foodborne illness has not been determined. most countries have some level of reporting of foodborne illness outbreaks, but few of these systems include viral foodborne illness (greening, ; newell et al., ) . due to the high rate of secondary transmissions, small initial foodborne events may rapidly present person-to-person outbreaks, if the initial introduction event was not recognized (efsa, ). some case-based surveillance exists for hav and evs, but usually it is not focused on detecting foodborne transmission as a source of the infection (newell et al., ; efsa, ) . as a result, national statistics on foodborne viral disease are not readily available and, where present, it likely reflects significant underreporting (mead et al., ; greening, ; fao/who, ) . routine harmonized surveillance of viral outbreaks and of virus occurrence in different foods would be recommended to aid source attribution studies. estimates of the proportion of illness caused by foodborne viruses that can be connected to consumption of contaminated food are based upon very few studies, and according to the efsa biohaz (efsa, ) would require the addition of systematic strain typing to routine surveillance, or more systematic studies to provide more reliable data for burden estimates. testing for viruses in food products is difficult, and there is considerable debate over interpretation of findings. as a consequence, data from food-product monitoring are at the least inconsistent (efsa, ). a problem for the detection, study, as well as for the control of most of the foodborne viruses is that some enteric viruses replicate poorly (hav) or not at all (nov) in cultured cells (atmar and estes, ). in addition, there are no laboratory animal models available for experimental studies of virus inactivation. for these reasons, detection methods currently rely on virus genome detection by molecular techniques such as reverse transcription polymerase chain reaction (rt-pcr). the application of molecular techniques such as real-time (rt)-pcr has enabled relatively rapid, sensitive, and specific detection of viral genome sequences. the problem of this methodology is the fact that the positive signal does not provide information on virus infectivity; rather it indicates the presence of the viral genomic segment. so, inactivated virus particles that pose no threat to public health may still contain intact rna and give a positive result (koopmans and duizer, ; stals et al., ) . the positive results of nov presence in food are of special concern in the absence of linked outbreaks. consequently, a potential risk for infection cannot be excluded, but the actual risk from rt-pcr nov-positive produce remains unknown. for this reason, studies should be designed determining the probability of infection related to the presence or levels of nov genomic copies . a lack of appropriate detection methods for confirmation of viruses as the etiological agent in food is also the reason for underreporting of foodborne virus outbreaks (baert et al., ) . although protocols are available for the detection of hav and nov as the viruses that are most frequently associated with foodborne outbreaks, few laboratories use them when investigating the causes of foodborne diseases, because the methods are considered to be too expensive and too time-consuming for the routine screening of foods (lopman et al., ) . from , an international organization for standardization (iso) methods (technical specifications) for the detection of hav and nov in foods exists: "horizontal methods for determination of hepatitis a virus and norovirus in food using real-time rt-pcr (iso ts - , and iso ts - , )," but still they are very expensive and time-consuming and not adequate for wide surveillance studies. currently, methods used for monitoring of foods using e. coli as microbiological criteria do not correlate consistently with presence or absence of viruses in foods. also, current safety standards for determining food quality typically do not specify what level of viruses should be considered acceptable (okoh et al., ) . as a consequence, the food industry and food safety authorities, at present, lack the tools that enable them to monitor virological quality control in contrast with the situation that exists for bacteriological contamination (efsa, ) . despite the fact that viruses are one of the most common pathogens transmitted via food, no systematic inspection and legislation exist regarding the presence of viruses in the food chain that would set up virological criteria for food safety (koopmans and duizer, ; okoh et al., ) . accordingly, the education of food-industry managers, producers, distributors, and consumers about hygienic regulations and conditions of food production and processing are essential (vasickova et al., ) . commission regulation (ec) / on microbiological criteria for foodstuffs lays down food safety criteria; however, no specific criteria are set for viruses. at the time of this writing, no routine monitoring of viruses in foodstuffs is performed; however, it would be highly beneficial to have such surveillance, including a system where data from food and environmental monitoring could be epidemiologically compared with data from outbreaks in the population (petrović, ) . molecular epidemiology and surveillance of food samples are necessary to elucidate the public health hazards associated with exposure to foodborne viruses and for the estimation of the true size of food-related cases (ecdc, 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least one infection in austria in an outbreak of hepatitis a associated with green onions enteric viruses in the aquatic environment sporadic acute or fulminant hepatitis e in hokkaido, japan, maybe food-borne, as suggested by the presence of hepatitis e virus in pig liver as food the authors would like to acknowledge funding from the project no. tr of ministry of education, science, and technological development of the republic of serbia. special thanks go to dr. nigel cook, fera, united kingdom, who introduced the research interest for food and environmental virology to the authors of this book chapter. key: cord- -xu bc eg authors: yu, pengbo; ma, chaofeng; nawaz, muhammad; han, lei; zhang, jianfang; du, quanli; zhang, lixia; feng, qunling; wang, jingjun; xu, jiru title: outbreak of acute respiratory disease caused by human adenovirus type in a military training camp in shaanxi, china date: - - journal: microbiol immunol doi: . / - . sha: doc_id: cord_uid: xu bc eg outbreaks of ard associated with hadv have been reported in military populations in many countries. here, we report an ard outbreak caused by hadv‐ in a military training camp in shaanxi province, china, from february to march of . epidemic data and samples from the patients were collected, and viral nucleotides from samples and viral isolations were detected and sequenced. igg and iga antibodies against hadv, and the neutralization antibodies against the viral strain isolated in this outbreak, were detected. epidemiological study showed that all personnel affected were males with an average age of . years. two peaks appeared on the epicurve and there was an ‐day interval between peaks. laboratory results of viral nucleotide detection carried out with clinical specimens were positive for hadv ( . %, / ). further study through serum antibody assay, virus isolation and phylogenetic analysis showed that hadv‐ was the etiological agent responsible for the outbreak. iga antibody began to appear on the th day after the onset and showed % positivity on the th day. the virus strain in the present outbreak was highly similar to the virus isolated in hanzhong shaanxi in . we conclude that hadv‐ was the pathogen corresponding to the outbreak, and this is the first report of an ard outbreak caused by hadv‐ in military persons in china. vaccine development, as well as enhanced epidemiological and virological surveillance of hadv infections in china should be emphasized. is classified into two subspecies b (types , , , , and ) and b (types , , , and ) . subspecies b cause respiratory infections, whereas subspecies b is usually associated with kidney and urinary tract infections but sometimes also associated with respiratory diseases ( , ) . shaanxi province, located in northwestern china, has had a few epidemic outbreaks of hadv in recent years. hadv- a (hadv- ) was reported in high school students in , while hadv- was reported in infants in ( , ) . in present study, we report a hadv- outbreak in a military training camp that affected about soldiers. this is the first report about a hadv outbreak in military recruits in china. since november , military training was started in a mtc in shaanxi province, china. there were a total of personnel in the mtc including recruits ( male and female) in squads of five companies, and support personnel in a tutor company. on february , three recruits from the same squad were reported ill with a body temperature of approximately . °c. eleven days later, this outbreak was reported to the sxcdc. definition of an ard case was given as an individual with a body temperature over . °c and with at least a respiratory symptom such as cough or sore throat. recruits who were randomly distributed in the mtc, but did not have any symptoms were chosen as healthy controls. until march, - ard cases per day were reported over an almost -week period, and patients were confirmed as having ard. on february, an epidemical survey for every patient was carried out and precautionary measures including separation, environmental disinfection and morning checks were implemented, and no new case was reported since march. on and february, new cases were discovered and in order to investigate the causative pathogen, swab specimens from these new cases were collected aseptically in -ml viral transport medium and transported to sxcdc. from these, eight and specimens were collected on and february, respectively. eighty serum samples from available persons who had been reported as having ard since february were also collected on february. on march, paired serum samples were collected again. throat swabs and serum samples were collected from healthy controls. sera and throat swab samples were stored at - and À °c, respectively, until further analysis. extraction and detection of viral nucleic acids from throat swabs viral nucleic acids were directly extracted from throat swab specimens using a qiaamp minielute virus spin kit (qiagen, valencia, ca, usa). viral rna was reverse transcribed by a first-strand cdna synthese kit (fermentas, vilnius, lithuania). pcr was carried out using the seeplex rv ace dection system (seegene, seoul, korea). this system can detect types of rna virus (including influenza a and b virus, human respiratory syncytial virus a and b, human metapneumovirus, human parainfluenzavirus , , , , human rhinovirus a, b, c, and human coronavirus e/nl and oc , human bocavirus / / / , and human enterovirus) and a dna virus (hadv), responsible for most respiratory diseases. hadv typing from samples dna from the clinical specimens were subjected to hadvspecific pcr on a biorad thermal cycler (c ; biorad, singapore) by using primer pairs adsd/ad as described by zhen, and the amplicon was targeted on the hexon gene of hadv ( ) . the amplicons were detected by % agarose gel. after purification, pcr products were sequenced directly by the dye terminator method (bigdye terminator, version . , cycle sequencing kit; applied biosystems, austin, tx, usa) using the same primers on an abi xl genetic analyzer (applied biosystems). nucleotide sequence homology was inferred from the identity scores obtained using the blastn program (national center for biotechnology information, bethesda, md, usa). throat swabs of patients positive for hadv-dna by pcr were separately inoculated into hep- cells and cultured in a maintenance medium (minimal essential medium containing % fcs, u/ml penicillin g, mg/ml streptomycin) at °c in a closed system in a % co incubator. cultures exhibiting an adenovirus-like cpe were passaged again to confirm the presence of the virus. primary identification of positive isolates was done by pcr with adenovirus-specific primers. a hadv strain (hadv sxwn ) was used as the neutralization virus, and ccid / ml was calculated as described previously ( ) . stored serum samples were inactivated at °c for min, filtered through a . -mm filter membrane, and diluted with the maintenance medium. a total of ml of several dilutions ( : - : ) of serum samples and ml of the viral antigen diluted in ccid of were added to the wells of a well microtiter plate. the contents were mixed well, and the plates were incubated for hr in an open system in the presence of % co . the hep- cell suspension was then added to each well. positive and negative controls were carried out. the plate was incubated again in the open system in the presence of % co , and the cpe was observed daily. to sequence the hexon gene of viral isolates, dna was extracted from cell culture supernatant using the qiaamp viral dna minikit (qiagen, hilden, germany) and the entire hexon gene was amplified by specific primers with three overlapping regions ( table ). the amplified products were sequenced in both directions, directly or after cloning into a pgem-t easy vector (ta cloning kit; invitrogen, leek, the netherlands). analysis of nucleotides and predicted amino acid sequence was carried out by using the bioedit program (http://www. mbio.ncsu.edu/bioedit/bioedit.html) ( ) . nucleotide and deduced amino acid identities were calculated by using the dna star program (dnastar, madison, wi, usa). the reference sequences were retrieved from genbank (www.ncbi.nlm.nih.gov/genbank). antibody against hadv in serum tested using elisa hadv iga was detected from patient sera collected from the acute phase and healthy control serum samples by using an elisa classic adenovirus iga kit (institute virion/serion gmbh, würzburg, germany). hadv igg was also detected from paired sera of igapositive samples in the acute period and healthy control serum samples. all these kits enabled the detection of serum antibodies against all types of hadv that are human pathogens. written informed consent from all patients was obtained and this research was permitted by the ethics committee of the school of medicine, xi'an jiaotong university (reference number - ). all statistical analyses were carried out using spss . (spss, chicago, il, usa). categorical variables were compared by x -test or fisher's exact test. noncategorical variables were compared by the mann-whitney u-test. a p-value < . was considered significant. all statistical operations were two-tailed. in this ard outbreak, the index cases were three men in the same squad with a body temperature of over . °c accompanied by a sore throat. a total of patients were involved and all the patients were males aged - years; no females were infected. the outbreak lasted for days and the distribution of daily cases is shown in figure . patients were reported in all six companies. the company with index cases had the most reported cases ( . %, / ) and the tutor company had seven reported cases ( . %). the case distribution in dormitory rooms showed clustering characteristics; the number of dormitories with one patient in each room was ; and those with two, three and four patients in each room were , and nine, respectively. clinical features of the patients are summarized in table . all infected individuals had fever, and most of them had sore throat or tonsillitis. eleven were sent to hospital and others were observed and treated on the spot. common symptoms for inpatients were cough and sore throat, and most of them had dyspnea ( . %). in non-hospitalized cases, conjunctivitis ( . %), abdominal pain ( . %), diarrhea ( . %), and vomiting ( . %) were also observed. iga antibody increased as the disease progressed and, in the first days of infection, iga antibody was negative but on the th day all cases became positive ( table ). the proportion of samples positive for hadv iga was significantly higher for the patients than for the controls (p < . ). thirty serum samples from patients positive for iga were further determined during convalescence days after onset. from paired serum samples (n ¼ ), were positive for igg in the acute phase, whereas were positive in the convalescence period. from control samples, two were positive in both acute and convalescence periods. the neutralization antibody against hadv sxwn was detected from paired sera, in which samples showed more than a fourfold increase, showed a twofold increase, five had no change, and three decreased. the neutralization antibody of two igapositive samples from the control group showed more than a fourfold increase (fig. ) . the present study describes an outbreak of febrile respiratory illness ( affected) in a military training unit in shaanxi, china, in early spring of . from the epidemical survey and laboratory examination, the etiological pathogen of the reported outbreak was confirmed as hadv- . hadv are classified into more than types belonging to seven species. hadv subspecies b (types , , ) and species e (type ) cause outbreaks in military and civilian communities ( ) . stress, fatigue, and crowding are important factors facilitating the transmission, and increase the susceptibility of different diseases in a military training unit ( , ) . many outbreaks have been reported in military units in the usa, the netherlands and portugal ( ) ( ) ( ) ( ) . this is the first report of an outbreak with a definite pathogen from a chinese military training camp and indicates the need for close surveillance in the future. adenoviral respiratory disease has been recognized as a frequent cause of illness in us active duty military populations, particularly in basic training installations, for more than several decades ( , ) . in , the us army started a vaccination program against hadv types and ( , ) that was ceased in - ( ) . in the vaccination period, there were only five reported adenovirus (hadv- and - )-associated deaths. in the post-vaccine period ( - ), eight hadv-associated deaths have been reported ( ) . after a -year absence, the hadv vaccination program has been resumed for military recruits since october ( ) . vaccination programs for chinese military recruits include vaccination against hepatitis b, measles, tetanus and neisseria meningitides. hadv vaccines are unavailable in china now, and indigenous hadv vaccines should be developed from the lessons of this outbreak. a series of hadv outbreaks have been reported from shaanxi province recently ( , ) . in march , the causative pathogen of an acute respiratory outbreak in qishan county, baoji prefecture, was found to be hadv- a, later renamed hadv- ( ) . during this infection, people including senior high school students were infected, which resulted in the death of one patient who had bone marrow megaloblastic anemia ( ). in table . iga antibody assay progress it is interesting that several types of hadv are circulating in shaanxi province which indicates the need for a surveillance network for adenovirus infections. different hadv- genome types have predominated in different areas and ( p, a- l) genome types have been found ( ) . the prototype strain gomen of hadv- p was isolated in an outbreak of ard among new military recruits in california in , while a was isolated in , b from paris in , c from south africa in , d from china in , e from brazil, f from the former soviet union, g from china, h from south africa, i from korea in , k from israel in , l from korea in , and m has recently been mentioned ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . both epidemiological and molecular evidence strongly suggest that unique patterns of genome type shifts are restricted to geographic areas. therefore, surveillance for hadv genome types in china should be strengthened. the iga antibody plays an important role in the diagonosis of hadv infection ( , ) . as we know that igm antibody predominates in early immune responses, this is always used as an early diagnosis for infection. however, kornadt et al. found that in adenoviruses infections, fewer antibody rises and weak reactions were observed in the igm test than in the iga test. a test for igm antibodies was found to be unrewarding and igm antibodies were present in individuals without fresh hadv infection. therefore, the igm antibodies test was not suitable for the early diagnosis of hadv infection ( ) . previous reports from the and outbreaks have shown . % and % iga positivity rates, respectively. similarly, serum samples from the acute phase in this study showed % iga positivity. from iga-positive samples, were also positive for igg both in the acute phase and in the convalescence phase. igg in the acute phase and in the convalescence phase showed no obvious change, whereas the neutralization antibody was significantly different in various phases. it was also noted that iga against hadv was negative in all samples in the first days of disease onset, but all were positive on the th day. from samples that were hadv positive by pcr, iga antibody was not present. it was noted that pcr could detect hadv within days from onset. two individuals from the control group (apparently healthy) were also positive for iga, indicating a possible non-apparent hadv infection. to confirm hadv infection, the paired sera titers of neutralization antibody against the viral strain isolated in this outbreak were detected. although most ( / ) titers of sera increased, in our study, three samples were found to be decreased. a decrease in neutralization antibody has been reported previously, but the reason is unknown ( ) . we assume that personal differences may play a role in this finding, but this needs to be studied in future work. from the present study, it is concluded that the etiological agent of an outbreak in military recruits in shaanxi province in the spring of was hadv- . the nucleotide sequence, virus isolation, iga antibody, and neutralization antibody were all attributed to the hadv infection. iga antibody began to appear on the th day after onset and showed % positivity on the th day. the virus strain in this outbreak was highly similar to the virus isolated in hanzhong prefecture, shaanxi in . recent outbreaks of hadv in shaanxi province indicate that vaccine 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against adenovirus hexon key: cord- -qmkrn pr authors: wong, bonnie c. k.; lee, nelson; li, yuguo; chan, paul k. s.; qiu, hong; luo, zhiwen; lai, raymond w. m.; ngai, karry l. k.; hui, david s. c.; choi, k. w.; yu, ignatius t. s. title: possible role of aerosol transmission in a hospital outbreak of influenza date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: qmkrn pr background. we examined the role of aerosol transmission of influenza in an acute ward setting. methods. we investigated a seasonal influenza a outbreak that occurred in our general medical ward (with open bay ward layout) in . clinical and epidemiological information was collected in real time during the outbreak. spatiotemporal analysis was performed to estimate the infection risk among patients. airflow measurements were conducted, and concentrations of hypothetical virus-laden aerosols at different ward locations were estimated using computational fluid dynamics modeling. results. nine inpatients were infected with an identical strain of influenza a/h n virus. with reference to the index patient's location, the attack rate was . % and . % in the “same” and “adjacent” bays, respectively, but % in the “distant” bay (p=. ). temporally, the risk of being infected was highest on the day when noninvasive ventilation was used in the index patient; multivariate logistic regression revealed an odds ratio of . ( % confidence interval, . – . ; p=. ). a simultaneous, directional indoor airflow blown from the “same” bay toward the “adjacent” bay was found; it was inadvertently created by an unopposed air jet from a separate air purifier placed next to the index patient's bed. computational fluid dynamics modeling revealed that the dispersal pattern of aerosols originated from the index patient coincided with the bed locations of affected patients. conclusions. our findings suggest a possible role of aerosol transmission of influenza in an acute ward setting. source and engineering controls, such as avoiding aerosol generation and improving ventilation design, may warrant consideration to prevent nosocomial outbreaks. nosocomial transmission of influenza is frequently reported [ ] [ ] [ ] . it typically occurs during seasonal peaks, and may involve almost all types of healthcare facilities [ , ] . its consequences are considerable: it may result in significant disease and even fatality among hospitalized patients, because these patients often are older and/or have multiple comorbidities [ ] [ ] [ ] . health care professionals are frequently involved, and the affected hospital units may require temporary closure with service suspension [ ] [ ] [ ] [ ] [ ] . lack of preexisting immunity toward the recently emerged pandemic influenza h n virus and its potential to cause serious disease in both young and older adults have further raised the importance of hospital infection control [ ] [ ] [ ] . however, how influenza is transmitted in the health care setting and what control measures are effective have remained largely unclear [ , [ ] [ ] [ ] [ ] [ ] . under natural conditions, influenza virus is transmitted predominantly via droplets and direct contact [ ] . thus, adequate spacing, hand washing, and droplet precautions, including the use of face masks, are likely effective in preventing transmission [ , , ] . however, in indoor health care settings, because of the special clinical and environmental conditions, aerosol transmission of diseases might become possible, as described for other viral and bacterial infections [ , , [ ] [ ] [ ] [ ] [ ] . emerging evidence suggests that influenza infection can also be transmitted via the aerosol route, as shown in animal models and in experimental studies involving human subjects [ , , , ] . in this study, we report an influenza outbreak that occurred in an acute medical ward. epidemiological, airflow and computational fluid dynamics analyses were performed. the possible role of aerosol transmission of influenza was examined. the implications of the results on hospital infection control strategies will be discussed. at prince of wales hospital (pwh; hong kong), an outbreak of influenza a occurred in an adult general medical ward in april . in hong kong, peak influenza activities occur in both spring (january-april) and summer (july-september) [ ] . pwh is a -bed acute care general hospital operated by the hospital authority of hong kong that serves an urban population of . million. each year, adult cases of confirmed influenza are being treated at pwh [ , , ] . a major nosocomial outbreak of severe acute respiratory syndrome (sars) occurred at pwh in [ , ] ; since then, all patients hospitalized with acute febrile respiratory illnesses are put on droplet precautions; if influenza is confirmed, the patients will be isolated or cohorted in designated wards [ , ] . as a hospital policy, all health care personnel working in medical wards are required to wear surgical face masks, and an on-duty nursing officer is responsible for monitoring compliance [ ] . outbreak investigation. nosocomial outbreaks of infectious diseases, once identified, would be investigated by the outbreak management team (which consisted of physicians, microbiologists, infection control practitioners, nurses, and hospital epidemiologists) as part of the management protocol [ ] . affected cases would be reviewed daily, and clinicoepidemiological information collected real time as the outbreak evolved. these data were studied and discussed in daily meetings throughout the whole outbreak period. control measures, including ward closure, patient isolation, and use of antiviral prophylaxis, would then be recommended. virological investigations for influenza have been described elsewhere [ , ] . in brief, nasopharyngeal aspirate specimens were collected from symptomatic individuals and subjected to immunofluorescence assay and virus culture for diagnosis [ , ] . in addition, for all confirmed cases, viral rna was directly extracted for sequencing of the whole length of the hemaggultinin gene, as described elsewhere [ ] ; the nucleotide sequences in individual cases were then compared. finally, a hemagglutination inhibition assay was performed (using the virus isolate obtained from the index patient as antigen source) to detect antibody rise in the paired serum samples collected from affected individuals [ ] . spatiotemporal analysis of epidemiological data. the epidemic curve for the outbreak was produced. the floor plan of the affected wards was studied; in pwh, the design of general medical wards followed an open bay ward layout [ ] . for the analysis, all patients who had ever stayed with the index patient during the period of his presence in the ward (from admission to transfer or isolation) and all health care workers (hcws) who had worked in the same ward during the period were included. attack rates of influenza among inpatients were calculated each day on the basis of their locating "bay" [ ] . univariate relationships between risk of acquiring influenza infection and spatiotemporal variables were analyzed using the x test or the fisher exact test. variables with a p value !. were entered into a multivariate (stepwise) logistic regression model to identify independent factors associated with infection. odds ratio (ors) and % confidence intervals (cis) were reported for explanatory variables. in all analyses, a p value of !. was considered to indicate statistical significance. all probabilities were -tailed. statistical analysis was performed using pasw statistics software, version . (spss). airflow measurements and fluid dynamics analyses. information on the ward's ventilation systems was collected during the outbreak investigation. these included the location and size of air supply diffusers, return grills, and the highefficiency particulate absorbing (hepa) air purifier units that were present in each ward bay. airflow rate through each supply diffuser, return grill, air purifier, and exhaust fan was measured in detail, as described elsewhere [ ] . dispersion of the hypothetical virus-laden aerosols, originated from the index patient's bed through the entire ward, was analyzed by computational fluid dynamics (cfd) method. the hypothetical virus-laden aerosols were modeled as gaseous and passive tracers, which have been shown to be able to model well the dispersion of droplet nuclei that were less than - microns in diameter. the commercial cfd software, fluent, version . , was used [ , ] . the predicted concentration fields were compared with the locations of affected patients found in the outbreak. the 'outbreak management team' was being alerted of a possible outbreak in a general medical ward on april , when inpatients were found to have developed fever and respiratory symptoms. the ward was immediately closed to new admissions, and transfer to other hospitals or institutes was suspended; sick patients were isolated. for all hcws and the remaining patients, strict droplet precautions were implemented, and the individuals were required to wear surgical masks at all times. hand hygiene was reinforced. postexposure prophylaxis with oseltamivir was offered, and both groups were monitored for development of symptoms. discharged patients were put under continuous home medical surveillance for week. the ward returned to normal function on april, when the outbreak was declared over. an epidemiological investigation was started on april. at the end of the outbreak, a total of inpatients (patients a-i) were found to have symptoms that fulfilled the case definition of influenza-like illness (figures and ) . no visitor was known to be affected. the symptom onset dates of the first (index) figure . epidemic curve of the influenza outbreak. patients were shown according to their symptom onset date (fever or new respiratory symptoms); the order does not necessarily reflect the order in which they acquired infection. the arrow indicates the time when the index patient (patient a) commenced bi-level positive airway pressure (bipap) ventilation support. prior to that, he was receiving supplemental oxygen therapy via nasal cannula. the bipap ventilation lasted for h; he was subsequently transferred to the intensive care unit. patient i started to receive oseltamivir prophylaxis on april (the ward was closed and sick patients were isolated); however, he soon became unwell and developed fever on april, despite receipt of prophylaxis. staff and had symptoms; however, the results of serological tests for recent influenza infection were negative (table ). case and the last case were march and april, respectively. all inpatients tested positive for influenza a by immunofluorescence assay and culture of nasopharyngeal aspirate specimens. all isolates belonged to the h n virus subtype (influenza a/brisbane/ / ) and were % identical, as determined by nucleotide sequence analysis (table ) . nasopharyngeal aspiration was not performed for the hcws who had reported symptoms; however, serological test results did not suggest recent influenza infection ( table ) . the index patient (patient a) ( figure ) was a -year-old man who had underlying chronic obstructive pulmonary disease. he was admitted on march with unresolved pulmonary shadows, despite having completed a course of antibiotic treatment, and increased dyspnea, which initially required supple- all secondary cases were detected to have fever and/or new onset of respiratory symptoms. once influenza was confirmed, the patients started to receive oseltamivir treatment ( mg twice per day for days) within h after symptom onset. the clinical courses of patients remained uncomplicated, and the patients were subsequently discharged. the remaining patient (patient c) (figure ) was a -year-old man who had originally been admitted for pseudomonas pneumonia that had complicated advanced bronchiectasis; although afebrile, he developed lower respiratory tract complication after influenza infection and died of progressive respiratory failure. spatiotemporal analysis. the outbreak ward was a male general medical ward consisting of beds arranged in major bays ( adjacent rear bays b and c separated by a ∼ -m wide corridor and front bay a) (figure ). the distance between adjacent beds was ∼ m. the index patient's bed was located at the wall end of bay c, right next to a hepa air purifier. in total, patients and hcws had stayed or worked on the ward during the period from march to april. the overall attack rate among patients was . % ( of subjects). we found that patients who had stayed in the "adjacent" bay b (attack rate, . %) were affected to a degree similar to those who stayed in the "same" bay c with the index patient (attack rate, . %); however, no patients in the front, "distant" bay a or side room were affected (attack rate, %; p p . , by the fisher exact test). when analyzed according to date, presence in rear bays was associated with attack rates of . %, . %, . %, and . % on the dates - march, respectively. the risk of being infected was highest on march ( . %; p p . ) and april ( . %; p p . ), which coincided with the time of bipap ventilation use in the index patient. in a final multivariate logistic regression model, staying in the rear bays on march was independently associated with a higher risk of acquiring influenza (or, . ; % ci, . - . ; p p . ). the attack rate among hcws was not analyzed in detail, because only were reported to have had symptoms, and neither had laboratory-confirmed infection. they reported close contact with patients staying at all bays while performing their routine duties. airflow measurements and analysis. air conditioning in the outbreak ward was provided by fan coil unit systems with a -way diffuser at the ceiling level in each of the bays. the return air grills were located at the ceiling of the corridor. a hepa air purifier was placed at the wall end of each bay ( figures and ) ; it functioned by drawing in air from a lower level, and after filtration, injecting the air back into the ward at an upper level. during the outbreak, the fan setting of the hepa air purifiers was found to set to low in bays a and b and to medium in bay c inadvertently, with injection velocity measuring . m/s, . m/s, and . m/s respectively. airflow measurements revealed that, under this situation, there was an imbalance in the air supply to and return from different bays, and the net flow toward the corridor was - l/s ( figure ). the injecting air velocities from the hepa air purifiers were substantially higher than that of the diffusers and thus dominated the overall airflow pattern. because of the higher air injection velocity from the air purifier in bay c compared with that in the adjacent bay b, air from bay c was expected to be "pushed" into the corridor and toward bay b (figure ). cfd simulations were performed, and the distributions of hypothetical virus-laden aerosols originated from the index patient are shown in figure . the normalized concentration of the hypothetical virus-laden aerosols was found to be the highest in bay c ("same"), followed by bay b ("adjacent"), and the lowest in bay a ("distant"). the estimated spatial distribution figure . the spatial distribution of normalized concentration of hypothetical virus-laden aerosols (modeled as gaseous tracer) in the outbreak ward at a height of . m. the flow rates used in this model were those described in figure . all high-efficiency particulate absorbing (hepa) filters were assumed to function with % filtration of the modeled droplet nuclei. the hepa air purifiers are shown as black boxes, the diffusers are shown by a square with an x, and the returns are shown as a small rectangular filled box. affected patients are represented by white ovals (the index patient is marked as a red oval). was found to correspond to the locations of affected patients in the outbreak. large droplets would not have accounted for such distribution because of their fast deposition onto surfaces [ , ] . we report a nosocomial outbreak of seasonal influenza in an acute ward setting. it was temporally related to the use of an aerosol-generating device in the index patient. this had occurred together with an imbalanced indoor airflow; and the spatial distribution of cases was found to follow the directional airflow and coincided with a cfd-estimated aerosol dispersal pattern. our findings suggest a possible role of aerosol transmission in this outbreak. we have previously reported aerosol transmission of sarsassociated coronavirus in a similar ward setting [ ] . in that study, cfd modeling demonstrated a close relationship between concentration of virus-laden aerosols and the risk of acquiring infection in various ward locations. we studied this outbreak using similar approach, and our findings provide further evidence to support the hypothesis that, under suitable clinical and environmental conditions, aerosol transmission of influenza virus can occur [ , ] . in this outbreak, we postulate that infectious aerosols were generated continuously through the use of noninvasive ventilation for the index patient (which projected for at least m sagittally to bed end) [ ] [ ] [ ] for h and these aerosols were blown toward the adjacent bay by an imbalanced indoor airflow created by an air purifier's outflow jet, which was located at patient's bed end. we believe that droplets and contact routes of transmission cannot entirely explain the outbreak because ( ) the epidemic curve suggested a point-source mode of infection, instead of successive propagation (especially for the aggregation of symptom onset on and april); ( ) the index patient and most other inpatients were immobile during their illnesses and, therefore, direct contacts should have been minimal; ( ) patients m away were affected; and ( ) locations of affected patients coincided with dispersal pattern of aerosols and the directional airflow. in this outbreak, patients in the "adjacent" and "same" bay were similarly affected, but the "distant" bay was spared. a more random distribution of infected cases would be expected if hcws had acted as vectors, because they were responsible for the care of patients in all bays (duties were assigned on the basis of function and not location) [ ] . similarly, close patient-patient contact, visits to a contaminated common area, and transmission through a wandering, sick visitor are unlikely explanations in our setting [ ] . finally, high air velocities ( m/s), which can carry even large droplets beyond m, were not found in our ward setting, and they would have been deposited too fast onto surfaces to account for the observed dispersal pattern [ , ] . we hold the view that the predominant modes of influenza transmission are via droplets and direct contact [ , , , ] . however, accumulating evidences suggest that the aerosol route may have a contributing role [ , , , ] . in animal models, influenza virus (eg, h n or h n ) has been shown to transmit efficiently through air, whereas fomite or contact spread is relatively inefficient [ , , , [ ] [ ] [ ] . in clinical studies, virus-laden particles less than - mm (ie, within the respirable aerosol fraction) have been detected in exhaled breaths of patients with influenza and in the air sampled from an acute healthcare setting during seasonal peak [ , , ] . in contrast to natural coughing or sneezing, artificially generated respiratory particles are often much smaller in size ( less than - mm), can penetrate more readily into the lower respiratory tract, and can cause infection with a smaller dose [ , , , ] . it has been shown that certain clinical procedures (eg, endotracheal intubation, cardiopulmonary resuscitation, noninvasive ventilation, and receipt of high-flow oxygen) can generate a large amount of respiratory aerosols [ , , , , , [ ] [ ] [ ] , and transmission of respiratory infection related to some of these procedures-despite implementation of droplet precautions-has been reported [ ] [ ] [ ] . since the outbreak, we have used a hierarchy of control measures to prevent influenza transmission in our hospital, such as administrative and source controls, engineering controls, and use of personal protective equipment [ , ] . the policy of isolating or cohorting patients with suspected or confirmed influenza is reinforced; application of an aerosol-generating procedure is allowed only in adequately ventilated single rooms before influenza can be excluded; all patients with respiratory infections are required to wear face masks, which are freely provided, until symptoms subside; air-conditioning units and their settings are regularly checked to avoid airflow imbalance; and hcws are advised to use n- respirators, face shields, gloves, and gowns while performing aerosol-generating procedures and to receive annual influenza vaccines [ , , , ] . we have adopted these measures on all medical wards, because there might be similar unsuspected or "invisible" patients with influenza acting as infection sources. we did not encounter another influenza outbreak in open wards during the subsequent month period, which included the first wave of the influenza h n pandemic [ , ] . although each institute's infrastructure may be different, our findings suggest that the strategies of source and engineering controls might be important considerations to prevent nosocomial influenza transmission. our study is limited by its descriptive nature. we could not analyze the impact of influenza vaccination on the size of outbreak, because such information was unavailable from many patients; however, the general vaccine uptake rate in our community was reported to be very low [ , ] . also, we could not entirely eliminate the role of sick hcws in transmitting infection, albeit no case of influenza was eventually confirmed among them. however, because all hcws were required to wear surgical face mask during work and to report any influ-enza-like illnesses through a daily reporting system (the presence of which would immediately exempt them from duty), the chance of hcws cross-infecting patients should be rather small [ ] . furthermore, the spatial distribution of cases could not be easily explained by hcw-to-patient or patient-to-patient transmission, as discussed above [ ] . our findings indicate the need to evaluate the infection risks of aerosol-generating procedures or devices, especially when applied to the disease state [ , , , , ] ; the effectiveness of various source and administrative control strategies [ , , , , ] ; the ventilation systems in different healthcare settings; and the impact of airflow and humidity on nosocomial influenza transmission with an architectural aerodynamics approach [ , , , ] . in conclusion, our findings suggest a possible role of aerosol transmission of influenza in an acute ward setting. source and engineering controls, such as avoiding aerosol generation and improving ward ventilation design, may warrant consideration to prevent nosocomial outbreaks. hospital-acquired influenza: a synthesis using the outbreak reports and intervention studies of nosocomial infection (orion) statement influenza in the acute hospital setting transmission of influenza: implications for control in health care settings disruption of services in an internal medicine unit due to a nosocomial influenza outbreak preventing healthcare workers from acquiring influenza a nosocomial outbreak of influenza during a period without influenza epidemic activity world health organization. pandemic (h n ) infection prevention and control in health care for confirmed or suspected cases of pandemic (h n ) and influenza-like illnesses interim guidance on infection control measures for h n influenza in healthcare settings, including protection of healthcare personnel physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review surgical mask vs n respirator aerosol transmission of influenza • cid : ( november) • for preventing influenza among health care workers: a randomized trial novel h n influenza and respiratory protection for health care workers transmission of influenza a in human beings evidence of airborne transmission of the severe acute respiratory syndrome virus temporal-spatial analysis of severe acute respiratory syndrome among hospital inpatients detection of airborne severe acute respiratory syndrome (sars) coronavirus and environmental contamination in sars outbreak 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experimental model to assess air and particle dispersion exhaled air dispersion during oxygen delivery via a simple oxygen mask the guinea pig as a transmission model for human influenza viruses transmission of influenza virus via aerosols and fomites in the guinea pig model transmission and pathogenesis of swine-origin a(h n ) influenza viruses in ferrets and mice measurement of airborne influenza virus in a hospital emergency department influenza virus in human exhaled breath: an observational study investigation of a nosocomial outbreak of severe acute respiratory syndrome (sars) in toronto, canada possible sars coronavirus transmission during cardiopulmonary resuscitation why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? cross-sectional and longitudinal factors predicting influenza vaccination in hong kong chinese elderly aged and above willingness of hong kong healthcare workers to accept pre-pandemic influenza vaccination at different who alert levels: two questionnaire surveys influenza virus transmission is dependent on relative humidity and temperature factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises we thank mr. li liu and ms caroline xiaolei gao for their participation in the field measurement in the outbreak ward.potential conflicts of interest. all authors: no conflicts. key: cord- -xf ukinp authors: al-abdallat, mohammad mousa; payne, daniel c.; alqasrawi, sultan; rha, brian; tohme, rania a.; abedi, glen r.; nsour, mohannad al; iblan, ibrahim; jarour, najwa; farag, noha h.; haddadin, aktham; al-sanouri, tarek; tamin, azaibi; harcourt, jennifer l.; kuhar, david t.; swerdlow, david l.; erdman, dean d.; pallansch, mark a.; haynes, lia m.; gerber, susan i. title: hospital-associated outbreak of middle east respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description date: - - journal: clinical infectious diseases doi: . /cid/ciu sha: doc_id: cord_uid: xf ukinp background: in april , the jordan ministry of health investigated an outbreak of lower respiratory illnesses at a hospital in jordan; fatal cases were retrospectively confirmed by real-time reverse transcription polymerase chain reaction (rrt-pcr) to be the first detected cases of middle east respiratory syndrome (mers-cov). methods: epidemiologic and clinical characteristics of selected potential cases were assessed through serum blood specimens, medical record reviews, and interviews with surviving outbreak members, household contacts, and healthcare personnel. cases of mers-cov infection were identified using us centers for disease control and prevention serologic tests for detection of anti–mers-cov antibodies. results: specimens and interviews were obtained from subjects. seven previously unconfirmed individuals tested positive for anti–mers-cov antibodies by at least of serologic tests, in addition to fatal cases identified by rrt-pcr. the case-fatality rate among the total cases was %. six subjects were healthcare workers at the outbreak hospital, yielding an attack rate of % among potentially exposed outbreak hospital personnel. there was no evidence of mers-cov transmission at transfer hospitals having acceptable infection control practices. conclusions: novel serologic tests allowed for the detection of otherwise unrecognized cases of mers-cov infection among contacts in a jordanian hospital-associated respiratory illness outbreak in april , resulting in a total of test-positive cases. serologic results suggest that further spread of this outbreak to transfer hospitals did not occur. most subjects had no major, underlying medical conditions; none were on hemodialysis. our observed case-fatality rate was lower than has been reported from outbreaks elsewhere. in april , the jordan ministry of health (jmoh) investigated a cluster of suspected pneumonia cases among healthcare personnel, of which were fatal, at a hospital in the city of zarqa [ ] . despite testing for multiple potential pathogens, the investigation did not identify a known etiology for these infections. following the discovery of middle east respiratory syndrome coronavirus (mers-cov) in september [ ] , specimens from the fatal cases in jordan were retrospectively tested and both yielded positive results for mers-cov by real-time reverse transcription polymerase chain reaction (rrt-pcr), and were reported to the world health organization (who). these were the first confirmed human cases of infection with this emergent virus, which continues to appear as sporadic cases and clusters internationally, and which is now the focus of worldwide public health investigation and response [ , ] . using newly developed serologic assays to determine mers-cov antibody responses among case contacts in this outbreak, epidemiologists from the jmoh, us centers for disease control and prevention (cdc), and regional partners conducted a retrospective seroepidemiologic investigation to ( ) confirm whether surviving outbreak members had presence of antibodies to mers-cov, ( ) ascertain whether viral transmission occurred among household contacts or to other healthcare personnel, and ( ) describe the clinical features of all detected mers-cov infections in jordan. we interviewed and collected serum specimens from available members of the initial outbreak (who were admitted to the focal outbreak hospital during the period from march to april with fever and dry cough, and with radiological evidence of pneumonia), their household contacts (who reported usually sleeping under the same roof as a defined outbreak member during february-april ), a sample of healthcare personnel from medical institutions that admitted outbreak subjects (nonsystematic enrollment, with preference toward those reporting close contact with outbreak members), and field investigators from the jmoh. hospitalized subjects meeting the initial outbreak case definition were subsequently transferred from the focal outbreak hospital to other hospitals in amman. participating healthcare personnel were employed at one of these hospitals or at jmoh during february-april . epidemiologic data were obtained through medical record reviews and personal interviews during our may investigation. interviews were conducted in arabic, and documented contact history (with outbreak members, household members, visiting travelers, and animals) and occupational exposures. we conducted medical record reviews and key informant interviews with clinicians who provided medical care to patients with suspected infection and heads of infection control units at each medical institution and at the jmoh. informed consent was obtained prior to serum collection and interviews. as a public health response to a disease outbreak, this investigation did not require institutional review board review. all work with live mers-cov was done in cdc biosafety level (bsl- ) containment facilities in atlanta, georgia. serum samples were inactivated using × rads γ-irradiation and stored at − °c until use. to maximize specificity, we defined mers-cov antibody positivity as subjects having correlated, positive laboratory results from the hku . n screening enzyme-linked immunosorbent assay (elisa), as well as confirmed positive results by either the mers-cov immunofluorescence assay (ifa) or the mers-cov microneutralization assay (mnt) (supplementary table ). an initial indeterminate test result was recorded for those subjects having only a single, uncorrelated positive test result. antibody detection by hku . nucleocapsid elisa and mers-cov ifa and mnt genetic sequencing data indicate that mers-cov is a β-coronavirus (subgroup c) similar to the bat covs hku and hku . the recombinant bthku . nucleocapsid proteinbased elisa was developed by the cdc to detect the presence of antibodies that cross-react with the hku . n protein in serum samples from possible mers cases. if cross-reactive antibodies were detected in serum samples, then confirmation of mers-specific antibodies was determined by either mers-cov mnt or ifa. pi-batcov hku . nucleocapsid (n) gene in pet- b (+) plasmid was provided by dr susanna lau, university of hong kong. his-tagged recombinant protein was expressed in escherichia coli and purified by metal affinity chromatography. recombinant hku . n protein indirect elisa was developed using a modified version of the severe acute respiratory syndrome (sars) cov n elisa described by haynes et al [ ] . sera were considered positive when the optical density (od) values were at or above the . cutoff value (mean absorbance at nm of sera from us blood donors plus standard deviations). the overall specificity of the assay was determined after screening serum samples from donors in the united states and the middle east and persons with other non-mers respiratory infections (eg, human coronavirus [hcov] oc , hcov- e, sars-cov, hcov-nl , rhinovirus, human metapneumovirus, h n ). the assay specificity was . % ( / ). serum from hku human serum was not available for evaluation; however, hku mouse hyperimmune serum did not cross-react with the hku . n protein. at a screening dilution of : , sera with od values at or near the cutoff were titered with serial -fold dilutions ( : - : ) and further evaluated using mers-cov (hu/jordan-n / ) (genbank kc . ) ifa and mnt. indirect immunofluorescence was performed by screening sera at a dilution of : or : on paraformaldehyde-fixed, acetone-methanol-permeabilized, mers-cov-infected oruninfected control vero cells. the source of the positive control for this assay was a serum sample from a patient infected with mers-cov hu/england-n / ( provided by m. zambon, public health england). antihuman immunoglobulin (ig) g, igm, and iga fluorescein isothiocyanate conjugate was used and specific fluorescence was detected under an immunofluorescence microscope. a positive result was scored when fluorescent intensity equaled or was higher than that of the positive control. a weakly positive result was scored when fluorescent intensity was lower than that of the positive control. serum samples were tested for the presence of neutralizing antibodies to mers-cov using a modified mnt method described for sars-cov [ ] . the neutralization titer was measured as the reciprocal of the highest serum dilution that completely inhibited vero cell monolayer lysis in at least of the triplicate wells. controls were included for each mnt assay performed, including the input virus back titration and mock-infected cells. all assay results were confirmed in separate assays, and representative data are presented. tests of statistical significance were performed between the mers-cov antibody-positive and -negative subjects, including fisher exact test and χ tests for categorical variables using sas software version . (sas institute, cary, north carolina). serologic specimens and interviews were obtained from subjects. we obtained serologic specimens and data from of the ( %) surviving members meeting the initial outbreak case definition; the remaining subjects were unable to be interviewed ( member was lost to follow-up and did not consent) ( figure ). we also enrolled household contacts and subjects who did not meet the initial outbreak case definition who worked in healthcare and allied professions. among the healthcare personnel interviewed, % were nurses, % were physicians, and the remaining were allied health professionals; approximately half were employed at the focal outbreak hospital. seven of the subjects tested positive for anti-mers-cov antibodies by both hku . elisa and ifa (table and supplementary figure ) , and all but also had detectable neutralizing antibody titers as determined by mnt. the subject who did not have detectable neutralizing antibodies was testpositive both by hku . n elisa and by a confirmative ifa. demographic and epidemiologic comparisons of seropositive and seronegative subjects are provided in supplementary table . sera from the fatal cases (designated outbreak subjects and ) having positive rrt-pcr tests were also tested by the described serology tests. a serum sample from outbreak subject (taken days after onset of respiratory symptoms) was positive by hku . n elisa and ifa and had detectable mers-cov neutralizing antibodies. two serum specimens from outbreak subject (collected and days after onset) were negative for anti-mers-cov antibodies. of the subjects found to be positive for anti-mers-cov antibodies during this investigation, were surviving members of the initial outbreak group and was previously unrecognized. thus, including the fatal cases previously detected and reported, a total of individuals in this outbreak had evidence of mers-cov infections by acute rrt-pcr tests (n = ) or convalescent antibody tests (n = ). the case-fatality rate among all test-positive subjects was % ( of ). we documented that each serologic test-positive subject had unprotected mers-cov exposure(s) to at least rrt-pcr test-positive subject. an additional subjects had single positive test results by either hku . n elisa or ifa, but their mers-cov antibody status was considered indeterminate because both tests were not positive (table ) . we obtained specimens and data from a total of healthcare personnel who worked during february-april, , representing a majority of intensive care (intensive care unit [icu] and coronary care unit [ccu]) personnel at the outbreak hospital as well as other personnel having close contact with initial outbreak investigation members ( figure ). these included surviving outbreak members who were healthcare personnel at the focal outbreak hospital and were not lost to follow-up, other personnel at the focal outbreak hospital, personnel at transfer hospital a, personnel at transfer hospital b, and jmoh's outbreak investigators. of the healthcare personnel at the focal outbreak hospital who survived and the who died, ( %) had cases of mers-cov. our investigation provided no evidence of mers-cov infections or transmission events among personnel at the receiving transfer hospitals, even though some patients were transferred temporally close to their symptom onset dates. interviews with surviving subjects and family members revealed that transmission opportunities among healthcare personnel were not restricted to the workplace. we obtained serologic specimens from members of households, including those from the initial outbreak group and another subjects who had resided in those outbreak member abbreviations: elisa, enzyme-linked immunosorbent assay; ifa, immunofluorescence assay; mers-cov, middle east respiratory syndrome coronavirus; mnt, microneutralization titer. a outbreak member was lost to follow-up, and outbreak member did not consent. outbreak members and were previously laboratory-confirmed positive by real-time reverse transcription polymerase chain reaction (rrt-pcr) and died. serum samples from outbreak members and were collected prior to death and stored. b serum specimens with optical density (od) values ≥ . at a : dilution against hku . n elisa were considered to be positive. specimens were further titered against hku . n at : , : , : , and : dilutions. the antibody titer was taken to be the highest antibody dilution above the cutoff od that yielded a ratio of the absorbance of the positive serum and negative serum (p/n) > . the value is the reciprocal of the dilution. c serum specimens that were positive by hku . n elisa were screened at either : or : by indirect ifa using mers-cov_jordan-infected vero cells. h outbreak members conformed to the original outbreak definition; however, some were retrospectively determined to be mers-cov test negative. they were part of the original, defined outbreak that our investigation used to trace a priori contacts and exposures, so this descriptive title is retained. i hku . n elisa od values for serum specimens from outbreak members , , and and from healthcare personnel were near the assay cutoff od value and rescreened by serial dilution. these serum samples were initially weakly positive by ifa and considered initially indeterminate. upon rescreen by ifa, the samples were determined to be negative for the presence of mers-cov antibodies. j although outbreak member was positive for mers-cov by rrt-pcr, his sera were antibody negative. presumably, this subject died before an antibody response was detectable. this case is considered to be confirmed by current who mers-cov diagnostic guidelines. households during the outbreak period. one household was lost to follow-up, and did not consent for participation. from one of these households was the symptomatic wife of an initial outbreak investigation member who tested positive for mers-cov antibodies. twelve household subjects were children < years old, all of whom were serologically test negative. a summary of underlying conditions for test-positive subjects, including the fatal cases initially identified by rrt-pcr (outbreak members and ), is presented in table . of the testpositive subjects, % were male, with a median age of years (range, - years) at illness onset. we found no evidence of underlying immunodeficiency or immunosuppressant medications/therapies among any of these subjects. one subject had an atrial septal defect, had a history of hypertension, were smokers at the time of illness, and reported a pregnancy of months' gestation. although diabetes mellitus has been observed as a potential risk factor for mers-cov [ ] , none of the subjects reported here had a prior diagnosis of diabetes mellitus and, based on serum glucose values taken during their hospitalizations, none had indications of undiagnosed diabetes mellitus. the most common presenting symptoms, as documented in medical charts, included fever ( %), cough ( %), dyspnea ( %), chest pain ( %), and malaise ( %). eight subjects presented for hospital care a median of days after symptom onset (range, - days). of these patients, ( %) had cough, ( %) had documented fever (temperature (≥ . °c), ( %) had dyspnea, ( %) had chest pain, and ( %) had malaise at some point during their disease course. less common symptoms included chills ( %), wheezing ( %), and diarrhea, vomiting, sore throat, palpitations, and confusion ( % each). seven subjects had abnormal chest radiographic findings reported within days of presentation, and of those had bilateral findings. of the remaining subjects with initial unilateral findings, went on to develop bilateral infiltrates later in their hospitalization, documented either by chest radiography or computed tomography (ct). one subject (outbreak member ) received an initial diagnosis of pericarditis, and a ct scan with abnormal pulmonary findings was reported days later ( table ) . seven of the subjects ( %) who presented to medical care were admitted; refused admission. six subjects ( %) required respiratory support with at least supplemental oxygen, and subjects ( %) received intensive care (in ccu or icu), but only the ( %) patients who died required mechanical ventilation, of which patient also required pressor support (dopamine and norepinephrine) for cardiorespiratory failure. complications among hospitalized subjects were also limited to the patients who died, of whom had hyperkalemia with associated ventricular tachycardia, disseminated intravascular coagulation, and eventual cardiac arrest; the other had pericarditis, pericardial and pleural effusions, and supraventricular tachycardia late in the course of illness. although leukopenia (< . × /l) was observed in subjects, lymphopenia (< . × /l) was observed in of the subjects who had documented complete blood counts with differentials ( %). elevated leukocyte counts (> × /l) were observed during the course for subjects ( %), both of whom died. these subjects also had laboratory abnormalities consistent with multiorgan system failure late in the course of disease. these included evidence of elevated alanine aminotransferase and aspartate aminotransferase (> u/l) and significant coagulopathy with an international normalized ratio of > . , as well as thrombocytopenia (< × /l). in addition, the subjects who died had elevated serum creatinine measurements (≥ µmol/l) on the day of their deaths. a third case had an isolated elevated creatinine measurement, but had a subsequent normal value the following day. no patient received hemodialysis (table ) . outbreak member died days after onset of symptoms (on day of hospitalization) and outbreak member died days after onset of symptoms (on day of hospitalization). the remaining subjects survived, and the who were hospitalized were discharged following a median of days (range, - days). despite having respiratory symptoms, the pregnant household subject did not seek medical care due to concerns regarding receiving chest radiography and medications. this pregnancy resulted in stillbirth during the course of her illness [ ] . surviving subjects and the family members of deceased patients reported that contact with animals was rare in this urbanized area, and no contact with camels was identified among subjects having early symptom onsets. furthermore, none of the subjects had traveled to, or had received visitors from, the arabian peninsula shortly prior to symptom onset. at the focal outbreak hospital, there were no physical barriers between ccu and icu beds, spaced approximately meters, with the exception of cloth drapes in the ccu. isolation or negativepressure rooms were not present, and infection control compliance issues were reported during the outbreak. infection control insufficiencies were not noted at the receiving transfer hospitals. we used novel serologic assays to determine antibody responses of subjects from a mers-cov outbreak investigation in jordan, including the earliest cases of this emerging virus yet discovered. in addition to fatal cases confirmed by rrt-pcr and reported to who, we discovered previously unconfirmed and unreported mers-cov infections. detection of these additional antibody-positive subjects, including healthcare personnel from the focal outbreak hospital and a family contact of antibody-positive subject, and the establishment of contacts with mers-cov infected subjects when potentially infectious, suggests that human-to-human transmission of mers-cov occurred. although community exposures were possible, healthcare-associated transmission was a plausible explanation for healthcare personnel infections. mers-cov infections were not detected among healthcare personnel at a transfer hospital having better adherence to infection control measures. compared with published descriptions of saudi arabian and french cases [ ] [ ] [ ] [ ] , among the total jordanian cases identified through our collaborative investigation, subjects were younger and had fewer underlying medical conditions, and there was a lower case-fatality rate. although all subjects with mers-cov infection in our investigation had acute respiratory illnesses during the outbreak period, % of those who were infected survived. most subjects had no underlying medical conditions and none were on hemodialysis or had indications of diabetes mellitus. one newly detected subject, who was a household contact, did not seek medical care. our data support the probability that, in outbreak settings, infections may remain undetected among subjects who have mild symptoms, lack predisposing conditions, or have barriers to accessing appropriate diagnostic care. therefore, the true mers-cov case-fatality rate may be lower than that based on symptomatic, hospitalized cases alone. the presenting symptoms we observed were largely consistent with those of previously described mers-cov cases [ ] [ ] [ ] [ ] and included fever with respiratory symptoms such as cough and dyspnea, and associated infiltrates on chest radiography. on initial presentation, many subjects did not have evidence of bilateral pneumonia. although gastrointestinal symptoms such as vomiting and diarrhea were documented for subjects, we did not observe these as presenting symptoms, as they were in saudi arabian and french cases. once hospitalized, lymphopenia, a prominent laboratory feature among previously described cases, was observed in the majority of our subjects. however, other laboratory abnormalities observed in previous reports, such as thrombocytopenia, were limited mostly to the fatal cases late in the course of illness, consistent with multiorgan system failure. also, unlike previously reported cases, renal failure was not a prominent clinical feature among our subjects, as renal dysfunction was observed only in the fatal cases on the day of death. rapid isolation of patients with suspected mers-cov and rigorous infection control practices at the receiving transfer hospitals may have been important in preventing transmission at these locations. hospitals should have established policies and procedures for the rapid identification of suspected or known mers-cov cases and implementation of appropriate infection prevention measures. the cdc recommends standard, contact, and airborne precautions for the management of hospitalized patients with known or suspected mers-cov infection [ ] . one jordanian patient was initially hospitalized with pericarditis, a manifestation similar to mers-cov case occurring in the kingdom of saudi arabia [ ] . although this jordanian patient's serologic specimens tested negative for mers-cov antibodies at periods throughout his hospital stay, acute specimen collected several days before death was confirmed positive for the virus by rrt-pcr. these laboratory findings and the patient's exposure in the ccu, where he was situated in the bed directly next to another patient with rrt-pcr-confirmed mers-cov, collectively suggest the likelihood that the patient was nosocomially infected with mers-cov and died before an antibody response was detectable. based on the knowledge of sars-cov antibody responses, igg and neutralizing antibodies to sars-cov peaked months following a patient's recovery from acute infection [ ] . antibody levels did decline over time, but detectable sars-cov neutralizing antibodies persisted up to years after onset of sars-cov symptoms [ , ] . approximately months had passed between our may investigation and the april outbreak. although this was sufficient time for infected subjects to produce an antibody response to mers-cov, the role of waning immunity on the antibody response [ ] and whether persistence of these antibodies is important for protection from reinfection remain unclear. we implemented a rigorous case definition based on an elisa-positive result plus at least correlating assay result to maximize specificity. infections with sars-cov triggered humoral and cellular immune responses in all studied humans [ ] , and high titers of neutralizing antibodies were observed in response to sars-cov infections, but such characteristics of the mers-cov immunologic response remain unknown. as for those indeterminate laboratory findings among subjects with documented mers-cov exposure(s) but having only an elisa-positive result and mild or absent respiratory symptoms, it is possible that the viral exposure to these subjects did not trigger a long-lasting ifa-or mnt-recognizable immune response. because obtaining appropriate lower respiratory specimens from subjects having mild or asymptomatic infections is challenging, the use of serologic assays to identify otherwise undetected cases of mers-cov has been demonstrated to be a useful tool. serological surveys have been conducted in retrospective case investigations around instances of mers-cov importations in europe [ ] , as well as for establishing estimates of mers-cov seroprevalence among populations at risk [ ] . further validation of serologic assays and assessments of how they complement rrt-pcr testing is needed. our investigation was unable to find evidence of any exposure (either zoonotic contacts, human contacts from the arabian peninsula, or among hospitalized contacts preceding the earliest symptomatic cases) that might explain the origin of the virus. the precise route(s) of mers-cov transmission remains unclear overall, but several mers-cov sequences have been identified in dromedary camel nasal secretions, including one that is indistinguishable from that found in infected humans [ ] . in conclusion, the jordan respiratory illness outbreak in april resulted in a total of test-positive mers-cov subjects. the source of the virus in these earliest known mers-cov cases remains unknown. compared with other reports, the improved survivability we observed is perhaps related to the youth and relative lack of underlying illnesses among the subjects we investigated. infection control practices at both transfer receiving hospitals may have been important in preventing mers-cov transmission in those facilities. since the discovery of the mers-cov, enhanced surveillance for severe acute respiratory illnesses in jordan has been implemented. international severe acute respiratory infection surveillance, collaborative investigations, and vigilance among healthcare providers are necessary components for addressing and preventing the further spread of mers-cov worldwide. supplementary materials are available at clinical infectious diseases online (http://cid.oxfordjournals.org). supplementary materials consist of data provided by the author that are published to benefit the reader. the posted materials are not copyedited. the contents of all supplementary data are the sole responsibility of the authors. questions or messages regarding errors should be addressed to the author. epidemiological findings from a retrospective investigation 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patients and their clinical significance neutralizing antibodies in patients with severe acute respiratory syndrome associated coronavirus infection sars immunity and vaccination contact investigation for imported case of middle east respiratory syndrome lack of mers coronavirus neutralizing antibodies in humans middle east respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in saudi arabia author contributions. d. c. p. had full access to all the data in the study and had final responsibility for the decision to submit for publication.disclaimer. the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the cdc.financial support. this work was supported by the us global disease detection operations center outbreak response contingency fund.potential conflicts of interest. all authors: no potential conflicts of interest.all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord- -gf wy a authors: idowu, abiodun benjamin; okafor, ifeoma peace; oridota, ezekiel sofela; okwor, tochi joy title: ebola virus disease in the eyes of a rural, agrarian community in western nigeria: a mixed method study date: - - journal: bmc public health doi: . /s - - - sha: doc_id: cord_uid: gf wy a background: ebola virus disease (evd) is a severe hemorrhagic disease caused by ebola virus. several outbreaks have been reported in africa and often originated from remote agrarian communities where there are enormous misconceptions of the disease, refusal of early isolation and quarantine, and unsafe burial rites practices which aggravates the epidemics. it is on this basis that this study was conducted to (assess) the knowledge, perceptions, beliefs and preventive practices against evd in a predominantly agrarian rural community in southwest nigeria. methods: this was a cross-sectional study conducted in igbogila town, yewa north local government area of ogun state, southwest nigeria in the latter part of during the evd outbreak. mixed methods were used for data collection. quantitative data collection was done using a pre-tested interviewer administered questionnaire. four hundred and seven respondents selected by multi-stage sampling technique were interviewed. descriptive and inferential statistics were done, and the level of significance was set at . . qualitative data collection involved four focus group discussions a year after the epidemic was declared over in the country. the discussions were recorded, transcribed and analyzed along major themes. results: all respondents were aware of evd with radio and television being the major sources of information. knowledge of the disease was however very poor with many misconceptions and it was significantly influenced by educational level of respondent. evd survivors will be welcomed back into the community by few residents ( . %) and a much fewer proportion ( . %) will freely entertain a survivor in their house. most would prefer local herbalists over orthodox medical practitioners to care for their loved one in case they contract evd. although respondents knew that burying a victim is dangerous, they opposed cremation. conclusion: there was poor knowledge of evd with a lot of misconceptions. community members were not pro-active about prevention with dire consequences in the event of an outbreak. continuous public education should be done via mass media, traditional institutions and other community-based channels as part of emergency preparedness. ebola virus disease (evd) is a severe hemorrhagic disease caused by ebola virus: a non-segmented, enveloped, negative-strand rna virus [ ] . the first case of evd was identified in , since then, several outbreaks have been reported in africa [ ] . in the last years, an outbreak of evd has been reported at least every years [ , ] . in ; the deadliest, most widespread (affected ten countries), evd outbreak that lasted approximately years occurred making it a global emergency [ ] . current corona virus disease (covid- ) pandemic has again brought to the fore, the need for countries to maintain a high standard of preventive measures and preparation for emergency response for any emerging or reemerging infectious disease. populace needs to be enlightened on evd preventive measures such as maintenance of careful hygiene (washing hands with soap and water or an alcohol-based hand rub), avoiding contact with non-human primates and bats, avoiding contact with infected person's body fluids or infected items, and avoiding funeral or burial rituals that require handling of the body of someone who has died from evd (confirmed or suspected) [ ] . public health response to evd outbreak include: case finding (suspected, probable and confirmed), contact tracing, isolation and early quarantine, treatment of symptomatic cases, and ensuring appropriate burial for the deceased [ ] . however, a closer look at past evd outbreaks revealed that they often originated from rural agrarian communities where there are many misconceptions about the disease, refusal of early isolation and quarantine, and unsafe burial rites practices which aggravate epidemics [ , ] . it is on this basis that this study was conducted to assess the knowledge, perception, beliefs and preventive practices among residents of an agrarian community in ogun state, southwest nigeria. findings will provide useful information to aid future outbreak prevention and control as well as emergency preparedness efforts. this was a descriptive cross-sectional study which employed mixed-method (quantitative and qualitative) approach in data collection. the study setting was igbogila town, ibeshe ward, yewa north local government area of ogun state, southwest nigeria. yewa north is located at the west end of ogun state sharing border with benin republic (a neighboring country). igbogila is predominantly rural and agrarian with many of the residents engaged in agro-forestry related occupations. at the time of the study, the town had one primary healthcare centre, two public secondary schools, five public primary schools, one major market, few churches and mosques. only residents between and years that had been living in the study area for at least months prior to the study participated in this study. quantitative data were collected during the ebola epidemic in nigeria (july -september ). sample size was determined using cochran's formula (n = z p( -p)/ e ) [ ] . the calculation was based on: prevalence of good knowledge (p) of % obtained from a similar study [ ] , standard normal deviate (z) at % confidence being . and % margin of error (e) resulting in a minimum sample size of . this was increased by % ( ) to make up for non-responses and incomplete questionnaires giving a total sample size of . multi-stage sampling was used to select the respondents. in the first stage, one ward (ibeshe) was selected from the eleven wards in yewa north using simple random sampling technique (balloting). in the second stage, one town (igbogila) was selected from the seven towns in ibeshe ward. igbogila comprises nine smaller communities which were all included in the study. respondents were equally allocated to the communities i.e. about respondents were required from each community. the third stage involved the selection of houses following enumeration and systematic sampling of houses. the houses in the communities largely had no numbering system, so, the research team carried out house numbering. in the fourth stage, households were selected from the houses. only one household was selected per house (simple random sampling (balloting) was used to select one when there were more than one household). in the final (fifth) stage, respondents were selected from households. only one respondent that met the inclusion criteria was interviewed per selected household (simple random sampling (balloting) was used to select only one respondent when there were more than one eligible respondent). respondents were interviewed face-to-face using a pre-tested interviewer administered questionnaire adapted from similar studies [ , ] . eight research assistants who were fluent in yoruba, english and 'pidgin' english were trained for data collection. the questionnaire sought information on socio-demographic characteristics, awareness, knowledge, attitude and perception of evd. knowledge was assessed using questions on cause, transmission, symptoms, prevention and cure of evd. perception and attitude to evd were assessed using respondents' agreement or disagreement to a set of likert statements. data were coded, entered and analyzed using epi info™ . statistical package [ ] . descriptive statistics (frequency, mean and standard deviation) and inferential statistics (chi-square test) was used to test association between categorical variables. level of significance was set at %. in the knowledge section, each correct response given by respondents was allotted one point. overall knowledge was assessed using five domains: cause ( point), transmission ( points), symptoms ( points), prevention ( points) and cure ( point). this gives a total maximum score of points converted to percentage. using % cut-off point; respondents with total score < % were graded as 'poor knowledge' while those with > % were graded as 'good knowledge'. attitude was scored using three points likert scale; the maximum obtainable score was and the least was . using the mid-point ( ) as cut-off point, respondents with score < were graded as having "poor attitude" while those with scores > were graded as having "good attitude". for the qualitative aspect, focus group discussions (fgds) were conducted in november , about a year after the epidemic was declared over by who [ ] . the main purpose for the fgds was to explore explanatory models for the disease in rural communities and their preventive practices against an outbreak. according to the who, this is important in any epidemic preparedness and response [ ] . discussants were approached face-toface and selected into one of four groups: higher secondary education students ( discussants), females of reproductive age ( discussants), adult male ( discussants), elderly female ( discussants). fgd participants were selected by purposive sampling as discussants in each group were selected to be of the same gender and about same age as suggested by ritchie and lewis qualitative research framework [ ] . in each group, one of the discussants volunteered his/her home for the discussion. fgds were moderated by the principal researcher with the assistance of one note taker and a time-keeper. each session lasted for about h. discussions were held mainly in local (yoruba) language understood by all the participants and taperecorded in addition to notes. each discussant was assigned a number. at the end of each session, discussants were given light refreshments. the recordings were later translated and transcribed in english. data was saturated in domains of cause, and spread of evd, but, unsaturated in domains of treatment. thematic analysis was done manuallyrecurring themes from the data were identified, emerging patterns noted, and report written based on these identified patterns. for the purpose of presentation, the groups were coded as follows: higher secondary school students (hs), adult males (am), older females (of), and women of reproductive age (rf). participation was voluntary and formal consent was obtained from each participant. respondents were informed of their right to withdraw at any point of the study without prejudice in line with helsinki declaration [ ] . a total of respondents completed their interviews while respondents withdrew their participation, making the response rate to be . %. mean age of respondents was . + . years with slightly more males (n = , . %). almost one-quarter, ( . %) had no formal education and half (n = ) earning less than , naira monthly (less than us dollars) ( table ) . all the respondents were aware of evd. majority, ( . %) heard of it through radio and television, ( . %) got to know from their friends or family members. print media such as newspapers and flyers were not reported as a source of information by the respondents. 'dirty environment' was the most commonly mentioned cause of evd ( . %), only ( . %) knew that a virus is implicated. few ( . , . and . % respectively) knew that eating poorly cooked bush meat or contact with non-human primates or contact with body fluids of infected persons pose risk of evd transmission. a minority knew fever ( . %), vomiting ( %) and headache ( %) as symptoms of evd. (table ) . a third ( . %) knew hand washing and avoidance of contact with non-human primates as preventive measures while only ( . %) knew that avoiding funeral or burial rituals involving contact with victims' corpses is a preventive measure (table ) . neither age nor sex of the respondents significantly influenced their knowledge of evd. however, those respondents with at least secondary education were more likely to have good knowledge of evd (p = . ) ( table ). a majority ( . %) believed that evd really exists and ( . %) perceived it to be very fatal. while ( . %) agreed that it is not curable, ( . %) believed that victims could survive if given prompt medical intervention. almost a quarter, ( . %) saw it as a political ploy that government officials wanted to use to embezzle funds and only about half ( . %) thought that the country was truly ebola free (table ). in respect to their attitude; ( %) reported that they would accept to be quarantined if they were found to have had close contact with a case, ( . %) would support and empathize with a friend or relative who is infected, however, only two-fifths ( %) would buy from a shopkeeper who has recovered from evd and even a lesser proportion ( . %) would welcome a survivor back to the neighbor-hood. only ( . %) would entertain a survivor in their homes. overall, respondents ( %) had a good attitude towards evd ( table ). sociodemographic characteristics of discussants the mean age of the fgd participants was + . years, ( %) were females, ( %) had no formal education while ( %) had tertiary education. the participants were largely farmers ( %), and petty traders ( %). one discussant was a herbalist (table ) . the recurring themes on how ebola disease can be contacted were: eating infected bush meat, unprotected contact with infected persons, and intercourse with multiple sexual partners. "it is gotten by coming in contact with infected animals, animals such as bats and bush meats" -hs ( years old male student). "the disease is catching whoever has sex with prostitutes …" -am ( year old bricklayer). more respondents believed that local herbalists know the cure for ailment. "i will call a herbalist to come and treat the person (a case) at home" -rf ( years old female farmer). "i believe that they are lying by saying there is no cure for the disease … … , if the victim is taken to good traditional healers, the person will be cured" -hs ( year old male student). when asked how best to handle the corpse of a close relative that died of evd, it was evident that the people knew that burying someone with evd is not without any risk. "i will not move close to the corpse. the people who died of the disease are usually burnt but i cannot allow my own dead family member to be burnt. i will just call them at the centre (primary health facility in the area) to come and help me bury the corpse" -hs ( year old male student). while some ( out of the ) of the respondents did not stop eating bush-meat (bats inclusive), many ( out of ) of the respondents stopped eating bush meat. the precautionary measure was however for a while as it was found that these respondents that initially restrained their intake of bush meat had resumed its consumption. "i stopped eating bush meat and bat, but when i later saw that people who ate bush meat did not die, i started eating them back" -am ( year old male farmer). the important theme that emerged on preventive measures for evd was the use of salt water. some respondents bathed with salt water, drank and mandated its use in their family till they experienced related adverse effects. "i bathed with salt water as instructed by my father" -hs ( years old male student). "my six children and myself used salt water to bath for some days but stopped when we started having skin rashes" -of ( year old female trader). their current preventive practices were explored (without prompting). majority of the respondents confessed that they were eating bush meat as before. they were mostly not taking any pro-active preventive measures to prevent evd such as limiting close physical contact or direct contact with bush animals. "i am not doing anything. i am eating bush meat …." -rf ( year old female farmer). "i am not doing anything … … i did not need to bother myself" -of ( year old female). at the outset of the evd outbreak, the nigerian government embarked on widespread health campaign with major attention on mass media. the mass-media platforms successfully raised evd awareness as all the rural dwellers in this study were aware of evd and they indicated that radio and television were their main sources of information. mass-media played similar pivotal role in purveying awareness for residents of urban communities in lagos, nigeria [ ] and for locals at epicenters in sierra leone [ ] . however, the high level of awareness did not translate to better knowledge of the disease. most respondents had poor knowledge riddled with many misconceptions. for instance, most of them either did not know the cause of evd or misconceived the cause to be dirty environment. there are evidences that have implicated bush-meats especially non-human primates e.g. bats in the spread of evd, yet only few ( %) knew that evd is spread by contact with infected non-primate animals [ , ] . the prominent misconception of the cause of evd as revealed in the fgd was the belief that ebola disease is acquired by leading a promiscuous lifestyle. this apparent disparity between biomedical and traditionally perceived etiology could stymie prevention in the event of another outbreak because based on etiological variances, local perception of prevention will conflict with orthodox suggestions [ ] . apart from the misconception of cause of evd, the knowledge of community-based modes of transmission (from infected individual to others, and from infected fomites/objects to man) of evd were also less known among the residents of the agrarian community. this is worrisome because during outbreaks, community-based transmissions are responsible for most secondary cases and thus responsible for perpetuating the spread of infection [ ] . the knowledge of prevention of evd was also found to be inadequate. more than % did not know that; avoiding direct contact with people, frequent hand washing, avoiding contact with non-human primates' body fluids and blood, and avoiding contact with infected items are precautionary measures. when the respondents were asked how they will handle the corpse of a relative that died of evd; it was evident that the people knew that burying someone with evd is not without risk but they opposed cremation -"… i cannot allow my own deceased family member to be burnt". cremation is rejected because it is not culturally acceptable in most parts of west-africa where autochthonous residents strongly believe that deceased soul will haunt living relatives if not given a traditionally acceptable burial [ ] . this has potential to impede effective burial of dead cases and it can aggravate epidemics as evidenced by catastrophic events that followed unsafe burial of cases at the early stages of the outbreak (in sierra leone and liberia) [ , ] . it may be beneficial to gradually institute interventions involving anthropologists and traditional institutions to discuss and relay such messages at the grass root level. exploring the respondent's knowledge of cure of evd, it was found that although some ( . %) knew that there is no cure for the disease, yet, most preferred local herbalists over orthodox medical practitioners to care for their loved one in case he/she contacts evd. being a rural setting, this is not surprising. the rationale behind this preference is the fear of having their relative isolated from them: "… ..once they carry the person (victims) away from you, you will not be allowed to see them again …" the discussants' preference of local herbalist over medical practitioners is another cause for concern as such misconceptions had made people in gulu district, uganda to resort to traditional practices such as 'ryemo gemo' rituals (wild shouting, jumping and running into nile river), 'chani labolo' rituals (slaughtering and littering intestines of several goats on ground) in kotido district of uganda, all in an attempt to 'cure' the disease. such practices only enhanced the spread of the disease and complicated the economic cost of the outbreak [ , ] . this also has implications for other highly infectious diseases such as lassa fever and covid- that require isolation of confirmed positive cases as part of containment. in such situations, similar preference for alternative treatment options may negatively impact control efforts. the factor that was found to significantly influence participants knowledge about evd was their educational status. the agrarian community dwellers with at least secondary education in this study were more likely to have good knowledge of evd compared to those with only primary or no formal education. this highlights the need to increase education coverage in local communities as the level of education of the populace could play an important role in determining the magnitude of spread as modelled by outcomes in two separate outbreaks in sudan [ ] . most respondents indicated stigmatizing attitudes towards evd survivors. a total of % stated that they will not buy any goods from a survivor, many expressed that they will not welcome a survivor back into the community nor allow survivor into their house. these discriminatory statements were similar to the initial problems local residents at ebola epicenters posed during early phases of the outbreak in liberia [ ] . the danger in this is that persons that suspect that they may have evd, and indeed any infectious disease hide it because of fear of stigmatization. this could drive disease outbreaks further. during the outbreak, the preventive method most respondents in this study observed was avoiding bush meat and use of salt water which are largely misconceptions. the use of salt water may have negative health consequences. though the exposure is there with consumption of bush meat, the key thing is close contact and method of handling during preparation of the animals. this was not really a big issue in evd outbreak in nigeria as the cases recorded were invariably linked to the imported case. the natives already exhibited poor knowledge and bush meat is commonly consumed due to their agro-forestry background hence the need for proper education. one year later, majority of the discussants stated that they had resumed bush meat consumption and were no longer taking any recommended precautions to prevent contracting evd. the main reason for this in-action could be linked to their religious belief, that 'god' protects them from 'evil diseases' like evd (table ) . unfortunately, this behavior may have serious consequences in the re-occurrence of evd outbreak in the country. the study was conducted in a setting that can be described as 'high risk' for evd outbreak. data was collected prospectively, and the mixed-method approach yielded more information necessary for understanding community explanatory models of the disease in the context of outbreak preparedness and control. the study did not emphasize on how local beliefs and practices could aid control efforts in such epidemics. more content could have been covered by adapting dunn's framework [ ] and this could be addressed in larger scale studies. the grading system adopted for measuring 'attitude' could have affected the result of the overall attitude (majority had good attitude) as their 'neutrality' was not factored into the grading system. no case of evd was recorded in the study area during the outbreak, nevertheless the limited data provides relevant information useful to researchers and other public health stakeholders in infectious disease prevention and control. the study has shown very poor knowledge of evd with misconceptions. though majority perceived the disease to be severe, some believed it was a ploy of whites against african countries and avenue for government officials to embezzle money. respondents exhibited stigmatizing attitude which may hinder control efforts in disease outbreaks. they were also not pro-active about prevention of possible future outbreak as most had gone back to harmful practices initially abandoned because the outbreak was declared to be over in the country. immunopathology of highly virulent pathogens: insights from ebola virus world health organization. ebola hemorrhagic fever in zaire, -report of an international commission outbreaks chronology: ebola virus disease emergencies preparedness response: ebola virus disease outbreak news overview, control strategies, and lessons learned in cdc response to the - ebola epidemic ebola response: package and approaches in areas of intense transmission of ebola virus. geneva: world health organization ebola viral hemorrhagic disease outbreak in west africa − lessons from uganda the ebola epidemic: a global health emergency sample size determination study on ebola virus disease knowledge, attitudes and practices of nigerians in lagos state public knowledge, perception and source of information on evd in epi infotm -a database and statistics program for public health professionals world health organization. who declares end of ebola outbreak in nigeria world health organization. recommended guidelines for epidemic preparedness and response: ebola hemorrhagic disease. geneva: world health organization qualitative research practice: a guide for social science students and researchers world medical association declaration of helsinki. ethical principles for medical research involving human subjects study on public knowledge, attitudes and practices relating to ebola virus disease prevention and medical care in sierra leone epelboin a mv. human ebola outbreak resulting from direct exposure to fruit bats in luebo, democratic republic of congo information note: ebola and food safety dilemma with the local perception of causes of illnesses in central africa: muted concept but prevalent in everyday life factors that contributed to undetected spread of ebola virus and impeded rapid containment; one year into the ebola epidemic the impact of traditional and religious practices on the spread of ebola in west africa: time for a strategic shift community perspectives about ebola in bong, lofa and montserrado counties of liberia. results of a qualitative study a time for fear: local, national and international responses to a large evd outbreak in uganda cultural contexts of ebola in northern uganda modelling the role of public health education in ebola virus disease outbreaks in sudan the liberia ministry of health. national knowledge, attitudes and practices study on ebola virus disease social determinants in tropical disease springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors wish to thank the research assistants and participants for their commitment throughout the period of study. special thanks to adebolu olayinka, ogundan olayinka and taiwo toyosi for their assistance with data entry and transcription. authors' contributions abi-was involved in the conception, design, acquisition, analysis, interpretation of data and drafting and revision of the manuscript. ipo-was involved in the conception, design, analysis, interpretation of data, drafting of the manuscript and substantively revised it. eso-was involved in the interpretation of data and substantive revision of the manuscript. tjo-was involved in interpretation of data and substantive revision of the manuscript. all authors read and approved the final manuscript. there were no external funding for this study. the datasets used and/or analyzed during the study are available from the corresponding author on reasonable request. ethical approval was obtained from health research ethics committee of the lagos university teaching hospital (approval number: adm/dcst/hrec/ app/ ). informed consent (in writing) was duly obtained from participants. not applicable. the authors declare that they have no competing interests. key: cord- -bmcsyfz authors: akdeniz, gulsum; kavakci, mariam; gozugok, muharrem; yalcinkaya, semiha; kucukay, alper; sahutogullari, bilal title: a survey of attitudes, anxiety status, and protective behaviors of the university students during the covid- outbreak in turkey date: - - journal: front psychiatry doi: . /fpsyt. . sha: doc_id: cord_uid: bmcsyfz a new coronavirus disease began on december in wuhan/china and has caused a global outbreak in only a few months resulting in millions being infected. in conjunction with its’ physical side effects, this outbreak also has a tremendous impact on psychology health. this study aims to assess the spread and frequency of protective behaviors, emotional and anxiety status among the turkish population using a rapid survey during the covid- outbreak. an online questionnaire was administered to , respondents between the ages of – . this cross-sectional study was conducted from apr to apr , . while questions related to the outbreak were created by members of our neuroscience department, the turkish version of the abbreviated beck anxiety inventory was included in our survey to measure anxiety status. pearson correlation coefficient was used for statistical analysis. we found that % of respondents report washing hands more frequently since the outbreak while % wear protective gloves. respondents were more fearful of their relatives catching the coronavirus disease than they were of themselves catching it. in response to the question, “what are your emotions about the coronavirus?”, % responded with “worried”. there was a significant correlation between anxiety status and consumption information from the media about covid- . individual early protection behaviors might slow transmission of the outbreak. our results showed that the behavior of the participants has changed in predictable ways during the covid- outbreak. understanding how emotional responses such as fear and anxiety status vary and the specific factors that mediate it may help with the design of outbreak control strategies. novel coronavirus disease began in wuhan, china in december and has spread worldwide since then. this new coronavirus disease turned into an outbreak reaching around the world in as little as three months showing the serious threat of this outbreak. the first patient with coronavirus disease was identified in turkey on march , (the republic of turkey, ministry of health, / / ). people display awareness of protective behaviors against diseases and develop health-protective attitudes during a health crisis, such as an outbreak. timely and accurate information plays a critical role in controlling the spread of illness and managing fear and uncertainty during an outbreak. furthermore, society's perception of risk and anxiety of being ill have an impact on prevention behaviors and measures to be taken. knowing what to do helps people feel safer and enhances the belief that they can take meaningful steps to protect themselves ( ) . in outbreaks, anxiety is one of the psychological problems that can be seen in humans because pandemics can be seen as events that can raise concerns. the use of a face mask ( ) and protective measures during the workplace are protective factors for mental health ( ) . anxiety and related disorders (such as posttraumatic stress disorder, and obsessive-compulsive disorder) can be seen due to stressful life events, and they are prevalent, debilitating, and costly ( , ) . the outbreak of covid- has been reported to cause mental health problems among the people in china ( ), japan ( ) , and wuhan ( ) . due to the sudden nature of the outbreak and the infectious power of the coronavirus, people may show psychological and stress-related reactions. some prohibitions and precautions were taken against the coronavirus disease outbreak such as social isolation, quarantine, travel restrictions, contact avoidance. these measures affect people's social life, emotional status, and psychological well-being. it is necessary to investigate and understand the publics' mental states during this tumultuous time ( ) . accordingly, psychological and behavioural measurement and evaluation are essential. psychological tests contribute to the identification of certain disorders, monitoring of disease, and make predictions in a way that reflects the variability in human behaviors ( ) . furthermore, psychological tests such as web-based surveys offer a rapid and efficient method of identifying problems, planning and monitoring a course of treatment, and assessing the outcomes of interventions ( ) . particularly in the severe covid- pandemic, the data obtained through these methods provide information about people's attitudes, emotions, and behaviors while providing a contemporary perspective to researchers. however, what type of psychological disorders are prevalent and how they distribute among the population are not know. therefore, a rapid assessment of outbreak-associated psychological disorders for the public is needed ( ) . so, the current study aims to determine the prevalence and distribution of anxiety and emotional status and protective behaviors among the young turkish population and examine their associations with media exposure with a rapid assessment during the covid- outbreak. this cross-sectional study was conducted online over a span of seven days from april to april , . participants were university students living in turkey. google documents were used as a platform to design online surveys that were automatically hosted via a unique url. the survey was created by the department of neuroscience at ankara yildirim beyazit university. respondents were asked about about (i) demographic and epidemiological information, (ii) protective behaviors to prevent catching the coronavirus, (iii) different emotions and thoughts caused by the covid- outbreak, (iv) anxiety status during the covid- outbreak, and (v) exposure to covid- outbreak on tv. respondents had to answer a yes-no question to confirm their willingness to participate voluntarily. after confirmation of the question, the participant was directed to complete the self-report survey. respondents were found from internet social media tools such as facebook and twitter. respondents gave free-text responses to questions about their name-surname, current age, and city. to measure the response of epidemiologically relevant behavior to information on the coronavirus disease outbreak, we asked seven yes/no questions about precaution actions taken by the respondents. in the survey, we asked: "washing hands more often with soap for seconds", "wearing protective gloves", "wearing a mask", "avoiding contact with hands, face, and eyes", "washing clothes at a minimum of degrees", "personal and social isolation", and "frequent ventilation of the room". all of these actions are recommended as protective measures by doctors. an important epidemiological question is how people's affective states and anxiety have undertaken change with progression of the outbreak. to measure this, we asked participants two critical questions: "how scared are you of catching the coronavirus disease (covid- )?" "how scared are you that a relative will catch the coronavirus disease (covid- )?" these questions were asked using a five-point ordinal scale with anchors at all points: "never", "somewhat", "moderate", "very", and "extremely". the two questions were compared to each other for the frequency distribution of perceived risk and fear of the new coronavirus disease outbreak. to assess emotional status in the survey, we asked: "what are your emotions about the coronavirus?". the respondents were asked to choose from five different emotions. the choices were: "afraid", "sad", "worried", "indifferent", and "temporary". respondents were also asked about anxiety status during the coronavirus disease outbreak. we used eight-items from the turkish version of abbreviated beck anxiety inventory: "fear of death", "scared", "difficulty in breathing", "fear of losing control", "feeling of choking", "nervous", "terrified or afraid", and "fear of the worst happening" ( , ) . additionally, we added the following anxiety statuses: "fear of losing your relative", "sad", "future anxiety". a self-report measure of anxiety severity experienced in the last days was also included. these statements were asked using a five-point ordinal scale with anchors at all points.: "never", "somewhat", "moderate", "serious", and "very serious". for our analysis of participants' responses to the threat of the coronavirus disease (covid- ), we used a variable called "survey day". april nd represents the first day of the survey and april th represents the last day. this survey was joined one time by each participant. we investigated the change in respondents' protective behavior status and emotional status for each day in the survey. media exposure was evaluated by asking how often respondents were exposed to news and information about covid- on tv over the past fifteen days. response options were "never", " - hours", " - hours", " - hours", and " or more hours". the correlation between protection behavior, sleep status, emotional status and information about covid- from the tv was investigated. statistical analyses were performed with the statistical package for the social sciences (spss . , spss inc., chicago, il) software. the pearson correlation coefficient (pcc) was used to evaluate a possible correlation between information about covid- on tv and protection behavior after determining the normal distribution of data. to assess the normality of a set of data, researchers usually report the skewness and kurtosis of such data. normality is tested according to the common rule-ofthumb, which is to run descriptive statistics to determine both skewness and kurtosis. pcc was used to assess the relationship between information about covid- on the tv and emotional status. pcc was also used to analyze the relationship between information about covid- on tv and sleep status. statistical tests were carried out with a level of significance at p= . . a total of , turkish university students ( , % female, , % male) ages - ( , ± , ) filled out the online survey named "web-based behavioral measurement related to covid- ". figure shows the distribution of the survey date and the number of respondents. table displays the epidemiological and demographic data of the respondents. figure shows the frequency distribution of protective behavior. respondents paid attention to hand washing ( %), social isolation ( %), and room ventilation ( %). the rate of wearing protective gloves and masks is notably lower ( %). figures a, b reveal the frequency distribution of perceived covid- risk and fear for respondents and their relatives. respondents had to moderate fear of catching constituted % while % stated that they did not have this fear. respondents' fear of their relatives being infected with the disease was much higher with % of them reporting their fear as high and extreme. figure includes responses to the question "what are your emotions about the coronavirus?". while % of the respondents stated that they were worried about the new coronavirus, there was a % portion that reported they were indifferent. in addition, % of the respondents' perceived this virus as temporary. according to tabachnick, data may be assumed to be normal if both skewness and kurtosis are within a value range of ± . . tables and present the results of skewness and kurtosis analysis on each of the items that measure the constructs of our study ( ) . there was a significant correlation between being exposed to information about covid- on tv, hand washing, and clothes ( table ) . however, as shown in table no significant correlation was found between being exposed to information about covid- on tv and other precautions. the correlations are summarized in tables and . in figure , we show the distribution of anxiety status during the covid- outbreak. "serious" and "very serious" options were high among the responses given to "future anxiety" and "fear of losing relatives". in addition, the "never" option was high in response to the questions about "difficulty in breathing" and "feeling of choking". in figures and , we plot the change in respondents' protective behavior and emotional status over the survey days. on the third (april th) and sixth day (april th) of the study, we see that the number of people reporting a calm emotional state is very high, and the number of people reporting the high values of the protective behaviors is significantly reduced. so, the current study aimed to determine the prevalence and distribution of anxiety and emotional status and protective behaviors among the young turkish population and examine their associations with media exposure using a rapid assessment during the covid- outbreak. our study is the first study to date that demonstrates the behavioral results of during the covid- outbreak in turkey. we preferred a web-based survey for assessment of behavioral responses because it is a faster. we found that respondents' behavior varies regularly with covariates from demographic, epidemiological, media, and emotional status. we determined the protective behaviors and anxiety of people in our country were excessive at the beginning of the survey. respondents' fear of their relatives catching the virus was more than the fear they had for catching the virus themselves. according to the results of our study, among the protective behaviors investigated, social isolation was very high at %. as a matter of fact, a study by filder smith and do freedman also stated that social distances would reduce transmission, as such outbreak diseases require a certain intimacy of people ( ) . another surprising point in this study was that use of masks and gloves was higher than we expected because there was no legal obligation to do so. although some studies ( ) emphasize that only individuals with respiratory symptoms should wear a mask, we think that this protection behavior positively reflects the decrease in the number of cases in our country. another study emphasized that it is very important to wash hands with soap and water before putting on the face mask as well as wearing a face mask ( ) . in regards to the results we obtained, the handwashing rate of the respondents' was quite high, and it was higher than the mask-wearing rate. in response to the question, "what are your emotions about the covid- ?", % of respondents said "worried". according to this result, it must be considered normal for respondents to figure | frequency of the protection behavior undertaken by the respondents, %. wash, washing hands frequently with soap for s; glove, wear protective gloves when going out; mask, wear protective mask when going out; face contact, avoid touch with hands face and eyes; cloth, washing clothes at least degrees; isolation, personal and social isolation; ventilation, frequent ventilation of the room. frontiers in psychiatry | www.frontiersin.org july | volume | article worry about their health. we interpreted this as a positive result that young people have supportive messages and encouraging information. worry could be increased by misperception in society ( ) . as evidence from prior outbreaks such as sars and ebola showed ( ) ( ) ( ) moderate amounts of worrying is effective for controlling the outbreak, but may lead to negative consequences of coronavirus disease control, if it is excessive. in response to the question, "how scared are you of getting the coronavirus disease (covid- )?", % of the respondents stated that they have a moderate level of fear. strikingly, in response to "how scared are you that a relative will catch the coronavirus disease (covid- )?" % of respondents said "extremely". the scare is directly associated with the covid- 's rapid and invisible transmission rate, as well as its morbidity and mortality rates ( ) . it appears that humans perceive it as their moral duty to protect relatives and may exhibit irrational behaviors to do so. consequently, elevated fears and misconceptions about covid- may result in a disorder of excessive emotional status. our study has some public health implications. our results demonstrate that respondents' protective behaviors vary consistently with media. because of strict social isolation precautions, people are maintaining connectivity now more than before using social media and networks, to facilitate human interaction and information sharing about covid- . the highest responses to protective behaviors during the covid- outbreak was for social isolation. previous research shows that respondents did not know that covid- could be transmitted by droplets, which might reduce certain precautionary measures ( ) . incompatible with this work were our results showing that respondents use of protective behaviors was high. effective visual videos, some with famous people, have been shared on social media in our country since the outbreak. hence it has increased accurate knowledge and positive attitudes of the public about coronavirus frontiers in psychiatry | www.frontiersin.org july | volume | article disease outbreak. we suggest that providing simple and repeated health education via social media is important for encouraging protective behaviors. our results have revealed that there was a significant correlation between using a computer or mobile phones and sleep patterns. previous studies support our conclusion that social media, computer games, and the internet cause poor sleep quality ( ) ( ) ( ) ( ) ( ) . when we pay attention to the anxieties caused by covid- , the most serious level of responses was fear of losing relatives and future anxiety. anxiety responses to the feeling of nervousness, sadness, and fear of the worst happening are moderate in our study. the anxiety of the respondents might be result in switching to online education, working from home as much as possible in business life, reducing working hours, social distancing, and other social measures taken across the country. recent research has indicated that the delay in academic activities was related to the emergence of anxiety symptoms with university students in china ( ) . another study has demonstrated that college students' anxiety about covid- might have been related to the effect of the coronavirus disease on their studies ( ) and future employment ( ) . prolonged lockdown had several adverse impacts on mental health, especially among young respondents who demonstrated a higher psychological impact of covid- in china ( ) . although covid- treatment and vaccine finding studies ( ) ( ) ( ) continue around the world, a cure has not yet been found. consequently, because coronavirus disease does not have an effective treatment, it results in high anxiety responses. we noted the change throughout the survey in respondent's protective behavior and emotional status. we observed that respondents' deployment of protective behavior is affected by their level of the outbreak and current information. we predict that the level of protection and anxious tendencies of people, the adaptation process, and protective behaviors may have been affected by this outbreak. in the study of jones and salathe, considering the progress of protection behaviors over time, an increase is observed on the first day, then a sharp decrease, and then a more stable progression is observed ( ) . our results showing a linear trend in the perception of outbreak dispersion is associated with a significant decrease in the level of protective behavior and anxiety status in our respondents' compared to the first survey days. in addition, the behavior and anxiety situation of respondents may be decreased due to the government's precautions such as the closure of restaurants and intercity restrictions on transportation in our country. in the last of the survey days, we think that the increase in respondents' anxiety status and protective behavior tendency is a result of the increase in cases in countries such as italy and spain. our research is scientifically important for the study of the spread of knowledge and its relationship to anxiety levels and behavioral change during the most uncertain time of an outbreak. several limitations should be noted in the present study. exposure to news about the covid- outbreak on the internet is not investigated. meng et al. reported that gender is a biological variable to be considered in the prevention and treatment of covid- ( ) . in another study, men were emphasized to have worse outcomes and risk of death than women, independent of age, with covid- ( ) . considering these studies, an important limitation of this study is that more than half of the participants are female participants. our participants consisted only of young adults. we did not evaluate the economic status of the participants. economic vulnerabilities may be the reason for people to seek medical assessment when they present with covid- symptoms ( ) . in conclusion, psychological and behavioral researches like this study could help to make progress in building a compassionate person and caring society which would be more effective in preventing and overcoming outbreaks. our findings to be obtained may shed light on future processes that seem ambiguous for now. although our study is web-based and has partial limitations for the general population, its rapid implementation, uncovering of unique and critical scientific data may increase the level of public awareness and perhaps lead to life-saving consequences. public health education programs purposed at improving covid- knowledge can useful encouraging optimistic attitudes towards covid- . in addition, cognitive-behavioral therapy can reduce stress and coherent copings ( ) . university students with good covid- knowledge may reduce negative emotions and deal with the risks from an infection outbreak with a more positive attitude. our study may have implications for young adult public health provision during outbreaks of infectious disease, including improvements in protective behavior. after the covid- outbreak, studies on the psychological and behavioral effects of the pandemic can also be conducted. the information we have obtained in behavioral dimensions will be an essential scientific reference for other covid- researchers in this vital and critical process and beyond. all datasets presented in this study are included in the article. written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. according to the world health organization guidelines on ethical issues in public health surveillance, a surveillance study in emergency outbreak situations is clearly exempted from ethical review and oversight (ho guidelines on ethical issues in public health 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sex-specific clinical characteristics and prognosis of coronavirus disease- infection in wuhan, china: a retrospective study of severe patients gender differences in patients with covid- : focus on severity and mortality characterize health and economic vulnerabilities of workers to control the emergence of covid- in an industrial zone in vietnam mental health strategies to combat the psychological impact of covid- beyond paranoia and panic the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. key: cord- -skrye w authors: hai, le thanh; bich, vu thi ngoc; ngai, le kien; diep, nguyen thi ngoc; phuc, phan huu; hung, viet pham; taylor, walter r.; horby, peter; liem, nguyen thanh; wertheim, heiman f.l. title: fatal respiratory infections associated with rhinovirus outbreak, vietnam date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: skrye w during an outbreak of severe acute respiratory infections in orphanages, vietnam, / hospitalized children died. all hospitalized children and / children from outbreak orphanages tested positive for rhinovirus versus / control children (p = . ). outbreak rhinoviruses formed a distinct genetic cluster. human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups. during an outbreak of severe acute respiratory infections in orphanages, vietnam, / hospitalized children died. all hospitalized children and / children from outbreak orphanages tested positive for rhinovirus versus / control children (p = . ). outbreak rhinoviruses formed a distinct genetic cluster. human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups. t he world health organization estimates that ≈ million children die each year from acute respiratory tract infection (ari), and most live in developing countries ( ) . human rhinovirus (hrv), a common cause of mild upper respiratory tract infections, may also cause severe ari in children. we report on an outbreak of severe ari caused by hrv in children living in orphanages in vietnam. during december -february , twelve infants < months of age with severe ari infection were admitted to hospitals in hanoi. because all infants lived in orphanages in hanoi, the national hospital of pediatrics (nhp) initiated an outbreak investigation. data on demographic characteristics, clinical features, and outcomes were collected for the infants. researchers visited of the outbreak orphanages and control orphanage ( km apart, no severe ari observed). patient histories were obtained from orphanage staff; all infants were examined, and nasal and pharyngeal swab specimens were collected. respiratory specimens were tested by bacterial culture and multiplex reverse transcription pcr (rt-pcr, seeplex rv kit; seegene, seoul, south korea) for the following respiratory viruses: infl uenza a/b viruses, respiratory syncytial virus (rsv), rhinovirus, coronavirus (oc /hku and e/nl ), adenovirus, parainfl uenzavirus, and human metapneumovirus ( ) . this outbreak investigation was approved by the scientifi c committee of nhp. twelve patients with severe ari were admitted to the nhp intensive care unit over days during the cool months of december -february (temperature °c- °c). the hospitalized infants ( female) were -to -months-old. most ( / ) were from orphanage, which was selected for investigation. two hospitalized children had a known underlying condition: congenital hypothyroidism (n = ) and hiv infection (n = ). seven infants were underweight (sex-specifi c weight-for-age; z score < sds). all exhibited cough, coryza, wheezing, and dyspnea, and ( %) had a documented fever. acute respiratory distress syndrome developed in all a mean of . ( % ci ± days) days after onset. mean pressure of arterial oxygen/fractional inspired oxygen ratio was . ( % ci ± . , range . - . ). chest radiographs showed extensive bilateral infi ltrates. blood cultures for bacteria were negative. despite mechanical ventilation and administration of intravenous broad-spectrum antimicrobial drugs, patients died and patients recovered ( were lost to follow up). hrv was detected by rt-pcr in all infants; patients were co-infected with rsv and adenovirus (table) . in addition, bronchoalveolar lavage specimen from patient was hrv positive. the outbreak orphanage was visited within week of outbreak detection. the visit revealed that several other infants had been hospitalized elsewhere, but we could not obtain detailed data about them. we tested nasal-pharyngeal swab specimens (pooled) from all infants ( % < months of age) living in the outbreak orphanage and nasal swab specimens from the youngest children ( . % < months of age) at the control orphanage within weeks of the outbreak. in both orphanages, - children lived in room and shared the same bed, wiping cloths, basic utensils such as cups, and clothing. most children in the outbreak orphanage were female ( / [ %]), compared with % ( / ) in the control orphanage. of children whose specimens were tested by rt-pcr, % ( / ) of the infants from the outbreak orphanage had at least symptom of respiratory tract infection compared with ( %) of infants at the control orphanage. among children from the outbreak orphanage (both hospitalized and nonhospitalized [n = ]), a single pathogen was identifi ed in ( . %) infants and > pathogens were found in ( . %) children (table) . the most frequently detected pathogen was hrv (n = ). in the control orphanage, ( . %) children tested positive for hrv, and children were infected with pathogens. only nonpathogenic bacteria were cultured from the respiratory specimens (data not shown). because hrv was the predominant pathogen detected, we genotyped all hrv isolates directly from the specimens using a molecular typing assay based on phylogenetic comparisons of a -bp variable sequence (p -p ) in the ′-noncoding region with homologous sequences of the known serotypes ( , ) . we were able to sequence the p -p fragment of hrv genome from specimens positive for hrv: were from hospitalized patients ( r and r) (figure) , were from the outbreak orphanage (identifi cation numbers starting with da), and were from the control orphanage (identifi cation numbers starting with bavi; figure) . the p -p phylogenetic tree showed that sequences obtained from isolates from the hospitalized infants were closely related to a subclade of cluster a sequences from nonhospitalized infants at the outbreak orphanage (figure) . hrvs from the control orphanage are also part of the a cluster but formed a distinct subcluster. several children (not hospitalized) from the outbreak orphanage were also infected with hrvs from the c cluster. no children had b cluster strains. we found that hrv was the main pathogen detected in an outbreak of severe ari in children living in an orphanage in vietnam. our fi ndings support recent studies showing that hrv may be associated with severe respiratory tract infection in infants and children ( ) ( ) ( ) . a study in central vietnam also showed that hrv is a notable cause of ari in children in vietnam ( ) . because we detected rhinovirus in all hospitalized infants, we believe that hrv was the main causal agent in this outbreak, although hospitalized infants were co-infected with rsv, an unambiguous respiratory pathogen. a deep lung specimen from hospitalized infant was also positive for hrv, which supports a causal relationship. furthermore, the outbreak orphanage had signifi cantly more hrv-positive patients than did the control orphanage, and sequence analysis showed that the outbreak isolates formed a distinct cluster, which also supports a causal role for hrv. in addition, we found that several infants from the outbreak orphanages were infected with hrv strains belonging to the c cluster, according to p -p sequence analysis. hrv-c has been associated with more severe infections and circulates worldwide ( , ( ) ( ) ( ) . we may have missed the hrv-c strains in the clinical case-patients, because we were only able to sequence the virus from samples from patients. we had to sequence directly from the specimens because we had no viral culture facility at the time of the outbreak. phylogenetic analysis of p -p sequences can distinguish hrv-b rhinoviruses, but it is limited in distinguishing hrv-a and hrv-c. full hrv sequence analysis would be able to provide this detail, but it was not feasible for this investigation. this outbreak investigation has some limitations. only a small number of controls were selected from a single orphanage, and the controls were sampled later than the hospitalized patients and children from the outbreak orphanage. these limitations may have led to underdiagnosis of hrv in controls. bacterial co-infection cannot be ruled out as a cause of more severe infection in the hospitalized infants because most were receiving antimicrobial drugs at the time respiratory specimens were collected. viral respiratory infections can be more severe in malnourished infants, which was likely the case for the hospitalized infants in this outbreak. in this study, co-infections ( . %) with other respiratory viruses were detected at a similar rate as in another study in central vietnam ( . %) ( ) . this fi nding is also consistent with previous work indicating that hrv infections can occur with other respiratory viruses and lead to more severe disease ( , ) . this outbreak illustrates that hrvs can cause severe pneumonia, leading to acute respiratory distress syndrome in young, vulnerable infants. hrv remains an underappreciated cause of severe pneumonia in vulnerable groups. children: reducing mortality. world health organization factsheet no multipathogen infections in hospitalized children with acute respiratory infections a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants molecular characterization of a variant rhinovirus from an outbreak associated with uncommonly high mortality serious respiratory illness associated with rhinovirus infection in a pediatric population global distribution of novel rhinovirus genotype viral pathogens associated with acute respiratory infections in central vietnamese children sequence analysis of human rhinoviruses in the rna-dependent rna polymerase coding region reveals large within-species variation human rhinovirus c infections mirror those of human rhinovirus a in children with community-acquired pneumonia clinical features and complete genome characterization of a distinct human rhinovirus (hrv) genetic cluster, probably representing a previously undetected hrv species, hrv-c, associated with acute respiratory illness in children genotyping of human rhinovirus (hrv) from outbreak and control specimens by p -p sequence analysis nucleotide distances were analyzed with dnadist, the neighbor-joining tree of bioedit package. the consensus tree was visualized by treeview v the opinions expressed by authors contributing to this journal do not necessarily refl ect the opinions of the centers for disease control and prevention or the institutions with which the authors are affi liated we thank the hospital and orphanage staff for their cooperation in this outbreak investigation. key: cord- - v asfa authors: asner, sandra; peci, adriana; marchand‐austin, alex; winter, anne‐luise; olsha, romy; kristjanson, erik; low, donald e.; gubbay, jonathan b. title: respiratory viral infections in institutions from late stage of the first and second waves of pandemic influenza a (h n ) , ontario, canada date: - - journal: influenza other respir viruses doi: . /j. - . . .x sha: doc_id: cord_uid: v asfa please cite this paper as: asner et al. ( ) respiratory viral infections in institutions from late stage of the first and second waves of pandemic a (h n ) , ontario, canada. influenza and other respiratory viruses ( ), e –e . we report the impact of respiratory viruses on various outbreak settings by using surveillance data from the late first and second wave periods of the pandemic. a total of / ( · %) outbreaks tested positive for at least one respiratory virus by multiplex pcr. we detected a(h n )pdm in · % of all reported outbreaks of which · % were reported by camps, schools, and day cares (csds) and · % by long‐term care facilities (lcfts), whereas enterovirus/human rhinovirus (ent/hrv) accounted for % outbreaks of which · % were reported by long‐term care facilities (lctfs). ent/hrv was frequently identified in ltcf outbreaks involving elderly residents, whereas in csds, a(h n )pdm was primarily detected. respiratory outbreaks are common in healthcare and community institutions such as long-term care facilities (ltcfs) and schools. , the most commonly identified viruses have been influenza and respiratory syncytial virus (rsv). , human rhinovirus (hrv) has more recently been identified as a major viral pathogen in ltcf outbreaks. recent data reported by public health ontario (pho) indicated that pandemic influenza a (h n ) [a(h n )pdm ] was a rare cause of ltcf respiratory outbreaks during the first period of wave i (april -june , ) of the pandemic. we used surveillance data from the late stage of the first wave and the duration of the second wave periods (june -november , ) to ascertain the impact of a(h n )pdm and other respiratory viruses on different outbreak settings such as ltcfs and schools. for the purpose of this study, we considered the period from april to august , , as wave i and the period from september to november , , as wave ii, although wave ii activity continued until january . we investigated all respiratory outbreaks in ltcfs and camps, schools, day cares (csds) tested at pho laboratories from june through november , , in ontario, canada. a confirmed respiratory infection outbreak in a ltcf, as defined by ontario's ministry of health (moh), requires two cases of acute respiratory illness within hours of which at least one has to be laboratory-confirmed, or three cases of acute respiratory illness occurring within hours in a geographic area, none of which are laboratory-confirmed. ]. an alternate multiplex naat kit (seeplex rv; seegene usa, rockville, md, usa) was used in conjunction with the luminex assay during periods of higher demand. an in-house assay specific for a(h n )pdm was also performed. a total of respiratory outbreaks in csds, ltcfs, and other facilities (hospitals, correctional facilities, and unknown) were reported to and tested at pho. molecular testing was performed on samples from different outbreak settings. the number of samples submitted per outbreak is shown in figure . of the average of four samples (range - ) tested per outbreak, the median number of positive samples per outbreak was (range - ). outbreak samples mostly originated from ltcfs ( ae %) and csds ( ae %). hospitals and correctional facilities comprised ( ae %) and ( ae %) of remaining outbreaks, respectively. facility type was unknown for ae % outbreaks tested. mean and median ages of all persons tested were ae and years, respectively (range - years). mean and median ages of ltcf outbreak cases were ae and years, respectively; csds had a much younger population with mean and median ages of ae and years, respectively. at least one viral agent was identified in ( ae %) of the outbreaks tested. of these, ( ae %) outbreaks had only one sample with a virus identified, and the remaining ( ae %) had the same virus identified in two or more samples (range - ). ent ⁄ hrv and a(h n )pdm were the most common viruses detected in ( %) and ( ae %) outbreaks, respectively. of the outbreaks in which a(h n )pdm was detected, ( ae %) occurred in csds, ( ae %) in ltcfs, and ( ae %) in other facilities. of the outbreaks in which ent ⁄ hrv was identified, ( ae %) occurred in ltcfs, ( %) in csds, and ( %) in other facilities ( figure ). both viruses were identified throughout the entire study period, reaching a peak during october of wave ii (figure ). two hundred and forty outbreaks ( ae %) were caused by a single virus, the most common being ent ⁄ hrv ( %) or a(h n )pdm ( ae %). one hundred and ninety of these single virus outbreaks occurred in ltcfs and in csds. more than one etiological agent was identified in ( %) of the outbreaks, of which ( %) had two or more viruses detected within the same sample (coinfection). the most common coinfection was a(h n )pdm ⁄ ent ⁄ hrv, detected in ( %) of the outbreaks with coinfections. in the three outbreaks where two or more samples had viral coinfection (range - samples with coinfection), the same two viruses were found in all coinfection samples. there was an increased likelihood of identifying multiple viruses if or more samples were tested (p < ae ; figure ). nineteen outbreaks with multiple viruses detected were reported in ltcfs and in csds. ent ⁄ hrv and a(h n )pdm were the most common co-circulating viruses reported in all outbreaks with multiple viruses detected, found in of the multiple virus outbreaks reported by ltcfs and of the multiple virus outbreaks reported by csds (table ) . was detected in the majority of respiratory outbreaks in ltcfs, where the vast majority of residents were elderly. recently published reports - have already highlighted these findings. however, this study provides a larger sample size and is unique in that both institutional (predominantly elderly) and community outbreak (predominantly children) settings are described. we also found an increased likelihood of detecting viruses causing outbreaks as the number of specimens tested increased. viruses causing coinfections may be co-transmitted between patients as part of the same outbreak, rather than circulating independently of each other. additional bacterial analysis would be required to conclude that hrv is the sole etiology of individual outbreaks. in contrast, the pandemic virus was detected in almost all csd outbreaks, which mostly involved children and younger adults as recently highlighted in the literature. , possible reasons for a lower prevalence of a(h n )pdm in ltcfs outbreaks include cross-protective antibodies from previous exposure to influenza a (h n ) strains among elderly or minimal exposure to individuals more likely to be infected by the pandemic strain, such as children. , from june to november , , we found that ent ⁄ hrv was frequently identified in ltcf outbreaks involving elderly residents, whereas in outbreak settings involving children and younger adults, a(h n )pdm was primarily detected. younger children were not well represented in the csd group, which had a median age of ae years. this likely reflects the age distribution of children that attend sleep away summer camps in ontario. limitations of our study include its observational design, which limits establishment of causality and also limits our ability to exclude the effect of measured or unmeasured confounders in our analysis. a distinction between upper and lower respiratory tract infections, the role of asymptomatic shedding, and comparison of severity of outbreaks could not be performed as clinical data were missing. in ontario, the local medical officer of health or designate determines whether an institutional outbreak meets the provincial case definition. pho laboratories do not receive sufficient outbreak information to make this determination. in this context, this study highlights the importance of submitting more than one sample to properly investigate an outbreak. other bacterial agents like mycoplasma pneumoniae or chlamydophila pneumonia could not be ruled out as the cause of outbreaks as samples were not routinely tested for them. a distinction could not be made between staff and resident cases in this study as staff information was not systematically reported. this highlights a current deficiency in the investigation and reporting of staff illness in ltcfs. an increased rate of ent ⁄ hrv outbreaks may have been observed during the pandemic because of increased vigilance by individuals to report symptoms to their healthcare providers, who in turn had a lower threshold to report outbreaks to the public health units who coordinate laboratory investigations. therefore, we might have seen increased specimen collection and testing that may have influenced our findings. identification of specific non-influenza organisms associated with outbreaks can assist with outbreak management as the period of patient isolation and when to declare an outbreak over are dependent on the incubation period and period of communicability, which varies by organism. documentation of hrv as a cause of ltcf outbreaks is important, as recent studies suggest that hrv outbreaks can cause severe and fatal disease in ltcfs, especially among the elderly. a study comparing viral outbreaks in different community ⁄ facility settings with prospective gathering of detailed clinical and epidemiological information, supported by comprehensive microbiological analysis, will help further understand the role of different respiratory viruses as etiologic agents. rhinovirus outbreaks in long-term care facilities influenza and respiratory syncytial virus in the elderly respiratory infection in institutions during early stages of pandemic (h n ) ontario agency for health protection and promotion (oahpp) appendix b: provincial case definitions for reportable diseases analytical and clinical validation of novel real-time reverse transcriptase-polymerase chain reaction assays for the clinical detection of swine-origin h n influenza viruses a rhinovirus outbreak among residents of a long-term care facility uncommon(ly considered) manifestations of infection with rhinovirus, agent of the common cold severe human rhinovirus outbreak associated with fatalities in a long-term care facility in ontario incidence of pandemic influenza a h n infection in england: a cross-sectional serological study estimated epidemiologic parameters and morbidity associated with pandemic h n influenza sandra asner, adriana peci, alex marchand-austin, anne-luise winter, romy olsha, and erik kristjanson have no conflicts of interest to declare.donald e. low participated in advisory board committee meetings for glaxosmithkline inc. and hoffman-la roche. he has also received research funding from both companies. jonathan b. gubbay has received a research grant from glaxosmithkline inc. to work on resistance to neuraminidase inhibitors. in june , oahpp received a research grant from glaxosmithkline to study phenotypic resistance in influenza virus. key: cord- - u nidw authors: davis, g. s.; sevdalis, n.; drumright, l. n. title: spatial and temporal analyses to investigate infectious disease transmission within healthcare settings date: - - journal: journal of hospital infection doi: . /j.jhin. . . sha: doc_id: cord_uid: u nidw summary background healthcare-associated infections (hcais) cause significant morbidity and mortality worldwide, and outbreaks are often only identified after they reach high levels. a wide range of data is collected within healthcare settings; however, the extent to which this information is used to understand hcai dynamics has not been quantified. aim to examine the use of spatiotemporal analyses to identify and prevent hcai transmission in healthcare settings, and to provide recommendations for expanding the use of these techniques. methods a systematic review of the literature was undertaken, focusing on spatiotemporal examination of infectious diseases in healthcare settings. abstracts and full-text articles were reviewed independently by two authors to determine inclusion. findings in total, studies met the inclusion criteria. there was considerable variation in the use of data, with surprisingly few studies (n = ) using spatiotemporal-specific analyses to extend knowledge of hcai transmission dynamics. the remaining studies were descriptive. a modest increase in the application of statistical analyses has occurred in recent years. conclusion the incorporation of spatiotemporal analysis has been limited in healthcare settings, with only % of studies including any such analysis. analytical studies provided greater data on transmission dynamics and effective control interventions than studies without spatiotemporal analyses. this indicates the need for greater integration of spatiotemporal techniques into hcai investigations, as even simple analyses provide significant improvements in the understanding of prevention over simple descriptive summaries. healthcare-associated infections (hcais) are problematic worldwide, with a recent report by the world health organization estimating hospital-wide prevalence in high-income countries at %. in addition to causing significant, yet preventable, morbidity and mortality in countries with centrallyfunded and managed healthcare systems, such as the uk national health service, hcais increase waiting times and reduce availability of resources to provide care to the population. hcais present a unique challenge as active transmissions are often only identified after numerous patients have been infected. additionally, the wide range of hcai facilitators (e.g. procedures, environment ) and increasingly susceptible patients complicate transmission dynamics, making prospective identification and control exceedingly difficult. when multiple cases of an infection occur within a hospital, it is difficult to differentiate a true nosocomial transmission from unrelated cases, and cohorting patients by risk group may lead to assumptions of a common source but molecular analyses often demonstrate lack of transmission. sophisticated spatiotemporal analyses can be used to confirm clustering statistically over time and/or space, which would increase confidence in assuming the relatedness of cases. these methods can also be used to control for the effects of cohorting and other patient characteristics that may give the spurious impression of clustering or transmission when it has not occurred. this, in turn, would provide better information on where interventions could be targeted most effectively, and when or where to anticipate outbreaks. these methods may also be useful in more rapid identification of a problem, as even small clusters (e.g. two or three cases) can be detected. even the introduction of more simplified analytical methods to evaluate spatial and temporal relationships could be beneficial. one example is the knox test, which has been used widely to detect timeespace clusters since the s. the null hypothesis in knox testing would be that all hcai cases are independent, and the test returns the number of pairs of cases that are deemed to cluster in time and/or space. the tool is simple to apply as it only requires information on cases, not controls or susceptible individuals, and can work on a minimal clinical dataset. nowadays, researchers are using geographic information systems (gis) to further extend understanding of spatiotemporal clustering and transmission. these are computer-based programs that combine cartography, statistical analysis and database technology to layer databases on top of a predefined map. they have been applied in a range of ecological investigations of disease, and to determine whether there is a spatial association between disease risk and environmental pollution. in this study, gis and spatial analysis were employed to investigate the risk of breast and lung cancer in a small region. after identification of significant clusters, it was possible to identify local risk factors specific to each cancer type, providing evidence of potential environmental contamination. the use of similar techniques to create hospital maps, on which infection data can be displayed and analysed, could increase understanding of local transmission and risk, and provide rapid dissemination of information through visualization. with healthcare systems worldwide under pressure to improve patient safety whilst cutting costs, use of the existing infrastructure of routinely collected data, which are often overlooked for hcai investigation and research, is an innovative solution. frequently, investigations of hcais provide a basic epidemiological description of cases over time by providing an epidemic curve, or show how cases are distributed across wards using a diagram. however, hospital databases contain laboratory results, building management data and floor plans, and information on patient admissions and movement that could easily be incorporated into more detailed analyses to improve understanding of local hcai epidemiology. use of interdisciplinary tools may increase the ability to identify transmission prospectively and implement preventive measures. the aims of this review were to determine the extent of use of spatiotemporal analyses for identifying and preventing hcai transmission, and to provide recommendations for expanding the use of gis and spatiotemporal statistical analyses within healthcare settings. a systematic review of the literature on spatiotemporal examination of infectious diseases in healthcare settings between january and june was conducted using the following search terms: infection (e.g. hcai, nosocomial, etc.); healthcare settings (e.g. hospital, intensive care, etc.); and time/space (e.g. spaceetime, spatial epidemiology, etc.). potential synonyms for each search term (e.g. infection, healthcare settings and time/space) were identified and combined using boolean operators. to ensure comprehensive capture of the literature, biosis, cochrane review, csa, dare, embase, heed, jstor, pubmed, science direct and web of science were searched for all indexed publications. additionally, google scholar was searched for indexed and grey literature using the above search terms. all papers, reports, abstracts and letters were included in the initial search. inclusion/exclusion was conducted in two stages: abstract/ title review and full-text review. all identified titles/abstracts were reviewed independently by two authors to ensure reliability in full-text retrieval. papers were retrieved if they mentioned time or space in the abstract, or no abstract was provided and the title did not provide enough information to assess inclusion. full-text papers were reviewed independently by two authors and included if they were: (a) published post- ; (b) written in english; (c) examined potential transmission in more than three patients; (d) provided more than a simple report of cases over time periods exceeding three months (i.e. not routine national surveillance reports); and (e) discussed time/space as a specific aim or discussion point of the study, rather than a simple mention in the results. any studies on which the reviewers did not agree were discussed and a consensus was reached. the methodologies of all included studies were reviewed and categorized into either descriptive or analytical studies of time/space, and further 'subtyped' based on the data and analyses employed. studies were classified as 'case reporting' if they only used temporal or spatial data as an overview (i.e. an epidemic curve). 'basic descriptive epidemiology' studies examined how the cases were linked by describing their locality in time and/or space and possible exposure events, but did not use statistical methods to determine the probability that they were linked. 'basic descriptive epidemiology with molecular data' studies focused on the genetic diversity of the organisms, including a description of the distribution of the strains in space and/or time. 'statistical spatiotemporal analysis' studies used statistical methods to explore hcai distribution in time or space. studies were classified as 'statistical spatiotemporal analysis with molecular data' if they combined molecular data with statistical analyses to investigate the dissemination of strains across time or space. the final category, 'spatiotemporal analysis using gis', included studies that used gis within hospital settings. findings were synthesized to evaluate the actual use of spatiotemporal analysis on infectious diseases in healthcare settings. meta-analysis was considered but was not deemed to be feasible due to the heterogeneity of research designs and outcome measures; as such, the findings were synthesized qualitatively. in total, , titles/abstracts were identified during the literature search ( figure ). of these, met the inclusion criteria for full-text retrieval. four of the included studies were not available, and were included in the review. most of the studies excluded did not meet the spatiotemporal criteria; provided some spatiotemporal results but did not discuss this information as it was not the focus of the study. others examined annual trends, were case studies or review papers, or focused on non-healthcare settings. six studies were excluded for being written in a language other than english. included studies were predominantly descriptive in their reporting of spatiotemporal data ( %), and varied greatly in encompassing a range of settings, populations and hcais. half of the studies were carried out hospital-wide ( %), % (n ¼ ) were performed on specific wards, and only seven ( %) were based within nursing homes. the majority of studies were retrospective ( %), often using data to investigate outbreaks after the event had ended. five ( %) studies combined retrospective analyses and prospective interventions to enhance surveillance, whilst the remaining % of studies were prospective. numerous hcais were investigated, with the most common group being bacteria ( %), such as meticillin-resistant staphylococcus aureus (mrsa) ( %) and clostridium difficile ( %). studies focusing solely on viral or fungal infections accounted for % of studies, including norovirus ( %), severe acute respiratory syndrome ( %) and aspergillus spp. ( %). among the molecular studies in this review, only five incorporated spatiotemporal analyses to understand the transmission dynamics. the studies were separated into two types, 'descriptive' and 'analytical', based on their use of spatiotemporal-specific statistical analyses. to enable clearer comparisons between the groups and to evaluate the variation in exploitation of clinical data, the studies were further classified into six subtypes (table i) . these are described in detail below. descriptive studies primarily focused on summarizing outbreak investigations, environmental assessments and cluster identification. for the vast majority of these studies, causes or sources of outbreaks, cases or clustering were the primary aim. however, simple qualitative descriptions were not sufficient in most cases to confirm or refute identified sources or clusters. case reporting studies basic descriptions of time and space were common ( %, n ¼ ) (table ii) . two-thirds of these studies provided a retrospective temporal description of the incidence of cases over time (i.e. an epidemic curve). many of these studies examined outbreaks e and evaluations of intervention strategies, e while others attempted to identify factors associated with potential nosocomial transmission (i.e. healthcare worker carriage, , direct contact with cases, , inadequate cleaning of medical equipment , and the physical layout of hospital utilities , ). only four studies described the spatial distribution of cases to show the impact of hospital renovations or the layout of cases across specialities, , , , with the majority of studies describing temporal trends in cases. , most case reporting studies examined bacteria ( %); however, the most informative studies were those examining organisms such as aspergillus spp. and legionella spp., where environmental contamination is considered to be the primary risk factor. , , e basic descriptive epidemiology investigations that described the temporal or spatial distribution of cases were categorized as basic epidemiology ( %, n ¼ ) (table ii) . a number of studies provided a retrospective evaluation of the incidence of cases by assessing temporal links between patients, while % of studies combined spatial and temporal elements to varying degrees in their evaluations. the main organisms considered were bacteria ( %); however, the studies that evaluated aspergillus spp. focused on spatial data to the greatest extent. indeed, the only study that focused solely on the spatial element examined fungal contamination of the hospital environment. some studies combined infection information with building 'schematics' to explain the physical layout of the ward or to display the location of patients. e however, these studies did not investigate the importance of the geographical distribution of cases, as has been highlighted in studies that have looked at the impact of construction on the incidence of fungal infections. , e in addition to evaluating the distribution of cases, some investigators used graphics to visualize the connections between cases, and attempted to identify possible clusters e or provide evidence of potential transmission. , a number of studies used timelines to evaluate how cases were linked. e chen et al. visualized the spread of severe acute respiratory syndrome within an emergency department. by combining temporal data with patient locations, the researchers identified distinct 'clusters' of cases, and prevented further dissemination of the disease by quarantining contacts of these individuals. whilst the outcome was positive, the assumed clusters were based purely on description of the patients' locations at certain times, and the lack of statistical analysis meant that the clusters were not proven to be statistically significant. basic descriptive epidemiology with molecular data most descriptive studies incorporated molecular data ( %; n ¼ ) (table ii) , presumably because a molecular link provided more evidence of clustering or transmission than purely describing potential clusters. numerous studies combined spatiotemporal and molecular data to attempt to develop a better understanding of strain dissemination e or potential sources e within the institutions in which they were conducted. integration of molecular and temporal data enabled investigators to highlight potential links between patients, and identify potential transmission events, e with greater substantiation than simple descriptive studies. in one study, researchers were able to differentiate between two consecutive outbreaks of stenotrophomonas maltophilia on their intensive care unit by visualizing the temporal distribution of isolates identified using restriction fragment length polymorphism (rflp) ; however, it is possible that these two distinct outbreaks could have encompassed several smaller events with the same rflp type introduced multiple times. descriptive studies that included molecular data covered a range of applications including outbreak investigations, e cluster identification and improving control interventions. , however, the most common applications of , e many studies evaluated the distribution of strains over time or space, e aiming to establish epidemiological links between cases, but were limited by lack of statistical analysis. the geographical layout of cases was used in some studies to suggest potential factors associated with their distribution. e the study by witte et al. mapped the distribution of mrsa strains at national level in germany to compare changes in resistance phenotypes with various local prescription practices across regions, but there were no statistical analyses to support or refute these qualitative observations. analytical studies tended to focus more on predictive modelling of future outbreaks and determining the impact of various changes within the healthcare setting, rather than describing an outbreak. they used a wide range of statistical modelling techniques, indicating a number of options for looking at spatiotemporal clustering. interestingly, a number of the descriptive studies focused on identifying the source of an outbreak, and found that they were unable to do so conclusively. in contrast, gis was shown to enable fast identification of possible sources during an outbreak, and enabled a targeted investigation that led to the source being discovered. this was possible using clinical data that are collected routinely, and required little additional data retrieval. thirteen studies ( %) conducted statistical analyses of temporal and spatial data (table iii) . all were undertaken in hospital settings, % (n ¼ ) were published in or later, and % (n ¼ ) focused on bacterial infections. the temporal studies (n ¼ ) tended to be retrospective and employed time-series analysis (e.g. weekly aggregated measures plotted over time) to demonstrate if antibiotic prescription had an effect on the incidence of mrsa e and c. difficile, or if control measures for multiple organisms reduced the incidence. without the incorporation of temporal analysis into these investigations, the impact of the interventions may have been masked by other factors, such as seasonality. additionally, temporal analysis was used to examine ways to improve infection control measures, , while haley and bregman used multi-variate statistical models to assess the temporal associations between infections and overcrowding, providing evidence that handwashing compliance is reduced markedly under these conditions. spatiotemporal studies (n ¼ ) typically aimed to model infections retrospectively to investigate outbreaks and to detect clustering. , by using modelling techniques, others were able to estimate the potential effect of interventions, beyond which descriptive studies could use the results to advocate their incorporation into standard control measures. statistical spatiotemporal analysis with molecular data only % (n ¼ ) of studies combined the use of molecular typing with spatial or temporal analyses (table iii) , which has the benefit of molecular differentiation and statistical evidence in confirming transmission. all of these studies were undertaken in or later, and analysed the retrospective distribution of bacteria while attempting to establish links between isolates. the earliest study in this category compared the effectiveness of molecular typing with spatiotemporal analysis. polymerase chain reaction was used to characterize toxin genes in c. difficile isolates, which were mapped to a grid representing each ward, and analysed statistically for clustering by knox test. this identified a single ward cluster compared with four clusters detected by molecular fingerprinting analysis, leading the investigators to conclude that the knox test was less effective for identifying nosocomial transmission than molecular fingerprinting. however, most studies have shown that in order to gain the most from available data, spatiotemporal and molecular analyses should be used in combination. the remaining studies evaluated potential transmission routes or attempted to gain a better understanding of outbreaks. nuebel et al. applied whole-genome sequencing of mrsa in a neonatal intensive care unit to compare accumulated sequence variation in the isolates, and used bayesian skyline analysis to reveal epidemiological links between patients, healthcare workers and parents. they concluded that integration of epidemiological mapping and genomic data was necessary to understand mrsa transmission. similarly, gandhi et al. performed a retrospective study to investigate epidemiological links between extensively-drug-resistant tuberculosis patients in south africa by combining rflp analysis and social network data to build transmission networks among genotypically similar patients. their findings showed that the epidemic was highly clonal, and network analysis indicated transmission across a network with high levels of interconnectedness. de celles et al. tried to estimate the variability in transmission between different multi-drug-resistant acinetobacter baumannii clonal groups using data on carriage on a surgical ward. they identified three clonal complexes by performing molecular fingerprinting, and applied stochastic transmission models to estimate transmission rates for each complex. results suggested that one of the clones had enhanced transmissibility compared with the other two clones, and further explained local epidemic dynamics. finally, kumar et al. optimized cluster identification by organizing multidrug-resistant gram-negative bacteria isolates from admitted patients into co-resistance groups, and using schematics of the ward layouts in a monte carlo simulation. they concluded that this was 'a powerful way to quickly identify outbreaks', and early detection is critical with the decreasing number of effective treatment regimens available. spatiotemporal analysis using gis gis was used in only % (n ¼ ) of studies identified in this review, demonstrating its limited uptake in the investigation of hcais (table iii) ; all of these studies were undertaken in or later. the studies were conducted hospital-wide, and all but one described a prospective application. kistemann et al. employed gis for a retrospective investigation of a salmonella outbreak, the source of which could not be identified by biological testing as food samples had been discarded. by mapping the distribution of cases across the hospital site and using analytical tools in gis, the researchers identified that the sole link between cases was food delivery from a central kitchen. this led to an investigation of food production and the source was discovered. kruger and steffen kwan et al. incorporated gis successfully in a wide range of hospital-based investigations. using gis as the central repository for spatial and temporal data of infectious disease cases, the collected data were queried and analysed to identify disease clusters. the results were then communicated to the appropriate personnel, helping decision makers to target control efforts. this review highlights numerous (n ¼ ) studies focusing on spatiotemporal investigations of infectious diseases within healthcare settings; however, very few of these (n ¼ ) used appropriate statistical methods to confirm transmission or clustering. this suggests that spatiotemporal data are regularly collected in healthcare settings to examine the potential for clustering, but confirmation using statistical analysis is infrequent, which introduces the risk of misinterpretation and hence development of less effective interventions and management of the problem. of note, most of the published descriptive analyses were also retrospective, and in the absence of further statistical testing, provide little information for future prevention or prediction activities. similarly, while half of all identified studies included molecular techniques for differentiating clusters, many of these were older techniques used to determine very large differences in bacteria, and are not conclusive. only % of studies that included molecular data also used statistical analyses to provide more quantitative evidence of transmission clusters. this review found that while the collection of spatiotemporal data has been integral to hcai prevention activities for decades, the use of spatiotemporal statistical analysis is relatively new to the study of hcais in comparison with infectious diseases occurring within the community. most of the studies identified in this review used spatial and temporal information to provide a qualitative description of disease occurrence by time/space, and in contrast to those that employed more sophisticated analyses, were limited in the scope of their findings. naturally, the ways in which spatial or temporal data are used within investigations of hcais varied greatly, and presentation depended upon the aim of each study. however, the large amount of data collected was often not used to its full potential, and opportunities to gain a more thorough understanding of the problem were missed. the ability of descriptive studies to identify any significant influences of infectious disease dynamics is limited. several studies discussed the significance of the geographical distribution of cases without undertaking any analyses, , , which is a serious issue as sharing the same geographical space does not prove that transmission has occurred. confounding factor (e.g. cohorting of high-risk patients). this highlights a missed opportunity to learn more about the spread of organisms within healthcare settings, and to develop more effective intervention strategies based upon transmission dynamics within that particular setting. maximizing data usage it is extremely important that hospitals are able to understand the local hcai epidemiology to inform their routine practice, rather than generalizing evidence from other settings. a major stumbling block can be the perception that these analyses may involve active data collection; however, an abundance of existing datasets could be used. examples of disparity in data usage are the studies by kroker et al. and mody et al., in which they attempted to identify potential clusters of c. difficile within their hospitals. , both studies were published in and used clinical patient notes and laboratory results for c. difficile toxin assays. mody et al. defined a cluster arbitrarily as one or more cases occurring within days of a previous case on the same nursing unit, and used this to identify temporal clusters within their dataset; however, they were unable to suggest potential factors related to the observed pattern. kroker et al. employed the knox test to identify timeespace clusters, which highlighted hospital geography and traffic between wards as significant factors, and enabled them to adapt their infection control procedures. incorporation of molecular data into investigations can have a profound impact on the effectiveness of any outbreak response. recent advances in molecular biology, such as rapid benchtop sequencing, have led to a revolution in the detail that can be gained from clinical samples. while many hospitals only perform basic identification of micro-organisms due to the resources available, this data, when available, can be useful to enhance current investigations. a study by adams et al. in investigated nosocomial infections on a paediatric intensive care unit, and was able to distinguish that there had been two separate outbreaks involving separate strains of herpes simplex virus type . the initial investigation, which had not included molecular data, concluded that all cases belonged to a single outbreak, and thus limited the impact of their initial control measures. molecular data can be invaluable in ruling out a link between cases; however, as emphasized in the study by helweg-larsen et al., clusters of infections can occur for many reasons and are often caused by factors other than nosocomial spread. therefore, incorporation of true temporal or spatial analysis, to eliminate similarity of micro-organisms by chance, alongside molecular techniques could lead to a better understanding of the true transmission dynamics, as inappropriate assumptions are often made about clustering when based solely on molecular data. prior to , only two studies were identified that had performed spatial or temporal analysis; in the last decade, this number has increased to . this may be due, in part, to the development of novel statistical methods and further advancement of user-friendly statistical and gis software; however, the majority of the statistical methods in these studies have been widely employed in other fields since before the s. the increased use of electronic databases in hospitals for storage of medical information has created a rich source of epidemiologically and clinically relevant information, allowing more detailed analyses to be performed. the major aim of this review was to identify how spatiotemporal analyses have been used previously, and to suggest how they can be employed to benefit practices within healthcare settings. the knox test is a simple analysis that can be used to identify clustering, and methods using outbreak thresholds are common within infection control reporting. however, the ideal situation is to design control programmes based upon the dynamics and processes observed within the local institution. as randomized controlled trials can be difficult or costly to undertake in clinical settings, some authors have employed predictive modelling techniques to build their own evidence base. for example, rushton et al. used a statistical approach to investigate clustering and patterns of spread of a number of organisms within an intensive treatment unit. they obtained data from pre-existing datasets including numbers of infected patients, admission details, duration of stay and bed movement, whilst they estimated some additional variables from evaluating nurseepatient contacts. they identified variation in the degree of clustering of different organisms, and tested the impact of potential control interventions in the model. the findings suggest that bed movement and staffepatient contacts have to be controlled, and control strategies may need to be organism-specific. spatiotemporal analysis can distil a much greater amount of relevant information from data collected on hcais than purely descriptive studies. analysis is key to furthering understanding of the epidemiology and dynamics of transmission of these organisms. the underuse of spatial and temporal data may be due to the primary focus of studies on retrospective actions in response to an outbreak, and this 'fire-fighting' approach may be propagated by institutional goals. however, new sophisticated techniques allow for greater adaptability to the current challenges in health care, including increased cohorting of atrisk patients, spread of resistance and the corresponding decrease in the number of available effective antimicrobials. a focused approach on development of understanding of hcai epidemiology is likely to lead to identification of significant risk factors and better prevention. molecular typing technology is quickly moving from research to clinical settings, and it is becoming more common for detailed molecular analyses to be undertaken to investigate nosocomial infections. from this review, it is clear that the uptake of statistical analyses is the limiting step in moving towards modern sophisticated analyses of hcais. few healthcare workers have the training to develop statistical models or perform in-depth analyses, and this is where collaboration with academic institutions can be exploited to improve the understanding of local disease dynamics without massively increasing the costs to hospitals. these collaborations would provide rich datasets for researchers to use, while enabling clinicians to employ cutting-edge methodologies that will inform their routine practice. one possible intermediary step would be to further the use of gis for hcai investigations, as it enables a wide range of analyses to be undertaken within one piece of software in which staff could be trained. whilst the initial implementation may be time and cost intensive, the benefits are clear from the few studies identified in this review. the combination of hcai datasets from numerous sources in one system and subsequent visualization can enable healthcare workers to incorporate up-to-date infection data into their clinical practice. as hospitals move to combine databases and increase the level of electronic recording, this presents an ideal time to incorporate gis into these systems and create a fully-integrated hospital information system. with movement of patients between care structures, differentiation between infection control in primary and secondary care is becoming more difficult. the small number (n ¼ , %) of studies based within nursing homes in this review suggests that less attention has been given to care units outside of hospitals. however, these could act as reservoirs of infections, and regular re-admission of their residents could lead to further hospital transmission. in addition to providing an analytical toolkit for spatial clustering, gis could improve the understanding of this relationship by enabling healthcare providers to consider the impact of their local community. the future potential applications in healthcare settings are ever expanding as more sophisticated molecular, statistical and computational techniques become increasingly commonplace. publication of analytical studies on hcai in major clinical journals rather than specialized niche journals, as observed in this review, could increase awareness of these techniques and widen their use. in structuring the search strategy for the review, the authors endeavoured to ensure the inclusion of studies from as broad a range as possible. however, due to the great variation in the terminology used across the numerous clinical and scientific fields, it is possible that a few studies were missed. further, the heterogeneity within the evidence base precluded metaanalysis of the findings. finally, publication bias cannot be fully avoided in a review. to truly understand and stem the growing problem of hcais worldwide, a multi-disciplinary approach is required. this is dependent on the skills and technology available to those investigating the problem, and is likely to require collaboration between experts. this review suggests that greater integration of spatiotemporal techniques into hcai investigations could prove invaluable in highlighting previously unobserved patterns of infections, and maximizing the understanding of disease dynamics. given that infections within a small contained area, such as a hospital, have greater potential for misclassification of clustering, it is necessary to use both molecular techniques and the appropriate spatiotemporal statistical techniques to maximize the accuracy of the study findings. given the expanding technology of information systems (e.g. electronic medical databases), advancement in molecular and statistical techniques, development of analytical platforms that enable greater access to non-experts and increased interdisciplinary collaboration, the potential for using pre-existing data to prevent future avoidable infections and improve patient safety can become a reality. report on the burden of endemic health care-associated infection 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nosocomial pathogens in an intensive care unit: a spaceetime clustering and structural equation modelling approach spatial and temporal analysis of clostridium difficile infection in patients at a pediatric hospital in california mrsa transmission on a neonatal intensive care unit: epidemiological and genomebased phylogenetic analyses nosocomial transmission of extensively drug-resistant tuberculosis in a rural hospital in south africa identifying more epidemic clones during a hospital outbreak of multidrug-resistant acinetobacter baumannii detecting clusters of multidrug-resistant gram-negative bacteria (mdrgn) using spaceetime analysis in a tertiary care hospital gis-supported investigation of a nosocomial salmonella outbreak hospital antibiotic resistance and gis for visualization and early warning implementing an animated geographic information system to investigate factors associated with nosocomial infections: a novel approach key: cord- -v kk i authors: dhama, kuldeep; khan, sharun; tiwari, ruchi; sircar, shubhankar; bhat, sudipta; malik, yashpal singh; singh, karam pal; chaicumpa, wanpen; bonilla-aldana, d. katterine; rodriguez-morales, alfonso j. title: coronavirus disease –covid- date: - - journal: clin microbiol rev doi: . /cmr. - sha: doc_id: cord_uid: v kk i in recent decades, several new diseases have emerged in different geographical areas, with pathogens including ebola virus, zika virus, nipah virus, and coronaviruses (covs). recently, a new type of viral infection emerged in wuhan city, china, and initial genomic sequencing data of this virus do not match with previously sequenced covs, suggesting a novel cov strain ( -ncov), which has now been termed severe acute respiratory syndrome cov- (sars-cov- ). although coronavirus disease (covid- ) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes should not be ruled out. compared to diseases caused by previously known human covs, covid- shows less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases globally. compared to other emerging viruses, such as ebola virus, avian h n , sars-cov, and middle east respiratory syndrome coronavirus (mers-cov), sars-cov- has shown relatively low pathogenicity and moderate transmissibility. codon usage studies suggest that this novel virus has been transferred from an animal source, such as bats. early diagnosis by real-time pcr and next-generation sequencing has facilitated the identification of the pathogen at an early stage. since no antiviral drug or vaccine exists to treat or prevent sars-cov- , potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating sars-cov, mers-cov, and other emerging viral diseases. in this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended to counter this pandemic virus. o ver the past decades, coronaviruses (covs) have been associated with significant disease outbreaks in east asia and the middle east. the severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers) began to emerge in and , respectively. recently, a novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), causing coronavirus disease (covid- ) , emerged in late , and it has posed a global health threat, causing an ongoing pandemic in many countries and territories ( ) . health workers worldwide are currently making efforts to control further disease outbreaks caused by the novel cov (originally named -ncov), which was first identified in wuhan city, hubei province, china, on december . on february , the world health organization (who) announced the official designation for the current cov-associated disease to be covid- , caused by sars-cov- . the primary cluster of patients was found to be connected with the huanan south china seafood market in wuhan ( ) . covs belong to the family coronaviridae (subfamily coronavirinae), the members of which infect a broad range of hosts, producing symptoms and diseases ranging from the common cold to severe and ultimately fatal illnesses, such as sars, mers, and, presently, covid- . sars-cov- is considered one of the seven members of the cov family that infect humans ( ) , and it belongs to the same lineage of covs that causes sars; however, this novel virus is genetically distinct. until , six covs were known to infect humans, including human cov e (hcov- e), hcov-nl , hcov-oc , hcov-hku , sars-cov, and mers-cov. although sars-cov and mers-cov have resulted in outbreaks with high mortality, others remain associated with mild upper-respiratory-tract illnesses ( ) . newly evolved covs pose a high threat to global public health. the current emergence of covid- is the third cov outbreak in humans over the past decades ( ) . it is no coincidence that fan et al. predicted potential sars-or mers-like cov outbreaks in china following pathogen transmission from bats ( ) . covid- emerged in china and spread rapidly throughout the country and, subsequently, to other countries. due to the severity of this outbreak and the potential of spreading on an international scale, the who declared a global health emergency on january ; subsequently, on march , they declared it a pandemic situation. at present, we are not in a position to effectively treat covid- , since neither approved vaccines nor specific antiviral drugs for treating human cov infections are available ( ) ( ) ( ) . most nations are currently making efforts to prevent the further spreading of this potentially deadly virus by implementing preventive and control strategies. in domestic animals, infections with covs are associated with a broad spectrum of furthermore, it acts as a critical factor for tissue tropism and the determination of host range ( ) . notably, s protein is one of the vital immunodominant proteins of covs capable of inducing host immune responses ( ) . the ectodomains in all covs s proteins have similar domain organizations, divided into two subunits, s and s ( ) . the first one, s , helps in host receptor binding, while the second one, s , accounts for fusion. the former (s ) is further divided into two subdomains, namely, the n-terminal domain (ntd) and c-terminal domain (ctd). both of these subdomains act as receptorbinding domains, interacting efficiently with various host receptors ( ) . the s ctd contains the receptor-binding motif (rbm). in each coronavirus spike protein, the trimeric s locates itself on top of the trimeric s stalk ( ) . recently, structural analyses of the s proteins of covid- have revealed amino acid substitutions within a , -amino-acid stretch ( ) . six substitutions are located in the rbd (amino acids to ), while four substitutions are in the rbm at the ctd of the s domain ( ) . of note, no amino acid change is seen in the rbm, which binds directly to the angiotensinconverting enzyme- (ace ) receptor in sars-cov ( , ) . at present, the main emphasis is knowing how many differences would be required to change the host tropism. sequence comparison revealed nonsynonymous changes between the early sequence of sars-cov- and the later isolates of sars-cov. the changes were found scattered over the genome of the virus, with nine substitutions in orf ab, orf ( substitutions), the spike gene ( substitutions) , and orf a (single substitution) ( ) . notably, the same nonsynonymous changes were found in a familial cluster, indicating that the viral evolution happened during person-to-person transmission ( , ) . such adaptive evolution events are frequent and constitute a constantly ongoing process once the virus spreads among new hosts ( ) . even though no functional changes occur in the virus associated with this adaptive evolution, close monitoring of the viral mutations that occur during subsequent human-to-human transmission is warranted. the m protein is the most abundant viral protein present in the virion particle, giving a definite shape to the viral envelope ( ) . it binds to the nucleocapsid and acts as a central organizer of coronavirus assembly ( ) . coronavirus m proteins are highly diverse in amino acid contents but maintain overall structural similarity within different genera ( ) . the m protein has three transmembrane domains, flanked by a short amino terminus outside the virion and a long carboxy terminus inside the virion ( ) . overall, the viral scaffold is maintained by m-m interaction. of note, the m protein of sars-cov- does not have an amino acid substitution compared to that of sars-cov ( ) . the coronavirus e protein is the most enigmatic and smallest of the major structural proteins ( ) . it plays a multifunctional role in the pathogenesis, assembly, and release of the virus ( ) . it is a small integral membrane polypeptide that acts as a viroporin (ion channel) ( ) . the inactivation or absence of this protein is related to the altered virulence of coronaviruses due to changes in morphology and tropism ( ) . the e protein consists of three domains, namely, a short hydrophilic amino terminal, a large hydrophobic transmembrane domain, and an efficient c-terminal domain ( ) . the sars-cov- e protein reveals a similar amino acid constitution without any substitution ( ) . the n protein of coronavirus is multipurpose. among several functions, it plays a role in complex formation with the viral genome, facilitates m protein interaction needed during virion assembly, and enhances the transcription efficiency of the virus ( , ) . it contains three highly conserved and distinct domains, namely, an ntd, an rna-binding domain or a linker region (lkr), and a ctd ( ) . the ntd binds with the = end of the viral genome, perhaps via electrostatic interactions, and is highly diverged both in length and sequence ( ) . the charged lkr is serine and arginine rich and is also known as the sr (serine and arginine) domain ( ) . the lkr is capable of direct interaction with in vitro rna interaction and is responsible for cell signaling ( , ) . it also modulates the antiviral response of the host by working as an antagonist for interferon (ifn) and rna interference ( ) . compared to that of sars-cov, the n protein of sars-cov- possess five amino acid mutations, where two are in the intrinsically dispersed region (idr; positions and ) , one each in the ntd (position ), lkr (position ), and ctd (position ) ( ) . besides the important structural proteins, the sars-cov- genome contains nsps, nsp to nsp and nsp to nsp , and accessory proteins ( a, b, p , a, b, b, b, and orf ) ( ) . all these proteins play a specific role in viral replication ( ) . unlike the accessory proteins of sars-cov, sars-cov- does not contain a protein and has a longer b and shorter b protein ( ) . the nsp , nsp , envelope, matrix, and p and b accessory proteins have not been detected with any amino acid substitutions compared to the sequences of other coronaviruses ( ) . the virus structure of sars-cov- is depicted in fig. . sequence percent similarity analysis. we assessed the nucleotide percent similarity using the megalign software program, where the similarity between the novel sars-cov- isolates was in the range of . % to %. among the other serbecovirus cov sequences, the novel sars-cov- sequences revealed the highest similarity to bat-sl-cov, with nucleotide percent identity ranges between . and . %. meanwhile, earlier reported sars-covs showed . to . % similarity to sars-cov- at the nucleotide level. further, the nucleotide percent similarity was . %, . % to . %, . % to . %, and . % to . % to the other four subgenera, namely, hibecovirus, nobecovirus, merbecovirus, and embecovirus, respectively. the percent similarity index of current outbreak isolates indicates a close relationship between sars-cov- isolates and bat-sl-cov, indicating a common origin. however, particular pieces of evidence based on further complete genomic analysis of current isolates are necessary to draw any conclusions, although it was ascertained that the current novel sars-cov- isolates belong to the subgenus sarbecovirus in the diverse range of betacoronaviruses. their possible ancestor was hypothesized to be from bat cov strains, wherein bats might have played a crucial role in harboring this class of viruses. splitstree phylogeny analysis. in the unrooted phylogenetic tree of different betacoronaviruses based on the s protein, virus sequences from different subgenera grouped into separate clusters. sars-cov- sequences from wuhan and other countries exhibited a close relationship and appeared in a single cluster (fig. ). the covs from the subgenus sarbecovirus appeared jointly in splitstree and divided into three subclusters, namely, sars-cov- , bat-sars-like-cov (bat-sl-cov), and sars-cov (fig. ) . in the case of other subgenera, like merbecovirus, all of the sequences grouped clinical microbiology reviews than italy. a john hopkins university web platform has provided daily updates on the basic epidemiology of the covid- outbreak (https://gisanddata.maps.arcgis.com/ apps/opsdashboard/index.html#/bda fd b e ecf ) ( ) . covid- has also been confirmed on a cruise ship, named diamond princess, quarantined in japanese waters (port of yokohama), as well as on other cruise ships around the world ( ) (fig. ) . the significant events of the sars-cov- /covid- virus outbreak occurring since december are presented as a timeline in fig. . at the beginning, china experienced the majority of the burden associated with covid- in the form of disease morbidity and mortality ( ), but over time the covid- menace moved to europe, particularly italy and spain, and now the united states has the highest number of confirmed cases and deaths. the covid- outbreak has also been associated with severe economic impacts globally due to the sudden interruption of global trade and supply chains that forced multinational companies to make decisions that led to significant economic losses ( ) . the recent increase in the number of confirmed critically ill patients with covid- has already surpassed the intensive care supplies, limiting intensive care services to only a small portion of critically ill patients ( ) . this might also have contributed to the increased case fatality rate observed in the covid- outbreak. the novel coronavirus was identified within month ( days) of the outbreak. this is impressively fast compared to the time taken to identify sars-cov reported in foshan, guangdong province, china ( days) ( ) . immediately after the confirmation of viral etiology, the chinese virologists rapidly released the genomic sequence of sars-cov- , which played a crucial role in controlling the spread of this newly emerged novel coronavirus to other parts of the world ( ) . the possible origin of sars-cov- and the first mode of disease transmission are not yet identified ( ) . analysis of the initial cluster of infections suggests that the infected individuals had a common exposure point, a seafood market in wuhan, hubei province, china (fig. ). the restaurants of this market are well-known for providing different types of wild animals for human consumption ( ) . the huanan south china seafood market also sells live animals, such as poultry, bats, snakes, and marmots ( ) . this might be the point where zoonotic (animal-to-human) transmission occurred ( ) . although sars-cov- is alleged to have originated from an animal host (zoonotic origin) with further humanto-human transmission (fig. ), the likelihood of foodborne transmission should be ruled out with further investigations, since it is a latent possibility ( ). additionally, other clinical microbiology reviews potential and expected routes would be associated with transmission, as in other respiratory viruses, by direct contact, such as shaking contaminated hands, or by direct contact with contaminated surfaces (fig. ) . still, whether blood transfusion and organ transplantation ( ) , as well as transplacental and perinatal routes, are possible routes for sars-cov- transmission needs to be determined (fig. ). from experience with several outbreaks associated with known emerging viruses, higher pathogenicity of a virus is often associated with lower transmissibility. compared to emerging viruses like ebola virus, avian h n , sars-cov, and mers-cov, sars-cov- has relatively lower pathogenicity and moderate transmissibility ( ) . the risk of death among individuals infected with covid- was calculated using the infection fatality risk (ifr). the ifr was found to be in the range of . % to . %, which is comparable to that of a previous asian influenza pandemic ( to ) ( , ) . notably, the reanalysis of the covid- pandemic curve from the initial cluster of cases pointed to considerable human-to-human transmission. it is opined that the exposure history of sars-cov- at the wuhan seafood market originated from humanto-human transmission rather than animal-to-human transmission ( ) ; however, in light of the zoonotic spillover in covid- , is too early to fully endorse this idea ( ). following the initial infection, human-to-human transmission has been observed with a preliminary reproduction number (r ) estimate of . to . ( , ) , and recently it is estimated to be . to . ( ) . in another study, the average reproductive number of covid- was found to be . , which is significantly higher than the initial who estimate of . to . ( ) . it is too early to obtain the exact r value, since there is a possibility of bias due to insufficient data. the higher r value is indicative of the more significant potential of sars-cov- transmission in a susceptible population. this is not the first time where the culinary practices of china have been blamed for the origin of novel coronavirus infection in humans. previously, the animals present in the liveanimal market were identified to be the intermediate hosts of the sars outbreak in china ( ) . several wildlife species were found to harbor potentially evolving coronavirus strains that can overcome the species barrier ( ) . one of the main principles of chinese food culture is that live-slaughtered animals are considered more nutritious ( ) . after months of struggle that lasted from december to march , the covid- situation now seems under control in china. the wet animal markets have reopened, and people have started buying bats, dogs, cats, birds, scorpions, badgers, rabbits, pangolins (scaly anteaters), minks, soup from palm civet, ostriches, hamsters, snapping turtles, ducks, fish, siamese crocodiles, and other animal meats without any fear of covid- . the chinese government is encouraging people to feel they can return to normalcy. however, this could be a risk, as it has been mentioned in advisories that people should avoid contact with live-dead animals as much as possible, as sars-cov- has shown zoonotic spillover. additionally, we cannot rule out the possibility of new mutations in the same virus being closely related to contact with both animals and humans at the market ( ) . in january , china imposed a temporary ban on the sale of live-dead animals in wet markets. however, now hundreds of such wet markets have been reopened without optimizing standard food safety and sanitation practices ( ) . with china being the most populated country in the world and due to its domestic and international food exportation policies, the whole world is now facing the menace of covid- , including china itself. wet markets of live-dead animals do not maintain strict food hygienic practices. fresh blood splashes are present everywhere, on the floor and tabletops, and such food customs could encourage many pathogens to adapt, mutate, and jump the species barrier. as a result, the whole world is suffering from novel sars-cov- , with more than , , cases and , deaths across the globe. there is an urgent need for a rational international campaign against the unhealthy food practices of china to encourage the sellers to increase hygienic food practices or close the crude live-dead animal wet markets. there is a need to modify food policies at national and international levels to avoid further life threats and clinical microbiology reviews economic consequences from any emerging or reemerging pandemic due to close animal-human interaction ( ) . even though individuals of all ages and sexes are susceptible to covid- , older people with an underlying chronic disease are more likely to become severely infected ( ) . recently, individuals with asymptomatic infection were also found to act as a source of infection to susceptible individuals ( ) . both the asymptomatic and symptomatic patients secrete similar viral loads, which indicates that the transmission capacity of asymptomatic or minimally symptomatic patients is very high. thus, sars-cov- transmission can happen early in the course of infection ( ) . atypical clinical manifestations have also been reported in covid- in which the only reporting symptom was fatigue. such patients may lack respiratory signs, such as fever, cough, and sputum ( ) . hence, the clinicians must be on the look-out for the possible occurrence of atypical clinical manifestations to avoid the possibility of missed diagnosis. the early transmission ability of sars-cov- was found to be similar to or slightly higher than that of sars-cov, reflecting that it could be controlled despite moderate to high transmissibility ( ) . increasing reports of sars-cov- in sewage and wastewater warrants the need for further investigation due to the possibility of fecal-oral transmission. sars-cov- present in environmental compartments such as soil and water will finally end up in the wastewater and sewage sludge of treatment plants ( ) . therefore, we have to reevaluate the current wastewater and sewage sludge treatment procedures and introduce advanced techniques that are specific and effective against sars-cov- . since there is active shedding of sars-cov- in the stool, the prevalence of infections in a large population can be studied using wastewater-based epidemiology. recently, reverse transcription-quantitative pcr (rt-qpcr) was used to enumerate the copies of sars-cov- rna concentrated from wastewater collected from a wastewater treatment plant ( ) . the calculated viral rna copy numbers determine the number of infected individuals. the increasing reports of virus shedding via the fecal route warrants the introduction of negative fecal viral nucleic acid test results as one of the additional discharge criteria in laboratory-confirmed cases of covid- ( ) . the covid- pandemic does not have any novel factors, other than the genetically unique pathogen and a further possible reservoir. the cause and the likely future outcome are just repetitions of our previous interactions with fatal coronaviruses. the only difference is the time of occurrence and the genetic distinctness of the pathogen involved. mutations on the rbd of covs facilitated their capability of infecting newer hosts, thereby expanding their reach to all corners of the world ( ) . this is a potential threat to the health of both animals and humans. advanced studies using bayesian phylogeographic reconstruction identified the most probable origin of sars-cov- as the bat sars-like coronavirus, circulating in the rhinolophus bat family ( ) . phylogenetic analysis of whole-genome sequences of sars-cov- showed that they are related to two covs of bat origin, namely, bat-sl-covzc and bat-sl-covzxc , which were reported during in china ( ) . it was reported that sars-cov- had been confirmed to use ace as an entry receptor while exhibiting an rbd similar to that of sars-cov ( , , , ) . several countries have provided recommendations to their people traveling to china ( , ) . compared to the previous coronavirus outbreaks caused by sars-cov and mers-cov, the efficiency of sars-cov- human-to-human transmission was thought to be less. this assumption was based on the finding that health workers were affected less than they were in previous outbreaks of fatal coronaviruses ( ) . superspreading events are considered the main culprit for the extensive transmission of sars and mers ( , ) . almost half of the mers-cov cases reported in saudi arabia are of secondary origin that occurred through contact with infected asymptomatic or symptomatic individuals through human-tohuman transmission ( ) . the occurrence of superspreading events in the covid- outbreak cannot be ruled out until its possibility is evaluated. like sars and mers, covid- can also infect the lower respiratory tract, with milder symptoms ( ) . the basic reproduction number of covid- has been found to be in the range of . to . based on real-time reports and . to . based on predicted infected cases ( ) . coronavirus infection in humans is commonly associated with mild to severe respiratory diseases, with high fever, severe inflammation, cough, and internal organ dysfunction that can even lead to death ( ) . most of the identified coronaviruses cause the common cold in humans. however, this changed when sars-cov was identified, paving the way for severe forms of the disease in humans ( ) . our previous experience with the outbreaks of other coronaviruses, like sars and mers, suggests that the mode of transmission in covid- as mainly human-to-human transmission via direct contact, droplets, and fomites ( ) . recent studies have demonstrated that the virus could remain viable for hours in aerosols and up to days on surfaces; thus, aerosol and fomite contamination could play potent roles in the transmission of sars-cov- ( ) . the immune response against coronavirus is vital to control and get rid of the infection. however, maladjusted immune responses may contribute to the immunopathology of the disease, resulting in impairment of pulmonary gas exchange. understanding the interaction between covs and host innate immune systems could enlighten our understanding of the lung inflammation associated with this infection ( ) . sars is a viral respiratory disease caused by a formerly unrecognized animal cov that originated from the wet markets in southern china after adapting to the human host, thereby enabling transmission between humans ( ) . the sars outbreak reported in to had , confirmed cases with total deaths ( . %) ( ) . the outbreak severely affected the asia pacific region, especially mainland china ( ) . even though the case fatality rate (cfr) of sars-cov- (covid- ) is lower than that of sars-cov, there exists a severe concern linked to this outbreak due to its epidemiological similarity to influenza viruses ( , ) . this can fail the public health system, resulting in a pandemic ( ) . mers is another respiratory disease that was first reported in saudi arabia during the year . the disease was found to have a cfr of around % ( ) . the analysis of available data sets suggests that the incubation period of sars-cov- , sars-cov, and mers-cov is in almost the same range. the longest predicted incubation time of sars-cov- is days. hence, suspected individuals are isolated for days to avoid the risk of further spread ( ) . even though a high similarity has been reported between the genome sequence of the new coronavirus (sars-cov- ) and sars-like covs, the comparative analysis recognized a furin-like cleavage site in the sars-cov- s protein that is missing from other sars-like covs ( ) . the furin-like cleavage site is expected to play a role in the life cycle of the virus and disease pathogenicity and might even act as a therapeutic target for furin inhibitors. the highly contagious nature of sars-cov- compared to that of its predecessors might be the result of a stabilizing mutation that occurred in the endosome-associated-protein-like domain of nsp protein. similarly, the destabilizing mutation near the phosphatase domain of nsp proteins in sars-cov- could indicate a potential mechanism that differentiates it from other covs ( ) . even though the cfr reported for covid- is meager compared to those of the previous sars and mers outbreaks, it has caused more deaths than sars and mers combined ( ) . possibly related to the viral pathogenesis is the recent finding of an -nucleotide (nt) deletion in orf , which appears to reduce the replicative fitness of the virus and leads to attenuated phenotypes of sars-cov- ( ) . coronavirus is the most prominent example of a virus that has crossed the species barrier twice from wild animals to humans during sars and mers outbreaks ( , ) . the possibility of crossing the species barrier for the third time has also been suspected in the case of sars-cov- (covid- ) . bats are recognized as a possible natural reservoir host of both sars-cov and mers-cov infection. in contrast, the possible intermediary host is the palm civet for sars-cov and the dromedary camel for mers-cov infection ( ) . bats are considered the ancestral hosts for both sars and mers ( ) . bats are also considered the reservoir host of human coronaviruses like clinical microbiology reviews hcov- e and hcov-nl ( ) . in the case of covid- , there are two possibilities for primary transmission: it can be transmitted either through intermediate hosts, similar to that of sars and mers, or directly from bats ( ) . the emergence paradigm put forward in the sars outbreak suggests that sars-cov originated from bats (reservoir host) and later jumped to civets (intermediate host) and incorporated changes within the receptor-binding domain (rbd) to improve binding to civet ace . this civetadapted virus, during their subsequent exposure to humans at live markets, promoted further adaptations that resulted in the epidemic strain ( ) . transmission can also occur directly from the reservoir host to humans without rbd adaptations. the bat coronavirus that is currently in circulation maintains specific "poised" spike proteins that facilitate human infection without the requirement of any mutations or adaptations ( ) . altogether, different species of bats carry a massive number of coronaviruses around the world ( ) . the high plasticity in receptor usage, along with the feasibility of adaptive mutation and recombination, may result in frequent interspecies transmission of coronavirus from bats to animals and humans ( ) . the pathogenesis of most bat coronaviruses is unknown, as most of these viruses are not isolated and studied ( ) . hedgehog coronavirus hku , a betacoronavirus, has been identified from amur hedgehogs in china. studies show that hedgehogs are the reservoir of betacoronavirus, and there is evidence of recombination ( ) . the current scientific evidence available on mers infection suggests that the significant reservoir host, as well as the animal source of mers infection in humans, is the dromedary camels ( ) . the infected dromedary camels may not show any visible signs of infection, making it challenging to identify animals actively excreting mers-cov that has the potential to infect humans. however, they may shed mers-cov through milk, urine, feces, and nasal and eye discharge and can also be found in the raw organs ( ) . in a study conducted to evaluate the susceptibility of animal species to mers-cov infection, llamas and pigs were found to be susceptible, indicating the possibility of mers-cov circulation in animal species other than dromedary camels ( ) . following the outbreak of sars in china, sars-cov-like viruses were isolated from himalayan palm civets (paguma larvata) and raccoon dogs (nyctereutes procyonoides) found in a live-animal market in guangdong, china. the animal isolates obtained from the live-animal market retained a -nucleotide sequence that was not present in most of the human isolates ( ) . these findings were critical in identifying the possibility of interspecies transmission in sars-cov. the higher diversity and prevalence of bat coronaviruses in this region compared to those in previous reports indicate a host/ pathogen coevolution. sars-like coronaviruses also have been found circulating in the chinese horseshoe bat (rhinolophus sinicus) populations. the in vitro and in vivo studies carried out on the isolated virus confirmed that there is a potential risk for the reemergence of sars-cov infection from the viruses that are currently circulating in the bat population ( ) . the disease caused by sars-cov- is also named severe specific contagious pneumonia (sscp), wuhan pneumonia, and, recently, covid- ( ) . compared to sars-cov, sars-cov- has less severe pathogenesis but has superior transmission capability, as evidenced by the rapidly increasing number of covid- cases ( ) . the incubation period of sars-cov- in familial clusters was found to be to days ( ) . the mean incubation period of covid- was found to be . days, ranging from . to . days ( ) . among an early affected group of patients, years was the median age, of which more males were affected ( ) . similar to sars and mers, the severity of this ncov is high in age groups above years ( , ) . symptoms of covid- include fever, cough, myalgia or fatigue, and, less commonly, headache, hemoptysis, and diarrhea ( , ) . compared to the sars-cov- -infected patients in wuhan during the initial stages of the outbreak, only mild symptoms were noticed in those patients that are infected by human-to-human transmission ( ) . the initial trends suggested that the mortality associated with covid- was less than that of previous outbreaks of sars ( ) . the updates obtained from countries like china, japan, thailand, and south korea indicated that the covid- patients had relatively mild manifestations compared to those with sars and mers ( ). regardless of the coronavirus type, immune cells, like mast cells, that are present in the submucosa of the respiratory tract and nasal cavity are considered the primary barrier against this virus ( ) . advanced in-depth analysis of the genome has identified amino acid substitutions between the amino acid sequences of sars-cov- and the sars/sarslike coronaviruses. these differences in the amino acid sequences might have contributed to the difference in the pathogenic divergence of sars-cov- ( ) . further research is required to evaluate the possible differences in tropism, pathogenesis, and transmission of this novel agent associated with this change in the amino acid sequence. with the current outbreak of covid- , there is an expectancy of a significant increase in the number of published studies about this emerging coronavirus, as occurred with sars and mers ( ) . sars-cov- invades the lung parenchyma, resulting in severe interstitial inflammation of the lungs. this is evident on computed tomography (ct) images as ground-glass opacity in the lungs. this lesion initially involves a single lobe but later expands to multiple lung lobes ( ) . the histological assessment of lung biopsy samples obtained from covid- -infected patients revealed diffuse alveolar damage, cellular fibromyxoid exudates, hyaline membrane formation, and desquamation of pneumocytes, indicative of acute respiratory distress syndrome ( ) . it was also found that the sars-cov- infected patients often have lymphocytopenia with or without leukocyte abnormalities. the degree of lymphocytopenia gives an idea about disease prognosis, as it is found to be positively correlated with disease severity ( ) . pregnant women are considered to have a higher risk of getting infected by covid- . the coronaviruses can cause adverse outcomes for the fetus, such as intrauterine growth restriction, spontaneous abortion, preterm delivery, and perinatal death. nevertheless, the possibility of intrauterine maternal-fetal transmission (vertical transmission) of covs is low and was not seen during either the sars-or mers-cov outbreak ( ) . however, there has been concern regarding the impact of sars-cov- /covid- on pregnancy. researchers have mentioned the probability of in utero transmission of novel sars-cov- from covid- -infected mothers to their neonates in china based upon the rise in igm and igg antibody levels and cytokine values in the blood obtained from newborn infants immediately postbirth; however, rt-pcr failed to confirm the presence of sars-cov- genetic material in the infants ( ) . recent studies show that at least in some cases, preterm delivery and its consequences are associated with the virus. nonetheless, some cases have raised doubts for the likelihood of vertical transmission ( ) ( ) ( ) ( ) . covid- infection was associated with pneumonia, and some developed acute respiratory distress syndrome (ards). the blood biochemistry indexes, such as albumin, lactate dehydrogenase, c-reactive protein, lymphocytes (percent), and neutrophils (percent) give an idea about the disease severity in covid- infection ( ) . during covid- , patients may present leukocytosis, leukopenia with lymphopenia ( ), hypoalbuminemia, and an increase of lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, bilirubin, and, especially, d-dimer ( ) . middle-aged and elderly patients with primary chronic diseases, especially high blood pressure and diabetes, were found to be more susceptible to respiratory failure and, therefore, had poorer prognoses. providing respiratory support at early stages improved the disease prognosis and facilitated recovery ( ) . the ards in covid- is due to the occurrence of cytokine storms that results in exaggerated immune response, immune regulatory network imbalance, and, finally, multiple-organ failure ( ) . in addition to the exaggerated inflammatory response seen in patients with covid- pneumonia, the bile duct epithelial cell-derived hepatocytes upregulate ace expression in liver tissue by compensatory proliferation that might result in hepatic tissue injury ( ) . coronavirus can cause disease in several species of domestic and wild animals, as well as humans ( ) . the different animal species that are infected with cov include horses, camels, cattle, swine, dogs, cats, rodents, birds, ferrets, minks, bats, rabbits, snakes, and various other wild animals ( , , , , , , ) . coronavirus infection is linked to different kinds of clinical manifestations, varying from enteritis in cows and pigs, upper respiratory disease in chickens, and fatal respiratory infections in humans ( ) . among the cov genera, alphacoronavirus and betacoronavirus infect mammals, while gammacoronavirus and deltacoronavirus mainly infect birds, fishes, and, sometimes, mammals ( , , ) . several novel coronaviruses that come under the genus deltacoronavirus have been discovered in the past from birds, like wigeon coronavirus hku , bulbul coronavirus hku , munia coronavirus hku , white-eye coronavirus hku , night-heron coronavirus hku , and common moorhen coronavirus hku , as well as from pigs (porcine coronavirus hku ) ( , ) . transmissible gastroenteritis virus (tgev), porcine epidemic diarrhea virus (pedv), and porcine hemagglutinating encephalomyelitis virus (phev) are some of the coronaviruses of swine. among them, tgev and pedv are responsible for causing severe gastroenteritis in young piglets with noteworthy morbidity and mortality. infection with phev also causes enteric infection but can cause encephalitis due to its ability to infect the nervous system ( ) . bovine coronaviruses (bocovs) are known to infect several domestic and wild ruminants ( ) . bocov inflicts neonatal calf diarrhea in adult cattle, leading to bloody diarrhea (winter dysentery) and respiratory disease complex (shipping fever) in cattle of all age groups ( ) . bocov-like viruses have been noted in humans, suggesting its zoonotic potential as well ( ) . feline enteric and feline infectious peritonitis (fip) viruses are the two major feline covs ( ) , where feline covs can affect the gastrointestinal tract, abdominal cavity (peritonitis), respiratory tract, and central nervous system ( ) . canines are also affected by covs that fall under different genera, namely, canine enteric coronavirus in alphacoronavirus and canine respiratory coronavirus in betacoronavirus, affecting the enteric and respiratory tract, respectively ( , ) . ibv, under gammacoronavirus, causes diseases of respiratory, urinary, and reproductive systems, with substantial economic losses in chickens ( , ) . in small laboratory animals, mouse hepatitis virus, rat sialodacryoadenitis coronavirus, and guinea pig and rabbit coronaviruses are the major covs associated with disease manifestations like enteritis, hepatitis, and respiratory infections ( , ) . swine acute diarrhea syndrome coronavirus (sads-cov) was first identified in suckling piglets having severe enteritis and belongs to the genus alphacoronavirus ( ) . the outbreak was associated with considerable scale mortality of piglets ( , deaths) across four farms in china ( ) . the virus isolated from the piglets was almost identical to and had % genomic similarity with horseshoe bat (rhinolophus species) coronavirus hku , suggesting a bat origin of the pig virus ( , , ) . it is also imperative to note that the sads-cov outbreak started in guangdong province, near the location of the sars pandemic origin ( ) . before this outbreak, pigs were not known to be infected with bat-origin coronaviruses. this indicates that the bat-origin coronavirus jumped to pig by breaking the species barrier. the next step of this jump might not end well, since pigs are considered the mixing vessel for influenza a viruses due to their ability to be infected by both human and avian influenza a viruses ( ) . similarly, they may act as the mixing vessel for coronaviruses, since they are in frequent contact with both humans and multiple wildlife species. additionally, pigs are also found to be susceptible to infection with human sars-cov and mers-cov, making this scenario a nightmare ( , ) . it is only a matter of time before another zoonotic coronavirus results in an epidemic by jumping the so-called species barrier ( ) . the host spectrum of coronavirus increased when a novel coronavirus, namely, sw , was recognized in the liver tissue of a captive beluga whale (delphinapterus leucas) ( ) . in recent decades, several novel coronaviruses were identified from different animal species. bats can harbor these viruses without manifesting any clinical disease but are persistently infected ( ) . they are the only mammals with the capacity for self-powered flight, which enables them to migrate long distances, unlike land mammals. bats are distributed worldwide and also account for about a fifth of all mammalian species ( ) . this makes them the ideal reservoir host for many viral agents and also the source of novel coronaviruses that have yet to be identified. it has become a necessity to study the diversity of coronavirus in the bat population to prevent future outbreaks that could jeopardize livestock and public health. the repeated outbreaks caused by bat-origin coronaviruses calls for the development of efficient molecular surveillance strategies for studying betacoronavirus among animals ( ) , especially in the rhinolophus bat family ( ) . chinese bats have high commercial value, since they are used in traditional chinese medicine (tcm). therefore, the handling of bats for trading purposes poses a considerable risk of transmitting zoonotic cov epidemics ( ) . due to the possible role played by farm and wild animals in sars-cov- infection, the who, in their novel coronavirus (covid- ) situation report, recommended the avoidance of unprotected contact with both farm and wild animals ( ) . the live-animal markets, like the one in guangdong, china, provides a setting for animal coronaviruses to amplify and to be transmitted to new hosts, like humans ( ) . such markets can be considered a critical place for the origin of novel zoonotic diseases and have enormous public health significance in the event of an outbreak. bats are the reservoirs for several viruses; hence, the role of bats in the present outbreak cannot be ruled out ( ) . in a qualitative study conducted for evaluating the zoonotic risk factors among rural communities of southern china, the frequent human-animal interactions along with the low levels of environmental biosecurity were identified as significant risks for the emergence of zoonotic disease in local communities ( , ) . the comprehensive sequence analysis of the sars-cov- rna genome identified that the cov from wuhan is a recombinant virus of the bat coronavirus and another coronavirus of unknown origin. the recombination was found to have happened within the viral spike glycoprotein, which recognizes the cell surface receptor. further analysis of the genome based on codon usage identified the snake as the most probable animal reservoir of sars-cov- ( ) . contrary to these findings, another genome analysis proposed that the genome of sars-cov- is % identical to bat coronavirus, reflecting its origin from bats ( ) . the involvement of bat-derived materials in causing the current outbreak cannot be ruled out. high risk is involved in the production of bat-derived materials for tcm practices involving the handling of wild bats. the use of bats for tcm practices will remain a severe risk for the occurrence of zoonotic coronavirus epidemics in the future ( ) . furthermore, the pangolins are an endangered species of animals that harbor a wide variety of viruses, including coronaviruses ( ) . the coronavirus isolated from malayan pangolins (manis javanica) showed a very high amino acid identity with covid- at e ( %), m ( . %), n ( . %), and s genes ( . %). the rbd of s protein in cov isolated from pangolin was almost identical (one amino acid difference) to that of sars-cov- . a comparison of the genomes suggests recombination between pangolin-cov-like viruses with the bat-cov-ratg -like virus. all this suggests the potential of pangolins to act as the intermediate host of sars-cov- ( ) . human-wildlife interactions, which are increasing in the context of climate change ( ) , are further considered high risk and responsible for the emergence of sars-cov. covid- is also suspected of having a similar mode of origin. hence, to prevent the occurrence of another zoonotic spillover ( ), exhaustive coordinated efforts are needed to identify the high-risk pathogens harbored by wild animal populations, conducting surveillance among the people who are susceptible to zoonotic spillover events ( ) , and to improve the biosecurity measures associated with the wildlife trade ( ) . the serological surveillance studies conducted in people living in proximity to bat caves had earlier identified the serological confirmation of sars-related covs in humans. people clinical microbiology reviews living at the wildlife-human interface, mainly in rural china, are regularly exposed to sars-related covs ( ) . these findings will not have any significance until a significant outbreak occurs due to a virus-like sars-cov- . there is a steady increase in the reports of covid- in companion and wild animals around the world. further studies are required to evaluate the potential of animals (especially companion animals) to serve as an efficient reservoir host that can further alter the dynamics of human-to-human transmission ( ) . to date, two pet dogs (hong kong) and four pet cats (one each from belgium and hong kong, two from the united states) have tested positive for sars-cov- ( ) . the world organization for animal health (oie) has confirmed the diagnosis of covid- in both dogs and cats due to human-to-animal transmission ( ) . the similarity observed in the gene sequence of sars-cov- from an infected pet owner and his dog further confirms the occurrence of human-to-animal transmission ( ) . even though asymptomatic, feline species should be considered a potential transmission route from animals to humans ( ) . however, currently, there are no reports of sars-cov- transmission from felines to human beings. based on the current evidence, we can conclude that cats are susceptible to sars-cov- and can get infected by human beings. however, evidence of cat-to-human transmission is lacking and requires further studies ( ) . rather than waiting for firmer evidence on animal-to-human transmission, necessary preventive measures are advised, as well as following social distancing practices among companion animals of different households ( ) . one of the leading veterinary diagnostic companies, idexx, has conducted large-scale testing for covid- in specimens collected from dogs and cats. however, none of the tests turned out to be positive ( ) . in a study conducted to investigate the potential of different animal species to act as the intermediate host of sars-cov- , it was found that both ferrets and cats can be infected via experimental inoculation of the virus. in addition, infected cats efficiently transmitted the disease to naive cats ( ) . sars-cov- infection and subsequent transmission in ferrets were found to recapitulate the clinical aspects of covid- in humans. the infected ferrets also shed virus via multiple routes, such as saliva, nasal washes, feces, and urine, postinfection, making them an ideal animal model for studying disease transmission ( ) . experimental inoculation was also done in other animal species and found that the dogs have low susceptibility, while the chickens, ducks, and pigs are not at all susceptible to sars-cov- ( ) . similarly, the national veterinary services laboratories of the usda have reported covid- in tigers and lions that exhibited respiratory signs like dry cough and wheezing. the zoo animals are suspected to have been infected by an asymptomatic zookeeper ( ) . the total number of covid- -positive cases in human beings is increasing at a high rate, thereby creating ideal conditions for viral spillover to other species, such as pigs. the evidence obtained from sars-cov suggests that pigs can get infected with sars-cov- ( ). however, experimental inoculation with sars-cov- failed to infect pigs ( ) . further studies are required to identify the possible animal reservoirs of sars-cov- and the seasonal variation in the circulation of these viruses in the animal population. research collaboration between human and animal health sectors is becoming a necessity to evaluate and identify the possible risk factors of transmission between animals and humans. such cooperation will help to devise efficient strategies for the management of emerging zoonotic diseases ( ) . rna tests can confirm the diagnosis of sars-cov- (covid- ) cases with real-time rt-pcr or next-generation sequencing ( , , , ) . at present, nucleic acid detection techniques, like rt-pcr, are considered an effective method for confirming the diagnosis in clinical cases of covid- ( ) . several companies across the world are currently focusing on developing and marketing sars-cov- -specific nucleic acid detection kits. multiple laboratories are also developing their own in-house rt-pcr. one of them is the sars-cov- nucleic acid detection kit produced by shuoshi biotechnology (double fluorescence pcr method) ( ) . up to march , the u.s. food and drug administration (fda) had granted in vitro diagnostics emergency use authorizations (euas), including for the rt-pcr diagnostic panel for the universal detection of sars-like betacoronaviruses and specific detection of sars-cov- , developed by the u.s. cdc (table ) ( , ) . recently, full-length genomic sequences of saras-cov- strains available in the national center for biotechnology information and gisaid databases were subjected to multiple-sequence alignment and phylogenetic analyses for studying variations in the viral genome ( ) . all the viral strains revealed high homology of . % ( . % to %) at the nucleotide level and . % ( . % to %) at the amino acid level. overall variation was found to be low in orf regions, with variation sites recognized in a, b, s, a, m, , and n regions. mutation rates of . % ( / ) and . % ( / ) were observed at nt (orf ) and nt (orf a) positions, respectively. owing to such selective mutations, a few specific regions of sars-cov- should not be considered for designing primers and probes. the sars-cov- reference sequence could pave the way to study molecular biology and pathobiology, along with developing diagnostics and appropriate prevention and control strategies for countering sars-cov- ( ) . nucleic acids of sars-cov- can be detected from samples ( ) such as bronchoalveolar lavage fluid, sputum, nasal swabs, fiber bronchoscope brush biopsy specimen, pharyngeal swabs, feces, blood, and urine, with different levels of diagnostic performance (table ) ( , , ) . the viral loads of sars-cov- were measured using n-gene-specific quantitative rt-pcr in throat swab and sputum samples collected from covid- -infected individuals. the results indicated that the viral load peaked at around to days following the onset of symptoms, and it ranged from to copies/ml during this time ( ) . in another study, the viral load was found to be higher in the nasal swabs than the throat swabs obtained from covid- symptomatic patients ( ) . although initially it was thought that viral load would be associated with poor outcomes, some case reports have shown asymptomatic individuals with high viral loads ( ) . recently, the viral load in nasal and throat swabs of symptomatic patients was determined, and higher viral loads were recorded soon after the onset of symptoms, particularly in the nose compared to the throat. the pattern of viral nucleic the results of the studies related to sars-cov- viral loads reflect active replication of this virus in the upper respiratory tract and prolonged viral shedding after symptoms disappear, including via stool. thus, the current case definition needs to be updated along with a reassessment of the strategies to be adopted for restraining the sars-cov- outbreak spread ( ) . in some cases, the viral load studies of sars-cov- have also been useful to recommend precautionary measures when handling specific samples, e.g., feces. in a recent survey from confirmed cases of sars-cov- infection with available data (representing days to after onset), stool samples from nine cases ( %; days to after onset) were positive on rt-pcr analysis. although the viral loads were lower than those of respiratory samples (range, copies per ml to . ϫ copies per ml), this has essential biosafety implications ( ) . the samples from sars-cov- -positive patients in singapore who had traveled from wuhan to singapore showed the presence of viral rna in stool and whole blood but not in urine by real-time rt-pcr ( ) . further, novel sars-cov- infections have been detected in a variety of clinical specimens, like bronchoalveolar lavage fluid, sputum, nasal swabs, fibrobronchoscope brush biopsy specimens, pharyngeal swabs, feces, and blood ( ) . the presence of sars-cov- in fecal samples has posed grave public health concerns. in addition to the direct transmission mainly occurring via droplets of sneezing and coughing, other routes, such as fecal excretion and environmental and fomite contamination, are contributing to sars-cov- transmission and spread ( ) ( ) ( ) ( ) . fecal excretion has also been documented for sars-cov and mers-cov, along with the potential to stay viable in situations aiding fecal-oral transmission. thus, sars-cov- has every possibility to be transmitted through this mode. fecal-oral transmission of sars-cov- , particularly in regions having low standards of hygiene and poor sanitation, may have grave consequences with regard to the high spread of this virus. ethanol and disinfectants containing chlorine or bleach are effective against coronaviruses ( ) ( ) ( ) ( ) . appropriate precautions need to be followed strictly while handling the stools of patients infected with sars-cov- . biowaste materials and sewage from hospitals must be adequately disinfected, treated, and disposed of properly. the significance of frequent and good hand hygiene and sanitation practices needs to be given due emphasis ( ) ( ) ( ) ( ) . future explorative research needs to be conducted with regard to the fecal-oral transmission of sars-cov- , along with focusing on environmental investigations to find out if this virus could stay viable in situations and atmospheres facilitating such potent routes of transmission. the correlation of fecal concentrations of viral rna with disease severity needs to be determined, along with assessing the gastrointestinal symptoms and the possibility of fecal sars-cov- rna detection during the covid- incubation period or convalescence phases of the disease ( ) ( ) ( ) ( ) . the lower respiratory tract sampling techniques, like bronchoalveolar lavage fluid aspirate, are considered the ideal clinical materials, rather than the throat swab, due to their higher positive rate on the nucleic acid test ( ) . the diagnosis of covid- can be made by using upper-respiratory-tract specimens collected using nasopharyngeal and oropharyngeal swabs. however, these techniques are associated with unnecessary risks to health care workers due to close contact with patients ( ) . similarly, a single patient with a high viral load was reported to contaminate an entire endoscopy room by shedding the virus, which may remain viable for at least days and is considered a great risk for uninfected patients and health care workers ( ) . recently, it was found that the anal swabs gave more positive results than oral swabs in the later stages of infection ( ) . hence, clinicians have to be cautious while discharging any covid- infected patient based on negative oral swab test results due to the possibility of fecal-oral transmission. even though the viral loads in stool samples were found to be less than those of respiratory samples, strict precautionary measures have to be followed while handling stool samples of covid- suspected or infected patients ( ) . children infected with sars-cov- experience only a mild form of illness and recover immediately after treatment. it was recently found that stool samples of sars-cov- -infected children that gave negative throat swab results were positive within ten days of negative results. this could result in the fecal-oral transmission of sars-cov- infections, especially in children ( ) . hence, to prevent the fecal-oral transmission of sars-cov- , infected covid- patients should only be considered negative when they test negative for sars-cov- in the stool sample. a suspected case of covid- infection is said to be confirmed if the respiratory tract aspirate or blood samples test positive for sars-cov- nucleic acid using rt-pcr or by the identification of sars-cov- genetic sequence in respiratory tract aspirate or blood samples ( ) . the patient will be confirmed as cured when two subsequent oral swab results are negative ( ) . recently, the live virus was detected in the selfcollected saliva of patients infected with covid- . these findings were confirmative of using saliva as a noninvasive specimen for the diagnosis of covid- infection in suspected individuals ( ) . it has also been observed that the initial screening of covid- patients infected with rt-pcr may give negative results even if they have chest ct findings that are suggestive of infection. hence, for the accurate diagnosis of covid- , a combination of repeated swab tests using rt-pcr and ct scanning is required to prevent the possibility of false-negative results during disease screening ( ) . rt-pcr is the most widely used test for diagnosing covid- . however, it has some significant limitations from the clinical perspective, since it will not give any clarity regarding disease progression. droplet digital pcr (ddpcr) can be used for the quantification of viral load in the samples obtained from lower respiratory tracts. hence, based on the viral load, we can quickly evaluate the progression of infection ( ) . in addition to all of the above findings, sequencing and phylogenetics are critical in the correct identification and confirmation of the causative viral agent and useful to establish relationships with previous isolates and sequences, as well as to know, especially during an epidemic, the nucleotide and amino acid mutations and the molecular divergence. the rapid development and implementation of diagnostic tests against emerging novel diseases like covid- pose significant challenges due to the lack of resources and logistical limitations associated with an outbreak ( ) . sars-cov- infection can also be confirmed by isolation and culturing. the human airway epithelial cell culture was found to be useful in isolating sars-cov- ( ). the efficient control of an outbreak depends on the rapid diagnosis of the disease. recently, in response to the covid- outbreak, -step quantitative realtime reverse transcription-pcr assays were developed that detect the orf b and n regions of the sars-cov- genome ( ) . that assay was found to achieve the rapid detection of sars-cov- . nucleic acid-based assays offer high accuracy in the diagnosis of sars-cov- , but the current rate of spread limits its use due to the lack of diagnostic assay kits. this will further result in the extensive transmission of covid- , since only a portion of suspected cases can be diagnosed. in such situations, conventional serological assays, like enzyme-linked immunosorbent assay (elisa), that are specific to covid- igm and igg antibodies can be used as a high-throughput alternative ( ) . at present, there is no diagnostic kit available for detecting the sars-cov- antibody ( ) . the specific antibody profiles of covid- patients were analyzed, and it was found that the igm level lasted more than month, indicating a prolonged stage of virus replication in sars-cov- -infected patients. the igg levels were found to increase only in the later stages of the disease. these findings indicate that the specific antibody profiles of sars-cov- and sars-cov were similar ( ) . these findings can be utilized for the development of specific diagnostic tests against covid- and can be used for rapid screening. even though diagnostic test kits are already available that can detect the genetic sequences of sars-cov- ( ), their availability is a concern, as the number of covid- cases is skyrocketing ( , ) . a major problem associated with this diagnostic kit is that it works only when the test subject has an active infection, limiting its use to the earlier stages of infection. several laboratories around the world are currently developing antibody-based diagnostic tests against sars-cov- ( ). chest ct is an ideal diagnostic tool for identifying viral pneumonia. the sensitivity of chest ct is far superior to that of x-ray screening. the chest ct findings associated with covid- -infected patients include characteristic patchy infiltration that later progresses to ground-glass opacities ( ) . early manifestations of covid- pneumonia might not be evident in x-ray chest radiography. in such situations, a chest ct examination can be performed, as it is considered highly specific for covid- pneumonia ( ) . those patients having covid- pneumonia will exhibit the typical ground-glass opacity in their chest ct images ( ) . the patients infected with covid- had elevated plasma angiotensin levels. the level of angiotensin was found to be linearly associated with viral load and lung injury, indicating its potential as a diagnostic biomarker ( ) . the chest ct imaging abnormalities associated with covid- pneumonia have also been observed even in asymptomatic patients. these abnormalities progress from the initial focal unilateral to diffuse bilateral ground-glass opacities and will further progress to or coexist with lung consolidation changes within to weeks ( ). the role played by radiologists in the current scenario is very important. radiologists can help in the early diagnosis of lung abnormalities associated with covid- pneumonia. they can also help in the evaluation of disease severity, identifying its progression to acute respiratory distress syndrome and the presence of secondary bacterial infections ( ) . even though chest ct is considered an essential diagnostic tool for covid- , the extensive use of ct for screening purposes in the suspected individuals might be associated with a disproportionate risk-benefit ratio due to increased radiation exposure as well as increased risk of cross-infection. hence, the use of ct for early diagnosis of sars-cov- infection in high-risk groups should be done with great caution ( ) . more recently, other advanced diagnostics have been designed and developed for the detection of sars-cov- ( , , ( ) ( ) ( ) . a reverse transcriptional loopmediated isothermal amplification (rt-lamp), namely, ilaco, has been developed for rapid and colorimetric detection of this virus ( ) . rt-lamp serves as a simple, rapid, and sensitive diagnostic method that does not require sophisticated equipment or skilled personnel ( ) . an interactive web-based dashboard for tracking sars-cov- in a real-time mode has been designed ( ) . a smartphone-integrated home-based point-of-care testing (poct) tool, a paper-based poct combined with lamp, is a useful point-of-care diagnostic ( ) . an abbott id now covid- molecular poct-based test, using isothermal nucleic acid amplification technology, has been designed as a pointof-care test for very rapid detection of sars-cov- in just min ( ) . a crispr-based sherlock (specific high-sensitivity enzymatic reporter unlocking) diagnostic for rapid detection of sars-cov- without the requirement of specialized instrumentation has been reported to be very useful in the clinical diagnosis of covid- ( ) . a crispr-cas -based lateral flow assay also has been developed for rapid detection of sars-cov- ( ) . artificial intelligence, by means of a three-dimensional deep-learning model, has been developed for sensitive and specific diagnosis of covid- via ct images ( ) . tracking and mapping of the rising incidence rates, disease outbreaks, community spread, clustered transmission events, hot spots, and superspreader potential of sars-cov- /covid warrant full exploitation of real-time disease mapping by employing geographical information systems (gis), such as the gis software kosmo . , web-based real-time tools and dashboards, apps, and advances in information technology ( - ). researchers have also developed a few prediction tools/models, such as the prediction model risk of bias assessment tool (probast) and critical appraisal and data extraction for systematic reviews of prediction modeling studies (charms), which could aid in assessing the possibility of getting infection and estimating the prognosis in patients; however, such models may suffer from bias issues and, hence, cannot be considered completely trustworthy, which necessitates the development of new and reliable predictors ( ) . recently emerged viruses, such as zika, ebola, and nipah viruses, and their grave threats to humans have begun a race in exploring the designing and developing of advanced vaccines, prophylactics, therapeutics, and drug regimens to counter emerging viruses ( ) ( ) ( ) ) . several attempts are being made to design and develop vaccines for cov infection, mostly by targeting the spike glycoprotein. nevertheless, owing to extensive diversity in antigenic variants, cross-protection rendered by the vaccines is significantly limited, even within the strains of a phylogenetic subcluster ( ) . due to the lack of effective antiviral therapy and vaccines in the present scenario, we need to depend solely on implementing effective infection control measures to lessen the risk of possible nosocomial transmission ( ) . recently, the receptor for sars-cov- was established as the human angiotensin-converting enzyme (hace ), and the virus was found to enter the host cell mainly through endocytosis. it was also found that the major components that have a critical role in viral entry include pikfyve, tpc , and cathepsin l. these findings are critical, since the components described above might act as candidates for vaccines or therapeutic drugs against sars-cov- ( ) . the majority of the treatment options and strategies that are being evaluated for sars-cov- (covid- ) have been taken from our previous experiences in treating sars-cov, mers-cov, and other emerging viral diseases. several therapeutic and preventive strategies, including vaccines, immunotherapeutics, and antiviral drugs, have been exploited against the previous cov outbreaks (sars-cov and mers-cov) ( , , ( ) ( ) ( ) ( ) . these valuable options have already been evaluated for their potency, efficacy, and safety, along with several other types of current research that will fuel our search for ideal therapeutic agents against covid- ( , , , , ) . the primary cause of the unavailability of approved and commercial vaccines, drugs, and therapeutics to counter the earlier sars-cov and mers-cov seems to owe to the lesser attention of the biomedicine and pharmaceutical companies, as these two covs did not cause much havoc, global threat, and panic like those posed by the sars-cov- pandemic ( ) . moreover, for such outbreak situations, the requirement for vaccines and therapeutics/drugs exists only for a limited period, until the outbreak is controlled. the proportion of the human population infected with sars-cov and mers-cov was also much lower across the globe, failing to attract drug and vaccine manufacturers and clinical microbiology reviews producers. therefore, by the time an effective drug or vaccine is designed against such disease outbreaks, the virus would have been controlled by adopting appropriate and strict prevention and control measures, and patients for clinical trials will not be available. the newly developed drugs cannot be marketed due to the lack of end users. the s protein plays a significant role in the induction of protective immunity against sars-cov by mediating t-cell responses and neutralizing antibody production ( ) . in the past few decades, we have seen several attempts to develop a vaccine against human coronaviruses by using s protein as the target ( , ) . however, the developed vaccines have minimal application, even among closely related strains of the virus, due to a lack of cross-protection. that is mainly because of the extensive diversity existing among the different antigenic variants of the virus ( ) . the contributions of the structural proteins, like spike (s), matrix (m), small envelope (e), and nucleocapsid (n) proteins, of sars-cov to induce protective immunity has been evaluated by expressing them in a recombinant parainfluenza virus type vector (bhpiv ). of note, the result was conclusive that the expression of m, e, or n proteins without the presence of s protein would not confer any noticeable protection, with the absence of detectable serum sars-cov-neutralizing antibodies ( ) . antigenic determinant sites present over s and n structural proteins of sars-cov- can be explored as suitable vaccine candidates ( ) . in the asian population, s, e, m, and n proteins of sars-cov- are being targeted for developing subunit vaccines against covid- ( ) . the identification of the immunodominant region among the subunits and domains of s protein is critical for developing an effective vaccine against the coronavirus. the c-terminal domain of the s subunit is considered the immunodominant region of the porcine deltacoronavirus s protein ( ) . similarly, further investigations are needed to determine the immunodominant regions of sars-cov- for facilitating vaccine development. however, our previous attempts to develop a universal vaccine that is effective for both sars-cov and mers-cov based on t-cell epitope similarity pointed out the possibility of cross-reactivity among coronaviruses ( ) . that can be made possible by selected potential vaccine targets that are common to both viruses. sars-cov- has been reported to be closely related to sars-cov ( , ) . hence, knowledge and understanding of s protein-based vaccine development in sars-cov will help to identify potential s protein vaccine candidates in sars-cov- . therefore, vaccine strategies based on the whole s protein, s protein subunits, or specific potential epitopes of s protein appear to be the most promising vaccine candidates against coronaviruses. the rbd of the s subunit of s protein has a superior capacity to induce neutralizing antibodies. this property of the rbd can be utilized for designing potential sars-cov vaccines either by using rbd-containing recombinant proteins or recombinant vectors that encode rbd ( ) . hence, the superior genetic similarity existing between sars-cov- and sars-cov can be utilized to repurpose vaccines that have proven in vitro efficacy against sars-cov to be utilized for sars-cov- . the possibility of cross-protection in covid- was evaluated by comparing the s protein sequences of sars-cov- with that of sars-cov. the comparative analysis confirmed that the variable residues were found concentrated on the s subunit of s protein, an important vaccine target of the virus ( ) . hence, the possibility of sars-cov-specific neutralizing antibodies providing cross-protection to covid- might be lower. further genetic analysis is required between sars-cov- and different strains of sars-cov and sarslike (sl) covs to evaluate the possibility of repurposed vaccines against covid- . this strategy will be helpful in the scenario of an outbreak, since much time can be saved, because preliminary evaluation, including in vitro studies, already would be completed for such vaccine candidates. multiepitope subunit vaccines can be considered a promising preventive strategy against the ongoing covid- pandemic. in silico and advanced immunoinformatic tools can be used to develop multiepitope subunit vaccines. the vaccines that are engineered by this technique can be further evaluated using docking studies and, if found effective, then can be further evaluated in animal models ( ) . identifying epitopes that have the potential to become a vaccine candidate is critical to developing an effective vaccine against covid- . the immunoinformatics approach has been used for recognizing essential epitopes of cytotoxic t lymphocytes and b cells from the surface glycoprotein of sars-cov- . recently, a few epitopes have been recognized from the sars-cov- surface glycoprotein. the selected epitopes explored targeting molecular dynamic simulations, evaluating their interaction with corresponding major histocompatibility complex class i molecules. they potentially induce immune responses ( ) . the recombinant vaccine can be designed by using rabies virus (rv) as a viral vector. rv can be made to express mers-cov s protein on its surface so that an immune response is induced against mers-cov. the rv vector-based vaccines against mers-cov can induce faster antibody response as well as higher degrees of cellular immunity than the gram-positive enhancer matrix (gem) particle vector-based vaccine. however, the latter can induce a very high antibody response at lower doses ( ) . hence, the degree of humoral and cellular immune responses produced by such vaccines depends upon the vector used. dual vaccines have been getting more popular recently. among them, the rabies virus-based vectored vaccine platform is used to develop vaccines against emerging infectious diseases. the dual vaccine developed from inactivated rabies virus particles that express the mers-cov s domain of s protein was found to induce immune responses for both mers-cov and rabies virus. the vaccinated mice were found to be completely protected from challenge with mers-cov ( ) . the intranasal administration of the recombinant adenovirus-based vaccine in balb/c mice was found to induce long-lasting neutralizing immunity against mers spike pseudotyped virus, characterized by the induction of systemic igg, secretory iga, and lung-resident memory t-cell responses ( ) . immunoinformatics methods have been employed for the genomewide screening of potential vaccine targets among the different immunogens of mers-cov ( ) . the n protein and the potential b-cell epitopes of mers-cov e protein have been suggested as immunoprotective targets inducing both t-cell and neutralizing antibody responses ( , ) . the collaborative effort of the researchers of rocky mountain laboratories and oxford university is designing a chimpanzee adenovirus-vectored vaccine to counter covid- ( ) . the coalition for epidemic preparedness innovations (cepi) has initiated three programs to design sars-cov- vaccines ( ) . cepi has a collaborative project with inovio for designing a mers-cov dna vaccine that could potentiate effective immunity. cepi and the university of queensland are designing a molecular clamp vaccine platform for mers-cov and other pathogens, which could assist in the easier identification of antigens by the immune system ( ) . cepi has also funded moderna to develop a vaccine for covid- in partnership with the vaccine research center (vrc) of the national institute of allergy and infectious diseases (niaid), part of the national institutes of health (nih) ( ) . by employing mrna vaccine platform technology, a vaccine candidate expressing sars-cov- spike protein is likely to go through clinical testing in the coming months ( ( ) . the process of vaccine development usually takes approximately ten years, in the case of inactivated or live attenuated vaccines, since it involves the generation of long-term efficacy data. however, this was brought down to years during the ebola emergency for viral vector vaccines. in the urgency associated with the covid- outbreaks, we expect a vaccine by the end of this year ( ) . the development of an effective vaccine against covid- with high speed and precision is the combined result of advancements in computational biology, gene synthesis, protein engineering, and the invention of advanced manufacturing platforms ( ) . the recurring nature of the coronavirus outbreaks calls for the development of a pan-coronavirus vaccine that can produce cross-reactive antibodies. however, the success of such a vaccine relies greatly on its ability to provide protection not only against present versions of the virus but also the ones that are likely to emerge in the future. this can be achieved by identifying antibodies that can recognize relatively conserved epitopes that are maintained as such even after the occurrence of considerable variations ( ) . even though several vaccine clinical trials are being conducted around the world, pregnant women have been completely excluded from these studies. pregnant women are highly vulnerable to emerging diseases such as covid- due to alterations in the immune system and other physiological systems that are associated with pregnancy. therefore, in the event of successful vaccine development, pregnant women will not get access to the vaccines ( ) . hence, it is recommended that pregnant women be included in the ongoing vaccine trials, since successful vaccination in pregnancy will protect the mother, fetus, and newborn. the heterologous immune effects induced by bacillus calmette guérin (bcg) vaccination is a promising strategy for controlling the covid- pandemic and requires further investigations. bcg is a widely used vaccine against tuberculosis in high-risk regions. it is derived from a live attenuated strain of mycobacterium bovis. at present, three new clinical trials have been registered to evaluate the protective role of bcg vaccination against sars-cov- ( ) . recently, a cohort study was conducted to evaluate the impact of childhood bcg vaccination in covid- pcr positivity rates. however, childhood bcg vaccination was found to be associated with a rate of covid- -positive test results similar to that of the nonvaccinated group ( ) . further studies are required to analyze whether bcg vaccination in childhood can induce protective effects against covid- in adulthood. population genetic studies conducted on genomes identified that the sars-cov- virus has evolved into two major types, l and s. among the two types, l type is expected to be the most prevalent (ϳ %), followed by the s type (ϳ %) ( ) . this finding has a significant impact on our race to develop an ideal vaccine, since the vaccine candidate has to target both strains to be considered effective. at present, the genetic differences between the l and s types are very small and may not affect the immune response. however, we can expect further genetic variations in the coming days that could lead to the emergence of new strains ( ) . there is no currently licensed specific antiviral treatment for mers-and sars-cov infections, and the main focus in clinical settings remains on lessening clinical signs and providing supportive care ( ) ( ) ( ) ( ) . effective drugs to manage covid- patients include remdesivir, lopinavir/ritonavir alone or in a blend with interferon beta, convalescent plasma, and monoclonal antibodies (mabs); however, efficacy and safety issues of these drugs require additional clinical trials ( , ) . a controlled trial of ritonavirboosted lopinavir and interferon alpha b treatment was performed on covid- hospitalized patients (chictr ) ( ) . in addition, the use of hydroxychloroquine and tocilizumab for their potential role in modulating inflammatory responses in the lungs and antiviral effect has been proposed and discussed in many research articles. still, no fool-proof clinical trials have been published ( , , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . recently, a clinical trial conducted on adult patients suffering from severe covid- revealed no benefit of lopinavir-ritonavir treatment over standard care ( ) . the efforts to control sars-cov- infection utilize defined strategies as followed against mers and sars, along with adopting and strengthening a few precautionary measures owing to the unknown nature of this novel virus ( , ) . presently, the main course of treatment for severely affected sars-cov- patients admitted to hospitals includes mechanical ventilation, intensive care unit (icu) admittance, and symptomatic and supportive therapies. additionally, rna synthesis inhibitors (lamivudine and tenofovir disoproxil fumarate), remdesivir, neuraminidase inhibitors, peptide (ek ), antiinflammatory drugs, abidol, and chinese traditional medicine (lianhuaqingwen and shufengjiedu capsules) could aid in covid- treatment. however, further clinical trials are being carried out concerning their safety and efficacy ( ) . it might require months to a year(s) to design and develop effective drugs, therapeutics, and vaccines against covid- , with adequate evaluation and approval from regulatory bodies and moving to the bulk production of many millions of doses at commercial levels to meet the timely demand of mass populations across the globe ( ) . continuous efforts are also warranted to identify and assess viable drugs and immunotherapeutic regimens that revealed proven potency in combating other viral agents similar to sars-cov- . covid- patients showing severe signs are treated symptomatically along with oxygen therapy. in such cases where the patients progress toward respiratory failure and become refractory to oxygen therapy, mechanical ventilation is necessitated. the covid- -induced septic shock can be managed by providing adequate hemodynamic support ( ) . several classes of drugs are currently being evaluated for their potential therapeutic action against sars-cov- . therapeutic agents that have anti-sars-cov- activity can be broadly classified into three categories: drugs that block virus entry into the host cell, drugs that block viral replication as well as its survival within the host cell, and drugs that attenuate the exaggerated host immune response ( ) . an inflammatory cytokine storm is commonly seen in critically ill covid- patients. hence, they may benefit from the use of timely anti-inflammation treatment. anti-inflammatory therapy using drugs like glucocorticoids, cytokine inhibitors, jak inhibitors, and chloroquine/hydroxychloroquine should be done only after analyzing the risk/benefit ratio in covid- patients ( ). there have not been any studies concerning the application of nonsteroidal anti-inflammatory drugs (nsaid) to covid- -infected patients. however, reasonable pieces of evidence are available that link nsaid uses with the occurrence of respiratory and cardiovascular adverse effects. hence, as a cautionary approach, it is better to recommend the use of nsaids as the first-line option for managing covid- symptoms ( ) . the use of corticosteroids in covid- patients is still a matter of controversy and requires further systematic clinical studies. the guidelines that were put forward to manage critically ill adults suggest the use of systemic corticosteroids in mechanically ventilated adults with ards ( ) . the generalized use of corticosteroids is not indicated in covid- , since there are some concerns associated with the use of corticosteroids in viral pneumonia. stem cell therapy using mesenchymal stem cells (mscs) is another hopeful strategy that can be used in clinical cases of covid- owing to its potential immunomodulatory capacity. it may have a beneficial role in attenuating the cytokine storm that is observed in severe cases of sars-cov- infection, thereby reducing mortality. among the different types of mscs, expanded umbilical cord mscs can be considered a potential therapeutic agent that requires further validation for managing critically ill covid- patients ( ) . repurposed broad-spectrum antiviral drugs having proven uses against other viral pathogens can be employed for sars-cov- -infected patients. these possess benefits of easy accessibility and recognized pharmacokinetic and pharmacodynamic activities, stability, doses, and side effects ( ) . repurposed drugs have been studied for treating cov infections, like lopinavir/ritonavir, and interferon- ␤ revealed in vitro anti-mers-cov action. the in vivo experiment carried out in the nonhuman primate model of clinical microbiology reviews common marmosets treated with lopinavir/ritonavir and interferon beta showed superior protective results in treated animals than in the untreated ones ( ) . a combination of these drugs is being evaluated to treat mers in humans (miracle trial) ( ) . these two protease inhibitors (lopinavir and ritonavir), in combination with ribavirin, gave encouraging clinical outcomes in sars patients, suggesting their therapeutic values ( ) . however, in the current scenario, due to the lack of specific therapeutic agents against sars-cov- , hospitalized patients confirmed for the disease are given supportive care, like oxygen and fluid therapy, along with antibiotic therapy for managing secondary bacterial infections ( ) . patients with novel coronavirus or covid- pneumonia who are mechanically ventilated often require sedatives, analgesics, and even muscle relaxation drugs to prevent ventilator-related lung injury associated with human-machine incoordination ( ) . the result obtained from a clinical study of four patients infected with covid- claimed that combination therapy using lopinavir/ritonavir, arbidol, and shufeng jiedu capsules (traditional chinese medicine) was found to be effective in managing covid- pneumonia ( ) . it is difficult to evaluate the therapeutic potential of a drug or a combination of drugs for managing a disease based on such a limited sample size. before choosing the ideal therapeutic agent for the management of covid- , randomized clinical control studies should be performed with a sufficient study population. several classes of routinely used antiviral drugs, like oseltamivir (neuraminidase inhibitor), acyclovir, ganciclovir, and ribavirin, do not have any effect on covid- and, hence, are not recommended ( ) . oseltamivir, a neuraminidase inhibitor, has been explored in chinese hospitals for treating suspected covid- cases, although proven efficacy against sars-cov- is still lacking for this drug ( ) . the in vitro antiviral potential of fad-approved drugs, viz., ribavirin, penciclovir, nitazoxanide, nafamostat, and chloroquine, tested in comparison to remdesivir and favipiravir (broad-spectrum antiviral drugs) revealed remdesivir and chloroquine to be highly effective against sars-cov- infection in vitro ( ) . ribavirin, penciclovir, and favipiravir might not possess noteworthy in vivo antiviral actions for sars-cov- , since higher concentrations of these nucleoside analogs are needed in vitro to lessen the viral infection. both remdesivir and chloroquine are being used in humans to treat other diseases, and such safer drugs can be explored for assessing their effectiveness in covid- patients. several therapeutic agents, such as lopinavir/ritonavir, chloroquine, and hydroxychloroquine, have been proposed for the clinical management of covid- ( ) . a molecular docking study, conducted in the rna-dependent rna polymerase (rdrp) of sars-cov- using different commercially available antipolymerase drugs, identified that drugs such as ribavirin, remdesivir, galidesivir, tenofovir, and sofosbuvir bind rdrp tightly, indicating their vast potential to be used against covid- ( ). a broadspectrum antiviral drug that was developed in the united states, tilorone dihydrochloride (tilorone), was previously found to possess potent antiviral activity against mers, marburg, ebola, and chikungunya viruses ( ) . even though it had broad-spectrum activity, it was neglected for an extended period. tilorone is another antiviral drug that might have activity against sars-cov- . remdesivir, a novel nucleotide analog prodrug, was developed for treating ebola virus disease (evd), and it was also found to inhibit the replication of sars-cov and mers-cov in primary human airway epithelial cell culture systems ( ) . recently, in vitro study has proven that remdesivir has better antiviral activity than lopinavir and ritonavir. further, in vivo studies conducted in mice also identified that treatment with remdesivir improved pulmonary function and reduced viral loads and lung pathology both in prophylactic and therapeutic regimens compared to lopinavir/ritonavir-ifn-␥ treatment in mers-cov infection ( ) . remdesivir also inhibits a diverse range of coronaviruses, including circulating human cov, zoonotic bat cov, and prepandemic zoonotic cov ( ) . remdesivir is also considered the only therapeutic drug that significantly reduces pulmonary pathology ( ) . all these findings indicate that remde-sivir has to be further evaluated for its efficacy in the treatment of covid- infection in humans. the broad-spectrum activity exhibited by remdesivir will help control the spread of disease in the event of a new coronavirus outbreak. chloroquine is an antimalarial drug known to possess antiviral activity due to its ability to block virus-cell fusion by raising the endosomal ph necessary for fusion. it also interferes with virus-receptor binding by interfering with the terminal glycosylation of sars-cov cellular receptors, such as ace ( ) . in a recent multicenter clinical trial that was conducted in china, chloroquine phosphate was found to exhibit both efficacy and safety in the therapeutic management of sars-cov- -associated pneumonia ( ) . this drug is already included in the treatment guidelines issued by the national health commission of the people's republic of china. the preliminary clinical trials using hydroxychloroquine, another aminoquinoline drug, gave promising results. the covid- patients received mg of hydroxychloroquine daily along with azithromycin as a single-arm protocol. this protocol was found to be associated with a noteworthy reduction in viral load. finally, it resulted in a complete cure ( ) ; however, the study comprised a small population and, hence, the possibility of misinterpretation could arise. however, in another case study, the authors raised concerns over the efficacy of hydroxychloroquine-azithromycin in the treatment of covid- patients, since no observable effect was seen when they were used. in some cases, the treatment was discontinued due to the prolongation of the qt interval ( ) . hence, further randomized clinical trials are required before concluding this matter. recently, another fda-approved drug, ivermectin, was reported to inhibit the in vitro replication of sars-cov- . the findings from this study indicate that a single treatment of this drug was able to induce an ϳ , -fold reduction in the viral rna at h in cell culture. ( ) . one of the main disadvantages that limit the clinical utility of ivermectin is its potential to cause cytotoxicity. however, altering the vehicles used in the formulations, the pharmacokinetic properties can be modified, thereby having significant control over the systemic concentration of ivermectin ( ) . based on the pharmacokinetic simulation, it was also found that ivermectin may have limited therapeutic utility in managing covid- , since the inhibitory concentration that has to be achieved for effective anti-sars-cov- activity is far higher than the maximum plasma concentration achieved by administering the approved dose ( ) . however, ivermectin, being a host-directed agent, exhibits antiviral activity by targeting a critical cellular process of the mammalian cell. therefore, the administration of ivermectin, even at lower doses, will reduce the viral load at a minor level. this slight decrease will provide a great advantage to the immune system for mounting a large-scale antiviral response against sars-cov- ( ). further, a combination of ivermectin and hydroxychloroquine might have a synergistic effect, since ivermectin reduces viral replication, while hydroxychloroquine inhibits the entry of the virus in the host cell ( ) . further, in vivo studies and randomized clinical control trials are required to understand the mechanism as well as the clinical utility of this promising drug. nafamostat is a potent inhibitor of mers-cov that acts by preventing membrane fusion. nevertheless, it does not have any sort of inhibitory action against sars-cov- infection ( ) . recently, several newly synthesized halogenated triazole compounds were evaluated, using fluorescence resonance energy transfer (fret)-based helicase assays, for their ability to inhibit helicase activity. among the evaluated compounds, -(cyclopent- -en- -ylamino)- -[ -( -iodophenyl) hydrazinyl]- h- , , -triazole- -thiol and -(cyclopent- -en- -ylamino)- -[ -( -chlorophenyl) hydrazinyl]- h- , , -triazole- -thiol were found to be the most potent. these compounds were used for in silico studies, and molecular docking was accomplished into the active binding site of mers-cov helicase nsp ( ) . further studies are required for evaluating the therapeutic potential of these newly identified compounds in the management of covid- infection. monoclonal antibodies (mabs) may be helpful in the intervention of disease in clinical microbiology reviews cov-exposed individuals. patients recovering from sars showed robust neutralizing antibodies against this cov infection ( ) . a set of mabs aimed at the mers-cov s protein-specific domains, comprising six specific epitope groups interacting with receptor-binding, membrane fusion, and sialic acid-binding sites, make up crucial entry tasks of s protein ( , ) . passive immunization employing weaker and strongly neutralizing antibodies provided considerable protection in mice against a mers-cov lethal challenge. such antibodies may play a crucial role in enhancing protective humoral responses against the emerging covs by aiming appropriate epitopes and functions of the s protein. the cross-neutralization ability of sars-cov rbd-specific neutralizing mabs considerably relies on the resemblance between their rbds; therefore, sars-cov rbd-specific antibodies could cross-neutralized sl covs, i.e., bat-sl-cov strain wiv (rbd with eight amino acid differences from sars-cov) but not bat-sl-cov strain shc ( amino acid differences) ( ) . appropriate rbd-specific mabs can be recognized by a relative analysis of rbd of sars-cov- to that of sars-cov, and cross-neutralizing sars-cov rbd-specific mabs could be explored for their effectiveness against covid- and further need to be assessed clinically. the u.s. biotechnology company regeneron is attempting to recognize potent and specific mabs to combat covid- . an ideal therapeutic option suggested for sars-cov- (covid- ) is the combination therapy comprised of mabs and the drug remdesivir (covid- ) ( ) . the sars-cov-specific human mab cr is found to bind with sars-cov- rbd, indicating its potential as a therapeutic agent in the management of covid- . it can be used alone or in combination with other effective neutralizing antibodies for the treatment and prevention of covid- ( ) . furthermore, sars-cov-specific neutralizing antibodies, like m and cr , failed to bind the s protein of sars-cov- , indicating that a particular level of similarity is mandatory between the rbds of sars-cov and sars-cov- for the cross-reactivity to occur. further assessment is necessary before confirming the effectiveness of such combination therapy. in addition, to prevent further community and nosocomial spread of covid- , the postprocedure risk management program should not be neglected ( ) . development of broad-spectrum inhibitors against the human coronaviral pathogens will help to facilitate clinical trials on the effectiveness of such inhibitors against endemic and emerging coronaviruses ( ) . a promising animal study revealed the protective effect of passive immunotherapy with immune serum from mers-immune camels on mice infected with mers-cov ( ) . passive immunotherapy using convalescent plasma is another strategy that can be used for treating covid- -infected, critically ill patients ( ) . the exploration of fully human antibodies (human single-chain antibodies; huscfvs) or humanized nanobodies (single-domain antibodies; sdab, vh/vhh) could aid in blocking virus replication, as these agents can traverse the virus-infected cell membranes (transbodies) and can interfere with the biological characteristics of the replicating virus proteins. such examples include transbodies to the influenza virus, hepatitis c virus, ebola virus, and dengue virus ( ) . producing similar transbodies against intracellular proteins of coronaviruses, such as papain-like proteases (plpro), cysteinelike protease ( clpro), or other nsps, which are essential for replication and transcription of the virus, might formulate a practical move forward for a safer and potent passive immunization approach for virus-exposed persons and rendering therapy to infected patients. in a case study on five grimly sick patients having symptoms of severe pneumonia due to covid- , convalescent plasma administration was found to be helpful in patients recovering successfully. the convalescent plasma containing a sars-cov- specific elisa (serum) antibody titer higher than : , and neutralizing antibody titer more significant than was collected from the recovered patients and used for plasma transfusion twice in a volume of to ml on the day of collection ( ) . at present, treatment for sepsis and ards mainly involves antimicrobial therapy, source control, and supportive care. hence, the use of therapeutic plasma exchange can be considered an option in managing such severe conditions. further randomized trials can be designed to investigate its efficacy ( ) . potent therapeutics to combat sars-cov- infection include virus binding molecules, molecules or inhibitors targeting particular enzymes implicated in replication and transcription process of the virus, helicase inhibitors, vital viral proteases and proteins, protease inhibitors of host cells, endocytosis inhibitors, short interfering rna (sirna), neutralizing antibodies, mabs against the host receptor, mabs interfering with the s rbd, antiviral peptide aimed at s , and natural drugs/medicines ( , , ) . the s protein acts as the critical target for developing cov antivirals, like inhibitors of s protein and s cleavage, neutralizing antibodies, rbd-ace blockers, sirnas, blockers of the fusion core, and proteases ( ) . all of these therapeutic approaches have revealed both in vitro and in vivo anti-cov potential. although in vitro research carried out with these therapeutics showed efficacy, most need appropriate support from randomized animal or human trials. therefore, they might be of limited applicability and require trials against sars-cov- to gain practical usefulness. the binding of sars-cov- with ace leads to the exacerbation of pneumonia as a consequence of the imbalance in the reninangiotensin system (ras). the virus-induced pulmonary inflammatory responses may be reduced by the administration of ace inhibitors (acei) and angiotensin type- receptor (at r) ( ) . several investigations have suggested the use of small-molecule inhibitors for the potential control of sars-cov infections. drugs of the fda-approved compound library were screened to identify four small-molecule inhibitors of mers-cov (chlorpromazine, chloroquine, loperamide, and lopinavir) that inhibited viral replication. these compounds also hinder sars-cov and human covs ( ) . therapeutic strategies involving the use of specific antibodies or compounds that neutralize cytokines and their receptors will help to restrain the host inflammatory responses. such drugs acting specifically in the respiratory tract will help to reduce virus-triggered immune pathologies in covid- ( ) . the later stages of coronavirus-induced inflammatory cascades are characterized by the release of proinflammatory interleukin- (il- ) family members, such as il- and il- . hence, there exists a possibility that the inflammation associated with coronavirus can be inhibited by utilizing anti-inflammatory cytokines that belong to the il- family ( ) . it has also been suggested that the actin protein is the host factor that is involved in cell entry and pathogenesis of sars-cov- . hence, those drugs that modulate the biological activity of this protein, like ibuprofen, might have some therapeutic application in managing the disease ( ). the plasma angiotensin level was found to be markedly elevated in covid- infection and was correlated with viral load and lung injury. hence, drugs that block angiotensin receptors may have potential for treating covid- infection ( ) . a scientist from germany, named rolf hilgenfeld, has been working on the identification of drugs for the treatment of coronaviral infection since the time of the first sars outbreak ( ) . the sars-cov s subunit has a significant function in mediating virus fusion that provides entry into the host cell. heptad repeat (hr ) and heptad repeat (hr ) can interact and form a six-helix bundle that brings the viral and cellular membranes in close proximity, facilitating its fusion. the sequence alignment study conducted between covid- and sars-cov identified that the s subunits are highly conserved in these covs. the hr and hr domains showed . % and % overall identity, respectively ( ) . from these findings, we can confirm the significance of covid- hr and hr and their vital role in host cell entry. hence, fusion inhibitors target the hr domain of s protein, thereby preventing viral fusion and entry into the host cell. this is another potential therapeutic strategy that can be used in the management of covid- . other than the specific therapy directed against covid- , general treatments play a vital role in the enhancement of host immune responses against the viral agent. inadequate nutrition is linked to the weakening of the host immune response, clinical microbiology reviews making the individual more susceptible. the role played by nutrition in disease susceptibility should be measured by evaluating the nutritional status of patients with covid- ( ) . for evaluating the potential of vaccines and therapeutics against covs, including sars-cov, mers-covs, and the presently emerging sars-cov- , suitable animal models that can mimic the clinical disease are needed ( , ) . various animal models were assessed for sars-and mers-covs, such as mice, guinea pigs, golden syrian hamsters, ferrets, rabbits, nonhuman primates like rhesus macaques and marmosets, and cats ( , ( ) ( ) ( ) ( ) ( ) ( ) . the specificity of the virus to hace (receptor of sars-cov) was found to be a significant barrier in developing animal models. consequently, a sars-cov transgenic mouse model has been developed by inserting the hace gene into the mouse genome ( ) . the inability of mers-cov to replicate in the respiratory tracts of animals (mice, hamsters, and ferrets) is another limiting factor. however, with genetic engineering, a - ϩ/ϩ mers-cov genetically modified mouse model was developed and now is in use for the assessment of novel drugs and vaccines against mers-cov ( ). in the past, small animals (mice or hamsters) have been targeted for being closer to a humanized structure, such as mouse dpp altered with human dpp (hdpp ), hdpp -transduced mice, and hdpp -tg mice (transgenic for expressing hdpp ) for mers-cov infection ( ) . the crispr-cas gene-editing tool has been used for inserting genomic alterations in mice, making them susceptible to mers-cov infection ( ) . efforts are under way to recognize suitable animal models for sars-cov /covid- , identify the receptor affinity of this virus, study pathology in experimental animal models, and explore virus-specific immune responses and protection studies, which together would increase the pace of efforts being made for developing potent vaccines and drugs to counter this emerging virus. cell lines, such as monkey epithelial cell lines (llc-mk and vero-b ), goat lung cells, alpaca kidney cells, dromedary umbilical cord cells, and advanced ex vivo three-dimensional tracheobronchial tissue, have been explored to study human covs (mers-cov) ( , ) . vero and huh- cells (human liver cancer cells) have been used for isolating sars-cov- ( ) . recently, an experimental study with rhesus monkeys as animal models revealed the absence of any viral loads in nasopharyngeal and anal swabs, and no viral replication was recorded in the primary tissues at a time interval of days post-reinfection in reexposed monkeys ( ) . the subsequent virological, radiological, and pathological observations indicated that the monkeys with reexposure had no recurrence of covid- , like the sars-cov- -infected monkeys without rechallenge. these findings suggest that primary infection with sars-cov- could protect from later exposures to the virus, which could help in defining disease prognosis and crucial inferences for designing and developing potent vaccines against covid- ( ). in contrast to their response to the sars outbreak, china has shown immense political openness in reporting the covid- outbreak promptly. they have also performed rapid sequencing of covid- at multiple levels and shared the findings globally within days of identifying the novel virus ( ) . the move made by china opened a new chapter in global health security and diplomacy. even though complete lockdown was declared following the covid- outbreak in wuhan, the large-scale movement of people has resulted in a radiating spread of infections in the surrounding provinces as well as to several other countries. large-scale screening programs might help us to control the spread of this virus. however, this is both challenging as well as time-consuming due to the present extent of infection ( ) . the current scenario demands effective implementation of vigorous prevention and control strategies owing to the prospect of covid- for nosocomial infections ( ) . follow-ups of infected patients by telephone on day and day are advised to avoid any further unintentional spread or nosocomial transmission ( ) . the availability of public data sets provided by independent analytical teams will act as robust evidence that would guide us in designing interventions against the covid- outbreak. newspaper reports and social media can be used to analyze and reconstruct the progression of an outbreak. they can help us to obtain detailed patient-level data in the early stages of an outbreak ( ) . immediate travel restrictions imposed by several countries might have contributed significantly to preventing the spread of sars-cov- globally ( , ) . following the outbreak, a temporary ban was imposed on the wildlife trade, keeping in mind the possible role played by wild animal species in the origin of sars-cov- /covid- ( ) . making a permanent and bold decision on the trade of wild animal species is necessary to prevent the possibility of virus spread and initiation of an outbreak due to zoonotic spillover ( ) . personal protective equipment (ppe), like face masks, will help to prevent the spread of respiratory infections like covid- . face masks not only protect from infectious aerosols but also prevent the transmission of disease to other susceptible individuals while traveling through public transport systems ( ) . another critical practice that can reduce the transmission of respiratory diseases is the maintenance of hand hygiene. however, the efficacy of this practice in reducing the transmission of respiratory viruses like sars-cov- is much dependent upon the size of droplets produced. hand hygiene will reduce disease transmission only if the virus is transmitted through the formation of large droplets ( ) . hence, it is better not to overemphasize that hand hygiene will prevent the transmission of sars-cov- , since it may produce a false sense of safety among the general public that further contributes to the spread of covid- . even though airborne spread has not been reported in sars-cov- infection, transmission can occur through droplets and fomites, especially when there is close, unprotected contact between infected and susceptible individuals. hence, hand hygiene is equally as important as the use of appropriate ppe, like face masks, to break the transmission cycle of the virus; both hand hygiene and face masks help to lessen the risk of covid- transmission ( ) . medical staff are in the group of individuals most at risk of getting covid- infection. this is because they are exposed directly to infected patients. hence, proper training must be given to all hospital staff on methods of prevention and protection so that they become competent enough to protect themselves and others from this deadly disease ( ) . as a preventive measure, health care workers caring for infected patients should take extreme precautions against both contact and airborne transmission. they should use ppe such as face masks (n or ffp ), eye protection (goggles), gowns, and gloves to nullify the risk of infection ( ) . the human-to-human transmission reported in sars-cov- infection occurs mainly through droplet or direct contact. due to this finding, frontline health care workers should follow stringent infection control and preventive measures, such as the use of ppe, to prevent infection ( ) . the mental health of the medical/health workers who are involved in the covid- outbreak is of great importance, because the strain on their mental well-being will affect their attention, concentration, and decision-making capacity. hence, for control of the covid- outbreak, rapid steps should be taken to protect the mental health of medical workers ( ) . since the living mammals sold in the wet market are suspected to be the intermediate host of sars-cov- , there is a need for strengthening the regulatory mechanism for wild animal trade ( ) . the total number of covid- confirmed cases is on a continuous rise and the cure rate is relatively low, making disease control very difficult to achieve. the chinese government is making continuous efforts to contain the disease by taking emergency control and prevention measures. they have already built a hospital for patients affected by this virus and are currently building several more for accommodating the continuously increasing infected population ( ) . the effective control of sars-cov- /covid- requires high-level interventions like intensive contact tracing, as well as the quarantine of people with suspected infection and the isolation of infected individuals. the implementation of rigorous control and preventive measures together might control the r number and reduce the transmission risk ( ) . clinical microbiology reviews considering the zoonotic links associated with sars-cov- , the one health approach may play a vital role in the prevention and control measures being followed to restrain this pandemic virus ( ) ( ) ( ) . the substantial importation of covid- presymptomatic cases from wuhan has resulted in independent, self-sustaining outbreaks across major cities both within the country and across the globe. the majority of chinese cities are now facing localized outbreaks of covid- ( ) . hence, deploying efficient public health interventions might help to cut the spread of this virus globally. the occurrence of covid- infection on several cruise ships gave us a preliminary idea regarding the transmission pattern of the disease. cruise ships act as a closed environment and provide an ideal setting for the occurrence of respiratory disease outbreaks. such a situation poses a significant threat to travelers, since people from different countries are on board, which favors the introduction of the pathogen ( ). although nearly cruise ships from different countries have been found harboring covid- infection, the major cruise ships that were involved in the covid- outbreaks are the diamond princess, grand princess, celebrity apex, and ruby princess. the number of confirmed covid- cases around the world is on the rise. the success of preventive measures put forward by every country is mainly dependent upon their ability to anticipate the approaching waves of patients. this will help to properly prepare the health care workers and increase the intensive care unit (icu) capacity ( ) . instead of entirely relying on lockdown protocols, countries should focus mainly on alternative intervention strategies, such as large-scale testing, contract tracing, and localized quarantine of suspected cases for limiting the spread of this pandemic virus. such intervention strategies will be useful either at the beginning of the pandemic or after lockdown relaxation ( ) . lockdown should be imposed only to slow down disease progression among the population so that the health care system is not overloaded. the reproduction number (r ) of covid- infection was earlier estimated to be in the range of . to . ( ); recently, it was estimated to be . to . ( ) . compared to its coronavirus predecessors, covid- has an r value that is greater than that of mers (r Ͻ ) ( ) but less than that of sars (r value of to ) ( ) . still, to prevent further spread of disease at mass gatherings, functions remain canceled in the affected cities, and persons are asked to work from home ( ) . hence, it is a relief that the current outbreak of covid- infection can be brought under control with the adoption of strategic preventive and control measures along with the early isolation of subsequent cases in the coming days. studies also report that since air traffic between china and african countries increased many times over in the decade after the sars outbreak, african countries need to be vigilant to prevent the spread of novel coronavirus in africa ( ) . due to fear of virus spread, wuhan city was completely shut down ( ) . the immediate control of the ongoing covid- outbreaks appears a mammoth task, especially for developing countries, due to their inability to allocate quarantine stations that could screen infected individuals' movements ( ) . such underdeveloped countries should divert their resources and energy to enforcing the primary level of preventive measures, like controlling the entry of individuals from china or countries where the disease has flared up, isolating the infected individuals, and quarantining individuals with suspected infection. most of the sub-saharan african countries have a fragile health system that can be crippled in the event of an outbreak. effective management of covid- would be difficult for low-income countries due to their inability to respond rapidly due to the lack of an efficient health care system ( ) . controlling the imported cases is critical in preventing the spread of covid- to other countries that have not reported the disease until now. the possibility of an imported case of covid- leading to sustained human-to-human transmission was estimated to be . . this can be reduced to a value of . by decreasing the mean time from the onset of symptoms to hospitalization and can only be made possible by using intense disease surveillance systems ( ) . the silent importations of infected individuals (before the manifestation of clinical signs) also contributed significantly to the spread of disease across the major cities of the world. even though the travel ban was implemented in wuhan ( ) , infected persons who traveled out of the city just before the imposition of the ban might have remained undetected and resulted in local outbreaks ( ) . emerging novel diseases like covid- are difficult to contain within the country of origin, since globalization has led to a world without borders. hence, international collaboration plays a vital role in preventing the further spread of this virus across the globe ( ) . we also predict the possibility of another outbreak, as predicted by fan et al. ( ) . indeed, the present outbreak caused by sars-cov- (covid- ) was expected. similar to previous outbreaks, the current outbreak also will be contained shortly. however, the real issue is how we are planning to counter the next zoonotic cov epidemic that is likely to occur within the next to years or even sooner (fig. ) . several years after the global sars epidemic, the current sars-cov- /covid- pandemic has served as a reminder of how novel pathogens can rapidly emerge and spread through the human population and eventually cause severe public health crises. further research should be conducted to establish animal models for sars-cov- to investigate replication, transmission dynamics, and pathogenesis in humans. this may help develop and evaluate potential therapeutic strategies against zoonotic cov epidemics. present trends suggest the occurrence of future outbreaks of covs due to changes in the climate, and ecological conditions may be associated with humananimal contact. live-animal markets, such as the huanan south china seafood market, represent ideal conditions for interspecies contact of wildlife with domestic birds, pigs, and mammals, which substantially increases the probability of interspecies transmission of cov infections and could result in high risks to humans due to adaptive genetic recombination in these viruses ( ) ( ) ( ) . the covid- -associated symptoms are fever, cough, expectoration, headache, and myalgia or fatigue. individuals with asymptomatic and atypical clinical manifestations were also identified recently, further adding to the complexity of disease transmission dynamics. atypical clinical manifestations may only express symptoms such as fatigue instead of respiratory signs such as fever, cough, and sputum. in such cases, the clinician must be vigilant for the possible occurrence of asymptomatic and atypical clinical manifestations to avoid the possibility of missed diagnoses. the present outbreak caused by sars-cov- was, indeed, expected. similar to clinical microbiology reviews previous outbreaks, the current pandemic also will be contained shortly. however, the real question is, how are we planning to counter the next zoonotic cov epidemic that is likely to occur within the next to years or perhaps sooner? our knowledge of most of the bat covs is scarce, as these viruses have not been isolated and studied, and extensive studies on such viruses are typically only conducted when they are associated with specific disease outbreaks. the next step following the control of the covid- outbreak in china should be focused on screening, identification, isolation, and characterization of covs present in wildlife species of china, particularly in bats. both in vitro and in vivo studies (using suitable animal models) should be conducted to evaluate the risk of future epidemics. presently, licensed antiviral drugs or vaccines against sars-cov, mers-cov, and sars-cov- are lacking. however, advances in designing 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recent advances and emerging trends point-of-care rna-based diagnostic device for covid- rapid colorimetric detection of covid- coronavirus using a reverse transcriptional loop-mediated isothermal amplification (rt-lamp) diagnostic plat-form: ilaco mapping the incidence of the covid- hotspot in iran-implications for travellers covid- : preparing for superspreader potential among umrah pilgrims to saudi arabia geographical tracking and mapping of coronavirus disease covid- /severe acute respiratory syndrome coronavirus (sars-cov- ) epidemic and associated events around the world: how st century gis technologies are supporting the global fight against outbreaks and epidemics policy decisions and use of information technology to fight novel coronavirus disease prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal consider pregnancy in covid- therapeutic drug and vaccine trials rational vaccine design in the time of covid- bacillus calmette guérin (bcg) vaccination use in the fight against covid- -what's old is new again? sars-cov- rates in bcg-vaccinated and unvaccinated young adults high throughput and comprehensive approach to develop multiepitope vaccine against minacious covid- on the origin and continuing evolution of sars-cov- covid- : the race for a vaccine all authors substantially contributed to the conception, design, analysis, and interpretation of data and checking and approving the final version of the manuscript, and we agree to be accountable for its contents.this compilation is a review article written, analyzed, and designed by its authors and required no substantial funding to be developed.all authors declare that there are no existing commercial or financial relationships that could, in any way, lead to a potential conflict of interest. with years of research and teaching experience in the areas of microbiology, immunology, virology, public health, medicine, and biomedicine as an eminent researcher, he has developed several diagnostics, vaccines, immunomodulatory modules, and hypotheses to counter infectious diseases of animals, poultry, and public health concerns. he has to his credit publications, books, and book chapters. dr. dhama has been recognized as an extremely productive researcher in the journal nature. he has been honored with best paper awards and other recognitions. he is an naas (national academy of agricultural science, india) associate and has worked as nodal officer, wto, and member, wildlife health specialist group (iucn). he is actively serving as editor-in-chief, co-eic, editor, and member, editorial board, of nearly scientific journals. his google scholar h-index is and scopus h-index is . sharun khan, m.v.sc., is currently working as a researcher in the stem cell laboratory, division of surgery, icar-indian veterinary research institute, izatnagar, india. his area of interest is regenerative medicine with a focus on understanding cell biology and molecular pathways involved in the maintenance and differentiation of stem cells originating from different tissues. he has particular interest and knowledge in the fields of veterinary medicine, pharmacology, infectious diseases of animals, wildlife diseases, diagnosis and therapy of animal diseases, nutrition, and biomedicine. with excellent academic records, he has received awards and recognitions (fellowships and scholarships) and participated in national and international workshops, training programs, and courses. he has a keen interest in learning excellent scientific writing skills and has published papers, including in international journals of repute. he is highly enthusiastic about gaining knowledge of advancements in educational and scientific research areas.ruchi tiwari is currently working as assistant professor in the department of veterinary microbiology, college of veterinary sciences, duvasu, mathura, india. she is currently pursuing her ph.d. (hons) degree from duvasu. with an excellent academic record and years of research and teaching experience, she has expertise in the field of diagnosis, prevention, and control of important livestock/poultry diseases/pathogens having public health significance, along with particular reference to veterinary microbiology, immunology, ethnoveterinary medicine, alternative and complementary therapies, and bacteriophage therapy. dr. tiwari has published research/review articles and book chapters. she has been honored with the young scientist award, best paper awards ( ) key: cord- - amiljnm authors: clements, bruce w.; casani, julie ann p. title: emerging and reemerging infectious disease threats date: - - journal: disasters and public health doi: . /b - - - - . - sha: doc_id: cord_uid: amiljnm this chapter describes the potential public health impact of emerging and reemerging disease. factors contributing to the emergence of diseases include increasing international travel and commerce, changes in human demographics and behavior, advances in technology and industry, microbial adaptation and the breakdown of public health systems. of emerging diseases, % are zoonotic, making the human–animal biome interaction critical. preparedness for an emerging disease relies on strong biosurveillance systems for early detection. control measures to prevent transmission must be implemented early. these include: rapid epidemiologic surveillance and investigations to characterize the disease; transmission prevention through containment and control measures; development and deployment of medical countermeasures; and emergency public information and warning. recovery after the outbreak of an emerging disease can result in a “new normal” with persistent endemic infection in the community. emerging and reemerging infectious disease threats objectives • describe why diseases "emerge" or "reemerge." • discuss the impact of emerging infectious diseases on public health preparedness. • list the likely sources of emerging infectious diseases in the future. • describe how international travel and commerce contribute to emerging infectious disease threats. • discuss how microbial adaptation contributes to emerging infectious disease threats. • list human demographic factors and behaviors contributing to emerging infectious disease threats. • identify the epidemiological clues indicating a possible emerging disease. • describe various types of surveillance approaches. • discuss the breakdown of public health measures and systems. • recognize the actions needed for responding to an emerging disease. on a friday afternoon before the labor day holiday weekend in , the phone at the new york city department of health was answered by the on-call epidemiologist. an infectious disease specialist was calling to report an unusually large number of encephalitis or meningitis cases (inflammation of the brain or covering of the brain and spinal cord) at several hospitals in the borough of queens. blood and spinal fluid were tested at the new york state and cdc laboratories and reported positive for saint louis encephalitis virus (slev), a virus known to occur in the united states but never in new york city. new york city officials immediately began mosquito control programs in an attempt to stop transmission from mosquitoes, the vector for slev. over the next week, test results appeared to be conflicting. unknown to many of the investigators of the human outbreak, a veterinarian at the bronx zoo was investigating an outbreak of central nervous system disease in birds. wildlife veterinarians were also observing large bird die-offs but could not find a clear cause. by mid-september, both sets of investigators believed the causative agent was not slev. by september , after expanding testing services to several federal and academic laboratories as well as to the wider family of flaviviridae, it was confirmed that the causative agent for the human outbreak, the avian outbreak, and sentinel mosquito sampling was west nile virus (see fig. - ). by , the new york city outbreak included confirmed cases and deaths (johnston and conly, ) . by that time, the west nile virus was documented as having spread halfway across the united states to the rocky mountains (roehrig, ) . on april , , a sample was routinely tested from a young girl with influenza-like illness as part of the us sentinel influenza network. the results indicated this was a uniquely novel strain of influenza a (see fig. - ). on april , , a similar result was confirmed miles from the originally identified case. testing also confirmed that this virus was resistant to both amantadine and rimantadine but sensitive to both oseltamivir and zanamivir, two readily available antiviral medications. there had been sporadic cases of influenza with infection of viruses in the swine lineage, and it was suspected and later confirmed that this novel influenza a, h n , was a unique combination of genes most closely related to north american swine-lineage h n and eurasian swine-lineage h n . in the two initial cases, no contact with pigs was discovered through extensive investigation, and it was determined that this novel virus had been spread to these cases by human-to-human transmission, a new behavior for h n . by april , additional cases were identified in texas, and samples collected from an outbreak in mexico were also positive for this new strain. by april , a public health emergency, the first in the history of the united states, was declared to allow for the rapid development of a vaccine, mobilization of antiviral medications through the federally resourced strategic national stockpile, and enhanced surveillance through reporting and testing. travel advisories were put into place, and upon discovery of additional cases internationally, the world health organization (who) raised the pandemic level from phase to the pandemic level phase . the largest number of cases occurred in people between the ages of and years old. major figure - a culex quinquefasciatus mosquito is known as one of the many arthropodal vectors responsible for spreading arboviral encephalitis or west nile virus to human beings through their bite. photo by james gathany courtesy of the centers for disease control and prevention, public health image library. morbidity (illness) and mortality (death) occurred in pregnant women, and middle-aged people with chronic diseases and obesity, but overall the fatality rate was low. few cases were reported in people over the age of , indicating that this group may have had immunity. levels of influenza illness remained high in the summer of , unusual for the north american continent. rapid molecular analysis of the viral genome led to rapid production of a vaccine. in the late summer, the food and drug administration announced the monovalent vaccine would be licensed via a "strain change" pathway, which is similar to how seasonal influenza vaccines are licensed. this meant production would be expedited, since the same methods would be used as those used to produce seasonal flu vaccine and additional safety and validation studies would not need to be completed. by september, , months after the first case was identified, prototype vaccine was delivered to us states for use. h n is now included in seasonal vaccines (gatherer, ). ebola virus disease (evd) was first described in in two simultaneous outbreaks in sub-saharan africa. in december , a small outbreak of evd was reported in a forested area in southeastern guinea (see fig. - ). it has been postulated that the index case, a boy, was in direct contact with bats. this was the th reported ebola outbreak in history but the first to be reported in west africa. evd then spread to liberia and sierra leone, all through direct contact with the outbreak in guinea (who, ) . in guinea, liberia, and sierra leone as of august , , there have been over , cases and , deaths. a small outbreak of cases occurred in nigeria, and one case occurred in senegal. several cases were reported outside of the area, mostly in healthcare or humanitarian workers returning to their home countries. there were also imported cases in the united states and spain which led to secondary infections of medical workers but did not spread further. in both countries, the management of companion animals and environmental cleanup were challenging issues. several factors contributed to the devastation of this epidemic: poverty, population density, infrastructure decline after years of armed conflict, serious gaps in health and medical infrastructure with little to no surge capacity, and a delay in coordinated response. in spite of the significant risk to underresourced healthcare workers (comprising % of the dead), a major humanitarian medical response was launched internationally. in october , controls on people traveling out of the area went into effect with exit screening for symptoms, entry screening in most countries, and active monitoring of travelers in some countries after arrival. this screening program controlled movement and by actively monitoring attempts to identify people who may become ill early in the course of the disease, getting them to healthcare in a controlled manner and with appropriate infection control practices in place. healthcare facilities and providers in many countries stockpiled personal protective equipment, implemented infection control training, and implemented screening processes in order to be prepared. on january , , the who reported for the first time since the week ending june , , that there had been fewer than new confirmed cases reported. the focus of the response shifted from slowing transmission to ending the epidemic. in july , results of early testing of a vaccine appeared very promising. by the end of , the ebola outbreak in west africa reached over , cases and , deaths making it the largest ebola outbreak in history (cdc, ) . prior to this, the largest was a - uganda outbreak with cases and deaths (cdc, ) . at the time this chapter was written, public health professionals around the world continued to watch closely the progression toward stopping, and continued success in recovering from, this devastating ebola epidemic. bacteria plural of bacterium. a single-celled microorganism that can exist independently as a free-living organism or as parasite dependent upon a host organism. emerging infectious diseases illnesses caused by pathogenic organisms with an increasing incidence in humans. infectious diseases with increased incidence over the past two decades or those which threaten to increase in the near future are considered "emerging." emerging infectious diseases include pathogens which are newly evolving, spreading to new geographic areas, are previously unrecognized, or are old infections reemerging due to lapses in public health measures. fungi single-celled or multicellular organisms which cause infections in healthy persons or serve as opportunistic pathogens in persons who are immune compromised. examples include histoplasmosis and aspergillosis. helminths parasitic worms which live in humans or other animals and derive nourishment from their host. examples include the tapeworm, fluke, or nematode. healthcare-associated infection (hai) an adverse localized or systemic infectious condition occurring in a healthcare setting with no evidence that the infection was present at the time of admission. pathogen a biological organism capable of causing disease or illness to its host. prion the smallest infectious particle. it is an infectious strand of protein which replicates and leads to disease, and is similar to a virus. prions are the causative agents of diseases such as mad cow disease and creutzfeldt-jakob disease. protozoa a single-celled parasitic organism that can only multiply inside a host organism. r nought (r ) a metric widely used in assessing disease transmissibility or the basic reproductive rate. it represents the average number of subsequent cases which one case generates during its infectious period. rickettsia a group of microorganisms requiring other living cells for growth like viruses, but having cell walls, using oxygen, and having metabolic enzymes like bacteria. rickettsia are typically transmitted by ticks, mites, or lice. typhus is one example of a disease caused by rickettsia. virus an infectious organism consisting of a nucleic acid molecule in a protein coat. it is only able to multiply inside the living cells of a host. emerging infectious diseases (eids) are some of the most challenging public health issues facing the global community. the hypothesis of "disease emergence" may have helped shaped the growth of global health initiatives, particularly at the world health organization (brown et al., ; lakoff, ) . eids are caused by pathogens that: ( ) have increased in incidence, geographic, or host range; ( ) have changed pathogenesis; ( ) have newly evolved; or ( ) have been discovered or newly recognized (lederberg et al., ) . in most developed countries, routine and seasonal outbreaks challenge health departments and healthcare systems, but reporting, investigation, and treatment protocols are typically in place, trained on, and easily implemented. vaccination programs and antiviral and antimicrobial medications mitigate many recurring infectious disease risks. those who have been exposed to or infected with recurring illnesses have developed some immunity. however, novel infectious diseases pose challenges that often exceed the immune function of populations and the capabilities of public health systems around the world. there are several factors that permit infections previously not seen globally or in specific locations to emerge or reemerge after periods of quiescence. those factors include: international travel and commerce and the movement of goods and people permits the movement of sick people and disease vectors into areas previously not visited, thereby exposing others to pathogens previously not encountered. international tourism has expanded consistently for over years. from to it grew more than ten-fold from million in to million in . it nearly doubled again between to reaching million and again by reaching . billion. annual growth in tourism is expected to grow by over % each year reaching . billion international annual tourist arrivals in (un, ). modern transportation systems allow for rapid movement of people and with them diffusion of illness at a greater speed than during the preavia tion travel era. when travel was slower, often by caravan or ship, those who were ill could recover, layover, or succumb without transporting disease as easily. increased international travel is believed to have played a major role in the spread of hiv/aids. some virologists suspect that hiv was present at very low levels in remote areas of west africa for perhaps as long as years in animals before the disease reached epidemic proportions and was officially isolated by scientists in (krause). hunting animals as a source of protein created greater exposure of humans to the disease, and development of the transcontinental highway from point-noire, zaire (now the democratic republic of congo) to mombasa, kenya, may have allowed truck drivers and traders along this route to carry the virus into the general population. airline travel has its own unique risks, with recirculated air in the confined space of an aircraft which could expose travelers to airborne diseases such as tuberculosis (see fig. - ) . passenger compartment conditions have some similarities to the holds of ships in sea-crossings known historically for harboring eids. with the ease of global travel, people with increased luxury income can visit developing countries, exposing those populations to novel diseases, or return home with novel infections after several hours of airline travel and before signs or symptoms of illness become apparent. economic development may result in changes of land use from agriculture to industry, disrupting established ecosystems. altering natural habitats by building dams and creating deforestation-reforestation programs alters the balance of ecosystems, allowing some species to overflourish or die out. additionally, there may be movement of people into land previously occupied by vegetation and animals, exposing those who resettle to novel or previously contained pathogens and/or vectors. zoonotic diseases, those which infect animals, comprise - % of eids (taylor et al., ) . in the coming plague: newly emerging diseases in a world out of balance, medical journalist laurie garret writes "in this fluid complexity, human beings stomp about with swagger, elbowing their way without concern into one ecosphere after another (garrett, ) ." in addition, the effect of climate change on emerging diseases is unknown; however, lindgren et al. ( ) point out that climate change interacts with "a complex web" of all drivers of emerging diseases and therefore cannot be ignored. alterations of the geographic ranges of birds in europe and north america have also been demonstrated. many migrating birds carry pathogens, and changes to migratory bird habitats may result in human exposures to new pathogens (fuller et al., ) . climate change may also have effects on vector development, vector physiology, and vector habitat, ultimately affecting human vector-borne disease risks (parham et al., ) . human demographic factors and behavior including population density, population growth, and population distribution not only may affect the spread of people into geographic regions not previously inhabited, but it also can expose them to new pathogens. in addition, it may affect how disease transmission occurs from human to human. in many parts of the world, an increase in urban population is not matched by an increase in urban infrastructure and is accompanied by poverty, poor sanitation, and inadequate housing. conflict can result in population shifts to new geographic areas, disruption of critical infrastructure (including public health and health systems), and economic stress. poverty from any cause not only affects sanitation and vector control, but may force people into risk behaviors such as entering the sex trade. once ill, people living in poverty may not have access to healthcare or even have basic hygiene resources. they also may be unable to comply with isolation measures. as populations continue to age and advanced medical interventions such as chemotherapy and immunosuppressive biologicals alter immune function, diseases previously not known to infect humans can emerge. behaviors such as sexual activity and illicit drug use may also impact novel disease transmission. understanding human relationships with animals provides additional insights into eid risks (see fig. - ). sixty percent of recent emerging diseases are zoonotic. colocation of open poultry markets and cohabitation with poultry has been identified as an important risk factor for human cases of avian influenza (dinh et al., ; thorson et al., ; choi et al., ) . human cases of high pathogenic avian influenza have occurred in workers depopulating flocks in the netherlands and canada (koopmans et al., ; tweed et al., ) . fortunately, few of these outbreaks to date have sustained human-to-human transmission. in , an investigation of a large multistate outbreak of monkeypox was traced back to prairie dogs sold as exotic pets. the prairie dogs had been in close contact with giant gambian rats from ghana (cdc, a) . this outbreak resulted in increased controls of imported exotic animals and markets. the source of the severe acute respiratory syndrome (sars) outbreak has never clearly been identified. the index cases were initially linked to catlike exotic pets related to raccoons called "civet cats" (cdc, b) . this resulted in extensive bans on civet cat transportation and commerce. however, detailed investigation links the causative coronavirus to several wild animals used as food, and there are suggestions that the trade of many types of animals used in food was the source (cdc, a,b; he, a,b; normille and enserink, ; guan et al., ; ng, ) . bats play an important role in ecosystems in vector control, seed dispersal, and pollination. however, it is increasingly recognized that bats also play a significant role in the reservoir and transmission of zoonotic infections. contact with bats has long been recognized as a potential source for rabies, but several findings indicate that bats have a wider spectrum of diseases and may be a reservoir for paramyxoviruses such as measles, mumps, distemper, parainfluenza (drexler et al., ; messenger et al., ) , and ebola (leroy et al., ) . freidl et al. ( ) recently discovered antibodies for influenza a h in bats. influenza a h is a zoonotic disease and is a possible candidate for a novel pandemic strain. human interactions with bats and their habitats can occur in the workplace, home or recreational venues. in an observational study in western ghana, nearly half of the residents had contact with bats and bat habitats (anti et al., ) . reengineering and reopening closed facilities where bats have populated must be made with prevention methods in place. entering caves where bats and other animals live must also be approached with infectious disease precautions in mind. technology and industry certainly have tremendous human benefits but may also expose populations to conditions which foster eids. some of the most significant issues are changes in food production. mass agricultural compounds and facilities create environments where changes occur in microbial ecology. globalization of the food supply allows transportation of organisms on and in food and through accompanying vectors. food transportation over large distances may also introduce breaches in food security. advances in medical technology introduce techniques that allow bacteria to infect people and spaces not formerly at risk. increases in invasive procedures can result in the introduction of novel organisms. n n n an epidemiological investigation in traced the source of a mysterious meningitis outbreak to contamination of methylprednisolone acetate, a steroid injected to relieve back pain. several lots of the drug were contaminated with a rare fungus called exserohilum rostratum. over , patients were potentially exposed and had confirmed infections, resulting in deaths across states (smith et al., ) . the cdc healthcare-associated infection (hai) survey of a large sampling of us acute care hospitals found on any given day, about in hospital patients has at least one hai (see table - ). there were an estimated , hais in us acute care hospitals in , and about , patients died during their hospitalizations. more than half of all hais occurred outside of the intensive care unit. contaminated gastrointestinal and bronchoscopy endoscopic devices are among the many advanced technologies associated with increasing outbreaks in healthcare settings, including those of organisms such as pseudomonas aeruginosa and salmonella spp. (kovalevaa et al., ) . the us food and drug administration, whose responsibilities include medical devices, issued a warning in march of raising awareness that several devices with complex designs may be difficult to adequately clean. many causative agents of healthcare associated infections are especially dangerous but their transmission is preventable. while some causative agents are more common bacteria and viruses such as escherichia coli or norovirus, many are less common, including acinetobacter, burkholderia, clostridium, and klebsiella. in addition, antibiotic-resistant strains such as carbapenem-resistant enterobacteriaceae, methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococci and s. aureus are more difficult to control and treat. after the establishment of the european union in the s and increased economic growth, patient transfer within and between countries expanded. after political changes and the opening of borders, medical care and technology improved. for example, the number of bone-marrow transplant units in central europe increased from to by , and the number of dialysis units increased from approximately to more than (krcmery, ) . however, vincent et al. ( ) reported in a one-day prevalence study that % of icu patients in western europe had nosocomial or healthcare-associated infections by microorganisms including p. aeruginosa and methicillin-resistant staphylococcus. microbial adaptation contributes to the development of "super-bugs." this includes both bacteria and viruses (see figs. - and - ). as discussed in the previous section, antimicrobial resistance is pervasive and is increasing in the face of widespread overuse and misuse of antibiotics. in addition, viruses rapidly adapt to immunologic responses. influenza viruses provide an example of genetic drift and shift which make them a persistent health threat. once formed, novel influenza viruses sometimes pose health risks for which humans and/or animals have little to no immunologic protection. these viruses can also develop an increased capacity for animal-to-animal or human-to-human sustained transmission. breakdown in public health systems and measures as a result of conflict, economicbased program cuts, or poor infrastructure can produce environments with increased risk and decreased prevention. this situation may result in disease emergence, but may also to read the full report, please visit the cdc hai prevalence survey (magill et al., ) . result in reemergence of diseases. diseases which had previously been controlled through sanitation, vector control, or vaccination programs can reemerge if any of the prevention programs fail or stop. in developed countries with successful vaccination campaigns, many diseases have been declared "controlled" or "eradicated." because of this, political and public interest in continued vaccination programs is waning, or personal risk is considered low relative to the risk (real or perceived) of vaccinations. in the united states there are also many states allowing "opt-out" programs so people may choose not to get vaccinated or have their children vaccinated. in numerous outbreaks this has proved problematic. n n n the us antivaccination movement has contributed to increased preventable illnesses and deaths. it is led by misguided conspiracy theorists, minor celebrities, and a small number of "healthcare professionals" who are either unfamiliar with or in denial of the science supporting vaccinations. the above headline appeared in january in the new york times (nagourney and goodnough, ) . notable quotes from this report include: • "we can expect to see many more cases of this preventable disease unless people take measures to prevent it," dr. gilberto f. chavez, the deputy director of the california center for infectious diseases, said. "i am asking unvaccinated californians to consider getting vaccinated against measles." • dr. james cherry, a specialist in pediatric infectious diseases at ucla, said the outbreak was " percent connected" to the anti-immunization campaign. "it would not have happened otherwise-it would not have gone anywhere," he said. "there are some pretty dumb people out there." • "the problem is that there are these pockets with low vaccination rates," said dr. jane seward, deputy director of the viral diseases division at the cdc. "if a case comes into a population where a lot of people are unvaccinated, that's where you get the outbreak and where you get the spread." n n n in ghent, belgium, a measles outbreak was associated with an anthroposophic school which promotes "complementary medicine" (braeye et al., ) . over cases of measles were identified in a school that had low vaccination rates because of the philosophical beliefs of the parents. leaders of the school were not against vaccination. striking the balance between individual rights and beliefs, relative risk perception and acceptance, and public health priorities is always challenging. while the next emerging disease can be of any species of infectious organism, trends in recent cases display patterns suggesting which threats may be imminent (see table - ). coronaviruses such as the causative agents of sars and middle east respiratory syndrome co-v (mers co-v); filoviruses such as ebola; and novel influenza viruses, are considered likely candidates. in a study by taylor et al., an analysis of emerging species revealed that of those known, there are currently emerging species. viruses and prions are less than half of the total ( %), and bacteria or rickettsia comprise just under one-third. these potential pathogens may be transmitted by several routes, and the most common route is direct contact ( %), followed by indirect contact ( %), vectors ( %), and for % the route of transmission is unknown (taylor et al., ) . while it may not be possible to predict which pathogens may emerge or reemerge, it is possible to build infrastructure and take general steps to make populations and public health systems better prepared for the next novel infectious disease outbreak. at the heart of these measures is epidemiological surveillance. identification of a new illness or disease requires surveillance systems which not only continually monitor "routine" illness, but also have the ability to recognize anomalies when something is not "routine." as described in chapter "bioterrorism," there have been extensive efforts toward developing early warning epidemiological and environmental surveillance systems for unusual diseases and pathogens. the vital link in identifying a novel disease in a community is the astute clinician. clinicians must be able to recognize a novel disease, report it appropriately, and feel confident that the information will be quickly analyzed and acted upon. laboratory support is vital to quickly identifying and characterizing an emerging threat. this includes testing for drug resistance to inform decision-making concerning appropriate medical countermeasures. continued epidemiological surveillance throughout an outbreak can produce data which may be useful in evaluating and improving the public health and medical response. n n n • surveillance • robust outbreak investigation practices • transmission prevention through containment and control measures • delivery of medical countermeasures, if any • public messaging • recovery to a "new normal" n n n along with surveillance is the ability of public health responders to perform detailed outbreak investigations to determine the characteristics of the disease. characterization of the outbreak, identifying the natural course of the illness, and recognizing key risks for infection are necessary in order to learn how the new illness behaves in a population (see fig. - ) . this information will also inform control measure decisions. a priority item in the initial characterization of an outbreak is the identification of transmissibility. unfortunately, as surveillance methods are enhanced and cases are increasingly recognized and reported, transmissibility may be a very difficult thing to quantify. for example, the current analyses of transmissibility for mers co-v suggest that it is not a likely pandemic threat because of its low reproduction number or "r nought" (r ). however, different cluster sizes, demographics, geographies, and public health and healthcare infrastructures may alter the outbreak characteristics and the reproduction number (r ) (fisman et al., ) . capturing critical data will allow for accurate characterization within the context of the outbreak and will direct response activities such as control measures and medical surge management. the primary control strategy in all infectious disease outbreaks is preventing transmission. even minimal biosecurity actions can prevent animal-to-human transmission. separation of potential source animals, such as exotic imported animals and poultry, from routines such as cooking can reduce risk. effective cleaning of animal waste and habitats should be performed with at least basic respiratory protection. to prevent human-to-human transmission, good hygiene practices such as hand washing, general surface cleaning, and careful waste disposal should be reinforced. during the - h n pandemic, people were advised to "cough hygienically" into their sleeve to prevent contamination of the hands and then others. of note, this technique was not without some controversy and was not recommended in the united kingdom and spain (anderson, ) . supplying hand wipes and hand sanitizer may be implemented in some locations of businesses, critical industries, and government agencies where other measures may not be reasonable. social distancing by school closures, limiting mass gatherings, and canceling large events may be necessary (see figs. - and - ). quarantine may be considered for individuals who have been exposed but are not yet sick, typically for two incubation periods of the disease. isolation separates those who are already ill from those who are not ill. in healthcare settings, isolation may begin from early screening of patients at points of entry. this may limit disease transmission to other patients who often have underlying conditions which increase their risks for severe illnesses and complications. risk management for communicable diseases in emergency departments includes signage to encourage patients to self-identify if they are sick or have an associated travel history. this allows for rapid triage to isolation areas and early institution of personal protective equipment for staff (puro et al., ) . in a study conducted of facilities in european countries, % had isolation rooms, but not all had anterooms, negative pressure, or hepa filtration. only . % had all components. personnel trained in the recognition of highly infectious diseases were available in of the , and management protocols were available in of the (fusco et al., ) . it would be interesting to see how attention paid to diseases such as ebola has impacted these numbers. in addition to human-to-human spread, animal-to-human spread is a common transmission route for eids. zoonotic disease professionals can develop recommendations for vector control when zoonotic diseases threaten human populations. mosquitoes are the most pervasive disease-carrying vectors. control measures include reducing standing water breeding sources or using larvicides and adulticides. the recent introduction of engineered aedes aegypti mosquitoes (ox a), which can reproduce and produce offspring which die rapidly, shows promise in areas with emerging dengue fever (specter, ) . once control measures are determined, public health agencies must have the legal and social authority to implement recommended measures. the majority of the population typically complies with basic containment measures such as improved hygiene, avoiding ill people, etc. however, some individuals may be reluctant or unable to comply. for example, minimally ill people without paid sick leave may not be able to stay at home without significant economic loss. people may, out of fear, choose to flee quarantine zones. in these cases, agencies need to have flexible, scalable authorities to limit travel outside areas known to have disease. the challenges with quarantine measures were apparent throughout the international response to the - west african ebola epidemic. in the united states as in many countries, the government has the authority to restrict stateto-state and international travel. state and local health agencies have authority to control intrastate activities. however, political pressure may make it difficult to enact some control measures. school closure is one of the more difficult decisions for government agencies during a public health emergency. for many communicable diseases, children can act as superspreaders because of their behaviors and hygiene lapses. however, many schools function not only as places of education but also deliver significant social programs: safe havens, meals, and day care for working parents with marginal income. to close these schools disrupts very necessary social welfare programs. quarantine laws must also respect civil liberties. in the united states for example, quarantine orders must be the least restrictive form of control, have very clear reasons, be timelimited and allow for appeal. enforcement of quarantine orders requires law enforcement officers to interact, sometimes in close physical proximity, with potentially contagious individuals. additionally, any enforcement of quarantine of an individual must be heard in the judicial system. the judiciary has its own constitutional constraints of process which are frequently in opposition to the goals of quarantine. if the eid is susceptible to antibiotics or a vaccine is quickly developed, rapid distribution and dispensing of these medical countermeasures must be conducted. if the illness is highly contagious, programs limiting public interaction during mass dispensing and mass vaccinations will need to be implemented. as discussed throughout this text, it is unlikely that there will be large quantities of medical countermeasures available early on in an emerging or reemerging infectious disease outbreak. therefore, plans must also be in place for the utilization of scarce resources while complying with ethical and legal frameworks. throughout the entire outbreak, appropriate public messaging must be delivered. messages will contain information about the illness, personal protective actions, and where to go for health care. these messages must communicate risk and how individuals can limit morbidity and mortality. general prescripted public health messages can often be adapted early in an outbreak when detailed information on the threat is not yet specific. trusted leaders in the community should be used to deliver messages in order to improve compliance and alleviate fear. a "new normal" may follow as a community recovers from a novel outbreak. some eids become endemic diseases in affected communities and must be included in recurring public health activities. for example, west nile virus was first introduced to the western hemisphere in the late s and is now an annual threat, causing , cases from to and deaths (cdc, ) . however, public health responses help to establish new practices in order to limit reemergence. these activities also prepare the community for similar eid threats. because of ongoing west nile virus threats in north america, the region is better prepared for emerging threats such as chikungunya and dengue. public health has been challenged with eids throughout human history. with globalization of populations, commerce, and travel comes globalization of infectious diseases. this exposes people and animals to novel diseases for which they have little to no natural immunity. rapid transportation and free movement allows sick individuals to spread illness and disease faster than ever before. preparedness efforts cannot predict the next emerging infection, but public health and healthcare capabilities developed, lessons learned from prior outbreaks, and institutionalization of routine infection control practices may serve to lessen the impact. european centre for disease prevention and control 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cord_uid: rafcdzhm background: severe acute respiratory syndrome (sars) coronavirus-like viruses continue to circulate in animal reservoirs. if new mutants of sars coronavirus do initiate another epidemic, administration of prophylactic antibodies to risk groups may supplement the stringent isolation procedures that contained the first sars outbreak. method: we developed a mathematical model to investigate the effects of hospital admission and targeted antibody prophylaxis on the reproduction number r, defined as the number of secondary cases generated by an index case, during different sars outbreak scenarios. results: assuming a basic reproduction number r( )= , admission of patients to hospital within . days of symptom onset is necessary to achieve outbreak control without the need to further reduce community-based transmission. control may be enhanced by providing pre-exposure prophylaxis to contacts of hospitalized patients, and through contact tracing and provision of post-exposure prophylaxis. antibody prophylaxis may also be employed to reduce r below one and thereby restrict outbreak size and duration. conclusions: patient isolation alone can be sufficient to control sars outbreaks provided that the time from onset to admission is short. antibody prophylaxis as supplemental measure generally allows for containment of higher r( ) values and restricts both the size and duration of an outbreak. severe acute respiratory syndrome (sars) was the first major outbreak of a newly emergent communicable disease in the st century, affecting over persons on multiple continents. its appearance stirred an unprecedented coordinated effort to control transmission and morbidity, motivated by fears that local outbreaks might give rise to a major pandemic within months. from the onset, mathematical modeling has proven to be a very useful tool for evaluating the impact of the control measures instigated. [ ] [ ] [ ] the sars outbreak originated in the guangdong province of china, from where it spread to hong kong and next to vietnam, singapore and canada. on march , the world health organization (who) issued a second global alert together with a name for the new disease and a case definition. the outbreak was fully contained by july , the last case occurring in canada. sars coronavirus, the causative agent of the new disease, , most likely was transmitted to humans by the masked palm civet (paguma larvata). adaptation to human transmission is possible through a single mutation in the spike glycoprotein of a civet sars-like virus. , as sars-like viruses continue to circulate in animal reservoirs, , the risk of another major outbreak remains. the identification of measures that make sars controllable is key in planning a public health response to future outbreaks. measures that successfully controlled the sars epidemic could probably be supplemented by specific antiviral strategies, such as protective ring vaccination or targeted antibody prophylaxis. although a protective vaccine against sars is still elusive, antibodies with neutralizing capacity have been characterized, specifically human monoclonal antibodies directed against the spike glycoprotein of sars coronavirus. prophylactic administration of such an antibody in ferrets before intratracheal challenge with a high dose of human sars coronavirus completely prevented the development of lung pathology and abolished viral shedding in pharyngeal secretions. these data suggest that antibody prophylaxis might offer clinical protection against sars and block air-borne transmission of sars coronavirus. to evaluate the potential of antibody administration as prophylaxis in sars outbreak control, we designed a mathematical model. in this model a distinction was made between sars transmission before and after an infected individual was hospitalized. we considered two qualitatively different strategies of antibody administration: first, pre-exposure prophylaxis targeted at susceptible persons coming into contact with hospitalized sars cases (e.g. health care workers or close friends and relatives); and second, post-exposure prophylaxis targeted at exposed persons having been identified through contact tracing of hospitalized sars cases. based on our model, we derived an expression for the effective reproduction number of sars to study conditions for containment and we explored how the size and duration of an outbreak depend on the efficacy of control. the model is a modification of the discrete-time seir model, the modification being that we distinguish between infectious individuals in the community and those that are hospitalized and possibly put in quarantine (fig. ) . we suppose that death or recovery only occur after a person has been admitted to hospital. in addition, we suppose that those infected or removed constitute only a small fraction of the total population, i.e. s is taken to be approximately constant. this simplifies the transmission dynamics to an essentially linear system. consequently, the model does not apply to the stage of an epidemic where saturation of incidence will occur due to high prevalence of infection and/or natural immunity. to allow for time-dependent transition and transmission probabilities, we divided every state into categories that denote either the time since infection or the time since onset of clinical symptoms. within each model state and category, independent identically distributed bernoulli trials are performed for every person to determine whether an asymptomatically infected person becomes symptomatic and thus infective (probability f); whether a symptomatic and infectious person is admitted to hospital (probability z); or whether a hospitalized patient recovers or dies from complications due to sars (probability g). the parameter f depends on the time since infection, whereas the parameters z and g depend on the time since onset of clinical symptoms. the infectivity of an individual also depends on the time since onset of clinical symptoms. the time from infection to onset of clinical symptoms and the duration of the symptomatic period reflect specific biological features of the virus-host interaction. we assume that their distributions are not affected by intervention measures. the assumption of invariant distributions seems reasonable because therapeutic treatment is currently not available for sars coronavirus infection. it follows that hospitalization does not alter the overall duration of the symptomatic period, although it may affect infectivity. conversely, the conditional probability that a hospitalized patient recovers or dies from complications due to sars depends on the cumulative probability that a person has article in press figure schema of the flow of individuals between epidemiological compartments. members of the susceptible population (compartment s) may become infected after contact with an infectious person. infected persons first enter an asymptomatic phase. because there is no evidence of pre-symptomatic transmission of sars, we assume that infectivity begins with the onset of clinical symptoms. hence, the exposed population (compartment e) is composed of non-infectious, asymptomatically infected individuals whereas the infectious population (compartment i) is composed of symptomatically infected individuals, some of which have been diagnosed with sars and are admitted to hospital (superscript h). as death from sars takes place on a similar timescale as recovery, we consider a composite endpoint of persons who have either died or recovered from sars (compartment r). been admitted to hospital, as follows: here, f t denotes the cumulative probability that an infected person becomes symptomatic at or before day t of infection; g t denotes the cumulative probability that a symptomatic person recovers or dies at or before day t of disease; and h t denotes the probability that a symptomatic person is admitted to hospital at or before day t of disease. with b t we denote the expected number of secondary infections at day t since onset of clinical symptoms. it is the product of the infectivity of an infected individual and the daily number of close contacts with susceptible persons. for simulation purposes, we assume that the number of secondary infections follows a poisson distribution with expectation b t . hospitalization results in a transmission rate reduction, such that the number of secondary infections follows a poisson distribution with expectation cb t with co . let h t denote the unconditional probability that a person is admitted to hospital at day t of disease. let u t;k be the probability that a person admitted to hospital at day t of disease is not discharged at or before day t þ k. we assume that discharge only occurs after a person has been admitted to hospital, hence g t ph t . the probability that a person is not discharged at or before day t þ k, conditional on being admitted to hospital at day t, is the reproduction number of an infectious disease is defined as the expected number of secondary cases generated by an index case. assuming that transmission before onset of clinical symptoms does not occur, the reproduction number can be formulated as we assume that f t and g t are both determined by the biological features of the virus and the human host. in contrast, h t and b t will change through adaptive behavior, although the extent to which these can be manipulated is limited by infrastructural and behavioral constraints. given functions for the distribution of onset-to-admission time and transmission rate before the implementation of public health measures, we define the basic reproduction number r as the average number of secondary cases before intervention is in place. general control measures are those not specifically aimed at sars coronavirus infection per se. in this paper, we focus on transmission rate reduction following hospitalization (lowering c) and shortening the time from onset of disease to hospital admission (altering h t ). contact rate reduction in the general population, also known as social distancing, will affect the expected number of secondary infections for any day prior to hospitalization (altering b t ). administration of antibodies can be considered in two ways. pre-exposure prophylaxis is aimed at preventing infection, whereas post-exposure prophylaxis to persons already infected may prevent clinical symptoms and block further transmission. to this end, we define v t as the probability that a contact of a person who transmitted infection at day t of disease will be supplied with antibodies before development of symptomatic disease. let w t;k denote the conditional probability that a person who transmitted infection at day t of disease is hospitalized at day t þ k, then we can write here, p denotes the traceable fraction of an index case's contacts, where we adopted a fixed duration of r days for a contact to be traced. if transmission occurs within the hospital, w t; ¼ and the expression reduces to else, w t;k should be evaluated conditional on the probability of not being admitted to hospital before day t. hence, if we assume that contact tracing with post-exposure prophylaxis will be performed once pre-exposure prophylaxis has brought hospital-based transmission to an end, then the expected number of secondary cases generated by an index case reduces to we define the critical immunization coverage as the minimal fraction p of contacts traced within r days to be immunized in order to reduce r below one given a particular r . model parameters and their baseline values are listed in table . f t has been fitted to a gamma distribution with mean . days and variance . days . g t was obtained by fitting a weibull distribution to the times from symptom onset to either death or recovery. using percentage survival minus discharge from hospital as reported for three age categories, we obtained a mean duration of . days. taken together, the total time spent in compartments e and i thus averages month. the expected number of secondary infections at day t since onset of clinical symptoms was assumed to obey the functional form: this form is suggested by the observation that viral load in pharyngeal secretions peaks in the second week after onset of clinical symptoms and declines thereafter. additional follow-up studies of viral shedding showed that one in four sars patients still tested positive month after symptom onset. by fitting b t to the percentage testing positive over time we obtained an estimate of the parameter a . the product of infectivity and contact rate was subsequently rescaled through a to obtain a given basic reproduction number r . the average number of secondary cases generated by an index case before the issuance of the first global sars alert was approximately , but varied substantially over time and between geographic locations. scaling of b t presumes knowledge of h t and c. h t was assumed to follow a gamma distribution, with variance set equal to mean . as we obtained most parameters from the literature pertaining to the sars outbreak in hong kong, we scaled infectiousness conditionally on a mean time from onset of disease to diagnosis of . days, which was the average interval for hospital admission during the weeks prior to the first global sars alert. in line with initial estimates that hospitalized patients transmitted infection at about % of the rate of symptomatic patients in the community, we took a baseline value c ¼ : . an outbreak cannot be contained whenever the expected number of secondary infections generated by an index case exceeds one. the condition for outbreak control can be formulated as here, y is the proportion of secondary infections occurring prior to hospital admission. clearly, an outbreak can only be contained when the average index case has not transmitted infection prior to hospital admission. thus, yro is a necessary condition for outbreak control. if this condition is not met, community-based transmission is enough to sustain epidemic growth. the condition yro can be met through social distancing or through admission interval reduction. using baseline parameter values, we estimate yr ¼ : , i.e. with a mean admission interval of . days approximately two out of every three infections occur prior to hospital admission. if social distancing alone was to account for outbreak control, contact rate would have to decline by ðr À Þ=yr ¼ %. shortening the time from onset of disease to hospital admission and thereby decreasing the opportunity for community-based transmission, is more efficient to control the spread of sars. an average admission interval of . days would bring yr just below one. however, at c ¼ : the number of secondary infections occurring within hospitals is in itself enough to sustain epidemic growth with an admission interval of . days (fig. a) . hospital transmission rate needs to be less than % of communitybased transmission in order to achieve ro without having to rely on contact rate reduction in the general population (fig. b) . the sars outbreaks in were characterized by a considerable degree of heterogeneity in the number of secondary cases generated by an index case. epidemic curves were particularly shaped by the occurrence of clusters of exceptionally high transmission, termed ''super-spreading events'' (sses). , the extent to which sses affect the reproduction number of infection depends on their relative frequency and magnitude, and these in turn determine the opportunity for outbreak control. we therefore investigated the robustness of control through admission interval reduction and patient isolation procedures in the containment of sars transmission over a range of basic reproduction numbers. reduction of the admission interval is insufficient to contain sars outbreaks with r ¼ at c ¼ : . if patients were already admitted to hospital before onset of clinical symptoms, corresponding to a zero admission interval, an hospital outbreak could be contained if r o . at c ¼ . ; if r o . at c ¼ . ; or if r o . at c ¼ . (fig. c) . reducing the relative rate of hospital transmission thus y cumulative distribution function in days since infection. z the mean and variance of the distribution are denoted by m and s , respectively. y cumulative distribution function in days since onset of clinical symptoms. z the shape and scale of the distribution are denoted by a and b, respectively. ÃÃ before implementation of control measures. yy the symbol t denotes the time (in days) since onset of clinical symptoms. zz fitted to the percentage sars patients with viral shedding in nasopharyngeal aspirate , and subsequently scaled to r . yy applies to model with pre-and/or post-exposure antibody prophylaxis. facilitates control over an extended range of r values, especially for short admission intervals. pre-exposure prophylaxis targeted at susceptible persons coming into contact with hospitalized sars patients could be very effective in reducing hospital transmission. even if prophylaxis would have limited efficacy, the range of reproduction numbers over which outbreak control can be achieved may increase significantly. if patients are already admitted to hospital before onset of clinical symptoms, the range of reproduction numbers that can be contained increases by a factor e , where e denotes the fraction of the target population that remains susceptible in spite of immunization. as an example, if antibody prophylaxis would render three out of four persons non-susceptible to infection, i.e. e ¼ , the range of reproduction numbers that can be contained would increase by a factor four (fig. c) . the range of reproduction numbers that can be contained with an admission interval greater than zero may also improve significantly through targeted pre-exposure anti-body prophylaxis. if hospital transmission could be blocked completely, the range of r values that can be contained increases steeply with admission interval reduction (fig. c) . when general measures (such as patient isolation procedures) are able to reduce hospital transmission rate to c ¼ . , outbreaks can be contained if r o . with a -day admission interval. pre-exposure antibody prophylaxis targeted at those coming into contact with hospitalized sars patients could improve the condition for outbreak control to r o . for e ¼ and to r o . for e ¼ . the critical coverage of an index case's contacts that must be supplied with post-exposure prophylaxis to achieve ro increases with r and with the time from onset of disease to hospital admission. for large admission intervals, outbreak control via contact tracing and post-exposure prophylaxis is only possible with relatively low transmissibility. for instance, full coverage with a -day admission interval would just suffice to keep an outbreak at bay if r o . , assuming no transmission occurs after hospitalization and table ). the dotted line in (a) refers to the condition for containment ro . in (b), the dotted line refers to the baseline value of c ¼ . . (c) shows how the condition for containment depends on the basic reproduction number, with the dotted line referring to the baseline value r ¼ . day is needed for a contact to be traced, i.e. c ¼ and r ¼ (fig. a) . with a -day admission interval, full coverage could be sufficient to contain an outbreak characterized by r o . post-exposure prophylaxis generally extends the range of r values that can be contained, but the extent to which control is facilitated depends on the admission interval. the extent to which post-exposure prophylaxis in the community can enhance control is also limited by the time that is required for contact tracing. the range of reproduction numbers that can be contained declines when more days are needed for a contact to be traced. for instance, with p ¼ . the range of reproduction numbers that can be contained with a -day admission interval reduces from r o . to r o . if contact tracing takes days instead of one (fig. b) . ongoing hospital transmission effectively reduces the range over which control can be achieved, especially for less effective contact tracing (fig. c) . antibody prophylaxis may be employed to achieve ro if this has not been achieved already through admission interval reduction and patient isolation procedures. antibody prophylaxis might also be employed to reduce r below one. the size and duration of an outbreak become increasingly restricted as r approaches zero. as the number of secondary infections follows a poisson distribution, the probability of an index case not transmitting infection is exp{-r}. the distribution of the size of an outbreak x generated from n initial cases is of the form : this distribution is appropriately defined for xxn and ro . when r is reduced by a factor j then the probability that no transmission occurs from n initial cases increases by a factor expfð jÞnrg. on the other hand, the probability that an outbreak generated from n initial cases attains a final size x n decreases by a factor j x n expfð jÞxrg. from this it can be inferred that the expectation of the size of an outbreak diminishes as r approaches zero. the benefit of antibody prophylaxis in reducing r below one was verified by stochastic simulation. estimates of outbreak size and duration are based on a thousand model runs, each seeded with n ¼ initial cases and r ¼ . in simulations, the average time from onset of disease to hospitalization is assumed to decline from the baseline value of . to days once the first couple of sars patients have been identified. hospital transmission rate is set at % of community-based transmission. these measures figure critical vaccination coverage for containment of sars transmission as a function of the basic reproduction number r and the time from onset of disease to hospital admission. in (a) and (b), it is assumed that hospital-based transmission is effectively blocked, i.e. c ¼ . the duration of contact tracing for post-exposure prophylaxis is set at r ¼ day in (a) and at r ¼ days in (b). in (c), the duration of contact tracing is set at r ¼ day, but hospital-based transmission is assumed to continue at % of the rate of community-based transmission, i.e. c ¼ . . yield r ¼ . , hence they are in principle enough to contain an outbreak. to investigate the additional benefit of antibody prophylaxis, we compare this baseline model to a model with pre-exposure prophylaxis, given to all persons who come into contact with hospitalized sars patients, and to a model with both pre-and post-exposure prophylaxis, given to a fraction of persons contacted prior to hospital admission. in the latter model, it is assumed that % of contacts can be traced within days of an index case's hospital admission. an outbreak may take considerable time to subside if public health measures result in r ¼ . (fig. a) . the total size of an outbreak expected from n ¼ initial cases is (sd ), while it takes on average (sd ) days until the last patient is discharged from hospital. pre-exposure prophylaxis, given to all persons who come into contact with hospitalized sars patients, results in r ¼ . (fig. b) . the impact of this reduction in the reproduction number is readily apparent, with outbreak size and duration decreasing to (sd ) cases and (sd ) days, respectively. adding post-exposure prophylaxis with p ¼ . and r ¼ days to the spectrum of control measures further reduces the reproduction number to r ¼ . (fig. c) . accordingly, the expected size of the outbreak is decreased to (sd ) cases and the time until the last patients is discharged from hospital is decreased to (sd ) days. the normal variation on a double logarithmic scale implies highly skewed distributions for both outbreak size and duration. indeed, large-scale outbreaks represent a significant proportion of outcomes with r ¼ . . the th percentiles for outbreak size and duration are cases and days, respectively (fig a) . large outbreaks are still possible, yet they become less likely, at lower reproduction numbers. the th percentile of outbreak size is cases with r ¼ . (fig. b ) and cases with r ¼ . (fig. c) . further reductions may be achieved through faster and more effective contact tracing or through admission interval reduction. with a -day interval for hospital admission and day for contact tracing, r ¼ . and the th percentiles of outbreak size and duration are cases and days, respectively (fig. d ). in this paper we present a generic model for the initial stage of a sars epidemic and evaluate the effect of different infection control measures on the reproduction number r, defined as the number of secondary cases generated by an index case. specifically, we studied how targeted administration of prophylactic antibodies might supplement stringent patient isolation procedures in a future sars outbreak. mathematic analysis and numeric simulation demonstrate that the addition of antibody prophylaxis to control measures generally allows for containment of higher r values and restricts both the size and duration of an outbreak. our model differs from most published mathematical sars models, , , [ ] [ ] [ ] in that we allow for non-constant infectivity over the course of infection. there is strong evidence that viral shedding slowly increases over the course of infection and reaches a peak in the second week after onset of clinical symptoms, , suggesting that the assumption of a constant infectivity does not hold. analysis of a model using non-constant infectivity revealed that control of sars through patient isolation was mainly established due to the relatively late infectivity peak during infection. hence, failure to capture this aspect in the transmission dynamics of sars could have led to misleading conclusions. our approach differs from other mathematical sars models where non-constant infectivity was used, , in that we explicitly allow for an asymptomatic period of infection during which transmission does not occur. hence, our model cannot be classified an ''age of infection'' model because infectivity depends on the time since onset of clinical symptoms rather than the time since infection. an ''age of infection'' model would allow transmission to occur before onset of clinical symptoms, a supposition that is-in the case of sars-not supported by data. however, our conclusions would not alter if we allowed for the possibility of pre-symptomatic transmission given that infectivity in the early stages of infection would be typically low. , finally, our model is parameterized through empirically defined waiting times. it has recently been demonstrated that ignoring the latent period of infection or making the common approximation of exponentially distributed waiting times gives rise to overtly optimistic predictions for the outcome of control strategies. although we have made simplifications in other aspects, notably the assumption of a constant pool of susceptible individuals, we feel that the model accurately describes the initial stage of an epidemic. it has been pointed out before that patient isolation can in principle contain an outbreak of sars, provided that the time from onset to admission is short. the contribution of other measures in the control of the sars epidemic, e.g. quarantine of exposed individuals and widespread use of facemasks, is debatable. a modeling study aimed at simulating the potential response to sars in japan concluded that quarantine of the exposed population would be one of the most effective policy procedures. it has even been suggested that, despite the considerable costs involved, quarantine measures in canada have not only saved lives but also costs. this impact of quarantine is remarkable given the lack of pre-symptomatic transmission of sars. within our modeling framework, the benefit of quarantining exposed individuals can only be interpreted in terms of admission interval reduction and contact rate reduction for any day prior to hospitalization. our results are in line with the finding that personal protection measures in the general population (such as the use of facemasks) offer little protection to the community. we also demonstrate that patient isolation procedures alone will not prevent a sars epidemic if the transmission rates are only slightly increased compared to the outbreaks in , unless additional measures-such as contact tracing -are put in place. these findings are reminiscent of modeling results obtained for smallpox control. , , if new variants of sars coronavirus do initiate another epidemic, the question is to what extent they will resemble the etiologic agent of the first outbreak. the sars epidemic was characterized by a high degree of heterogeneity in the number of secondary cases generated by an index case. , whether this heterogeneity represents variability in viral biology or host behavior is unclear, but the available data suggests that sars can be highly contagious. as the etiologic agent of sars continues to circulate in natural host species it may evolve into a more transmissible strain. , to maximize the opportunity of containment of potentially more transmissible sars coronavirus variants, and to minimize the size and duration of an outbreak, existing control strategies should be supplemented with specific antiviral strategies. passive immunization would seem appropriate in a contingency situation, as it can provide a person with instant albeit short-lived protection against infection and could also be used as a post-exposure prophylaxis to prevent disease progression. in rabies, passive immunization is commonly used in combination with vaccination to prevent rabiesexposed individuals from becoming symptomatic. community-wide containment of infectious disease outbreaks by means of antibody prophylaxis has only been described in a number of cases. in the late s, an outbreak of hepatitis a in a religious community provided an opportunity to assess the impact of immune globulin on the course of the outbreak. here, the incidence of hepatitis among immune globulin recipients stopped weeks after a -day campaign of mass administration. passive immunization using polyclonal sera has also been reported to prevent infection with respiratory viruses. we have previously characterized monoclonal antibodies directed against the spike glycoprotein of sars coronavirus, which were highly effective when tested in ferrets. results from pre-clinical development demonstrate that a combination of two monoclonal antibodies against sars acts synergistically, hinting at the prospect of an antibody cocktail as a feasible and efficient prophylaxis. the monoclonal antibody cocktail is targeted at two distinct epitopes on the receptor-binding domain of the spike glycoprotein, one of which recognizes the residue that was critical for adaptation to human transmission. , , evolution towards human transmission of novel sars-like coronaviruses would likely require the same adaptation, thus preserving the neutralization potential of the antibody cocktail in case a new sars outbreak occurs. the extent to which antibody prophylaxis may enhance sars outbreak control measures hinges on the transmissibility of the disease and on the effectiveness with which general infection control measures are introduced. a comprehensive contingency plan for controlling future sars outbreaks should aim to maximize the range of r values that can be contained, and to minimize the size and duration of an outbreak. our analysis demonstrates that antibody prophylaxis would be an effective addendum to the array of existing public health measures to control sars. world health organization. consensus document on the epidemiology of severe acute respiratory syndrome (sars) geneva: department of communicable disease surveillance and response, who epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions transmission dynamics and control of severe acute respiratory 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control and prevention. prevention of varicella: recommendations of the advisory committee on immunization practices (acip). mmwr recomm human monoclonal antibody combination against sars coronavirus: synergy and coverage of escape mutants key: cord- -yzum k authors: moon, suerie; sridhar, devi; pate, muhammad a; jha, ashish k; clinton, chelsea; delaunay, sophie; edwin, valnora; fallah, mosoka; fidler, david p; garrett, laurie; goosby, eric; gostin, lawrence o; heymann, david l; lee, kelley; leung, gabriel m; morrison, j stephen; saavedra, jorge; tanner, marcel; leigh, jennifer a; hawkins, benjamin; woskie, liana r; piot, peter title: will ebola change the game? ten essential reforms before the next pandemic. the report of the harvard-lshtm independent panel on the global response to ebola date: - - journal: lancet doi: . /s - ( ) - sha: doc_id: cord_uid: yzum k nan the west african ebola epidemic that began in exposed deep inadequacies in the national and international institutions responsible for protecting the public from the far-reaching human, social, economic, and political consequences of infectious disease outbreaks. the ebola epidemic raised a crucial question: what reforms are needed to mend the fragile global system for outbreak prevention and response, rebuild confi dence, and prevent future disasters? to address this question, the harvard global health institute and the london school of hygiene & tropical medicine jointly launched the independent panel on the global response to ebola. panel members from academia, think tanks, and civil society have collectively reviewed the worldwide response to the ebola outbreak. after diffi cult and lengthy deliberation, we concluded that major reforms are both warranted and feasible. the panel's conclusions off er a roadmap of ten interrelated recommendations across four thematic areas: preventing major disease outbreaks all countries need a minimum level of core capacity to detect, report, and respond rapidly to outbreaks. the shortage of such capacities in guinea, liberia, and sierra leone enabled ebola to develop into a national, and worldwide, crisis. • recommendation : the global community must agree on a clear strategy to ensure that governments invest domestically in building such capacities and mobilise adequate external support to supplement eff orts in poorer countries. this plan must be supported by a transparent central system for tracking and monitoring the results of these resource fl ows. additionally, all governments must agree to regular, independent, external assessment of their core capacities. • recommendation : who should promote early reporting of outbreaks by commending countries that rapidly and publicly share information, while publishing lists of countries that delay reporting. funders should create economic incentives for early reporting by committing to disburse emergency funds rapidly to assist countries when outbreaks strike and compensating for economic losses that might result. additionally, who must confront governments that implement trade and travel restrictions without scientifi c justifi cation, while developing industry-wide cooperation frameworks to ensure private fi rms such as airlines and shipping companies continue to provide crucial services during emergencies. when preventive measures do not succeed, outbreaks can cross borders and surpass national capacities. ebola exposed who as unable to meet its responsibility for responding to such situations and alerting the global community. • recommendation : a dedicated centre for outbreak response with strong technical capacity, a protected budget, and clear lines of accountability should be created at who, governed by a separate board. • recommendation : a transparent and politically protected who standing emergency committee should be delegated with the responsibility for declaring public health emergencies. • recommendation : an independent un accountability commission should be created to do systemwide assessments of worldwide responses to major disease outbreaks. rapid knowledge production and dissemination are essential for outbreak prevention and response, but reliable systems for sharing epidemiological, genomic, and clinical data were not established during the ebola outbreak. • recommendation : governments, the scientifi c research community, industry, and non-governmental organisations must begin to develop a framework of norms and rules operating both during and between outbreaks to enable and accelerate research, govern the conduct of research, and ensure access to the benefi ts of research. • recommendation : additionally, research funders should establish a worldwide research and development fi nancing facility for outbreak-relevant drugs, vaccines, diagnostics, and non-pharmaceutical supplies (such as personal protective equipment) when commercial incentives are not appropriate. we do not have the capacity to respond to this crisis on our own. if the international community does not stand up, we will be wiped out. we need your help. we need it now.n aimah jackson, team leader, médecins sans frontières ebola treatment center, monrovia. address to the un security council, sept , the west african ebola epidemic that began in was a human tragedy that exposed a global community altogether unprepared to help some of the world's poorest countries control a lethal outbreak of infectious disease. the outbreak engendered acts of outstanding courage and solidarity, but also immense human suff ering, fear, and chaos, largely unchecked by high-level political leadership or reliable and rapid institutional responses. the outbreak continues as of november, . it has infected more than people and claimed more than lives, brought national health systems to a halt, rolled back hard-won social and economic gains in a region recovering from civil wars, sparked worldwide panic, and cost several billion dollars in short-term control eff orts and economic losses. , guinea, liberia, and sierra leone were most badly aff ected. the ebola outbreak is a stark reminder of the fragility of health security in an interdependent world, and of the importance of building a more robust global system to protect all people from such risks. a more humane, competent, and timely response to future outbreaks needs greater willingness to assist aff ected populations, and systematic investments to enable the global community to perform four key functions: . strengthen core capacities within and between countries to prevent, detect, and respond to outbreaks when and where they occur. . mobilise faster and more eff ective external assistance when countries are unable to prevent an outbreak from turning into a crisis. . rapidly produce and widely share relevant know ledge, from community mobilisation strategies to protective measures for health workers, and from epidemiological information to rapid diagnostic tests. . provide stewardship over the whole system, entailing strong leadership, coordination, priority-setting, and robust accountability from all involved. the ebola outbreak emphasised failures in performing all four of these functions. clarity about roles, responsibilities, and rules-and accountability for adherence to them-is essential in a complex system that must involve local, national, regional, and international actors spanning the public, private, and non-profi t sectors. yet, this clarity and accountability was fundamentally absent. without addressing these governance issues, we will remain wholly unprepared for the next epidemic, which might very well be more devastating, virulent, and transmissible than ebola or previous disease outbreaks. [ ] [ ] [ ] the independent panel on the global response to ebola is a joint initiative of the harvard global health institute and the london school of hygiene & tropical medicine to review the global community's response to the ebola outbreak. the members come from academia, think tanks and civil society around the world, with expertise in ebola, disease outbreaks, public and global health, international law, development and humanitarian assistance, and national and global governance. the panel took a global, system-wide view with a special focus on rules, roles, and responsibilities to identify changes necessary to prevent and prepare for future outbreaks. this panel report outlines the main weaknesses exposed during diff erent phases of the ebola outbreak, followed by ten concrete, interrelated recommendations across four thematic areas: preventing major disease outbreaks, responding to major disease outbreaks, research-production and sharing of data, knowledge, and technology, and governing the global system, with a focus on who. our primary goal is to convince high-level political leaders worldwide to make necessary and enduring changes to better prepare for future outbreaks while memories of the human costs of inaction remain vivid and fresh. the ebola outbreak witnessed many types of failures. for analytical purposes, we divide the epidemic roughly into four phases, underlining the most salient issues that arose. during the initial phase from december, , to march, , the fi rst infections occurred in a remote rural area of guinea where no outbreaks of ebola had previously been identifi ed. the lack of capacity in guinea to detect the virus for several months was a key failure, allowing ebola eventually to spread to bordering liberia and sierra leone. this phase underscored the problem of inadequate investments in health infrastructure, despite national governments' formal commitments to do so under the international health regulations ( ), and awareness among donors that many lower income countries would need substantial external support. it also underscored inadequate arrangements between governments and who to share, validate, and respond robustly to information on outbreaks. in march, , a second phase began in which intergovernmental and non-governmental organisations began to respond, starting with médecins sans frontières, which already had teams on the ground. that month, both guinea and liberia confi rmed ebola outbreaks to who. by march , ebola was confi rmed in conakry, home to more than one in seven guineans. two months later ebola had spread to three capital cities with international airports. without any approved drugs, vaccines or rapid diagnostic tests, health workers struggled to diagnose patients and provide eff ective care. without suffi cient protective gear, and initially without widespread understanding of the virus, hundreds of health workers themselves became ill and died. despite médecins sans frontières' warnings about the unprecedented scope of the outbreak, national authorities in guinea downplayed it for fear of creating panic and disrupting economic activity. , internal documents suggest similar concerns might have infl uenced who, which publicly characterised the outbreak in march as "relatively small still". who's global alert and response network sent an expert team to support national eff orts, as did others such as the us centers for disease control and prevention. however, those teams withdrew from guinea and liberia in may when reported cases decreased, even as viral transmission continued. in late may, sierra leone became the third country to declare an ebola outbreak to who. for the fi rst time in the known history of ebola, the virus had spawned sustained outbreaks in three countries. this should have raised substantial alarm, as coordination was weak between the national governments of liberia, guinea, and sierra leone, the borders extremely porous, and human movement and trade highly fl uid. in late june, médecins sans frontières labelled the situation as "out of control" and publicly called for more international attention and resources. this second phase witnessed three interrelated failures. first, in a failure of political leadership, some national authorities did not call for greater international assistance despite the humanitarian crisis, and in some cases downplayed the outbreak. second, who's in-country technical capacity was weak, shown by its decision to withdraw its international team too soon and its poor responses in guinea and sierra leone to requests for technical guidance from ministries of health and health-care providers. , third, who did not mobilise global assistance in countering the epidemic despite ample evidence the outbreak had overwhelmed national and non-governmental capacities-failures in both technical judgment and political leadership. the third phase began in july as cases, global attention, panic, and responses all grew. funding increased, with the world bank committing us$ million in the fi rst major external fi nancing response. media attention and public interest substantially increased after the evacuation of two infected us aid workers from liberia. fear and hysteria in response to ebola infections in the usa later led to quarantines of returning aid workers and other measures counterproductive for controlling the epidemic. dozens of countries, private companies, and universities began implementing travel restrictions, and many airlines ceased fl ying into the region. on aug , who convened the international health regulations emergency committee, and the next day the director-general offi cially designated the ebola outbreak a public health emergency of international concern ("an extraordinary event which is determined...to constitute a public health risk to other states through the international spread of disease and to potentially require a coordinated international response." ) detected cases grew expon entially. ebola treatment centres in all three countries were stretched beyond capacity and forced to turn away patients at their gates. a growing lack of trust between population groups and government authorities hindered community mobilisation and public education. in the ensuing weeks, the global community mobilised, with new commitments of fi nancing, health personnel, and logistical support from the african union, china, cuba, the european union, the uk, the usa, the world bank, the international monetary fund, and the un agencies. the un security council passed resolution declaring the outbreak a threat to international peace and security, the only time it has done so regarding an outbreak and only the second resolution ever (after hiv/aids in ) to focus on a disease. the un secretary general created a new entity to coordinate the international response, the un mission for emergency ebola response. additionally, trials for two candidate vaccines were launched in europe and the usa, and who convened an expert group to develop guidance for the ethics of using experimental therapies. despite increased mobilisation of political attention and resources, this third phase witnessed several failures. first, public and private restrictions on trade and travel further harmed an already suff ering region and hindered control eff orts. , second, the operational response commenced slowly, taking months for funding, personnel, and other resources to reach the region. [ ] [ ] [ ] third, the creation of the un mission for emergency ebola response bypassed the pre-existing un body for emergency coordination, the offi ce for the coordination of humanitarian aff airs, further blurring the lines of responsibility for international coordination. fourth, fi eld staff often reinvented strategies for community mobilisation and contact tracing because relevant lessons from previous ebola outbreaks in uganda and the democratic republic of congo were not eff ectively transferred. fifth, international staff with ebola sometimes received experimental therapies (albeit, the effi cacy and risks of which were unknown) and were evacuated while national staff largely were not, a demoralising and often deadly distinction for many health workers. , sixth, there was poor understanding of how to take into account community beliefs, practices, and solutions, properly address rumours, and involve local leaders-with sometimes fatal consequences for health workers and communities. a fourth phase began towards the end of as the epidemic turned a corner. the total number of cases began to decline in the hardest hit countries as community leaders and organisations joined control eff orts, even before large-scale global assistance arrived. ebola had been imported into nigeria, mali, and senegal in the second half of . nevertheless, rapid information sharing, and mobilisation of health workers for contact tracing and patient care had limited the outbreak in senegal to one confi rmed infection. in nigeria, the nigerian center for disease control, previous experience with polio eradication eff orts and a lead poisoning emergency were all cited as important factors in successful control of the outbreak in africa's most populous country. by the end of january, , more than $ billion had been committed for the ebola response (although the proportion of these funds actually spent on ebola and in the aff ected countries remains unclear). research and development eff orts were quickly operationalised despite uncertainty on processes for regulatory approval, with at least three vaccine candidates, three blood products, and fi ve drug candidates in clinical trials, with who playing a coordinating role. during this phase, the binding constraints were no longer political attention, funding, or human resources, but operational coordination, accountability for eff ective use of funds, and maintaining momentum to prevent new infections. amidst the crisis, many acts of courage, solidarity, innovation, and leadership prevailed, often at a substantial personal cost. in west africa more than local health workers contracted ebola caring for the sick; more than of those caregivers died. community members volunteered to trace contacts, local leaders educated communities, and religious authorities promoted new burial practices to prevent transmission. several non-governmental organisations vocally advocated for a stronger global response, treated patients, trained health workers, supported community mobilisation and longer-term recovery eff orts. additionally to massive funding from traditional donors, the african union, the economic community of west african states, cuba, and china made substantial contributions of personnel, funding, logistics, and technology (huang y, council on foreign relations, personal communication). private foundations and companies contributed funds, with $ million from the top fi ve contributors, along with meaningful in-kind assistance, such as air lifts. the initiation and conduct of clinical trials were accelerated amidst the challenging conditions of an outbreak, enabled by the cooperative eff orts of industry, research funders, regulatory authorities in the usa, europe, and west africa, scientists, and directly aff ected communities. these positive steps notwithstanding, this panel's overarching conclusion is that the long-delayed and problematic international response to the outbreak resulted in needless suff ering and death, social and economic havoc, and a loss of confi dence in national and global institutions. failures of leadership, solidarity, and systems came to light in each of the four phases (panel ). recognition of many of these has since spurred proposals for change. we focus on the areas that the panel identifi ed as needing priority attention and action. preventing small-scale outbreaks from becoming largescale emergencies needs a minimum level of core capacities in all countries to detect, report, and respond rapidly (panel ). in the wake of the severe acute respiratory syndrome (sars) outbreak, governments committed to developing such core capacities by under the revised international health regulations ( ), with the deadline extended for some countries to , then after ebola struck. according to self-assessments, as of , two-thirds of countries had not met their core capacity requirements and countries had not responded to who queries regarding their readiness. the international health regulations did not include binding obligations for donors to provide support to poorer countries to meet these obligations, nor to fund who to fulfi l its mandate to provide technical assistance. these shortcomings did not attract serious action or funding until the ebola outbreak. despite unprecedented international fi nancing during the past decade to combat particular diseases in developing countries, health systems in many resource-poor settings remain ill-prepared for outbreak response. no alternate strategy has been developed to supplement these national-level weaknesses. if countries remain unable to detect outbreaks in a timely way, the rest of the chain of international health regulation-stipulated notifi cations and responses will fail once again. additionally, according to the international health regulations, countries agreed to report potential health emergencies within h to who for joint risk assessment, with the option of doing so confi dentially. who was also permitted to receive, analyse, and ask for verifi cation of outbreak information received from non-governmental sources. governments might hesitate to report outbreaks publicly for fear of political and economic repercussions, as occurred in china with sars in . yet, history has shown that early reporting is essential to reduce both the health toll of an outbreak and its political and economic consequences. governments agreed in the international health regulations to prompt notifi cation, and in return, were reassured of the curtailment of unwarranted trade or travel restrictions and support from who technical assistance. during the ebola outbreak, however, countries and many private fi rms implemented restrictions on travel or trade, despite who's recommendations against such measures and the security council's warnings about the resulting isolation of aff ected countries. , , [ ] [ ] [ ] [ ] we conclude that several concrete steps must be taken to prevent future outbreaks from becoming large-scale catastrophes. who should convene governments and other major stakeholders within months to begin developing a clear global strategy to ensure that governments invest domestically in building core capacities and to mobilise adequate external support to supplement eff orts in poorer countries. there is growing momentum in the wake of ebola for such investments: the us government has committed $ billion to build core capacities in at least developing countries, including guinea, liberia, and sierra leone. this work is being coordinated under the global health security agenda, a us-launched initiative that now consists of nearly countries. at its june, , summit, the group of (g ) announced support for countries, although the g did not explicitly commit funds nor agree to a concrete plan. financial commitments for recovery have also been made at various ebola conferences and summits. - other initiatives might also contribute to core capacity building. these include the gates foundation's child health and mortality prevention surveillance network, the joint institut pasteur-china centers for disease control initiative to train west african scientists in outbreak response, the merieux foundation's laboratory strengthening activities in west africa, and the uk's £ million fleming fund for antimicrobial resistance. these welcome signals need to become sustained budget commitments to support national or regional plans, such as the mano river union post-ebola socioeconomic recovery programme, and reviewed systematically beyond this initial phase at forums such as the g , the g , and the world health assembly. furthermore, dialogues about health security should not be isolated from broader discussions about development fi nancing, including of the sustainable development goals, as ebola exposed how substantially an epidemic could roll back hard-won development gains. a clear, coordinated plan, supported by a transparent central system for tracking and monitoring these resource fl ows, will be needed to minimise fragmentation and ensure that core capacities are systematically built and sustained. the proposed accountability commission for disease outbreak prevention and response (recommendation ) should monitor investments and results for core capacity building. further analysis is needed to estimate the required level of additional funding. strategic investments for international health regulation core capacities can and should also strengthen broader health systems. , for example, health information systems can support surveillance and monitoring of outbreaks and routine health services; training and payment of community health workers and civil society service providers can help achieve universal health coverage, while providing an essential trained workforce during emergencies. additionally, regional and subregional actors should develop capacities to supplement gaps at the national level. for example, in africa, national governments, the african development bank, and other donors should invest in the infrastructural backbone for a network of laboratories, information systems, and training of african national emergency responders based in centres of excellence. the pan american health organization has shown the feasibility of a regional network of centres for disease control, and building such a network could be a central task of the proposed african centres for disease control and prevention. although the african centres for disease control and prevention might be perceived as a competitor to the who regional offi ce for africa, a clear delineation of responsibilities for outbreak response versus other health issues should enable close collaboration between the two. finally, governments must agree to regular, independent, external assessment of their core capacities. monitoring requirements should accompany external fi nancing. assessments will also be needed in self-fi nancing countries. some governments objected at the world health assembly to independent assessment. nevertheless, a method for peer assessment piloted by fi ve countries through the global health security agenda could provide a basis for a monitoring process acceptable for all countries. political leaders, governments, and international organisations must strengthen the set of incentives and disincentives so that governments report disease outbreaks early. among these should be stronger disincentives for implementing trade and travel restrictions without a scientifi c or public health basis. who should promote transparency by publishing lists of countries that delay reporting disease outbreaks, while commending countries that rapidly share public information as mexico did in with h n . who publicly challenged china's government to be more transparent about sars, showing the organisation's potential political power. who should also publicly disclose lists of countries that implement trade and travel restrictions when who temporary recommendations advise against them and countries that do not provide a science or public health rationale for such measures (as required by the international health regulations). doing so will require a delicate balancing act between who's role as trusted interlocutor with governments on sensitive outbreak-related information, and its role as guardian of the international health regulations. although an individual government might object to such scrutiny in the short term, politically supporting who's prerogative to do so serves the long-term interests of global public health. funding bodies such as the world bank, the asian infrastructure investment bank, the african development bank, and the new development bank (previously known as the brics development bank) should create economic incentives for early reporting by committing to disburse emergency funds rapidly to assist countries when outbreaks strike and compensating for economic losses that might result. the world bank's proposed pandemic emergency financing facility or the african union's african risk capacity agency off er the possibility of insurance to mitigate the economic costs linked to outbreak reporting. the trigger for disbursement should be a risk assessment done under the aegis of who. because private fi rms such as airlines and shipping companies are not directly bound by public international law, alternate governance mechanisms are needed to prevent isolating countries when outbreaks strike. the these could include designating a un focal point for the private sector during outbreaks, designing industry-wide cooperation frameworks, and developing codes of conduct. if preventive measures fail and an outbreak escalates into a major crisis, responsibility for taking action and alerting the broader global community must be clearly designated (fi gure ). as noted, countries agreed as part of the international health regulations to notify who of any potential public health emergency of international concern within h of assessment. who rapidly shares information with the global alert and response network, a loose network coordinated by who of academics, government scientists, non-governmental organisations, and health volunteers. the global alert and response network analyses and assesses reports, deploys investigators, conducts laboratory examination and identifi cation of the outbreak cause, and advises on further measures, including, as a fi nal resort, a potential public health emergency of international concern declaration. however, the global alert and response network's skeleton staff is too small to deploy in multiple suspected outbreaks, its budget has been severely cut, and it is not authorised by who to draw public attention to a crisis. responsibility for declaring a public health emergency of international concern belongs to the who director-general, who convenes an emergency committee of independent experts for a recommendation. however, the director-general did not use her international health regulation-granted authority to convene the emergency committee nor declare a public health emergency of international concern until months after guinea and liberia had notifi ed who. in view of the severity of ebola virus disease, rapid cross-border spread, weaknesses of the aff ected national health systems, the post-confl ict setting, and repeated warnings from nongovernmental organisations in the region, the director-general had ample reason to raise international attention by convening the emergency committee or declaring a public health emergency of international concern earlier. the committee responsible for reviewing who's performance during the ebola outbreak (the who ebola interim assessment panel) and leaked internal emails suggest several reasons for the delay including concerns about political opposition from west african leaders, economic ramifi cations, and a culture within who discouraging open debate about sensitive issues, such as emergency declarations. , who might also have hesitated because it was sharply criticised for creating panic by declaring a public health emergency of international concern during the relatively mild h n pandemic. whatever the root causes, the delay emphasised the risks inherent in vesting such consequential decision making power in a single individual. this risk is heightened when there is no institutional mechanism of accountability for leadership failures. after the public health emergency of international concern declaration, a substantial global response was mobilised. however, this response arrived late, was slow to deliver funds and health workers, was infl exible in adapting to rapidly changing conditions on the ground, was inadequately informed about cultural factors relevant to outbreak control, and was poorly coordinated. the result was, in essence, a $ billion scramble. an excessive burden fell on national and international nongovernmental organisations and local communities to do the highest-risk work such as patient care and burials. the creation of the un mission for emergency ebola response as an ad hoc body operating outside established humanitarian response structures reportedly made coordination of the crisis response even more diffi cult. , funding was low until the upsurge of commitments in september, , and, even then, there were long lags between pledges and disbursement. by one account, national surveillance identifies event of concern assessment of public health risk ( h) affected country reports to who ( h) response at who headquarters response in country who director-general convenes emergency committee to assess for public health emergency of international concern; director-general consults affected state emergency committee advises director-general who issues temporary recommendation if national capacity is outstripped, international actors should supplement national efforts director-general withdraws public health emergency of international concern declaration in case of state failure, actors operate under un coordination public health emergency of international concern controlled emergency committee reviews public health emergency of international concern status and recommendation if disease crosses borders, affected governments coordinate responses with support from regional and global organisations nearly $ billion had been pledged by the end of but only a third of this money was disbursed. furthermore, transparency of fi nancial fl ows is crucial to minimise duplication, to ensure aid goes to areas of most need rather than those easiest to assist, and to ward against mismanagement. however, transparency was, and remains, wholly inadequate: on the donor side, multiple tracking systems exist but it remains impossible to construct a clear, comprehensive picture of monetary and in-kind pledges and disbursements across the many public and private donors. on the recipient side, who received what funds to do which tasks also remains an opaque puzzle-and assessing the eff ect or effi cient use of those funds is more diffi cult still. we off er three further recommendations to tackle these issues. high-level political leaders must clearly designate who is responsible for responding when disease outbreaks outstrip national capacities, invest in the capacity to respond, and ensure accountability for fulfi lment of these responsibilities. although national governments and nongovernmental organisations working on the ground are the fi rst line of defence when outbreaks arise, who is crucial for the second line of defence when governments need international support or when an outbreak strikes more than one country. to strengthen who's capacity during outbreaks, we welcome the stocking panel's recommendation to create a who centre for emergency preparedness and response, and off er several additional recommendations regarding its key functions and attributes. the centre should merge the outbreak risk assessment and response capacities that reside in the global alert and response network with who's humanitarian teams, which presently respond to natural disasters, refugee crises, and other large catastrophes. its operational lines of authority from headquarters to regions and countries should be clearly designated. the centre should assess risks on the basis of the information that countries and others provide to who, and mobilise necessary laboratory, epidemiological, clinical, communications, and logistical responses. it should have powerful analytical, data processing, and advisory capacity to command respect in both policy and scientifi c communities. the centre should develop rapid response and strong coordinating capacity, and be able to assemble the world's best expertise to tackle disease threats. between crises, the centre should develop protocols, build relationships, and negotiate agreements with governments, multilateral organisations, non-governmental organisations, private fi rms, and other actors to mobilise rapidly during emergencies, including strengthening capacities in developing countries so that they might better respond nationally and participate internationally. in a multicountry outbreak, the centre should ensure government-to-government coordination by establishing channels of direct communication for rapid information sharing. it should be responsible for building a virtual global health workforce from both industrialised and developing countries by setting standards for certifying crisis responders, ranging from communications experts and logisticians to surgeons and managers. these responders would continue working for their home organisations, but provide surge capacity in a crisis. finally, the centre should provide technical assistance to countries to build and maintain international health regulation-mandated core capacities. the centre should have its own executive director who is accountable for performance jointly to a separate board of directors and to the director-general. the multistakeholder board should include broad repre sentation of governments from each who region, scientifi c expertise including about animal health, operational responders from all sectors, and funders. the executive director should inform the board immediately when the centre's risk analysis suggests that coordinated international action is needed and mobilise an appropriate response. similar governing structures have worked eff ectively for who-affi liated entities including the global polio eradication initiative, the international agency for research on cancer, unitaid, and the special programme for research and training in tropical diseases. the centre's budget should be protected and adequately resourced through a dedicated revolving fund. the fund should immediately disburse money for rapid scale-up when a crisis strikes, then be replenished from funds raised for that crisis to be ready for the next one. the centre and its board should work closely and routinely with the director-general so that the highest levels of leadership are constantly aware of evolving disease threats, and can marshal who's legal, political, and human resources at regional and country levels when needed. who should use its international health regulation-granted authority to expedite access to aff ected sites by technical teams and pressure any state that impedes international responses to, or obscures, disease threats in its territory. the centre must have access to sensitive outbreak information that countries are required to share with who; further analysis is needed as to whether this would require amendment to the international health regulations. a third line of defence will be needed if the initial response does not succeed and an outbreak becomes a humanitarian crisis (eg, a un level emergency ), threatening not only public health, but also political, economic, and social stability. international coordination of the large-scale eff ort needed in this case should be done by the offi ce for the coordination of humanitarian aff airs. however, because the offi ce for the coordination of humanitarian aff airs (and most other humanitarian actors) do not specialise in crises precipitated by disease outbreaks, they should develop in-house capacity and a broad coordination framework with the health sector for such emergencies. member states should amend the international health regulations to broaden responsibility for declaring a public health emergency of international concern. the director-general convenes, and is advised by, an ad hoc emergency committee constituted from a list of independent experts; however, authority and responsibility to declare a public health emergency of international concern rests exclusively with the director-general. we recommend the creation of a standing emergency committee that meets regularly, with the mandate to declare a public health emergency of international concern by a majority vote of its members. the emergency declaration should trigger other actions, such as fi nancial disbursements by development banks, emergency data-sharing and specimen-sharing rules, and emergency regulatory procedures for new drugs, vaccines, and diagnostics (recommendations and ). the director-general should chair, communicate, and explain the standing emergency committee's decisions. following an open call for nominations, the director-general would appoint the fi rst members; thereafter, the standing emergency committee itself would periodically vote in new members to preserve its independent character. minutes and votes of standing emergency committee members should be published immediately following each meeting for the sake of transparency, to build external confi dence, reduce political interference, and strengthen the committee's hand against resistant states. similarly to other institutions responsible for technically complex yet politically consequential decisions, such as central banks or drug regulatory authorities, the standing emergency committee must be protected from political pressure that might interfere with its judgment. the committee should possess high-level public health expertise and base its decisions on scientifi c principles and evidence, assessing risks for human health, disease spread, and international traffi c. the standing emergency committee should have adequate economic expertise to weigh the risks of disrupted trade and travel against those posed by the outbreak and advise on how to ameliorate economic harm. the standing emergency committee should also issue early warnings of major potential risks on the basis of continuing assessments done by the who centre. the committee should also consider replacing the present binary system, which calls for determining the presence or absence of a public health emergency of international concern, with a graded system of warnings. finally, the standing emergency committee should publish an annual report detailing its activities to ensure public accountability and continued political attention to health threats. the committee should be fi nanced purely through assessed contributions to protect against undue donor infl uence. a committee does not by defi nition operate more eff ectively than an individual, and might succumb to risk aversion and dysfunction; nevertheless, the combination of measures described above should provide the standing emergency committee with the autonomy and capacity for credible, authoritative decision making. the un secretary general should create an accountability commission as an independent body comprised of civil society, academia, and independent experts doing realtime and retrospective system-wide assessment of global responses to major disease outbreaks. the accountability commission would track and analyse the contributions and results achieved by national governments, donors, un agencies, international and national nongovernmental organisations, and the private sector. all major actors would be expected to share information promptly with the accountability commission about fi nancial, in-kind, or operational contributions; the the accountability commission should publish the names of organisations unwilling to share such information. the accountability commission would assess aid eff ectiveness, including funds committed, paid, dis bursed, and spent; both short-term and long-term accomplishments achieved with those funds; and the timeliness, eff ectiveness, cultural appropriateness, and equity of the response for intended benefi ciaries. the accountability commission should liaise directly with and provide a forum for representatives of communities directly aff ected by outbreaks. finally, it should monitor eff orts to build and sustain national core capacities. the accountability commission would report to the world health assembly and the security council's global health committee (recommendation ), and publish its fi ndings regularly during and after each public health emergency of international concern. after an open call for nominations, the secretary general would appoint the fi rst members; thereafter, the accountability commission itself would periodically vote in new members to preserve its independent character. the accountability commission would off er an important multistakeholder platform for various constituencies involved in and aff ected by disease outbreak responses. this proposal builds on analogous eff orts to strengthen system-wide accountability for other global eff orts, such as the un commission on information and accountability for women's and children's health and the independent monitoring board of the global polio eradication initiative, credited with helping to reinvigorate the performance of this eff ort. the accountability commission would be a more permanent institution, however, with a broader mandate than these two previous initiatives. producing and rapidly sharing knowledge during outbreaks is essential. however, reliable systems for rapid transmission of epidemiological, genomic, and clinical data were not established during the ebola epidemic. although governments in the three worst aff ected countries transmitted epidemiological information to who, robust channels were not established for direct data exchange and coordination between the three capitals. although some researchers shared genomic sequencing data early in the outbreak through an open access database, other researchers later withheld such data from the public domain. and although care providers and researchers collected thousands of patient samples, now housed in laboratories in west africa and worldwide, no clear arrangements exist for scientists to access those samples, for their safe handling, or to ensure that west african patients benefi t from the fi ndings or technology that might result. previous epidemics show that better arrangements are feasible. during the sars outbreak, who established online systems for data sharing among a worldwide network of scientists, enabling researchers to identify the virus, sequence its genome, and understand its characteristics. in , an international consortium of researchers agreed to data sharing norms for infl uenza, which enabled real-time dissemination and publication of epidemiological and clinical data during h n in . the consortium for the standardization of infl uenza seroepidemiology helps to coordinate a global community of researchers working on infl uenza serology. furthermore, after years of intergovernmental negotiations, the who pandemic infl uenza preparedness framework achieved a delicate balance between sharing samples and access to the resulting technology. , however, no analogous framework exists for other pathogens. access to knowledge embodied in the form of technologies has been a particularly diffi cult issue. as noted, no drugs, vaccines, or rapid diagnostic tests had been approved for ebola when the outbreak began. although scientists had identifi ed the virus nearly four decades earlier and basic research had advanced understanding of the disease, ebola was not an attractive target for industry investment in research and development, nor was it high on the public health research agenda. somewhat serendipitously, the us and canadian governments had years earlier made defence-related investments in ebola, which meant that university and pharmaceutical industry researchers had developed several experimental drug and vaccine candidates when the outbreak hit. as noted, clinical trials for vaccines and drugs were launched in record time (with encouraging results for one vaccine candidate reported in july, ). nevertheless, the overall research and development eff ort could have moved faster if there had been investments beforehand to advance candidate products through phase or trials and a system to prioritise the most important technologies. for example, eff ective rapid point-of-care diagnostics could have enhanced contact tracing, counteracted community resistance and denial, protected health workers, reduced patient loss to follow-up, eased overburdened treatment centres, and supported the continued operation of shipping and airline services. a systematic way of posing and answering operational research questions, such as the relative merits of using intravenous fl uids for patient care, would also have strengthened the response. furthermore, who provided valuable technical leadership about the ethics of using unproven therapies, but little guidance on how strictly limited quantities of drugs should be rationed. west african health workers and patients were largely denied access to the stocks sometimes available to international staff . in several instances, who proved its capacity to lead, convene, coordinate, and establish norms among a broad range of public and private actors on research and development and data sharing. additionally to its guidance about experimental therapies, who convened research and development actors in mid- and late- , and again at a global ebola research and development summit in may, . in july, , who also issued guidance about accelerating regulatory approval of technologies in emergencies. who also convened a meeting in september, , to build norms for open data sharing as part of an eff ort to develop a "blueprint" to guide the collective research and development eff orts of industry and governments for emergencies. these successful eff orts should be institutionalised to better govern knowledge production and sharing in future outbreaks. before the world health assembly, who should convene governments, the scientifi c research community, industry and non-governmental organisations to begin developing a framework of norms and rules for research relevant to disease outbreaks. the framework's goal would be to provide guidance on three interrelated issues: . access to data and samples to enable and accelerate research, which would involve rapid sharing of epidemiological surveillance and clinical data to inform outbreak control strategies; incentives and platforms for open sharing and access to genomic sequencing data; access to specimen samples (with appropriate biosafety measures). . appropriate conduct of research, including improved ethical standards for research and development (eg, including involving aff ected populations in setting research priorities, patient participation and consent); previous agreement about experimental protocols, such as trial design, to speed clinical trials when outbreaks strike; access to clinical trial data, such as publication of negative and positive results; clear pathways for approval by stringent regulatory authorities and in countries of use; and building on and investing in research capacities in epidemicaff ected countries. . equitable access to the benefi ts of research, including priority, aff ordable access to newly developed health technologies for aff ected populations, including health workers; and ethical guidelines for rationing products with limited availability. an overarching framework is needed to bring coherence and fi ll gaps in the fragmented system of international rules shaping outbreak-related research (including the international health regulations, pandemic infl uenza preparedness framework, convention on biological diversity and its nagoya protocol, agreement on trade related aspects of intellectual property rights, and numerous guidelines and agreements for data ownership and sharing among scientists). the framework would include both nonbinding norms such as guidelines or codes of conduct, and binding rules such as contractual obligations or international law. further analysis is needed to specify the most appropriate instruments for each issue area. some norms would apply at all times to prepare for potential outbreaks; others could be limited to and triggered by a public health emergency of international concern declaration. establishment of such norms in advance would strengthen preparedness and reduce counter-productive competition between researchers or institutions during emergencies. ideally, such a normative framework would cover all pathogens with the potential to cause major outbreaks. however, in view of the complexity and political diffi culties reaching agreement on these issues, a feasible starting point might be to develop a pilot framework for one or several diseases such as viral haemorrhagic fevers. lessons from this pilot could subsequently be applied to expanding the framework to other pathogens. the accountability commission (recommendation ) should monitor progress towards developing this framework and subsequently monitor adherence to it. recommendation : establish a global facility to fi nance, accelerate, and prioritise research and development. the un secretary general and the who director-general should convene in a high-level summit of public, private, and not-for-profi t research funders to establish a global fi nancing facility for research and development for health technology relevant for major disease outbreaks. the facility would support manufacturing, research, and development for drugs, vaccines, diagnostics, and other non-pharmaceutical supplies (such as personal protective equipment) where the commercial market does not off er appropriate incentives. for known pathogens, the facility could invest in bringing candidate drugs, vaccines, technology platforms, and other relevant products through proof of concept, phase , and phase testing in humans, so that they are ready for wider testing, manufacturing, and distribution when an outbreak strikes. during an outbreak the facility would rapidly mobilise fi nance for priority research and development projects, such as diagnostics for novel pathogens. the establishment of a similar fund for diseases aff ecting developing countries was a central recommendation of the report of the who consultative expert working group on research and development. as a result, a pooled international fund was created to support "demonstration projects" that test new research and development business models, such as open knowledge innovation and delinkage of research and development fi nancing from end product prices. with a management structure already established, the demonstration projects off er an important option for pursuing research and development for ebola or other diseases. the global fi nancing facility should be a lean, effi cient entity that mobilises and strategically deploys resources. it would not be a monolithic entity nor the sole funder for epidemic-related research and development because some pluralism and competition among funders is desirable. nevertheless, a global facility would off er the advantage of enabling coordination between diff erent research funders through a common framework, strengthening networks between researchers, estab lishing processes for priority setting, and reducing transaction costs for both grantees and smaller donors. , it could also require information sharing between researchers as a condition of funding, thereby giving teeth to the data-sharing framework (recommendation ). intellectual property or any other asset resulting from these investments should be managed as a public good to enable follow-on innovation, open knowledge sharing, access to technology, and a fair public return on investment. support for a global research and development fi nancing mechanism now seems to be growing, as shown in calls for a $ billion global fund for vaccine development for pandemics, a $ billion global fund for antimicrobial resistance, and a $ - billion global fund that would cover emerging infectious diseases, neglected diseases, and antimicrobial resistance. an eff ective global system for preventing and responding to outbreaks needs well coordinated and appropriately resourced actors to fulfi l clearly defi ned roles and responsibilities and to hold each other accountable for doing so (table). many actors have crucial roles in this complex system: national governments have the main responsibility for their populations' health. national governments are also responsible for immediately sharing information with neighbouring countries and the international community in the event of a potential public health emergency of international concern. they also hold responsibility for calling for international assistance if domestic capabilities prove inadequate. in turn, international actors are responsible for supporting national governments individually and collectively. who should play a central part in monitoring, assessing, and responding to disease outbreaks. national and regional agencies for disease control and academies of science also off er important technical capacities for managing outbreaks. development banks are responsible for mobilising and disbursing fi nancing to support governments and collective action. the international humanitarian system, including the offi ce for the coordination of humanitarian aff airs, unicef, the world food programme, the un high commissioner for refugees, other un bodies, and non-governmental organisations are responsible for mounting an eff ective operational response if an outbreak escalates into a humanitarian crisis. the research community is responsible for producing relevant knowledge on the outbreak, and developing and producing technologies to intervene. civil society, including academia and the media, play a crucial part in drawing attention to unmet needs, neglected challenges, and systemic failings, and demanding accountability from responsible actors. finally, the un security council is responsible for addressing threats to international peace and security. ebola developed from a relatively small outbreak into a large-scale emergency because of the failures of multiple actors to fulfi l their mandated roles and responsibilities. our fi nal three recommendations outline the institutional changes needed to prevent such failures from recurring. in recognition of health as an essential facet of human and national security, the un security council should establish a global health committee consisting of government representatives. the com mittee's main goal would be to expedite and elevate political attention to health issues posing a serious risk to international peace and security and provide a prominent arena to mobilise political leadership. specifi cally, the committee would monitor and publish an annual report on progress in building a strong and eff ective global health security system, taking into account analyses from the accountability commission and who. the committee would also address alleged non-compliance with international health regulation provisions on trade and travel measures. the committee would not declare public health emergencies of international concern. this decision would remain technically driven and under the authority of who. the committee would not be able to strengthen core capacities within and between countries to prevent, detect, and respond to outbreaks support governments with technical and scientifi c knowledge and advice financing by major public and private donors; technical assistance by specialised agencies and non-governmental organisations mobilise external assistance when countries unable to prevent an outbreak from becoming a crisis raise awareness of major disease events; declare public health emergencies of international concern as appropriate; early-stage rapid response to outbreaks; convening for resource mobilisation who is an essential hub in the global system for health security. however, evidence of confusion and disagreement about its role is ample. since the th century, cross-border disease control was the fi rst and most widely accepted rationale for intergovernmental health cooperation. yet, in the wake of the global fi nancial crisis when who laid off more than a tenth of its headquarters staff , outbreak response capacity was deeply and disproportionately cut. disease outbreaks are not the only important work for who, but they are foundational to the organisation's mandate. within a global system for disease outbreak response, what should be who's essential role? who's near-universal state membership, governance structure, and deep relationships with health ministries situate it uniquely to perform four core functions (table): support governments in building national core capacities for prevention, surveillance, and response through technical and scientifi c knowledge and advice; assess and provide rapid early response to outbreaks, raise awareness of major disease events, and declare public health emergencies of international concern when appropriate; establish technical norms, standards and guidance; and convene actors to set goals, mobilise resources, resolve confl icts, and negotiate rules. performance of these functions needs strong political, scientifi c, and normative leadership with solid backing from member states. however, who's failings on these core functions during the ebola outbreak have now produced an existential crisis of confi dence. ebola exacerbated a trend since the s of many governments and other organisations working around who. decades of reducing assessed contributions in real terms has starved the organisation of resources. donors have earmarked voluntary contributions, eff ectively controlling nearly % of who's budget by . the result is an organisation that seems to have lost its way. although the budget has more than doubled from us$ · billion in - to us$ billion in - , the organisation itself controlled an ever-shrinking share. one casualty of recent decisions was who's reduced ability to control cross-border disease outbreaks, a core task for which it was created in . in the wake of ebola, the organisation's traditional claims of legitimacy based on near-universal state membership no longer seem suffi cient. a true recovery will need far greater willingness by member states to entrust resources and delegate authority to who, but it has rarely been in a weaker position to command such trust and authority. confi dence in the organisation's capacity to lead is at an all-time low. calling for additional staff or a larger budget will not address this. who must fi nd a way to prioritise what it does, and regain its credibility, independence, and legitimacy to perform its core functions (table) . breaking out of this -year impasse will demand clear commitment and a diff erent kind of leadership by who to implement fundamental reforms under a tight timeline, matched by an equally clear commitment by member states to reward such reform with appropriate authority and resources. who performed a key coordinating function in research and development during the ebola epidemic. it was also central to controlling nine previous ebola outbreaks, sars, and other epidemics. these examples are important reminders of what who can do under determined leadership. who is in a formal reform process that was spurred by a budget crisis in ; in some ways, it has been in a perennial process of reform since at least the s. these previous eff orts are a reminder that high-level political leadership, such as the engagement of heads of state, will be needed if the outcome is to be diff erent this time. at this point, anything less than fundamental reform will mean continued marginalisation and decline, alongside increasing vulnerability for global public health. to rebuild trust, respect, and confi dence within the international community, who should maintain its broad defi nition of health, but substantially scale back its expansive range of activities to focus on core functions. the scope of who's work would thus continue to embrace the full range of health issues, but its functions should be far more circumscribed. we restrict our analysis to core functions in infectious disease outbreaks. however, there remains the need to defi ne who's core functions in other key areas of work, such as non-communicable diseases, injuries, environmental health, health systems, and social determinants of health. for this purpose, the january executive board should launch a fundamental review of the organisation's constitution and mandate to defi ne its core functions. this review should identify and hand over non-core activities to other actors, thereby streamlining who's activities. it should also examine which core functions are not being fulfi lled or adequately funded. the fi nancing model for who is unstable and politically vulnerable. the january executive board should also begin developing a new fi nancing model for assessed contributions focused on core functions and draft a transparently implemented policy about when to accept or reject voluntary contributions at headquarters, regional, and country offi ces. if who strictly defi nes its core functions and accelerates other good governance reforms (recommendation ), member states should shift most of its fi nancing to assessed and non-earmarked voluntary contributions. recommendation : good governance of who through decisive, timebound reform, and assertive leadership. restoring credibility demands that who institutionalises accountability mechanisms, strengthens and clarifi es how it works with other actors, and fosters strong leadership. the january executive board should launch a process to implement four new policies for who to meet basic principles of good governance: establish a freedom of information policy, with appropriate safeguards; create a permanent inspector general's offi ce to monitor overall performance of the organisation and its entities, reporting to the executive board; conclude continuing work on the framework of engagement with non-state actors to better govern the way who interacts with civil society, academia, foundations, and the private sector; and revise human resource policies to attract or retain well qualifi ed staff , including for leadership positions, while letting go of chronic underperformers. the executive board should seize the short window of opportunity available for such reforms by giving a strong mandate to an interim deputy for managerial reform reporting to the director-general to implement these policies by july, (before the next director-general takes offi ce). in line with the reformed approach to human resources, all upcoming leadership selection and election processes at headquarters, regional, and country offi ces should be based on personal, technical, and leadership merits. the executive board, with the participation of civil society, should do an annual appraisal of senior leadership to strengthen accountability. as the next director-general election approaches, member states should insist on a dynamic leader with a strong record of focusing on people, able to manage crises, implement reforms, and communicate strategically. a key attribute should be proven high-level political leadership with the character and capacity to challenge even the most powerful governments when necessary to protect public health. it is in the collective interest of member states to have a strong, empowered leader heading the who. taken together, the panel's ten recommendations provide a vision for a more robust, resilient global system able to manage infectious disease outbreaks (panel , fi gure ). preventing small outbreaks from becoming large-scale emergencies demands investment in minimum capacities in all countries and encouragement of early international reporting of outbreaks by adhering to agreed international rules. responding eff ectively to outbreaks demands much stronger operational capacity within who and within the broader aid system if outbreaks escalate into humanitarian emergencies, a politically protected process for who's emergency declarations, and strong mechanisms for the accountability of all involved actors, from national governments to non-governmental organisations and from un agencies to the private sector. mobilisation of the knowledge needed to combat outbreaks will require an international framework of rules to enable, govern, and ensure access to the benefi ts of research, and fi nancing to develop technology when commercial incentives are inappropriate. finally, eff ective governance of this complex global system demands high-level political leadership and a who that is more focused and appropriately fi nanced and whose credibility is restored through the implementation of good governance reforms and assertive leadership. the human catastrophe of the ebola epidemic that began in shocked the world's conscience and created an unprecedented crisis. it exposed deep inadequacies in the national and international institutions responsible for protecting the public from the far-reaching human, social, economic and political consequences of disease outbreaks. the reputation and credibility of who has suff ered a particularly fi erce blow. ebola brought to the forefront a central question: is major reform of international institutions feasible to restore confi dence and prevent future catastrophes? or should leaders conclude the system is beyond repair and take ad hoc measures when the next major outbreak strikes? research: producing and sharing data, knowledge, and technology . develop a framework of rules to enable, govern, and ensure access to the benefi ts of research . establish a global facility to fi nance, accelerate, and prioritise research and development governing the global system . sustain high-level political attention through a global health committee of the security council . a new deal for a more focused, appropriately fi nanced who . good governance of who through decisive, time bound reform and assertive leadership international health regulation emergency committee. the standing emergency committee will meet and receive information from the emergency centre regularly, with the mandate to declare a public health emergency of international concern by a majority vote of its members. the director-general would chair this committee. a permanent inspector general's offi ce is proposed, along with other good governance reforms (not depicted in the fi gure) such as a freedom of information policy. after diffi cult and lengthy deliberation, our panel concluded major reforms are warranted and feasible. the panel refi ned its recommendations into a roadmap of ten interrelated reforms that in combination can strengthen the global system for outbreak prevention and response. the roadmap gives greatest weight to clarifi cation of the roles and responsibilities of the many actors involved in outbreak response, investing in capacities to fulfi l those roles, and demanding accountability for meeting those responsibilities. these measures are concrete, actionable, and measurable. success requires one other essential ingredient: high-level political leadership determined to translate this roadmap into enduring systemic reform so that the immense human suff ering of the ebola outbreak will not be repeated. msf addresses un security council emergency session on ebola ebola situation reports un offi ce of the special envoy on ebola. resources for results iii appeal: ebola virus outbreak-overview of needs and requirements (inter-agency plan for guinea global health security: the wider lessons from the west african ebola virus disease epidemic governance challenges in global health the next epidemic-lessons from ebola preparing for the next outbreak report of the review committee on the functioning of the international health regulations ( ) in relation to pandemic (h n ) ground zero in guinea: the outbreak smouldersundetected-for more than months pushed to the limit and beyond: a year into 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uniting in seoul to extinguish epidemic threats through the global health security agenda leaders declaration international ebola recovery conference world bank group provides new fi nancing to help guinea, liberia and sierra leone recover from ebola emergency the bill & melinda gates foundation to fund disease surveillance network in africa and asia to prevent childhood mortality and help prepare for the next epidemic train africa's scientists in crisis response clinical laboratory networks contribute to strengthening disease surveillance: the resaolab project in west africa fleming fund launched to tackle global problem of drug-resistant infection a wake up call: lessons from ebola for the world's health systems the ebola review: parts i and ii who criticizes china over handling of mystery disease. hong kong: the new york times african risk capacity insurance mechanism report of the ebola interim assessment panel ebola virus disease epidemic in west africa: lessons learned and issues arising from west african countries saving lives: the civil-military response to the ebola outbreak in west africa ebola virus outbreak -overview of needs and requirements (inter-agency plan for guinea inter-agency standing committee working group. humanitarian system-wide emergency activation: defi nitions and procedures commission on information and accountability for women's and children's health. keeping promises, measuring results the power of straight talk: the independent monitoring board of the global polio eradication initiative data sharing: make outbreak research open access ebola researchers plead for access to virus samples proposed ebola biobank would strengthen african science sars: a global response to an international threat a global initiative on sharing avian fl u data infl uenza preparedness framework advisory group technical expert working group on genetic sequence data the who pandemic infl uenza preparedness framework: a milestone in global governance for health effi cacy and eff ectiveness of an rvsv-vectored vaccine expressing ebola surface glycoprotein: interim results from the guinea ring vaccination cluster-randomised trial opting against ebola drug for ill african doctor who consultative expert working group on research and development. research and development to meet health needs in developing countries: strengthening global fi nancing and coordination establishing a global vaccine-development fund demonstration fi nancing: considerations for the new international fund for r&d securing new drugs for future generations: the pipeline of antibiotics a global biomedical r&d fund and mechanism for innovations of public health importance what's the world health organization for?: fi nal report from the centre on global health security working group on health governance the world health organization. abingdon: routledge cuts at w.h.o. hurt response to ebola crisis who. proposed programme budget all authors contributed to study concept, data analysis and interpretation, and provided critical revisions of the manuscript for important intellectual content. pp, akj, map, and ds chaired and co-chaired the panel, respectively, providing high level content and directional oversight. sm supervised the study design, data collection, data analysis, and data interpretation; drafted the manuscript; and led all revisions. bh, jal, and lrw contributed to the data collection, data analysis and data interpretation; creation of fi gures; and provided administrative, technical, and material support. we thank julio frenk for initial discussions that led to the creation of the panel, and robert marten and the rockefeller foundation for supporting the london meeting of the panel, and research and dissemination eff orts. we are grateful to emily anne robinson for research and organisational support for the boston meeting, and to zoe mark lyon for research support. key: cord- - bb authors: brownstein, john s; freifeld, clark c; reis, ben y; mandl, kenneth d title: surveillance sans frontières: internet-based emerging infectious disease intelligence and the healthmap project date: - - journal: plos med doi: . /journal.pmed. sha: doc_id: cord_uid: bb john brownstein and colleagues discuss healthmap, an automated real-time system that monitors and disseminates online information about emerging infectious diseases. the opportunity as developed nations continue to strengthen their electronic disease surveillance capacities [ ] , the parts of the world that are most vulnerable to emerging disease threats still lack essential public health information infrastructure [ , ] . the existing network of traditional surveillance efforts managed by health ministries, public health institutes, multinational agencies, and laboratory and institutional networks has wide gaps in geographic coverage and often suffers from poor and sometimes suppressed information flow across national borders [ ] . at the same time, an enormous amount of valuable information about infectious diseases is found in web-accessible information sources such as discussion sites, disease reporting networks, and news outlets [ , , ] . these resources can support situational awareness by providing current, highly local information about outbreaks, even from areas relatively invisible to traditional global public health efforts [ ] . these data are plagued by a number of potential hazards that must be studied in depth, including false reports (mis-or disinformation) and reporting bias. yet these data hold tremendous potential to initiate epidemiologic follow-up studies and provide complementary epidemic intelligence context to traditional surveillance sources. this potential is already being realized, as a majority of outbreak verifications currently conducted by the world health organization (who)'s global outbreak alert and response network are triggered by reports from these nontraditional sources [ , ] . in one of the most frequently cited examples [ ] , early indications of the severe acute respiratory syndrome (sars) outbreak in guangdong province, china, came in november from a chinese article that alluded to an unusual increase in emergency department visits with acute respiratory illness [ , ] . this was followed by media reports of a respiratory disease among health care workers in february , all captured by the public health agency of canada's global public health intelligence network (gphin) [ , , ] . in parallel, online discussions on the promed-mail system referred to an outbreak in guangzhou, well before official government reports were issued [ ] . these web-based data sources not only facilitate early outbreak detection, but also support increasing public awareness of disease outbreaks prior to their formal recognition. through lowcost and real-time internet data-mining, combined with openly available and summary points diseases is found in web-accessible information sources such as discussion forums, mailing lists, government web sites, and news outlets. sources can play an important role in early event detection and support situational awareness by providing current, highly local information about outbreaks, even from areas relatively invisible to traditional global public health efforts. useful, information overload and difficulties in distinguishing "signal from noise" pose substantial barriers to fully utilizing this information. automated real-time system that monitors, organizes, integrates, filters, visualizes, and disseminates online information about emerging diseases. real-time intelligence on a broad range of emerging infectious diseases for a diverse audience, from public health officials to international travelers. and other nontraditional sources of surveillance data can facilitate early outbreak detection, increase public awareness of disease outbreaks prior to their formal recognition, and provide an integrated and contextualized view of global health information. user-friendly technologies, both participation in and access to global disease surveillance are no longer limited to the public health community [ , ] . the availability of web-based news media provides an alternative public health information source in under-resourced areas. however, the myriad diverse sources of infectious disease information across the web are not structured or organized; public health officials, nongovernmental organizations, and concerned citizens must routinely search and synthesize a continually growing number of disparate sources in order to use this information. with the aim of creating an integrated global view of emerging infections based not only on traditional public health datasets but rather on all available information sources, we developed healthmap, a freely accessible, automated electronic information system for organizing data on outbreaks according to geography, time, and infectious disease agent [ ] ( figure ). operating since september , healthmap (http://www.healthmap. org/) is a multistream real-time surveillance platform that continually aggregates reports on new and ongoing infectious disease outbreaks [ ] . the system performs extraction, categorization, filtration, and integration of these reports, facilitating knowledge management and early detection ( figure ). through this approach, we seek a unified and comprehensive view of current infectious disease outbreaks in space and time worldwide. healthmap is designed to provide a starting point for real-time intelligence on a broad range of emerging infectious diseases for a diverse range of end users, from public health officials to international travelers [ , , ] . the system currently serves as a direct information source for approximately , unique visitors per month, as well as a resource for libraries, local health departments, governments (e.g., the us department health and human services and department of defense), and multinational agencies (e.g., the united nations), which use the healthmap data stream for day-to-day surveillance activities. many regular users come from the who, the us centers for disease control and prevention, and the european centre for disease prevention and control. knowledge sources. healthmap relies on a variety of electronic media sources, including online news sources through aggregators such as google news, expert-curated discussion such as promed-mail [ , , ] , and validated official reports from organizations such as the who. currently, the system collects reports from sources, which in turn represent information from over , web sites, every hour, hours a day. internet search criteria include disease names (scientific and common), symptoms, keywords, and phrases. the system collects an average of reports per day, with the majority acquired from news media sources ( . %). although most of the reports collected to date have been in english, healthmap also monitors information sources in chinese, spanish, russian, and french, with additional languages such as hindi, portuguese, and arabic under development. as healthmap reports are acquired solely from free news sources, operational costs are minimal. the web site is freely accessible on the internet without subscription fees. the use of international news media for public health surveillance has a number of potential biases that merit consideration. while local news sources may report on incidents involving a few cases that would not be picked up at the national level, such sources may be less reliable, lacking resources and training, and may report stories without adequate confirmation. furthermore, other biases may be intentionally introduced for political reasons through disinformation campaigns (false positives) or state censorship of information relating to outbreaks (false negatives). we have attempted to better understand some of these issues through ongoing analysis and evaluation research. we ran a -week evaluation of healthmap data, covering the period of october , through july . we found that pathogen diversity was substantial across news sources, with unique infectious disease categories reported through the google news feed alone (table ) . we found the frequency of reports about particular pathogens to be related not to their associated morbidity or mortality impact, but rather to the direct or potential economic and social disruption caused by the outbreak. for instance, we found substantial skew towards reporting on stories about avian influenza and food-borne illnesses. over the evaluation time period, countries had reports of infectious disease outbreaks, with the greatest reporting from the united states (n = ), the united kingdom (n = ), canada (n = ), and china (n = ) ( figure a ). there was a clear bias towards increased reporting from countries with higher numbers of media outlets, more developed public health resources, and greater availability of electronic communication infrastructure (approximated by number of internet hosts) ( figure b ). these trends are highly relevant for users of the system, and thus the individual impact of these factors on surveillance will form the basis of a detailed user guide currently under development. knowledge extraction. the system characterizes disease outbreak reports by means of a series of text mining algorithms. (a complete technical description of the system may be found elsewhere [ ] .) characterization stages include: (a) identifying disease and location; (b) determining relevance-namely, whether a given report refers to any current outbreak; and (c) grouping similar reports together while removing exact duplicates. once the reports are automatically processed, curators correct the misclassifications of the system where necessary (figure ) . currently, only one analyst reviews and corrects the posts. however, additional resources would enable more detailed multilingual curation and annotation of collected reports. extracting location and disease names from text reports presents the most formidable challenge. healthmap draws from a continually expanding dictionary of pathogens (human, plant, and animal diseases) and geographic names (country, province, state, and city) to classify outbreak alert information. however, disease and place names are often ambiguous, colloquial, and subject to change, and may have multiple spellings (e.g., diarrhea, common in the us, and diarrhoea, common in the uk). thus, the expansion and editing of the database requires extensive manual data entry. once location and disease have been identified, articles are automatically tagged according to their relevance. specifically, we identify whether a given report refers to a current outbreak ( "breaking news"), as opposed to reporting on other infectious disease-related news, such as vaccination campaigns, scientific research, or public health policy. in this case, healthmap makes use of a bayesian machine learning algorithm, trained on manually characterized existing reports, to automatically tag and separate breaking news. finally, duplicate reports are filtered, identified, and grouped based on the similarity of the article's headline, body text, and disease and location categories. using a similarity score threshold, the system groups related articles into clusters that provide the collective information on a given outbreak. knowledge integration and dissemination. healthmap is particularly focused on providing users with news of immediate interest and reducing information overload. overwhelming public health officials with information on outbreaks of low public health impact may distract them from investigating outbreaks of greater priority that might receive reduced media attention. thus, only articles classified as breaking news are posted to the site. although they are filtered from the initial display, other article types and duplicate articles are shown in a related information window, providing a situational report on an ongoing outbreak as well as recent reports concerning either the same disease or location, and links for further research (figure ) . healthmap also addresses the computational challenges of integrating multiple sources of unstructured information by generating meta-alerts of disease outbreaks. as false alarms can often be reduced by thorough aggregation and cross-validation of reported information, a composite activity score (or heat index) is calculated based on (a) the reliability of the data source (for instance, increased weight is given to who reports and reduced weight to local media reports); and (b) the number of unique data sources, with increased weight to multiple types of information (e.g., discussion sites and media reports on the same outbreak). this meta-alert derivation is based on the idea that multiple sources of information about an incident provide greater confidence in the reliability of the report than any one source alone. a wide range of further improvements are currently being developed across all components of the healthmap system. in particular, population and geography gaps in the coverage of the monitored sources need to be better understood and accounted for. for example, there are critical gaps in media reporting in tropical and lowerlatitude areas, including major parts of africa and south america-the very regions that have the greatest burden and risk of emerging infectious diseases (figure ) [ ] . monitoring other internet-based sources such as blogs, discussion sites, and listservs could complement news coverage. the use of click-stream data and individual search queries is also a promising new surveillance source [ ] . multilingual surveillance is critical for capturing greater geographic coverage and for providing earlier and more comprehensive reporting from local news media. potential future challenges include the possibility that news data sources that are freely available now will no longer be available if current business models change. in addition, the way news is reported online (content, format, communication standards, etc.) may change and develop in the coming years, which will require a re-tooling of the system in order to capture the appropriate information. potential future benefits of technological advances include better meta-data tagging if/when the semantic web becomes a reality. also, as location-based services become more widespread, including on portable devices, healthmap feeds can be tailored and targeted to specific users and their locations. future work must also focus on improving natural language processing capability to clearly identify the pathogen, filter nonpertinent reports and duplicates, and enhance the spatial resolution of location extraction. however, while improvements in machine learning techniques are undoubtedly critical, they cannot currently replace human analysis. the success of wikipedia has shown that leveraging collaborative human networks of trained public health professionals has the potential to support improved classification, severity assignment, conflict resolution, geocoding, and confirmation of reports on rare or unknown infectious diseases [ ] . a recently established collaboration between healthmap and promed-mail (http://www. healthmap.org/promed) is helping to pave the way for such a bidirectional system of classification and curation of information flow [ ] . continued system evaluation is also essential. the fundamental characteristics of different news source types need to be quantified, including sensitivity, specificity, and timeliness [ , , , ] . consideration should also be given to integrating unstructured online information sources with other health indicator data to provide a broader context for reports. pertinent data sets include mortality and morbidity estimates, laboratory data, field surveillance (e.g., vector and animal reservoir distribution), environmental predictors (e.g., climate and vegetation), population density and mobility, and pathogen seasonality and transmissibility. such integration could all articles related to a given outbreak are aggregated by text similarity matching in order to provide a situational awareness report. furthermore, other outbreaks occurring in the same geographic area or involving the same pathogen are provided. the window also provides links to further research on the subject. in this example, we show all alerts relating to a recent cholera outbreak in nigeria. yield a more precise relevance score for a given report, define populations at risk, and predict disease spread. healthmap is a member of a new generation of surveillance systems that mine media sources in near realtime for reports of infectious disease outbreaks, including gphin [ , ] , medisys, developed by the directorate general health and consumer affairs of the european commission [ ] , the us government-funded argus [ ] , and epispider [ ] . while internet-based online media sources are becoming a critical tool for global infectious disease surveillance, important challenges still need to be addressed. since regions with the least advanced communication infrastructure also tend to carry the greatest infectious disease burden and risk, system development must be aimed at closing the gaps in these critical areas. hence, achieving global coverage requires attention to creating and capturing locally feasible channels of communication. it also involves making the outputs of the system more accessible to users in these regions through user interfaces in additional languages and low-bandwidth display options, including mobile phone alerts. ultimately, the monitoring of diverse media-based sources will augment epidemic intelligence with information derived outside the traditional public health infrastructure, yielding a more comprehensive and timely global view of emerging infectious disease threats. a truly open and accessible system can also assist users in overcoming existing geographical, organizational, and societal barriers to information, a process that can lead to greater empowerment, involvement, and democratization across the increasingly interconnected global health sphere. implementing syndromic surveillance: a practical guide informed by the early experience disease surveillance needs a revolution global trends in emerging infectious diseases the new international health regulations: considerations for global public health surveillance rumors of disease in the global village: outbreak verification hot spots in a wired world: who surveillance of emerging and re-emerging infectious diseases use of the internet to enhance infectious disease surveillance and outbreak investigation official versus unofficial outbreak reporting through the internet global surveillance, national surveillance, and sars global public health intelligence network (gphin). th conference of the association for machine translation in the americas sars and population health technology the global public health intelligence network and early warning outbreak detection: a canadian contribution to global public health the internet and the global monitoring of emerging diseases: lessons from the first years of promed-mail internet and computer-based resources for travel medicine practitioners traveller's medicine on the internet healthmap: the development of automated real-time internet surveillance for epidemic intelligence infectious disease surveillance and detection: assessing the challenges-finding solutions netwatch: diseases on the move technology and public health: healthmap tracks global diseases get your daily plague forecast global awareness of disease outbreaks: the experience of promedmail promed-mail: background and purpose healthmap: global infectious disease monitoring through automated classification and visualization of internet media reports infodemiology: tracking flu-related searches on the web for syndromic surveillance internet encyclopaedias go head to head interactive map of promed reports available the emerging science of very early detection of disease outbreaks integrating syndromic surveillance data across multiple locations: effects on outbreak detection performance finding leading indicators for disease outbreaks: filtering, cross-correlation, and caveats identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system health threats unit at directorate general health and consumer affairs of the european commission a heuristic indication and warning staging model for detection and assessment of biological events scanning the emerging infectious diseases horizon-visualizing promed emails using epispider blog: a regularly updated online journal containing news or commentary on a particular topic, generally produced by an individual or a small group of people. a sequential record of the actions performed by a user while browsing the internet, including web sites visited, searches performed, and hyperlinks followed.event-based surveillance: unstructured data gathered from sources of intelligence of any nature. structured data collected through routine public health surveillance systems.informal surveillance: information from individuals or news media sources, as opposed to official government or government-sponsored reports.listserv: an automated email forwarding system that allows any member of a group of people to easily send a message to all other members of the group. multistream surveillance: an approach that monitors multiple sources of information and may also integrate them into a unified analytical framework. key: cord- -mfjyjjer authors: lee, min hye; lee, gyeoung ah; lee, seong hyeon; park, yeon-hwan title: a systematic review on the causes of the transmission and control measures of outbreaks in long-term care facilities: back to basics of infection control date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: mfjyjjer background: the unique characteristics of long-term care facilities (ltcfs) including host factors and living conditions contribute to the spread of contagious pathogens. control measures are essential to interrupt the transmission and to manage outbreaks effectively. aim: the aim of this systematic review was to verify the causes and problems contributing to transmission and to identify control measures during outbreaks in ltcfs. methods: four electronic databases were searched for articles published from to . articles written in english reporting outbreaks in ltcfs were included. the quality of the studies was assessed using the risk-of-bias assessment tool for nonrandomized studies. findings: a total of studies were included in the qualitative synthesis. the most commonly reported single pathogen was influenza virus, followed by group a streptococcus (gas). of the studies that identified the cause, about half of them noted outbreaks transmitted via person-to-person. suboptimal infection control practice including inadequate decontamination and poor hand hygiene was the most frequently raised issue propagating transmission. especially, lapses in specific care procedures were linked with outbreaks of gas and hepatitis b and c viruses. about % of the included studies reported affected cases among staff, but only a few studies implemented work restriction during outbreaks. conclusions: this review indicates that the violation of basic infection control practice could be a major role in introducing and facilitating the spread of contagious diseases in ltcfs. it shows the need to promote compliance with basic practices of infection control to prevent outbreaks in ltcfs. four electronic databases were searched for articles published from to . articles written in english reporting outbreaks in ltcfs were included. the quality of the studies was assessed using the risk-of-bias assessment tool for nonrandomized studies. a total of studies were included in the qualitative synthesis. the most commonly reported single pathogen was influenza virus, followed by group a streptococcus (gas). of the studies that identified the cause, about half of them noted outbreaks transmitted via person-toperson. suboptimal infection control practice including inadequate decontamination and poor hand hygiene was the most frequently raised issue propagating transmission. especially, lapses in specific care procedures were linked with outbreaks of gas and hepatitis b and c viruses. about % of the included studies reported affected cases among staff, but only a few studies implemented work restriction during outbreaks. outbreak of an infectious disease is defined as the occurrence of a disease above the expected level [ ] . over the past several years, many countries have experienced serious economic and health consequences due to outbreaks of infectious diseases such as the middle east respiratory syndrome in and severe acute respiratory syndrome in . long-term care facilities (ltcfs) are facing a great need for preparation for infection outbreaks because of an increase in the number of residents with global aging. ltcfs are exposed to the risk of outbreaks owing to several factors. first, older residents in ltcfs are susceptible to infectious diseases because of aging and health conditions [ ] and are known to be dependent with regard to activities of daily living. thus, among residents, self-hygiene is observed to be poor. loss of independence in residents creates unique and frequent contact opportunities between healthcare workers (hcws) and residents [ ] . second, hcws in ltcfs tend to be poorly informed about infection prevention and control (ipc), and compliance with ipc is generally low [ , ] . third, the environment in ltcfs offers challenges for ipc, like the sharing of rooms, group living, and difficulty with the isolation of infected persons [ , ] . finally, ltcfs have limited resources and capacities for diagnosis of infection [ ] . this leads to a delay in the detection of hidden carriers and infection. all these factors contribute to the onset and spread of outbreaks in ltcfs. outbreaks in ltcfs threaten the life and health of both residents and hcws, and thus, eliminating the risk of outbreaks is a matter of concern in such facilities. however, ltcfs vary in their individual capacities to respond to outbreaks [ ] . the keys to outbreak control are as follows: identification of the transmission causes and minimization of the spread through early initiation of control measures. therefore, it is essential to understand the causes of transmission and the applied measures to control outbreaks in ltcfs. there are several gaps and limitations in previous studies to comprehensively understand outbreaks in ltcfs. first, in many previous researches that addressed outbreaks, the focus was on pathogens, burdens, and adverse outcomes such as mortality [ , ] . based on the perceived importance of control measures, one of the purposes of this review was to explore and analyze in detail the control measures reported in studies. secondly, pharmaceutical measures may have some limitations on effectiveness against newly emerging infectious diseases or resistant strains [ ] and some pathogens may not have pharmaceutical interventions to be considered during outbreaks. non-pharmaceutical interventions (npis) such as hand hygiene and precautions should be utilized to prevent the transmission of outbreak pathogens, regardless of the evolution of infectious diseases. however, little attention has been paid to npis in studies concerning outbreaks in ltcfs [ ] . this review focused on npis and ascertains the control measures based on the guideline for prevention and control of influenza outbreaks in ltcfs of the world health organization (who) [ ] . finally, to our knowledge, there is no published systematic review addressing overall outbreaks in ltcfs in the past years. after pilot data extraction, two reviewers independently extracted data such as information on participants, pathogens, case definitions, number of cases and non-affected persons, overall attack rate, causes and problems that led to transmission, and control measures. control measures. general control measures considered were the formation of outbreak control team, active surveillance, standard precautions, transmission-based precautions, training and education, employee work restriction, environmental control, containment measures, and prophylaxis based on the who guideline [ ] . the quality of studies was assessed using risk of bias assessment tool for nonrandomized study (robans) by two reviewers [ ] . robans is an evaluation tool for the risk of bias of non-randomized studies, with moderate reliability and acceptable validity and compatible with domains of the cochrane risk-of-bias tool [ ] . six domains were evaluated including the selection of participants, confounding variables, exposure measurement, blinding for outcome assessment, incomplete outcome, and selective outcome reporting. according to the instruction for evaluation [ ] , the risk of bias for each domain was determined as low risk, unclear risk and high risk. studies with full-text including case-control analysis, cohort study was involved in the quality assessment. studies that simply described the results of investigation without comparative analysis were not able to evaluate the domains of the tool. thus, the quality evaluation was not conducted with this type of study. any difference was discussed between the two reviewers, and, if necessary, an agreement was reached with the corresponding author. cinahl ti (infection or infections or outbreak � or transmission) and ti ("nursing home � " or "skilled nursing � " or "long-term care") and ti (control � or outcome � or factor � ) not ti (surgery or cancer or "neoplasm" or "intensive care unit" or child or children or "operative") the result of quality assessment was displayed using review manager (revman) version . software (the cochrane collaboration, oxford, uk). a total of , studies were retrieved from databases and hand searched. the duplicate records were removed (n = ), and the eligibility criteria were applied for the selection process. after reviewing the full text, articles were excluded for the following reasons: irrelevant for the research topic (n = ) and population (n = ), unavailable full-text (n = ), review article (n = ), and duplicated report (n = ). finally, articles were included in this review (fig ) . characteristics of the eligible studies are presented in table . over half of the included studies (n = ) were published since . the majority of the included studies were reported in the united states (n = ) and europe (n = ) followed by asia (n = ). the quality of studies was assessed and the results are summarized in fig . one study was at high risk for five criteria [ ] . six studies were at low risk for all criteria [ ] [ ] [ ] [ ] [ ] [ ] . problems related to recall bias and standardization of self-reported measurement created a high risk of bias for the measurement of the exposure domain in seven studies [ , [ ] [ ] [ ] [ ] [ ] [ ] . lack of consideration for confounders led to a high risk of bias in four studies [ , [ ] [ ] [ ] . the problem related to missing data resulted in a high risk of bias for the incomplete outcome domain in five studies [ , , , , ] . characteristics of the outbreaks are presented in tables - . fifteen studies reported outbreaks caused by bacteria [ - , , , , , - ] and studies were outbreaks by viruses [ , , , , , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the largest number of a single pathogen was influenza viruses [ ] [ ] [ ] [ ] [ ] [ ] , followed by group a streptococcus (gas) [ , , , , ] . the most affected site was respiratory tract (n = ) [ , , , - , , ] , followed by gastrointestinal (gi) tract (n = ) [ , , , , , , , , , ] . other sites including skin and soft tissue and eyes were affected. the majority of the eligible studies reported one outbreak involving one facility (n = ), while the study by nguyen and middaugh [ ] described a gastroenteritis outbreak that was transmitted to eight facilities. three studies analyzed the data of multiple outbreaks of viral gastroenteritis and influenza-like illness that occurred in multiple facilities for a certain period of time [ , , ] . the outbreaks in studies affected both the residents and hcws [ , , , , , , , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and the outbreaks of studies affected only the residents [ - , , , , , , , , , ] . in total, studies reported , outbreaks (affecting , residents and staff members) in , facilities. there were three prolonged gas outbreaks of multiple consecutive clusters for over months. the overall attack rates ranged widely from . % to . % in studies. among the studies, the median of the overall attack rate was . %: . % for bacterial outbreaks and . % for viral outbreaks (table ). in studies, it was not possible to calculate the rate due to lack of information. the highest attack rate of . % was reported in an outbreak of respiratory syncytial virus (rsv) and human metapneumovirus (hmpv) [ ] , followed by clostridium difficile ( . %) [ ] and viral gastroenteritis caused by norovirus and rotavirus ( . %) [ ] . influenza-like illness had the median overall attack rate of . %. the median attack rate among staff was highest for the acute gastroenteritis outbreaks. the duration of outbreaks ranged from less than one month to over months. outbreaks in studies lasted for over months: studies by hepatitis b virus, by gas, by tuberculosis (tb), by multi-drug resistant organisms (mdros), by viral gastroenteritis, by c. difficile, and by hepatitis c virus [ , , - , , , , , , , ] . outbreaks in long-term care facilities: sr if only one study of the outbreaks was reported, the attack rate of the study was displayed. if the number of reports was , only the range of attack rate was displayed. outbreaks in long-term care facilities: sr causes and critical problems contributing to transmission. causes of transmission in the eligible studies were reported as person-to-person transmission, contaminated water and food, and problems in practice (tables and ). the following studies (n = ) did not report or could not identify the cause of the outbreaks: studies on influenza viruses, on non-typeable haemophilus influenzae, on hepatitis c virus, on c. difficile, on adenovirus, on norovirus, and on rsv and hmpv [ , , , , , , , , , , , ] . the most commonly reported route of transmission was person-to-person [ , - , , , , , , , , , , ] . of these studies, the human source of transmission was identified as the hcws in six outbreaks [ , , , , , ] and the residents in two outbreaks [ , ] . the skin of a hcw was a reservoir for methicillin-resistant staphylococcus aureus (mrsa) outbreaks, leading to cross-infection, in the study by maltezou et al. [ ] . the large gastroenteritis outbreak affecting people in facilities was attributed to staff who worked at multiple facilities [ ] . one study showed that three outbreaks of gas recurred for three years because of continued person-to-person transmission from colonized residents [ ] . in the study by Šubelj and učakar [ ] , person-to-person transmission resulted from delayed implementation of control measures. contaminated water and food were sources of infection in five studies [ , , , , ] . hepatitis e outbreak was caused by contaminated tap water after heavy rain [ ] , while the consumption of tap water was the suspected cause of one viral gastroenteritis outbreak [ ] . foodborne causes such as contaminated cake or meals were noted in three studies regarding clostridium perfringens, salmonella enteritidis, and gastroenteritis [ , , ] . most of the reviewed studies pointed out several issues in practice that might have facilitated the occurrence and spread of outbreaks. the most frequently observed problem was suboptimal hand hygiene, followed by personal protective equipment (ppe), and cleaning and disinfection. investigation for the gas outbreak in the study by nanduri et al. [ ] revealed that hand hygiene compliance among employees was - %. additionally, poor hand hygiene became a more critical factor that facilitated the transmission of acute gastroenteritis, particularly in ltcfs having close living conditions with frequent close contact between the staff and dependent residents [ ] . issues related to ppe had been addressed including inappropriate use of glove and improper storage of ppe [ , , , , , ] . there were reports indicating the potential to cross-contamination by not-changing gloves between residents or by storage of ppe in the room of the index case [ , ] . breaches in disinfection and cleaning of the environment and equipment were associated with many outbreaks, most of them were gas [ , , ] or hepatitis b and c outbreaks [ , ] . three reports of gas outbreaks found lapses in wound care practice such as inconsistent cleaning and disinfection [ , , ] . the outbreaks of mdros and hepatitis b reported device related issues including sharing of a device and inappropriate use of reusable devices [ , , , ] . hepatitis b and c outbreaks commonly reported that lapses during podiatry care and point-of-care testing procedures (blood glucose test and international normalized ratio monitoring) caused the transmission of bloodborne pathogens among residents [ , , , , ] . the lapses included the sharing of contaminated equipment, improper disinfection, and poor hand hygiene adherence. some studies noted failure of environmental infection control [ , , , ] . two of those studies were tb epidemics, and the investigation revealed that the case residents were exposed to insufficient room ventilation. an influenza outbreak in the summer was facilitated by a heating preventive measure that placed all the residents in one limited area [ ] . the response to outbreaks also could influence the progress of outbreaks. nine reports underlined early notification of outbreaks to public health authorities and implementation of control measures within days of onset of the first case, which affected the attack rates and duration of the outbreaks [ , , , , , , [ ] [ ] [ ] . some studies on influenza outbreaks discussed issues related to vaccines. of the three influenza outbreaks in a well-vaccinated population, two studies pointed out that a mismatch between the circulating strains and the vaccine strains affected this population [ , ] , and the other study noted an insufficient vaccine effectiveness [ ] . especially, the study by burette et al. [ ] identified that in addition to the mismatch, several defects including a vaccination rate of % among staff and untimely vaccination among residents led to the outbreaks. in addition, they raised the issue of the knowledge and proficiency of general practitioners in influenza diagnosis, treatment, and prevention. moreover, three studies suspecting transmission from staff to residents placed emphasis on work restriction of the ill staff [ , , ] . there were other problems including poor personal hygiene of staff members [ ] , lack of communication between institutions [ ] , and understaffing [ ] . several studies demonstrated host factors associated with the outbreaks in case-control analysis, that were identified as: age [ ] , sex [ ] , cognitive impairment [ ] , nutritional status [ ] , comorbidities [ , ] , use of an indwelling device [ , ] , and dependence level [ ] . although not the result of the case-control analysis, the study by spires et al. [ ] reported that all cases of rsv and hmpv were dependent dementia patients, implicating that dependence was an important factor. control measures. strategies to control outbreaks were reported in of the reviewed papers, as summarized in table . all studies reported that one or more npis were applied to control the outbreaks. from a rigorous perspective, only one study on a multidrug-resistant pseudomonas aeruginosa (mrpa) outbreak implemented all the measures recommended to control an outbreak by pathogens [ ] . work restriction of ill workers was less frequently reported compared to other measures. only five studies reported the creation of outbreak control teams for effective management of the outbreaks [ , , , , ] . most facilities notified public health authorities or institutions about the outbreaks and received advice and assistance to manage the outbreaks. all four studies applying limitation or cessation of group activities were recently published since [ , , , ] . gastroenteritis outbreaks (n = ). three studies on gastrointestinal infection, in which adherence to hand hygiene among hcws was crucial to prevent its spread, reported control measures including stringent hand hygiene practice and reinforcement of standard precautions [ , , ] . only two studies implemented barrier precautions by use of ppe [ , ] . all five studies that reported control measures used various types of social distancing measures including isolation, restriction of new admission and visitors, or cessation of group activities [ , , , , ] . active surveillance by symptom reporting for early detection of new cases was reported in two studies [ , ] . although four studies reported that staff members were affected by the outbreaks, only one study implemented work exclusion for ill employees and showed the lowest attack rate among staff [ ] . four studies reported intensive cleaning and disinfection of the environment [ , , , ] . the implementation of more stringent procedures for cleaning and disinfection with diluted bleach was reported for outbreaks of c. difficile [ ] . the study by luque et al. [ ] on viral gastroenteritis reported a relatively small number of interventions, showing a high attack rate of . %. on the other hand, the study by Šubelj and učakar [ ] with the largest number of control measures among the five studies had a lower attack rate of . % compared to the other outbreaks. influenza virus outbreaks (n = ). five of the six reports implemented prophylactic oseltamivir for the residents and/or hcws [ ] [ ] [ ] [ ] [ ] . both droplet precaution and active surveillance were reported in of the six studies. five of the studies on influenza outbreaks reported a total of cases among staff, but only three of the studies implemented the measure of work restriction [ , , ] . the study by burette et al. [ ] reported the lowest number of control measures including prophylaxis and isolation and had the highest attack rate of . % among the five reports on influenza a. tuberculosis outbreaks (n = ). following the detection of the index case, two reports on tuberculosis outbreaks conducted case finding among residents and staff by contact tracing [ , ] . responding to the outbreaks, measures for the cases included isolation and transfer to a hospital in one study [ ] , but the other study only restricted new admissions [ ] . neither of them mentioned airborne precautions taken such as n respirators. investigations in both reports found that the air exchange rates of the rooms were inadequate. the study by lai et al. [ ] corrected the failure of the environmental infection control by increasing the ventilation rates in the building. both outbreaks involved cases among workers, but there was no description about the work status of the affected staff after the occurrence. mdros outbreaks (n = ). three outbreaks of mdros were caused by mrsa, mrpa, or klebsiella pneumoniae carbapenemase-producing klebsiella pneumonia (kpc-kp) [ , , ] . the mrsa outbreak study applied mupirocin eradication for the residents and staff [ ] . all three outbreaks used transmission-based precautions and quarantine measures to prevent the spread of mdros. in addition, they all provided re-education for the staff to improve infection control practice. furthermore, two of the reports on mrpa and kpc-kp intensified the cleaning of the environment to interrupt the contamination of the environment. the study by kanayama et al. [ ] demonstrated that the sharing of a device such as a suction device was linked with the mrpa cases; thus, the control measures included stopping the sharing of devices. the unexpected occurrence of the kpc-kp cases led to contact surveillance for additional exposure cases [ ] . the investigation for the kpc-kp outbreak revealed poor hand hygiene compliance among staff; thus, interventions including frequent audit and feedback were implemented. gas outbreaks (n = ). three of the five gas outbreaks provided antibiotic prophylaxis to the residents and staff [ , , ] . all five studies conducted surveillance culture for active case finding. none of the five outbreaks reported droplet precautions, but the study by thigpen et al. [ ] mentioned an enhanced respiratory hygiene practice. although three of the gas outbreaks lasted for a long period due to an unsolved person-to-person transmission [ , , ] , none of the studies implemented social distancing measures. two studies improved the availability of hand dispensers to address the suboptimal hand hygiene practice that was revealed during their observation [ , ] . none of the studies on the three outbreaks involving sick employees reported encouragement of work exclusion for ill staff [ , , ] , but some studies reported that there were voluntary sick leaves of employees before the recognition of the outbreaks. hepatitis virus outbreaks (n = ). prophylaxis of hepatitis b vaccine and immuno-globulin were implemented for hepatitis b virus outbreaks in two studies [ , ] . there is not much generally recommended npis for the hepatitis b and c outbreaks; thus, the studies on these outbreaks reported fewer npis than those on the other outbreaks. three of the studies on the hepatitis virus outbreaks tried to find additional cases by serologic screening [ , , ] . all the studies on the hepatitis b and c virus outbreaks employed the principle of single-use device or individual equipment to break the chain of infection [ , , , ] . improvement of the care room was done in two studies that found lapses in the environment of the procedure room [ , ] . interventions for drinking water standards and toilets were reported in the hepatitis e virus outbreak caused by contaminated water [ ] . heamophilus influenzae outbreaks (n = ). one of the two h. influenzae outbreaks reported droplet precaution during the outbreak [ ] , and the other study restricted new admissions to prevent additional transmission [ ] . other outbreaks (n = ). the study on the rsv and hmpv outbreak reported various measures including active surveillance, isolation, contact precaution, antiviral prophylaxis for residents and work restriction for ill staff to control respiratory pathogen transmission [ ] . in the epidemic keratoconjunctivitis outbreak, control measures involved universal precaution with enhanced hand hygiene, isolation and restriction of visitors, and work restriction for affected workers [ ] . we updated the understanding of outbreaks in ltcfs with more recently published reports. this review also explored and summarized critical issues facilitating the spread of the outbreaks and the control measures, which have not been addressed in detail in the previous review [ ] . lessons learned from the results of this review would enable better prevention and control of outbreaks in ltcfs in the future. implications and suggestions for achieving the best response to epidemics by ltcfs, and for future research concerning outbreaks, have been described in this review. the most common outbreaks in ltcfs in this review were respiratory infections followed by gi infections, showing consistency with the findings of a previous study on nursing homes [ ] . interestingly, there is a difference in the outbreak reports for mdros compared to the previous review [ ] . this review identified three reports including mrsa, mrpa, and kpc-kp, suggesting the increase of multidrug-resistant organisms, given that the prior review found only two reports of mrsa [ ] . as the prevalence of mdros is increasing in ltcfs [ ] , they become a particular concern in these facilities. with drug resistance on the rise, mdro related outbreaks may occur in ltcfs with growing frequency. it shows that staff and managers of ltcfs need to be aware of the significance of this trend and to prepare a plan. influenza viruses and gas accounted for a large number of single pathogens. this is similar to the results of the previous review showing that the largest number of aetiologic agents affecting outbreaks was influenza viruses in ltcfs from to [ ] . first, in this review, five of the six influenza virus outbreaks occurred by the influenza a virus and the other by influenza b virus. influenza-like illness included in the studies showed a median attack rate of . %, similar to that of seasonal influenza, usually - % [ ] . vaccine-related issues have been raised in influenza outbreaks that have occurred in ltcfs of highly immunized residents. this finding suggests some implications to prevent influenza outbreaks in ltcfs. regarding vaccination coverage among staff, the study by thomas [ ] found that influenza episodes were reduced if an employee was vaccinated, and the centers for disease control and prevention (cdc) recommend that all healthcare worker get vaccinated annually [ ] . therefore, influenza vaccination among healthcare personnel should be considered to mitigate the risk of influenza outbreaks in ltcfs. additionally, because vaccination does not provide complete protection, active daily surveillance for influenza-like illness is still recommended for all persons in ltcfs during influenza season [ ] , which is evident by the outbreaks occurring in highly immunized ltcf population. secondly, the gas infection rate among older adults in ltcfs is from to -fold higher than that of community-dwelling older adults, due to risk factors such as grouped living conditions, and underlying diseases [ , ] . five of the studies on the gas outbreaks in this review reported a median attack rate of . % in ltcfs, which is within the range of - % reported in the previous study [ ] . three of them were long-lasting outbreaks with multiple clusters for more than months, which suggested that an accurate identification of how pathogens spread was a fundamental step in outbreak control. this review also explored critical issues on practices that propagated the occurrence and spread of outbreaks. consequently, failure to adhere to basic infection control practice, including hand hygiene, disinfection, and cleaning, was found to be a practical issue of great importance on the transmission of the outbreaks in ltcfs. some reports even mentioned that this issue ultimately caused their outbreaks [ , , ] . most studies showed that this problem contributed to their outbreaks by causing cross-contamination between hands, environments, and equipment. first, the hands of hcws may be the sources of the outbreaks. frequent close contacts between residents and hcws in ltcfs increase the risk of widespread outbreaks. incorrect hand hygiene among hcws can result in hands remaining contaminated, and this may lead to the transfer of organisms to the environment and to other residents [ ] . like previous studies that already confirmed poor compliance with hand hygiene among hcws [ ] , one of the included studies reported that hand hygiene compliance was less than % [ ] . semmelweis demonstrated the role of hand hygiene in preventing infections transmitted by person-to-person [ ] . hand hygiene has a significant effect on reducing gi and respiratory infections [ ] . the who recommends that hand hygiene should be performed at the following key moments: before and after touching a patient, before clean/aseptic procedures, after body fluid exposure risk, and after touching a patient's surroundings [ ] . promotion of hand hygiene compliance through multimodal strategies has been proven to reduce healthcare-associated infection [ ] . multifaceted interventions such as who- strategies (including system change, training and education, monitoring and feedback, reminder and communication, and culture of safety) are generally effective in increasing and sustaining hand hygiene compliance at various settings [ ] [ ] [ ] [ ] [ ] . the same evidence has been reported from studies on ltcfs, suggesting improved hand hygiene reduces the infection rate or respiratory outbreaks [ , ] . secondly, lapses in cleaning and disinfection could make equipment and the environment become a reservoir for transferring pathogens [ ] . most of the studies regarding this issue were on outbreaks of gas, gastroenteritis, and hepatitis b and c virus, and they found a failure to adhere to proper disinfection and cleaning principles. first of all, the outbreaks of gas and hepatitis b and c were linked with breaches in specific procedures. gas outbreaks were usually relevant to wound care and hepatitis b and c to point-of-care testing. with the aforementioned hand hygiene, disinfection and cleaning were basic infection control practices that are included in standard precautions. the standard precautions consist of hand hygiene, environmental cleaning, reprocessing and disinfection of care equipment, waste and linen management, the prevention of needle stick injuries, and the use of personal protective equipment (ppe), if necessary [ ] . the practice of standard precautions is the imperative basic approach for ipc that was applied to all residents assuming they had the potential for pathogen transmission [ ] . standard precautions are necessary practice, especially in ltcfs where the systems for diagnostic tests are poor and active surveillance is not generally done. tailored ongoing education with multimodal strategies for hcws would ensure that basic infection control principles and standard precautions are integrated into daily practice such as point-ofcare testing [ ] . as a result, a reduction in threats of outbreaks can be guaranteed, as well as the safety and health of persons residing or working in ltcfs. meanwhile, the studies on the outbreaks of gastroenteritis reported that there were lapses in decontaminating environment. environmental contamination may have a critical role in the spread of these outbreaks. importantly, norovirus and c. difficile that are capable of surviving in the environment for long periods of time require more consideration in environmental disinfection [ , ] . for norovirus, the cdc has recommended more frequent cleaning and disinfection of rooms and high-touch surfaces with a hypo-chlorite ( - ppm) or other proper disinfectant [ ] . the most effective control method for c. difficile was reported as disinfection and cleaning of rooms and high-touch surfaces with a chlorine-based solution ( ppm) [ , ] . this systematic review identified control measures taken during the outbreaks, especially non-pharmaceutical interventions. the results showed that the actual application of control measures may be far from what is recommended and implied that there are several challenges to overcome in outbreak management at ltcfs. first, acute care facilities like hospitals can successfully manage outbreaks through collaborative efforts with multiple experts [ ] . however, most of the ltcfs in this review requested advice from public health authorities and organizations for unexpected outbreaks instead of organizing a multidisciplinary team. this may imply that ltcfs do not have sufficient capacity and expertise to individually plan, implement, and evaluate the management of outbreaks. forming a local support network between acute hospitals and ltcfs at a regional level would be a potential way to close the gaps and to enhance outbreak control practices in ltcfs without adequate capacity [ ] . furthermore, training infection control professionals in facilities could facilitate early detection of outbreaks and timely interventions. secondly, this review found that many ltcf employees were affected by the outbreaks, which is consistent with the finding of the previous review [ ] . however, it also revealed that work restriction for ill staff was not implemented well during the outbreaks in the ltcfs, which was not reviewed in the prior review [ ] . gastroenteritis outbreaks in this review had a higher median attack rate among staff than the other outbreaks, but only one study among them reported the application of work exclusion. moreover, there were some reports that implied transmission attributable to sick employees. these results pointed out the role of presenteeism in ltcfs. presenteeism among sick employees may have a role in either introducing pathogens or facilitating the transmission of outbreaks. the cdc recommends work restrictions for health care workers infected with or exposed to diseases such as diarrheal diseases, gas, tuberculosis, and viral respiratory infection [ ] . however, it may be challenging for ltcfs with fewer available resources to implement the exclusion of ill staff during outbreaks, given the fact that one study reported difficulty from understaffing as a result of work restriction [ ] . the study by widera et al. [ ] suggested that daily screening of all staff members for symptoms during outbreaks on every shift may mitigate the impact of presenteeism. considering that presenteeism is associated with various factors such as job security and lack of paid sick leave [ ] , further discussion is needed for plans addressing this issue in ltcfs. lastly, additional challenges in managing the outbreaks in ltcfs were reported. they included understaffing, insufficient supply of products such as ppe, lack of expertise, and limited application of isolation [ , , , ] . many long-term care facilities have difficulty in applying isolation of infected persons due to the limited availability of isolation rooms [ ] and concern about the adverse effects of isolation and additional precautions may affect the compliance with related practices [ ] . for the same reason, some studies in this review used minimal types of isolation like enteric isolation. if single rooms are not available, facilities should consider applying the cohort measure or bed curtains as another method of isolation. in regard to this challenge, a study by dumyati et al. [ ] suggested a shift towards enhanced standard precautions or risk-based application of transmission-based precautions to uphold the quality of life of residents by hcws. future research should identify the rationale for the safety and effectiveness of this strategy or other options. additionally, one qualitative study found that misunderstanding of the key concepts and recommendations of ipc contributed to under-utilization of transmission-based precautions [ ] . thus, emphasis should be on training and education of hcws on transmission-based precautions. a majority of the reviewed studies assessed infection control practice as part of the investigation to identify the problem areas of the outbreaks. most studies attempted on-site direct observation of infection control practices and product availability. some studies of retrospective design used survey and interview among employees. however, it is difficult to find a study that investigated the compliance rate of control measures during the outbreaks. only a few studies described gaps in the actual application after recommendations for control measures were made. even several studies overlooked reporting control measures, especially npis [ ] . although this does not necessarily mean that they did not apply measures, for the purpose of this review some studies were excluded from the analysis of control measures. the outbreak reports and intervention studies of nosocomial infection (orion) statement was developed and recommended, to improve the quality of outbreak reporting [ ] . according to the statement, control measures should be included in the paper. future studies should consider following the orion statement for reporting of outbreaks [ ] , which would facilitate the formation of a body of evidence for outbreak management in ltcfs. this study has several limitations. first, we only included studies written in english. it is possible that our review missed articles of interest written in other languages. second, we conducted only a qualitative review due to the variability of the outbreak reports. third, the quality assessment was conducted on studies of certain design including case-control and cohort study due to applicability of the quality assessment tool. fourth, the results of this review have limited generalizability due to publication bias, given that either successfully controlled outbreaks or outbreaks with higher attack rates or fatality rates tend to be published. this update for understanding outbreaks in ltcfs by reviewing recent studies indicates that staff members and residents are still at risk for contagious disease outbreaks including influenza, gastroenteritis, and gas infection. as for the problem aspects, rather than by new or unexpected issues, violation of basic infection control practices was found to facilitate the occurrence and onward transmission of pathogens. the results of this review suggest that ltcfs need to inspect basic infection control practice and to implement them thoroughly in daily care as priorities. efforts should be directed to promoting consistent and optimal adherence to the basic practice of infection control among hcws at all times in ltcfs. when an outbreak occurs, non-pharmaceutical control measures should be utilized to interrupt transmission. however, work restriction was infrequently taken compared to other measures. given the fact that over half of the included studies reported at least one employee ill and their possible role in the spread of pathogens, it is necessary that symptomatic staff members temporarily preclude themselves from working. in addition to work restriction, though, ltcfs with poor resources have faced various challenges in outbreak management. further discussion and studies are needed to identify the way addressing these challenges. world health organization. disease outbreaks shea/apic guideline: infection prevention and control in the long-term care facility influenza outbreak control 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outbreak reports and intervention studies of nosocomial infection key: cord- -daiikgth authors: van velsen, lex; beaujean, desirée jma; van gemert-pijnen, julia ewc; van steenbergen, jim e; timen, aura title: public knowledge and preventive behavior during a large-scale salmonella outbreak: results from an online survey in the netherlands date: - - journal: bmc public health doi: . / - - - sha: doc_id: cord_uid: daiikgth background: food-borne salmonella infections are a worldwide concern. during a large-scale outbreak, it is important that the public follows preventive advice. to increase compliance, insight in how the public gathers its knowledge and which factors determine whether or not an individual complies with preventive advice is crucial. methods: in , contaminated salmon caused a large salmonella thompson outbreak in the netherlands. during the outbreak, we conducted an online survey (n = , ) to assess the general public’s perceptions, knowledge, preventive behavior and sources of information. results: respondents perceived salmonella infections and the outbreak as severe (m = . ; five-point scale with as severe). their knowledge regarding common food sources, the incubation period and regular treatment of salmonella (gastro-enteritis) was relatively low (e.g., only . % knew that salmonella is not normally treated with antibiotics). preventive behavior differed widely, and the majority ( . %) did not check for contaminated salmon at home. most information about the outbreak was gathered through traditional media and news and newspaper websites. this was mostly determined by time spent on the medium. social media played a marginal role. wikipedia seemed a potentially important source of information. conclusions: to persuade the public to take preventive actions, public health organizations should deliver their message primarily through mass media. wikipedia seems a promising instrument for educating the public about food-borne salmonella. with an estimated . million cases each year, foodborne salmonella infections are a worldwide concern [ ] . in developing areas in africa, asia and south-america, salmonella typhi and paratyphi are an important cause of severe illness, leading to more than million cases and . deaths in children and young people every year [ ] . a typical salmonella infection can lead to fever, diarrhea, nausea, vomiting, abdominal cramps, and headache. symptoms usually appear between to hours after eating contaminated food, and last three to seven days. the incidence rate of salmonella is highest among infants and young children. as there are many different types of food-borne salmonella, each with their own food sources, control is difficult. proper hygiene in the kitchen (e.g., washing hands, thoroughly heating and baking meat) can prevent a salmonella infection. however, studies among the general public in italy [ ] , turkey [ ] and new zealand [ ] showed that compliance with preventive hygiene advice is low to very low. a possible explanation is that most people believe that a food-borne infection is "something that happens to others" [ , ] . educating the public about food safety is crucial in preventing food-borne infections. according to medeiros and colleagues [ ] , food-borne salmonella infections should be prevented by educating the general public about adequate cooking of food, and by instructing them about the risks of cross-contamination. traditional communication means, such as flyers, are well suited to achieve these educational goals [ ] . however, when a food-borne infection breaks out on a large scale, the dynamics of the situation shift tremendously. due to an uncertain course of events, decisions have large consequences, the general public is stressed, and the media is eager for news [ ] . in these circumstances, health organizations should inform the public about the situation and persuade them to take preventive actions. to be effective in this endeavor, they should use the communication channels the general public expects them to use, and provide the public with the information they want and need. a study among malaysians during the a(h n ) influenza outbreak in , uncovered that their main sources of information were newspapers, television and family members; their information needs were instructions on how to prevent or treat infections [ ] . in the netherlands, the severe acute respiratory syndrome (sars) outbreak and the enterohaemorrhagic e. coli (ehec) outbreak showed us that the dutch general public mostly turns to traditional media (i.e., television and radio), and news websites [ , ] . in recent years, the rise of social media (e.g., facebook, twitter) has provided new avenues for reaching the general public during infectious disease outbreaks. although social media have proven very valuable during disaster relief as a crowdsourcing tool [ ] , an exploratory study of their worth as a communication tool during an infectious disease outbreak suggested their value to be limited [ ] . research on the information behavior of the general public during infectious disease outbreaks is scarce. but this knowledge is crucial in serving the general public in their information needs, and in maximizing citizen compliance with preventive advice. in this study, we uncovered the general public's perceptions, knowledge, preventive behavior, and sources of information during a large, national salmonella outbreak by a large-scale online survey. as a result, we were able to answer our main research question: which information should health organizations convey during a largescale salmonella outbreak, and by which channels, to maximize citizen compliance with preventive advice? in the beginning of august , an outbreak of salmonella thompson occurred in the netherlands [ ] , later traced back to contaminated smoked salmon from one producer. by september , all smoked salmon of this producer was recalled. in the following week, other products containing this producer's smoked salmon (e.g., salads) were also recalled. citizens were advised to check the batch number of their products and to dispose of possible contaminated products. after implementing those measures, the number of cases decreased rapidly and by the end of , the outbreak came to an end. , laboratory-confirmed patients and four deaths were reported [ ] . the actual number of patients is thought to be higher, as individual cases of salmonella gastro-enteritis are not mandatory notifiable in the netherlands and laboratory confirmation usually merely takes place in a fraction of all patients presenting with diarrhea. according to dutch standards, this situation classifies as a large-scale outbreak, as it is an occurrence of disease greater than would otherwise be expected at a particular time and place. normally around four cases of salmonella thompson are seen in the netherlands per year. we developed an online survey to assess the general public's perceptions, knowledge, preventive behavior, and information use during the salmonella thompson outbreak. the instrument was constructed on the basis of the health belief model [ ] , and research on citizen channel choice for medical information [ , ] . the survey contained questions, and was divided into five domains: participants' information intake about the outbreak through the media, and where they went to look for answers to questions related to salmonella infections and the outbreak. perceptions were assessed by multiple statements with five-point likert scales (ranging from disagree ( ) to agree ( ) ). items were based on bults et al. [ ] . knowledge was assessed by nine true/false statements. preventive behavior was assessed by multiple-choice questions about what respondents did after hearing about the outbreak. sources of information were determined by questioning how often and where respondents saw, heard or read about the outbreak. next, we asked respondents if they had wanted more information about the outbreak or an answer to a specific question about the outbreak. if so, we asked where they had sought this information or the answer. if they had so through the internet, then we asked them if they had found it through a google search, whether they had found what they were looking for, how satisfied they were with the website, and how much they trusted the information. to keep the length of the survey acceptable, we only posed these questions for one website the participants named. if they named more than one website, the website was chosen at random. the survey can be found in additional file . respondents were recruited by a commercial panel that also hosted the survey in their online environment. the panel supplied standard demographics for each respondent (e.g., age and income). a stratified sample was taken to create a representative group of the dutch population. the minimum age for participation was years. the target sample size was , respondents, to allow for satisfactory statistical power, and to maximize our chances of including people who contracted a salmonella infection. respondents received points for participating, with which they could buy gifts in an online shop. panel participants received an individual invitation via email of which the first was sent out on november , . the survey was closed on november , . due to the method of recruitment, a response rate could not be calculated. written informed consent was obtained from each respondent for publication of this report. the nature of this general internet-based survey among healthy volunteers from the general population does not require formal medical ethical approval according to dutch law [ ] . descriptive statistics were performed for the demographics, respondents' preventive behavior, and sources of information. cronbach's alpha was calculated to assess internal consistency for the psychological rating scales. these scores were . for perceived severity of salmonella, . for perceived severity of the outbreak, . for carefulness with salmon preparation during the outbreak, . for carefulness with general food preparation during the outbreak, . for interest in health information, and . for perceived health. next, mean scores were computed for the aforementioned psychological rating scales, while the statements for assessing knowledge about salmonella infections resulted in a sum score (ranging from to , where is no knowledge and is very high knowledge). to establish the influence of factors determining respondents' application of preventive measures during the outbreak (dependent variable), we performed stepwise backward regression analyses. following [ ] [ ] [ ] , we included the following independent variables in the initial model: the demographics age, education, income and sex, and the factors perceived severity of a salmonella infection, perceived severity of the outbreak, knowledge about salmonella infections, and increased general kitchen hygiene during the outbreak. education was recoded into a new variable with three options: low, middle or high, while sex was included in the regression analyses as a dummy variable. these actions make it possible to include these nominal variables in this kind of regression analysis. factors were removed from the model if p > . . the procedure was repeated for determining the factors that influence the consumption of information about the salmonella outbreak for different media. here, consumption of information on a medium was the dependent variable for the different models (each model explaining the information consumption for a specific medium.). we included the following independent variables in the initial models: the demographics age, having children, education, income, and sex (based on [ , ] ), as well as the factors perceived severity of a salmonella infection, perceived severity of the salmonella outbreak, knowledge about salmonella infections, interest in health information, and perceived health (based on [ ] ), as well as the application of measures to prevent a salmonella infection, and increased carefulness with preparing food (following [ ] ). for the variables using twitter or not, and having children or not, we also created a dummy variable. these analyses allowed us to formulate recommendations in line with our main research question: which information should health organizations convey during a large-scale salmonella outbreak, and by which channels, to maximize citizen compliance with preventive advice? in total, , respondents completed the survey. table displays their demographics, showing that the sample is fairly representative for the dutch population. figure shows how often the respondents made use of different media. most respondents watched television more than two hours a day. radio was less popular, although one quarter listened to this medium more than four hours a day. the majority spent some time each day reading a newspaper. most respondents used the internet intensively. finally, . % had a twitter account, . % a hyves (a dutch social network) account, and . % a facebook account. respondents perceived salmonella thompson to be quite a severe infection (m = . ; sd = . ). this finding is corroborated by the comparison respondents made between a salmonella infection and other illnesses. this comparison is displayed in table , and shows that salmonella is estimated as severe as asthma and diabetes. the outbreak was also estimated as quite severe (m = . ; sd = . ). respondents' mean interest in health information (m = . ; sd = . ), and their perceived health (m = . ; sd = . ) were neutral. we assessed respondents' knowledge about salmonella infections by nine true/false statements (see table ). the respondents appeared to be well informed, with a few exceptions. % was unaware of the common sources of a salmonella infection, , % unaware of its incubation period, and , % was unaware of how salmonella is treated in general. we calculated a sum score for each respondent's knowledge (with a maximum of ). the mean score was . (sd = . ). respondents' self-reported application of measures to prevent a salmonella infection during the outbreak was below the neutral point (m = . ; sd = . ), as was their estimation of an increase in kitchen hygiene during the outbreak (m = . ; sd = . ). however, in both cases standard deviations are quite high, implying that there were people who increased their kitchen hygiene tremendously, and people who absolutely did not. our regression analysis showed that the application of preventive measures (dependent variable) was influenced by increased general kitchen hygiene during the outbreak (β = . ; p < . ), by perceived severity of the outbreak (β = . ; p < . ), and by the demographics income (β = . ; p < . ) and sex (higher for women; β = . ; p < . ). a significant beta means that a factor influences the dependent variable (in this case application of preventive measures). a low beta stands for a small influence, a high beta for a large influence. in this case, the betas show that four factors influence the application of preventive measures; of which increased general kitchen hygiene is by far the greatest influence. explained variance (r ) for the model was . (which means that the dependent variable is explained for a large part by the identified independent variables, but also by some, as of yet, unidentified variables). in our sample, eight respondents (. %) indicated to have gotten a salmonella infection from eating contaminated salmon. a larger group ( respondents; . %) knew someone in their close vicinity (friends or family) who ate contaminated salmon and then got a salmonella infection. we asked the respondents whether they checked if they had salmon at home when they heard of the outbreak. it turned out that: respondents ( . %) checked but did not have salmon at home; respondents ( . %) checked and did have salmon at home; respondents ( . %) did not check if they had salmon at home. next, we assessed what the respondents did who had salmon at home: respondents ( . %) found out their salmon was not contaminated; respondents ( . %) threw all salmon away; respondents ( . %) found out they had contaminated salmon and threw it away; respondents ( . %) found out they had contaminated salmon, but did eat it; respondents ( . %) did something else, mostly returning contaminated salmon to the supermarket. in assessing the information behavior of the general public during the salmonella outbreak, we made a distinction between passive and active information behavior [ ] . passive information behavior consists of situations in which a person receives information without actively searching for it (e.g., listening to the radio, stumbling upon an item when surfing on a news website). in other words, a person is exposed to information without a direct and specific need for this information. active information is caused by a question or explicit need for information, after which a person actively seeks out information. figure displays the channels and popular online sources from which the respondents have passively received information about the salmonella outbreak. television was the medium that delivered most information, followed by radio and newspapers. news website nu.nl was also a relevant source of information. finally, social media played a marginal role, whereby social network sites were more important than twitter. next, we assessed what factors influence passive information consumption for each channel or source (dependent variables). results for the different regression analyses can be found in table (each column representing the regression analysis for a specific medium). time spent on the medium was the most influential predictor for passive consumption of information for several media or sources. interest in health information, and perceived health influenced passive consumption of information for all media and sources, except for social media. perceived severity of the salmonella outbreak played a small role in the passive consumption of outbreak-related information through traditional media. the other factors and demographics played no or a marginal role, with one exception for age in the case of nu.nl (a popular news website in the netherlands), where lower age was an important predictor. we also encountered active information behavior among the respondents. ninety-one respondents ( . %) finally, we focused on a specified range of online sources, and if a website was visited by a respondent, we asked how the website was found, whether it provided the information the respondent was looking for, how satisfied he/she was with it, and whether he/she trusted the information. the number of respondents who answered these questions was relatively low (ranging from for the nvwa website, to for facebook and hyves). most online sources were either found through a google search or directly by entering the url. the nvwa website and wikipedia were predominantly found through a google search, and newspaper websites were mostly accessed directly. virtually all sources provided the seekers with the information they were looking for. satisfaction with the source was high for wikipedia, the nvwa website, and if you have symptoms from salmonella (like vomiting or diarrhea), you are temporarily not allowed to work in healthcare. true salmonella can predominantly be found on chicken, raw vegetables, and fruit. true . % after you have eaten salmonella-contaminated food, it can take weeks before you become ill. false . % salmonella is almost always treated with antibiotics. false . % figure number of times news about the salmonella outbreak was received per source (n = , ). note: nu.nl is a popular news website in the netherlands. the website of the municipal health service, while it was low for facebook and hyves. trust in the online source was relatively high for the websites of the government organizations: the rivm, the nvwa, and the municipal health service. trust in the website of the company that was the source of the outbreak and of the social networks facebook and hyves was relatively low. our results show that shortly after salmonella thompson broke out nationally in the netherlands, the general public perceived salmonella gastro-enteritis as a serious illness, comparably severe to asthma and diabetes. they also perceived the outbreak as severe. respondents' knowledge of salmonella (gastro-enteritis) was appropriate, except for the common food sources of a salmonella infection, the duration of the incubation period, and the fact that treatment with antibiotics is usually not needed. this study reveals gaps in the public's knowledge on salmonella infections, and shows where health education efforts should be put in by health organizations. moreover, it also shows that it is important to assess existing public knowledge regarding different infectious diseases, in order to improve health communication, and to fill knowledge gaps. despite warnings through mass media channels, the majority of the respondents neither checked whether they had contaminated batches of smoked salmon products at home, nor did their kitchen hygiene increase during the outbreak. while the perceived severity of the outbreak influenced the adoption of preventive measures to some degree, increased general kitchen hygiene during the outbreak appeared to be the most important antecedent. this suggests that being careful to avoid a foodborne infection during an outbreak is primarily done by people who are already concerned about food safety. since salmon is very popular and processed in many other products, it is well possible that people did not realize they owned contaminated products. some people even knowingly ate contaminated salmon, thereby neglecting health officials' advice to throw contaminated salmon away, or to return it to the supermarket. during the infectious disease outbreak, the general public mostly receives information through traditional media and popular news(paper) websites. health organizations should focus on these media to inform the general public, and to persuade them to take preventive actions. we came to a similar conclusion after studying information behavior during the german ehec outbreak [ ] . we uncovered that people do not use social media in these situations, as they think healthrelated information is 'out of place' there, or unreliable [ ] . investing time and effort in a social media campaign may serve only a very small portion of the population, resulting in a low return on investment. the consumption of outbreak-related information through a traditional medium and twitter was mostly determined by time spent on the medium, suggesting that consuming outbreak-related information is for a large part coincidental, and highly determined by the news selection of the different media. a higher interest in health information also resulted in more outbreakrelated information consumption. however, this could also be due to a recall bias, as those interested in such information might more easily remember receiving it. other predictors played no or a marginal role, with the exception of lower age for the popular dutch news website nu.nl. only a small sample of our respondents actively searched for information about salmonella or the outbreak. those who did mostly turned to the internet. there, they consulted multiple sources, found through a google search or by entering the url, like national food safety institutes, online newspapers, websites of municipal health services, and wikipedia. the latter has also been found to be an important source of information during other infectious disease outbreaks [ , ] . it should be noted, however, that the popularity of wikipedia could be due to the high ranks it receives in google. the website of the national institute for public health and the environment (the dutch equivalent of the american centers for disease control and prevention) was consulted less than the aforementioned sources. this implies that such national institutes should not solely rely on their own communication efforts, but they should collaborate with local health organizations, and they should contribute to relevant wikipedia articles. there has been some debate, however, concerning the quality of wikipedia articles for the goal of public health education, and studies on this matter show mixed results. the quality of medical wikipedia articles has been found to be good but inferior to official patient information [ ] , of similar quality as official patient information [ ] , or incomplete, which might have harmful effects [ ] . these results imply that if health organizations decide to use wikipedia to inform the public during a large-scale salmonella outbreak, they should make a continuous effort to continuously monitor the relevant articles and to improve their quality. our analysis did not result in a clear set of predictors for consuming outbreak-related information through social media. also, the predictors that are often found for consuming health information through traditional media (like interest in health information, and perceived health) did not hold for these services. if we are to find a set of predictors for this contextpresuming they do exist, considering the little use the general public made of social media during the outbreakwe will have to step off the beaten path and gather a set of new predictors. we conducted the survey at the end of the salmonella outbreak. while this allows for a good retrospective view, the general public's perceptions and behavior may evolve during an outbreak. different phases induce different information needs, related to the uncertainties of the situation (e.g., fear may play a bigger role when the outbreak source is still unknown) [ ] . a longitudinal setup would provide insight in these developments, and it would be an interesting direction for future research. second, the number of people in our study that actively searched for more information or for answers to their questions was relatively low. it is therefore difficult to base generalizable conclusions on these results, and our efforts should be viewed as explorative. they do provide valuable input for in-depth studies aimed at assessing people's outbreak-related information seeking processes. such studies have already generated important insights for the health domain (e.g., [ ] ). but it is also possible that, in this context, people actively searching for more information is a rarity, possibly due to the fact that the information provided by the different media is perceived as adequate. other studies should acknowledge or refute this thesis. finally, our study was restricted to the dutch general public. we do not have any indications that these results would not hold for other western european countries, but these should be validated for countries where the process of outbreak-related information provision and the internet penetration rate are fundamentally different. this study aimed to determine which information health organizations should convey during a large-scale salmonella outbreak, and by which channel, to maximize citizen compliance with preventive advice. we found that after the outbreak, the general public perceived salmonella gastro-enteritis as severe, but the public did not wholeheartedly apply the advised preventive measures. health organizations should use traditional media, and news and newspaper websites to inform the public, and to persuade them to take preventive actions. they should increase knowledge about salmonella infections, and stimulate citizens to check for possibly contaminated products at their home, and to increase kitchen hygiene. future research should focus on the role wikipedia can play during infectious disease outbreaks, not only those caused by salmonella. we are especially interested in case studies in which health organizations have used wikipedia as a public health education tool, and in how they experienced this in terms of public appreciation, and organizational investment. furthermore, studies assessing the quality and completeness of health-related wikipedia articles can be very valuable in helping health organizations decide on which articles they should use or improve the quality of. finally, our study pointed out that there is a group of people who knowingly take risks the global burden of nontyphoidal salmonella gastroenteritis global trends in typhoid and paratyphoid fever food safety at home: knowledge and practices of consumers the knowledge and practice of food safety by young and adult consumers van der logt p: survey of domestic food handling practices in new zealand consumer perceptions of food safety risk, control and responsibility south and east wales infectious disease group: differences in perception of risk between people who have and have not experienced salmonella food poisoning food safety education: what should we be teaching to consumers? development and evaluation of a risk-communication campaign on salmonellosis risk communication for public health emergencies public sources of 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preventive behavior during a large-scale salmonella outbreak: results from an online survey in the netherlands by eating contaminated products during a salmonella outbreak. a future study should focus on this group, and uncover their motivations for doing so (e.g., by interviewing patients with an infection who were seen by doctors during a salmonella outbreak), to improve health education for this group. additional file : survey.abbreviations ehec: enterohaemorrhagic e. coli; nvwa: the netherlands food and consumer product safety authority; rivm: national institute for public health and the environment. the authors declare that they have no competing interests. lvv contributed to the study design and collection of data, analyzed the data, and drafted the manuscript as the lead writer. djmab contributed to the study design and collection of data, and critically reviewed the first draft of the paper. jewcgp and jes contributed to the study design. at contributed to the study design and collection of data, and critically reviewed the first draft of the paper. all authors approved the final version. key: cord- - pclxek authors: cohen, liza miriam; grøntvedt, carl andreas; klem, thea b.; gulliksen, stine margrethe; ranheim, birgit; nielsen, jens peter; valheim, mette; kielland, camilla title: a descriptive study of acute outbreaks of respiratory disease in norwegian fattening pig herds date: - - journal: acta vet scand doi: . /s - - -z sha: doc_id: cord_uid: pclxek background: respiratory diseases are major health concerns in the pig production sector worldwide, contributing adversely to morbidity and mortality. over the past years there was a rise in reported incidents of respiratory disease in pigs in norway, despite population wide freedom from aujeszky´s disease, porcine reproductive and respiratory syndrome, porcine respiratory corona virus and enzootic pneumonia. the main objective of this study was to investigate acute outbreaks of respiratory disease in conventional norwegian fattening pig herds. the study included herds. in seven herds with reported outbreaks of acute respiratory disease, data on clinical signs was recorded and samples for laboratory examination were collected. diagnostic protocols were compared by parallel analysis of clinically healthy pigs from seven non-outbreak herds. results: the most commonly reported clinical signs were sudden deaths and dyspnea. an average compartment morbidity of %, mortality of % and case fatality of % was recorded in the outbreak herds. post-mortem examinations revealed acute lesions resembling porcine pleuropneumonia in all pigs investigated from the outbreak herds and in of the ( %) pigs from the non-outbreak herds. chronic lesions were recorded in another pigs ( %) from the non-outbreak herds. actinobacillus pleuropneumoniae serovar was isolated from lungs and/or pleura from all tested pigs (n = ) in the outbreak herds, and from out of pigs ( %) in the non-outbreak herds, one pig with an acute and another pig with a chronic infection. no other significant bacterial findings were made. seroconversion to a. pleuropneumoniae antibodies was detectable in all outbreak herds analyzed and in six out of seven non-outbreak herds, but the risk ratio for seroconversion of individual pigs was higher (risk ratio . [ . - . % ci; p < . ]) in the outbreak herds. all herds tested positive for porcine circovirus type and negative for influenza a viruses on oral fluid rt-qpcr. conclusion: the main etiological pathogen found during acute outbreaks of respiratory disease was a. pleuropneumoniae serovar . all pigs from outbreak herds had typical lesions of acute porcine pleuropneumonia, and only a. pleuropneumoniae serovar was identified. co-infections were not found to impact disease development. are however hard to determine in field conditions. studies show that coinfections with different respiratory agents are common in pigs [ , ] . viral infections often predispose for secondary bacterial infections. this has been studied under experimental conditions, i.e. coinfections of porcine reproductive and respiratory syndrome virus (prrsv) and mycoplasma hyopneumoniae [ ] , prrsv and actinobacillus pleuropneumoniae [ ] , swine influenza virus (siv) and bordetella bronchiseptica [ ] . moderate to marked fever, lethargy, coughing, sneezing and dyspnea are common clinical signs during disease outbreaks [ , ] . the presence of multiple pathogens often increases the severity of disease and occurrence of lesions in the respiratory tract [ , , ] . there are differences in occurrence and distribution of pathogens between countries, regions and herds [ , ] that contribute to the complexity of respiratory disease. due to strict import regulations in norway, there is negligible import of live pigs to the commercial pig population [ ] . the national yearly yield was approximately . million slaughtered pigs in , originating mainly from registered fattener pig herds with a concession limit of maximum slaughtered pigs per year [ , ] . the norwegian pig production is also characterized by stringent regulation of antimicrobial drug use and a tradition of eradicating diseases from animal populations [ , ] . the commercial pig population in norway has documented freedom from several important respiratory pathogens including aujeszky's disease virus, prrsv, siv (apart from influenza a [h n ]pdm ) [ ] and m. hyopneumoniae [ ] . after the pandemic in / , antibodies to siv (h n )pdm have been detected regularly from to % of examined herds in norway [ ] , but siv (h n )pdm infections in the norwegian pig population has been considered to have limited clinical impact [ ] . in cases of respiratory disease in norwegian herds, a. pleuropneumoniae has regularly been isolated from lungs of carcasses submitted for routine diagnostics [ ] . several studies from other countries conclude that a. pleuropneumoniae is normally present in most conventional pig herds, having a main reservoir in the tonsils of carrier pigs [ , ] . accordingly, outbreaks in conventional herds are most often triggered by factors related to animal housing, management and environment rather than an introduction of the bacteria in a naïve herd [ ] . preceding infection with a primary viral pathogen is also a possible triggering factor [ ] . in the years between and there was an increase in reported acute cases of respiratory disease requiring veterinary treatment in norway [ ] . a systematic investigation of porcine respiratory disease outbreaks in norway has not recently been performed, and updated knowledge is needed for appropriate disease prevention and intervention. the main objective of this study was to investigate clinical outbreaks of acute respiratory disease in norwegian fattening pig herds, using a group of non-outbreak herds to compare diagnostic procedures. the source population was the conventional fattening pig herds located in central and southern parts of norway in the period between september and october . the conventional herds are not part of the norwegian specific pathogen free (spf) sub-population, in which herds are free from e.g. toxin producing pasteurella multocida and all serotypes of a. pleuropneumoniae. seven conventional fattening pig herds with acute outbreaks of respiratory disease (outbreak herds) and seven pig herds without respiratory disease outbreaks (nonoutbreak herds) were included in this study. the inclusion criteria for outbreak herds were; three or more pigs displaying acute signs of respiratory disease including fever and coughing and/or dyspnea, and/ or otherwise reduced general condition e.g. lethargy or inappetence. non-outbreak herds inclusion criteria were; absence of acute clinical signs of respiratory disease at the time of sampling, situated in the same geographical area as the outbreak herds. the non-outbreak herds were not matched to the outbreak herds by means of other parameters. herds were included only if there were more than three weeks until planned slaughter, due to follow-up sampling per protocol. two herds were excluded, due to treatment with antimicrobial drugs before sampling could be carried out, and insufficient time from outbreak to planned slaughter, respectively. descriptive herd data are listed in table . a network of veterinary practitioners was established to collect samples and herd data. the practitioners were contacted through emails, letters, meetings and announcements in relevant journals and national newspapers. the veterinarians contacted the project group immediately upon being called out to examine pigs with symptoms of acute respiratory disease. outbreak herds were recruited for participation by the veterinary practitioners after meeting the inclusion criteria. non-outbreak herds were then recruited by the veterinary practitioners contacting herd owners meeting the matching criteria, asking their participation and arranging a visit. complete kits containing materials and detailed instructions for sample collection, preservation and transport were pre-distributed to designated pick up points at abattoirs and veterinary practice offices and sent to veterinarians across the country upon request. each outbreak herd was visited on three occasions ( fig. , green boxes) ; the first visit was conducted as soon as possible during the reported outbreak for initial sampling. the second visit was performed to days later to conduct interviews and register herd demographic data. during the third and final visit two to four weeks after the first, follow-up samples were collected, as described in fig. . non-outbreak herds were visited on two occasions, once for initial sampling, farmer interviews and herd registrations, and secondly for follow up sampling. details about the diagnostic sampling are shown in fig. . diagnostic sampling in outbreak herds was performed the day the veterinarian was notified about the disease. the veterinary practitioner reported observed clinical signs on a standardized submission form. in these herds, three to five pigs were selected for organ collection, pigs were sampled in total. the selection was made from pigs with clinical signs of respiratory disease prior to death or euthanasia by captive bolt and exsanguination. short time from death to sampling was considered, no additional criteria for sampling were applied. in non-outbreak herds three to five pigs were haphazardly selected, pigs were sampled in total. lungs and mediastinum (including pericardium, excluding the heart) and trachea caudal to the thoracic inlet were collected. within each herd, care was given not to sample pigs treated with any antimicrobial drugs up to days prior to the sampling. blood sampling was performed on a total of pigs per herd by haphazard selection from as many pens in the compartment as possible, up to pens. a total of pigs were sampled. the pigs were selected regardless of clinical presentation and restrained by snaring the upper jaw. during restraint the pigs were ear-tagged for individual identification at follow-up sampling during the final visit. rectal temperature was measured, and blood samples were collected (details in fig. ). pooled oral fluid (of) samples were collected from two haphazardly selected pens (n = pooled of samples from pens) using chewing rope as described by prickett et al. [ ] . care was given to keep the stress of the animals during sampling to a minimum. demographic data sampling was obtained by interviewing the farmers using a purpose-built questionnaire, see details in fig. . relevant information regarding the disease outbreaks including information about the first days after noticing the first clinical signs was registered in table overview of descriptive data in both outbreak and non-outbreak herds (n = ) a herd type: finishers, farrow-to-finish. herds: one compartment affected and tested. herd: two compartments affected and tested, compartment average presented b herd type: finishers, farrow-to-finish. one compartment tested per herd fig. overview of the timeline and procedure of the study outbreak herds. the following data was registered: dates of the pigs' arrival to compartment, a description of earliest observed clinical signs, onset of disease, time to veterinary contact, time from the first clinical signs to the initial sampling, numbers of pigs displaying clinical signs, applied antibiotic treatment, and number of sick and dead pigs from the start of the outbreak until the time of the interview. during the final visit, second blood samples were collected from individually ear tagged pigs, and rectal temperature measured in the same pigs. procedures for sample handling are presented in fig. . organs from pigs were subject to post-mortem examination. the pericardium, pleura, trachea, bronchi, lung parenchyma and tracheobronchial lymph nodes from to pigs from outbreak herds and non-outbreak herds respectively, were examined at the norwegian veterinary institute (nvi) according to a standardized protocol (additional file ). tissue samples from the lungs, pleura and lymph nodes were fixed, processed, sectioned and stained for histological examination (additional file ). in total, histological sections from the outbreak herds and sections from non-outbreak herds were examined following a standardized protocol (additional file ). sampling (on charcoal transport swabs) for bacterial cultivation was performed during postmortem examination of lungs and pleurae, see details in table . the lung surface was flamed and aseptically incised before swabbing of lung tissue. the swabs were cultivated as a part of the routine diagnostics at nvi (additional file ). serovar identification of cultured a. pleuropneumoniae (n = isolates) was performed on sequence data, generated through whole genome sequencing of the a. pleuropneumoniae isolates at statens serum institut (ssi), copenhagen, denmark. the serovar was determined based on the presence of the serovar specific cps operons [ , ] . details regarding the method are described in additional file . the serum samples (n = ) were analyzed using commercial diagnostic kits for antibodies to a. pleuropneumoniae, influenza a virus, prrsv, prcv and m. hyopneumoniae. the analyses were performed as described by the manufacturers; details are given in additional file . interpretation of the test results were categorical, based on the cut-off values recommended by the test manufacturers. presence of antibodies to prrsv, porcine respiratory corona virus (prcv) and m. hyopneumoniae were tested in the second serum sample (n = ). serum elisa was conducted on paired serum samples (n = ) from individual pigs for antibodies to influenza a virus and a. pleuropneumoniae. the presence of influenza a virus and porcine circovirus type (pcv ) nucleic acids in pooled oral fluids (n = ) were analyzed with real time polymerase chain reaction (pcr) by in-house procedures (additional file ). a cycle threshold (ct) value for influenza virus below was considered positive. pcv quantitative pcr (qpcr) is a quantitative test where results are given as measured nucleotide copies in µl sample, calculated from repeated measures at different ct values and results are reported as low (< copies), moderate ( - copies) or high (> copies). our sample size of serum samples per herd was chosen based on an estimate of at least one positive animal if the prevalence of our disease in question is around % at a % confidence level. the same sample size was used for agents not present in the population, that we did not expect to find, due to practical reasons. statistical analyses of the data were performed using the software stata (stata se/ for windows; stata corp., college station, tx, usa). descriptive numeric results are presented as average values and the standard deviation (sd) for data with a normal distribution, or median value followed by the interquartile range (iqr) for data that was not normally distributed. rectal temperatures from the first visit and from the final visit to the herd were compared. the variable "fever" was defined as a rectal temperature above . °c. odds ratios for fever during the outbreak sampling compared to fever during follow-up visits, were calculated using a stata case-control odds-ratio calculator. morbidity was measured as the proportion of pigs with clinical signs of respiratory disease of the total number of pigs in the herd (herd morbidity) and in the compartment (compartment morbidity). mortality was measured as the proportion of pigs dying during the outbreak, out of the total number of pigs in the herd (herd mortality) and in the compartment (compartment mortality). case fatality, an indicator of pathogen virulence and disease lethality, was measured as the proportion of pigs that died during the outbreak and displayed clinical signs of respiratory disease prior to their death, out of the total number of pigs displaying respiratory disease. a herd was classified as seroconverted if at least one pig shifted from negative to positive status and no pigs shifted from positive to negative status. the proportion of seroconverted pigs in each herd was calculated. samples from pigs that could not be identified by ear tags (one herd, n = ) were excluded. when calculating the incidence proportion and risk ratios for seroconversion to a. pleuropneumoniae, pigs that were seropositive on the first serum sample were excluded from the population at risk. incidence proportion was defined as the proportion of the seronegative pigs that seroconvert during the time at risk. time at risk was defined as time between paired serum samples. the risk ratio (rr) for a pig to seroconvert in outbreak herds, compared to nonoutbreak herds, was calculated using a stata cohort study risk-ratio calculator the % confidence interval (ci). the statistical significance of the calculated association, whether it was likely that the rr was different from , was indicated by the reported p value. median number of days from the farmers noticed clinical signs of respiratory disease until calling the local veterinary practitioner was day. onset of outbreak was days (median, iqr ) after the pigs arrived at the compartment. the severity of the clinical signs varied between outbreak herds. clinical signs reported by the veterinary practitioner were mainly sudden deaths (four herds) and dyspnea (three herds). signs such as fever, bloody froth from oronasal openings, cough and lethargy were also reported, and it was observed that sick pigs were reluctant to chew on the cotton ropes used for of sampling. in all herds, intramuscularly administrated procaine benzylpenicillin was used to treat sick pigs over to days. in one herd, tiamulin was additionally administered in the drinking water for days. treatments were started by the veterinary practitioner during the first visit after the outbreak of disease. all herd owners reported the treatment to effectively reduce acute clinical signs and stop the further spread of disease. the average compartment morbidity during the outbreak was % (sd , range - %), while herd morbidity was % (sd , range . - %) in the outbreak herds. case fatality rate during the disease outbreaks was on average % (sd , range - %) over days, suggestive of a low virulent agent. during the outbreaks, compartment mortality was % on average (sd , range - %), while herd mortality was % (sd , range - %). proportion of pigs in the outbreak herds measuring a rectal temperature above . °c was . % (n = ) and % at the first and final visit, respectively. for the non-outbreak herds the proportion of pigs with a rectal temperature above . °c was . % (n = ) and % at first and final visit, respectively. the odds for a temperature above . °c were higher (odds ratio = . , % ci . - . ), during outbreak than during follow-up in the outbreak herds. there were no dropouts among the study animals, the number of animals tested at the visits was the same. median number of days between first and final visit was days (iqr ) in outbreak herds and days (iqr ) in non-outbreak herds. results from the pathological examinations of organs are presented on herd level in table . gross pathology of the lungs was detected in all pigs (n = ) from the outbreak herds. acute pleural lesions were reported in of these pigs ( %) and chronic pleural lesions, were found in one. typical lesions of acute pneumonia were found in all the pigs. the acute lesions were principally dorsally distributed in all lung lobes, but the caudal lobes were the most affected. chronic lung lesions were observed in one pig. moderate to severe enlargement of the tracheobronchial lymph nodes was a prevalent finding (n = , %) in the pigs with pneumonia. characteristic gross lung lesions are shown in fig. . in the non-outbreak herds various gross lung lesions were detected in seven of the pigs ( %). pleuritis was observed in two of pigs ( %), where one had an acute pleuritis, and the second pig focal chronic pleuritis. pneumonia was observed in four other pigs. mild, focal, acute lesions were seen in two of them, while similar acute lesions and abscess formation was seen in another. multifocal, necrotizing, chronic pneumonia was diagnosed in the fourth pig. a single pig from a non-outbreak herd had gross lung lesions of multifocal bleeding and mottled grayish green areas indicative of larval migration by ascaris suum. diagnostic results for individual herds, including the gross findings are summarized in table . histopathological changes agreed with the acute macroscopic lesions observed. histological examination revealed fibrin and neutrophil deposits on the pleura. in the lung parenchyma there was alveolar filling with necrotic leukocytes, neutrophils and fibrin. interstitial edema and hemorrhage, peribronchial and peribronchiolar leukocyte infiltration was observed. subacute to chronic, necrotic lesions of varying sizes were demarcated by macrophages, lymphocytes and plasma cells table results from gross pathology, bacteriology, serology and virology from seven outbreak herds (from to ) and seven non-outbreak herds (from to ) of on the pleura or in alveolar lumen, and areas of interstitial bleeding. actinobacillus pleuropneumoniae was cultured from all sampled pigs (n = ) from outbreak herds (n = ). abundant growth of a. pleuropneumoniae was present in lung tissue in all pigs and on pleura in pigs. in samples from of the lungs and pleurae, a. pleuropneumoniae was the sole microbial species detected. in the remaining samples, a range of bacteria were detected in addition to a. pleuropneumoniae and the results are shown in table . swabs from non-outbreak pigs' lungs produced mostly negative bacteriology. from non-outbreak herds, a. pleuropneumoniae was isolated from lung parenchyma in two out of pigs. the a. pleuropneumoniae isolates originated mainly from areas with acute gross pathology ( table ). in one non-outbreak pig a. pleuropneumoniae was cultured from a chronic lung lesion. serotyping of a. pleuropneumoniae on genome level revealed that all sampled isolates belonged to serovar . the serum samples were successfully analyzed in one session. antibodies to a. pleuropneumoniae were detected in samples from six ( %) outbreak herds and four ( %) non outbreak herds. at the first serum sample, % ( of ) of the pigs in the outbreak herds were seropositive, and % ( of ) in the non-outbreak herds. at the second serum sample, % ( of ) and % ( of ) of the pigs were positive in the outbreak and non-outbreak herds respectively, details are listed in table . six outbreak herds and six non-outbreak herds were considered seroconverted, indicative of an active infection in the period from the first to the second visit. seroconversion in the seventh outbreak herd could not be assessed due to missing ear tags. proportion of seroconverted pigs in each outbreak herd ranged from to %, and from to % in non-outbreak herds ( table ) . incidence proportion was . (sd . ) in outbreak herds over the median time at risk of days. incidence proportion in the non-outbreak herds was . (sd . ) over the median time at risk of days. the risk for seroconversion was more than double compared to pigs from non-outbreak herds (rr . [ . - . % ci; p < . ]). antibodies to influenza a virus were detected in one outbreak herd, where one pig seroconverted during the sampling period, and two pigs were found to have a reduced antibody titer to below cutoff. influenza a-antibodies were not detected in the remaining six outbreak herds or the non-outbreak herds. the proportion of siv seropositive herds was % out of the herds combined. antibodies to m. hyopneumoniae, prcv and prrsv were not detected in samples from any herds. the pooled of samples from pens, median number of pigs per pen was (range [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , were all negative for influenza a viruses. quantification of pcv by rt-qpcr turned out low or moderate in all samples, results per herd are shown in table . field outbreaks of acute respiratory disease in norwegian fattening pigs were investigated and a. pleuropneumoniae serovar was the main pathogen detected, with negligible presence of co-infections. clinical signs reported were in agreement with previous reports of a. pleuropneumoniae infections, which are described to have a diverse clinical presentation [ ] . even with the large variation in morbidity and mortality rates, the results from this study were in line with observations from other studies, as research on outbreak characteristics of respiratory disease show that morbidity can range from to % [ ] . mortality during outbreaks of acute porcine pleuropneumonia is usually reported to be between and % [ ] . case fatality rates are not commonly included in this research literature but is a more precise measure of the lethality of a disease, especially if little information about other illnesses is available. disease that affects mortality are likely to have common risk factors [ ] and the use of case fatality rate is a more robust measurement and less subjected to confounders such as that of other illnesses. even as a single infectious primary agent, a. pleuropneumoniae can cause severe clinical signs. during acute porcine pleuropneumonia, high fever is common [ , ] . for pigs in the age range from to months, body temperatures normally span from . to . °c [ ] , and the proportion of pigs displaying a fever can be indicative of an outbreak. in the present study, the pigs were restrained by snaring the upper jaw during clinical examination and blood collection, which is stressful for the animal [ ] . the cutoff for fever at . °c + . was used in the study to compensate for this stress. higher odds for displaying fever in the herds during outbreak than at the final visit were found among the pigs in this study. this signified body temperature as a disease characteristic during outbreaks of porcine pleuropneumonia, although technical biases like personnel and thermometers used might have influenced our results. this coincided with results from a recent study from finland [ ] . there are acknowledged a. pleuropneumoniae serovars, of which some were recently described [ ] . from the norwegian pig population, serovars , , , and have previously been reported [ ] . serovar has been most commonly associated with clinical disease in recent years, followed by type [ ] . however, these previous findings were all based on antibody agglutination tests which are prone to cross-reactions, for instance between serovars , , and [ ] . all a. pleuropneumoniae strains in this study belonged to type , raising questions about the importance of serovar . underestimation of serovar has occurred in canada [ ] , england and wales [ ] . serovar is typically viewed as low virulent and is less often associated with clinical disease globally. in a study describing clinical presentation of different serovars in experimentally infected pigs [ ] , serovars that were less commonly associated with disease were able to produce severe clinical signs, including high fever. this could perhaps be a result of absence of other respiratory agents including more virulent serovars of a. pleuropneumoniae. the macro-and histopathologic findings were typical for acute pleuropneumonia caused by a. pleuropneumoniae [ ] [ ] [ ] , supporting that a. pleuropneumoniae was the main etiologic pathogen in these outbreaks. direct agent detection, primarily by bacteriological culturing in affected lung tissue obtained during necropsy, is considered the most adequate method for diagnosing porcine pleuropneumonia [ ] . direct pcr is a method that would be expected to yield similar results but would not allow for storing of the bacterial isolates for further molecular testing, as was done in this study. we observed a low incidence of pathological lesions in non-outbreak herds, and a. pleuropneumoniae was only isolated from lesions resembling porcine pleuropneumonia. other bacteria, including p. multocida and streptococcus spp., were also detected in a few samples in this study. both are known opportunistic bacteria that colonize the upper respiratory tract of healthy pigs [ ] . streptococcus suis is the most important streptococcal swine pathogen found to contribute to bronchopneumonia [ ] . it is not unlikely that the bacteria could colonize areas already infected with a. pleuropneumoniae. the lesions might then be hard to distinguish from the primary pathogen, particularly if large parts of the lungs are affected. in one outbreak herd all five lungs had growth of other bacteria. they could have been contaminated during collection, transport or sampling. alternatively, these pigs were all colonized by secondary bacterial pathogens. the number of herds included in this study was too low to investigate whether the presence of these bacteria was linked to any differences in outbreak characteristics or diagnostic results. the low occurrence of common secondary invaders could have been explained by the short time span between registered disease and sampling. it has been questioned whether the actions that led to the eradication of m. hyopneumoniae from the norwegian pig population [ ] also significantly reduced the occurrence of other pathogens. this has not yet been investigated. treatment with procaine benzylpenicillin was in line with the therapeutic guidelines published by the norwegian medicines agency as the drug of choice for acute porcine pleuropneumonia [ ] . similar recommendations have been published in finland and sweden [ , ] . in denmark, tilmicosin and tulathromycin have been commonly used against acute pleuropneumonia [ ] partly due to the convenience of peroral administration, not due to reduced susceptibility to benzylpenicillin. national surveillance programs for antimicrobial resistance in these countries have recently reported a high proportion of a. pleuropneumoniae isolates being susceptible to benzylpenicillin [ ] [ ] [ ] . nevertheless, there are no recently published studies on the efficacy of procaine benzylpenicillin for porcine pleuropneumonia in norway. such knowledge of causative pathogens is the fundament for correct and prudent use of antimicrobials. the details to antimicrobial resistance patterns of a. pleuropneumoniae in norway are currently being studied further. seroconversion to a. pleuropneumoniae had occurred in most of the herds, in many cases in absence of clinical disease. the risk for seroconversion to a. pleuropneumoniae for pigs in outbreak herds was more than double compared to pigs from non-outbreak herds, despite small within-herd populations at risk due to many seropositive pigs in the first serum samples. seroconversion to less virulent strains might have happened without resulting in a cross-protection to the outbreak-causing serovar. in finland, haimi-hakala et al. observed no difference in either prevalence of seroconverted herds or proportion of seroconverted pigs per herd in the outbreak case group and non-outbreak control group [ ] . they discuss that neither single or paired serum sampling for the diagnosis of acute respiratory disease in field conditions is of much value due to both a lack of details concerning the initiation time of infection and a high prevalence of subclinical infections with a. pleuropneumoniae. the risk for seroconversion was not addressed in their paper. a danish study from investigated correlations in seroconversion to a. pleuropneumoniae and concluded that variation in seroconversion was mainly explained by a common batch level factor, that varies between farms and batches within a farm [ ] . outbreaks of disease might be viewed as a batch level factor in this sense. in cases of all-in-all-out rearing by compartment, which is common, batches of pigs are usually housed separately. as we observed, the outbreaks were often restricted to single compartments. risk factors can be related to animal housing, management and environment [ ] , and infection pressure might be increased during clinical disease and is a likely trigger for seroconversion. risk factor analyses were beyond the scope of this paper due to a lower number of herds in our study than what was expected. the seeming decrease in outbreak occurrence might have resulted from of a collective effort in the norwegian pig production system to increase the health status of herds with reoccurring problems with respiratory disease prior to our sampling. when investigating siv antibody titers we found that only one outbreak herd was seropositive. even though one pig seroconverted during the sampling period, two pigs were found to have reduced antibody titer. since a single false-positive serological reactor could not be excluded, the true status of these animals was uncertain. there being multiple false-positive reactions in one herd, which would have been the case here, was perhaps less likely. the proportion of seropositive herds in this study was less than what is found on a national level, where approximately % of the herds are reported positive [ ] . the virology results from our study suggested that neither siv nor pcv contributed to the disease outbreaks in the study population. the absence of siv in all of samples supported the lack of pathological lesions and serological results indicative of siv infection. no difference was detected in pcv levels between the outbreak-and the non-outbreak herds. reluctancy of sick pigs to chew on the ropes could have resulted in unrepresentative pcv levels. since pcv levels was tested on pooled samples we have no information on the individual pig's contribution to the sample. the health status of the norwegian pig population is very good and have many similarities to the one of finland in the sense that they are free from m. hyopneumoniae, prrsv and until recently prcv [ ] . in finland, a more diverse outbreak etiology has been observed [ ] . in the finnish study, a. pleuropneumoniae was found to be the most likely cause of disease in of the sampled herds. in most of these herds, a. pleuropneumoniae was the only etiologic pathogen identified. similarly, outbreaks of respiratory disease were studied in the netherlands [ ] concluding that five of these were most likely caused by a. pleuropneumoniae, while seven were caused by siv (h n ) and (h n ). like in our study, they did not find any clear evidence of specific dual infections. the main etiological pathogen of acute outbreaks of respiratory disease in the included norwegian fattening pigs was a. pleuropneumoniae. all pigs from outbreak herds were found to have typical lesions of acute porcine pleuropneumonia, and only a. pleuropneumoniae serovar was identified. the clinical presentation and pathology of a. pleuropneumoniae was in line with previous reports on field outbreaks internationally. co-infections did not seem to be of impact on disease development. supplementary information accompanies this paper at https ://doi. org/ . /s - - -z. additional file . protocol for postmortem sampling. a scheme for a standardized postmortem evaluation and sampling of pigs' lungs. the scheme was compiled at the pathology department at the norwegian veterinary institute to be used in the study of acute respiratory disease outbreaks. additional file . histology protocol. a scheme for a standardized histologic evaluation of sections from pigs' lungs, pleura and tracheobronchial lymph nodes, including a description of section preparation. the scheme was compiled by members of the project group grisefine lunger to be used in the study of acute respiratory disease outbreaks. additional file . details of sample handling and diagnostics. a document containing extended details of sample handling and laboratory diagnostic methods performed in the study of acute respiratory disease outbreaks. we would like to thank professor mari heinonen at the university of helsinki and tijs tobias (dvm, ph.d., msc) for their advice and contributions to the planning of this study. at the norwegian veterinary institute several people at different departments have contributed significantly to the diagnostic work that is presented in this study. we would especially like to thank pathologists Øyvor kolbjørnsen and helene wisløff, bacteriologist marianne gilhuus, molecular biologist torfinn moldal. in preparation for the field trial, there had been a substantial marketing campaign for the project, reaching out to pig farmers, veterinarians and farm advisors throughout the country. we would like to thank everyone involved in the sampling and data collection for their time and attention. results presented in this article have not been previously published. authors' contributions lmc, cag, tbk, smg, br and ck planned this study, lmc, ck and br performed the outbreak investigations/collected materials. lmc, mv and ck analyzed and interpreted the data. lmc and ck prepared the tables and figures. lmc had the primary responsibility of writing and revising the manuscript. all authors contributed to revising the manuscript. all authors read and approved the final manuscript. we are grateful for the funding provided by the agricultural agreement research fund and the foundation for research levy on agricultural products, grant number nfr- . thanks to our collaborators who also funded the research: animalia, nortura and klf. the norwegian veterinary institute covered all costs related to administration of sampling equipment and sample analysis for this study. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. to be able to perform sampling from live animals, the norwegian food safety authority approved the study design for 'grisefine lunger' in september , maintaining compliance of ethical guidelines and the three r's. fots norwegian food safety authority reference id . diseases of swine effect of pneumonia on growth rate and feed efficiency of minimal disease pigs exposed to actinobacillus pleuropneumoniae and mycoplasma hyopneumoniae a tool to assess the economic impact of pleurisy in slaughter pigs porcine respiratory disease complex associations between pathogens in healthy pigs and pigs with pneumonia mycoplasma hyopneumoniae potentiation of porcine reproductive and respiratory syndrome virus-induced pneumonia enriched housing reduces disease susceptibility to co-infection with porcine reproductive and respiratory virus (prrsv) and actinobacillus pleuropneumoniae (a. pleuropneumoniae) in young pigs influenza virus coinfection with bordetella bronchiseptica enhances bacterial colonization and host responses exacerbating pulmonary lesions porcine respiratory disease complex (prdc): a review i etiology, epidemiology, clinical forms and pathoanatomical features survey of infectious agents involved in acute respiratory disease in finishing pigs kinetics of single and dual infection of pigs with swine influenza virus and actinobacillus pleuropneumoniae interaction between mycoplasma hyopneumoniae and swine influenza virus an investigation of the pathology and pathogens associated with porcine respiratory disease complex in denmark association of porcine circovirus with porcine respiratory disease complex annual report koorimp and kif b e ef bf e cc a e /koori mp-arsme lding - -web.pdf. accessed des . . regulation on swine and poultry production annual statistical report the successful eradication of mycoplasma hyopneumoniae from norwegian pig herds - years later. in: abstract book of the th european symposium of porcine health management the norwegian livestock industry´s joint action plan on antimicrobial resistance influenza a(h n )pdm virus infection in norwegian swine herds / : the risk of human to swine transmission the surveillance programme for specific viral infections in swine herds in norway adverse effects of influenza a(h n )pdm virus infection on growth performance of norwegian pigs-a longitudinal study at a boar testing station the norwegian veterinary institute transmission of actinobacillus pleuropneumoniae in pigs under field-like conditions: emphasis on tonsillar colonisation and passively acquired colostral antibodies actinobacillus pleuropneumoniae infections in closed swine herds: infection patterns and serological profiles simulation study of the mechanisms underlying outbreaks of clinical disease caused by actinobacillus pleuropneumoniae in finishing pigs respiratory disease in pigs-an increasing problem? oral-fluid samples for surveillance of commercial growing pigs for porcine reproductive and respiratory syndrome virus and porcine circovirus type infections comparative sequence analysis of the capsular polysaccharide loci of actinobacillus pleuropneumoniae serovars - , and development of two multiplex pcrs for comprehensive capsule typing complete genome sequence of midg , a genetically tractable serovar clinical isolate of actinobacillus pleuropneumoniae hennig-pauka i. update on actinobacillus pleuropneumoniae-knowledge, gaps and challenges risk factors for mortality in grow-finishing pigs in belgium convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research: over m website views per year ready to submit your research ? choose bmc and benefit from evaluation of actinobacillus pleuropneumoniae diagnostic tests using samples derived from experimentally infected pigs detection of actinobacillus pleuropneumoniae in pigs by real-time quantitative pcr for the apxiva gene herd evaluation restraint, but not frustration, induces prostaglandinmediated hyperthermia in pigs etiology of acute respiratory disease in fattening pigs in finland proposal of serovars and of actinobacillus pleuropneumoniae based on serological and genotypic analysis occurrence of lung lesions and antibodies to serotypes and of actinobacillus pleuropneumoniae and haemophilus parasuis in slaughter weight pigs from elite herds in norway quantitation of serotype-specific and crossreacting group-specific antigens by coagglutination and immunodiffusion tests for differentiating actinobacillus (haemophilus) pleuropneumoniae strains belonging to cross-reacting serotypes , , and the challenge of detecting herds sub-clinically infected with actinobacillus pleuropneumoniae actinobacillus pleuropneumoniae serovar predominates in england and wales diseases of swine an abattoir survey of pneumonia and pleuritis in slaughter weight swine from selected herds. i. prevalence and morphological description of gross lung lesions an abattoir survey of pneumonia and pleuritis in slaughter weight swine from selected herds. iii. serological findings and their relationship to pathomorphological and microbiological findings diseases of swine docum ents/veter in%c %a rme disin /terap ianbe falin ger/ terap ianbe falin g_bruk% av% ant ibakt eriel lt% mid ler% til % pro duks recommendations for the use of antimicrobials in the treatment of the most significant infectious and contagious diseases in animals dling srek-vet/rek% -% dos ering % av% ant ibiot ika% til l% gri s% b % d national food institute. danmap -use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in denmark finres-vet : finnish veterinary antimicrobial resistance monitoring and consumption of antimicrobial agents. finnish food authority publications swedres-svarm : consumption of antibiotics and occurrence of resistance in sweden intra-unit correlations in seroconversion to actinobacillus pleuropneumoniae and mycoplasma hyopneumoniae at different levels in danish multi-site pig production facilities springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -j glby authors: bodrud-doza, md.; shammi, mashura; bahlman, laura; islam, abu reza md. towfiqul; rahman, md. mostafizur title: psychosocial and socio-economic crisis in bangladesh due to covid- pandemic: a perception-based assessment date: - - journal: front public health doi: . /fpubh. . sha: doc_id: cord_uid: j glby background: the spread of the covid- pandemic, the partial lockdown, the disease intensity, weak governance in the healthcare system, insufficient medical facilities, unawareness, and the sharing of misinformation in the mass media has led to people experiencing fear and anxiety. the present study intended to conduct a perception-based analysis to get an idea of people's psychosocial and socio-economic crisis, and the possible environmental crisis, amidst the covid- pandemic in bangladesh. methods: a perception-based questionnaire was put online for bangladeshi citizens of years and/or older. the sample size was , respondents. datasets were analyzed through a set of statistical techniques including principal component and hierarchical cluster analysis. results: there was a positive significant association between fear of the covid- outbreak with the struggling healthcare system (p < . ) of the country. also, there was a negative association between the fragile health system of bangladesh and the government's ability to deal with the pandemic (p < . ), revealing the poor governance in the healthcare system. a positive association of shutdown and social distancing with the fear of losing one's own or a family members' life, influenced by a lack of healthcare treatment (p < . ), reveals that, due to the decision of shutting down normal activities, people may be experiencing mental and economic stress. however, a positive association of the socio-economic impact of the shutdown with poor people's suffering, the price hike of basic essentials, the hindering of formal education (p < . ), and the possibility of a severe socio-economic and health crisis will be aggravated. moreover, there is a possibility of a climate change-induced disaster and infectious diseases like dengue during/after the covid- situation, which will create severe food insecurity (p < . ) and a further healthcare crisis. conclusions: the partial lockdown in bangladesh due to the covid- pandemic increased community transmission and worsened the healthcare crisis, economic burden, and loss of gdp despite the resuming of industrial operations. in society, it has created psychosocial and socio-economic insecurity among people due to the loss of lives and livelihoods. the government should take proper inclusive steps for risk assessment, communications, and financial stimulus toward the public to alleviate their fear and anxiety, and to take proper action to boost mental health and well-being. the novel coronavirus disease (covid- ) began spreading in november , in wuhan, china. following this, the world health organization (who) announced covid- as a global pandemic on march th, ( ) . covid- has advanced into a pandemic, starting initially as small clusters of transmission that combined into larger clusters in many countries, subsequently resulting in a widespread transmission ( ) . social isolation, institutional and home quarantine, social distancing, and community containment measures were applied without delay ( ) . through quick administrative action and raising awareness for individuals on social-distancing, stringent steps were taken to manage the spread of the disease by canceling thousands of locations that involved social gathering including offices, classrooms, reception centers, clubs, transport services, and travel restrictions, leaving many countries in complete lockdown ( ) . the remarkable actions and ventures in public health to quarantine mass numbers has prevented this virus from spreading exponentially between humans in china, singapore, hong kong, and south korea, despite initial cases ( , ) . however, a surge of covid- outbreaks in all inhabitable continents, with , deaths alone in the usa, indicates that the infection had passed the tipping point ( , ) . today, as of the th of may , total global covid- cases have risen to , , , with the total number of deaths escalating to , , ( ) . the accelerating spread of covid- and its outcomes around the world has led people to experiencing fear, panic, concern, anxiety, stigma, depression, racism, and xenophobia ( ) . bangladesh confirmed their first covid- case on the th of march ( ), followed by a nationwide lockdown from march which had been extended several times until th may to prevent human transmission. the government deployed armed forces to facilitate social distancing on march th. emergency healthcare services and law enforcement were exempt from this announcement. yet more than million people left dhaka to return to their home districts and thus helped spread the diseases nationwide. moreover, from the th of april , all ready-made-garment (rmg) factories, industries, private offices, and business centers were allowed to open, leading to a "partial lockdown" in the country. the migration of rmg workers to the industrial districts and less community awareness about the disease has increased the transmission among millions of people. the institute of epidemiology disease control and research (iedcr), under the ministry of health and family welfare (mfhw) and directorate general of health services (dghs), is responsible for researching epidemiological and communicable diseases such as covid- in bangladesh, as well as disease control and surveillance. initially, iedcr was the single and centralized laboratory for covid- testing in bangladesh ( ) . the dghs, on the other hand, is the responsible body for the coordination of testing and sample collections of covid- patients ( ) . as of the th of may , according to iedcr, the total number of covid- positive cases stands at , with deaths (figures a,b) . according to iedcr, those aged between and are with the highest number of cases ( %), while those aged above have had fatal cases of the disease ( %). at present, the fatality rate in bangladesh is . % ( th may ) which was initially . % ( th april ) ( ) . although the number of laboratories for covid- testing has increased to , all these labs are in major urban areas of bangladesh and to get tested requires long waiting hours. more often the tests have been done after the patients had died. very recently, more than % of those tested daily have tested as positive (figure c) , and the ratio of testing is , / million people. in addition, it also takes a long time to get the result of the tests. furthermore, there are only , intensive care unit (icu) beds in the country, of which beds are in government hospitals and in private hospitals. it is predicted that as the number of patients rise, the required number of icu facilities will not be adequate ( ) . in addition, the healthcare staff and doctors were given low quality/no personal protective equipment (ppe) which has caused a high infection rate among them ( ) . moreover, as laboratory staff, healthcare staff, and doctors have become increasingly infected, there is also a shortage of specialized trained personal to perform covid- tests, meaning patient treatment will be disrupted. amidst the lockdown, due to the fear of contact transmission, private hospitals and clinics are not providing any services ( ) . the shortage of healthcare facilities for primary and critical care patients have therefore been depleted. the healthcare workers who have treated patients and become infected have been criticized socially and have faced social stigma from local people. in many locations public protests were observed against the establishment of quarantine facilities, covid- care hospitals, and clinics. social humiliation was a common practice of law enforcement authorities and government officials. on many occasions, family members left the infected and the deceased in the hospitals. the deceased were even denied burials in local graveyards, which are basic cultural rights as a muslim ( ) . moreover, the lockdown hit hard for those who earn daily wages and low and middle-income people who lost their jobs and their income source. the anxiety and fear of death from hunger or death from infection led to several suicide cases ( ) . predictably, any contagious epidemic outbreak has harmful effects on individuals and society ( ) . considering the population density, educational status, social structure, cultural norms, healthcare capacity, and often flawed policies taken by the government of bangladesh, it is hard to lock down a country of million people. moreover, bangladesh hosts the largest refugee camps in the world in the cox's bazar district. the rohingya refugees who fled from myanmar reside in the camps of cox's bazar. confirmed cases were found in the camps while the district had reported confirmed cases ( ) . this depicts the scenario of public anxiety which should be immediately dealt with by the government, along with the alliance groups, with proper information. amidst the current societal levels of anxiety and fear, the possibility of natural disasters such as tropical cyclones and monsoon floods and the potential for a dengue outbreak, seasonal influenza, or other infections are potentially overlooked. furthermore, the consequences of incorrect disposal of used personal protective equipment (ppe) from covid- hospitals without proper treatment in landfill sites has the potential for further disease transmission among the waste management personal and further environmental transmission. considering the given circumstance, this study was designed to analyze the psychosocial, socio-economic, and possible environmental crisis based on public perception in bangladesh due to the covid- outbreak. this assessment may inform the government and policymakers of countries with a similar socioeconomic and cultural structure to bangladesh. to understand the possible psychosocial, socio-economic, and environmental impact of the covid- outbreak in bangladesh, we considered and identified several relevant and possible items based on the socio-economic situation, political analysis, the existing healthcare system, environmental analysis, possible emerging issues utilized from scenario developments, analysis of local and global reports of the covid- pandemic from the print and electronic media, and a literature review. we prepared the questionnaire considering the demographic characteristics of bangladesh, societal mental health conditions (mh), the healthcare system in bangladesh (hsb), governance and political issues (gpi), socio-economic issues (sei), immediate emerging issues (iei) and enduring emerging issues (eei). a total of items were considered in the drafted questionnaires to understand people's perception of the covid- outbreak in bangladesh. furthermore, expert consultation was considered to set and validate these items. we prepared the online-based questionnaire through google to operate the survey nationwide. an introductory paragraph describing the objective of the questionnaire was shared with the respondents through email and through social platforms commonly used by bangladeshi groups on facebook, messenger, linkedin, and whatsapp. relevant people were selected for targeted sampling. an online database of target participants was prepared by reviewing relevant websites and online social platforms of different groups in bangladesh. the sample group was targeted considering bangladeshi citizenship, their age, current activities, occupation, social and economic responsibilities, and engagement related to covid- response, planning, and policymaking. the questionnaire survey was conducted from march to march during the lockdown period. the respondents belonged to different social categories, such as university faculty members and scholars, government officials, development workers or practitioners, doctors, engineers and technologists, youth leaders and students, businessmen and industry officials, banking and finance corporates, and independent researchers, among others. the answers to the survey questionnaire were voluntary. data from respondents were collected through this online survey initially using the simple random sampling method following keeble et al. ( ) . following the removal of incomplete questionnaires, , responses were finally retained for this study. a five-point ( to ) likert scale was used for testing the statement descriptions that ranged from strongly disagree to strongly agree with the statements ( table ) . there was a limitation of the rapid assessment on the publicperception on the psychosocial and socio-economic crisis in bangladesh due to the covid- pandemic. as the study was conducted during the lockdown period, it was not possible to reach to general people physically. therefore, we had to keep our samples limited to internet users only. there are more than million mobile internet users in bangladesh and, as a youthdividend country, the majority of the mobile internet users are young educated people. the descriptive statistics [e.g., frequencies, percentages, and ttest (data provided in supplementary tables)] were employed to understand respondents' characteristics. an investigation of psychometric characteristics was included in the classical test theory (ctt) analysis. a set of statistical techniques, including linear regression analysis (lra), principal component analysis (pca), and hierarchical cluster analysis (ca), were applied to explore the association between the items. pca is a data reduction tool that demonstrates each potentiality of parameters and their confidence level in large sample datasets. before conducting the pca, kaiser-maier-olkin (kmo) and bartlett's sphericity tests were applied to confirm the necessity of this analysis. the results of the kmo at > . (the kmo value was . in this work) and the significance of bartlett's sphericity test at p < . supported our datasets to be fitted for the pca ( ) . the number of factors chosen was based on the kaiser's principle, where the only factors with eigenvalues> . were considered. cronbach's alpha was employed to test the consistency and reliability of the factor loadings in this study. cronbach's alpha values at > . (the cronbach's alpha value was . ) are regarded to be suitable in social science research ( ) . the ca is a crucial means of detecting associations among many psychosocial and environmental parameters. ca assists to demarcate a population into various groups based on the same feature of a set of the dataset that may reveal causes, effects, and/or the source of any unidentified relationships among the items. furthermore, hierarchical clustering was used to determine the probable number of clusters. statistical package for the social sciences (spss) v. . was used for the analysis of the datasets. the consent of the respondents was taken before the survey, and their anonymity was guaranteed. all the participants were informed about the specific objective of this study before proceeding to the questionnaire. participants were able to complete the survey only once and could terminate the survey at any time they desired. anonymity and confidentiality of the data were ensured. formal ethical permission of this study was taken from the respective authority. a total of , (=n) responses were recorded in this study. the proportion of male to female respondents was : [males (n = ; . %) and females (n = ; . %)]. the composition of age groups of the respondents was as follows: . % ( - years old), . % ( - years old), . % ( - years old), . % ( - years old), and . % (> years old). the average age of the respondents was . years (sd ± . ). on average, the respondents had . years of formal education (sd ± . ). % of the youth group were mostly students or at the brink of finishing their studies. the remaining % of the respondents were from various professions, including doctors and healthcare workers, civil service officials, non-government officials (ngos), teachers and scholars, policymakers, researchers, and businessmen. the descriptive statistics containing the statements are shown in table . the category of statements were grouped as follows: mental health condition (mh) comprised five statements (mh - ), the healthcare system of bangladesh (hsb) comprised ten statements (hsb - ), the governance and political issues (gpi) comprised statements (gpi - ), the socio-economic issues comprised statements (sei - ), the immediate emerging issues comprised statements (iei - ), and for enduring emerging issues statements were considered (eei - ). in the following section of mental health status, healthcare system, governance and political perspective, socio-economic aspects, and emerging issues, we have discussed the descriptive statistics. in the statement of "i am afraid of the recent outbreak of coronavirus in bangladesh" (mh ) . % of the respondents strongly agreed, followed with a mean of . ± . . in the second statement (mh ), "i am afraid of getting infected with coronavirus" the difference among strongly agreed ( . %) and agreed ( . %) statement with a mean value of . ± . . for statement three, . % of the respondents strongly agreed to the (mh ) "i am afraid of losing my life or my relatives' life due to this outbreak" with a mean value of . ± . . in the fourth % of the respondents strongly agreed to the statement that the healthcare system of bangladesh is fragile and unable to deal with the recent outbreak of covid- (hsb ), with a mean value of . ± . . for the second statement, % of respondents with a mean value of . ± . strongly agreed that "a huge population is a pressure to the existing healthcare system to deal with covid- " (hsb ). % of the respondents with a mean value of . ± . strongly agreed that "there is a lack of awareness of basic healthcare issues in most of the citizens of bangladesh" (hsb ). moreover, % of the respondents with a mean value of . ± . strongly agreed that there is "a lack of trained doctors and healthcare professionals to deal with the covid- " (hsb ). with a mean value of . ± . , . % of the respondents strongly agreed that "the lack of healthcare facilities will be unable to combat the covid- outbreak in bangladesh" (hsb ). again, % of respondent with a mean of . ± . strongly agreed with "the lack of healthcare infrastructure to deal with covid- " (hsb ). for statement seven, . % of respondents with a mean value of . ± . strongly agreed that "there is a severe lack of bio-medical and hospital waste management facilities in bangladesh" (hsb ). moreover, % of respondents with a mean value of . ± . strongly agreed that "there is a lack of covid- testing facility in bangladesh" (hsb ). . % of respondents ( . ± . ) strongly agreed that "the budget is inadequate or there is a lack of financial support to respond to this outbreak" (hsb ). finally, . % of respondents with a mean value of . ± . strongly agreed that "most of the poor people will not have access to the existing healthcare facilities if they are infected with covid- " (hsb ). regarding the statement of "the bangladesh government can deal with this outbreak" (gpi ), the public opinion did not vary significantly with a mean value of . ± . . similar responses were also found in response to "the government is taking this outbreak seriously" (gpi ) with a mean value of . ± . and "the government is taking proper decisions at the right time" (gpi ) with a mean value of . ± . . . % of respondents strongly agreed that "the government needs support from the general public to reduce the impact of covid- " (gpi ) with a mean value of . ± . and that "the government needs to formulate a policy and action plan and implement it immediately" (gpi ) with a mean value of . ± . . about . % of respondents agreed that "developed nations are going to support bangladesh in response to covid- " (gpi ) with a mean value of . ± . . nearly - % of respondents strongly agreed that "the shut down or lockdown of regular activities was a good decision to reduce the chance of infection of covid- " (sei ) (mean . ± . ), "this will have an economic and social impact in the future" (sei ) (mean . ± . ), and that "both formal and informal businesses will be hampered" (sei ) (mean . ± . ). for the fourth statement, . % of respondents strongly agreed that "poor people living off daily wages will be severely affected" (sei ) with a mean of . ± . , while . % strongly agreed that "most of the poor people living in urban areas have to leave the city due to not having any options for income" (sei ) (mean . ± . ). . % (mean . ± . ) of the respondents agreed that "many people will lose their livelihood/ jobs at this time" (sei ). a further . % (mean . ± . ) strongly agreed that "there will be a reduced supply of basic goods/ products for daily use" (sei ) and . % (mean . ± . ) strongly agreed that "there was or will be increased prices for basic products" (sei ). consequently, "poor people will suffer food and nutritional deficiency" (sei ) was strongly agreed with by . % respondents (mean value of . ± . ). "the shutdown of education institutes will hamper those currently receiving formal education" (sei ), to which % respondents strongly agreed (mean value of . ± . ). for "if there is a chance of social conflict due to this outbreak" (sei ), the mean response was . ± . . . % (mean . ± . ) of respondents strongly considered that "there is a chance of community transmission of covid- in bangladesh" (iei ) and that "a huge number of people will be infected" (iei ) with a mean value of . ± . . moreover, % of the respondents strongly agreed (mean value . ± . ) that "there is a chance that many infected patients will not be detected due to a lack of testing facilities and this will not show the actual number of infected cases" (iei ). approximately - % of the respondents strongly agreed that "there is a chance of an increasing numbers of deaths from infection due to a lack of proper health facilities" (iei ) with a mean value of . ± . . "a lack of bio-medical waste management facilities in the hospitals will create further transmission" (iei ) received a mean value of . ± . . for the sixth statement, . % of respondents (mean value of . ± . ) strongly agreed that "there will be many people psychosocially shocked due to this outbreak" (iei ) and that "the general public will lose trust in the government" (iei ) was strongly agreed with by . % respondents with a mean value of . ± . . we have considered emerging enduring issues (eei), such as potential natural calamities and infectious disease outbreaks, as the monsoon season is approaching. six statements were considered for enduring emerging issues (eei - ). regarding the statement that "there is a chance of a disaster such as a flood, cyclone, or drought in considering the vulnerability of bangladesh to climate change" (eei ), there was a mean response of . ± . . but the statement "if any disaster (flood, cyclone, landslide) occurs after/during covid- , the situation will create a double burden to the country" (eei ) was strongly agreed with by % of respondents with a mean of . ± . . . % of respondents agreed with a mean of . ± . that "there is a chance of severe food scarcity in the country due to these events (covid- + disasters)" (eei ). a strong agreement from participants (varied from to %) was observed for the statements: "there is a high possibility of huge economical loss" (eei ) with a mean value of . ± . , "there is a high possibility of increasing poverty level" (eei ) with a mean value of . ± . , and "there is a high possibility of severe socio-economic and health crisis" (eei ) with a mean value of . ± . . the association of affected psychosocial wellbeing and the fragile healthcare system during covid- outbreak from the regression analysis, among the variables, only five variables showed statistically significant associations with the fragile healthcare system of bangladesh (hsb ) to deal with the recent outbreak of covid- in the country ( table ) . hsb , hsb , and iei statistically pose a significant positive effect on the fragile healthcare system of bangladesh (p < . ). this relationship implies that a huge population and a lack of healthcare facilities are contributing to the community transmission of covid- in bangladesh. the presence of community transmission in bangladesh within a short time is present as predicted by the iedcr, who announced a mildlevel community transmission possibility in bangladesh on st april in their press release ( ). this assumption is further validated by the number of deaths from covid- reported in the news, after the announcement of the partial lockdown, and the opening of rmg factories from april . the number of covid- patients increased significantly in industrial zones. there was also a positive significant association between the fear of the covid- outbreak (mh ) with the struggling healthcare system (p < . ). also, the negative association between hsb and government political decision gpi (p < . ) reveals that the government is unable to make proper decisions at the right time due to the poor governance in the existing healthcare system. the results of linear regression showed that among the variables, only variables showed statistically significant associations with fear of the covid- outbreak ( table ) . for instance, mental health variables mh , mh , and mh statistically pose a significant positive effect on fear of the covid- outbreak (p < . ). on the other hand, there is a statistically positive association between fear of the covid- outbreak (p < . )and the healthcare system in bangladesh (hsb and hsb ), due to the lack of testing facilities and a fragile healthcare system contributing to the fear that has been experienced due to the covid- pandemic in bangladesh. the socioeconomic issues (sei ) and immediate emerging issues (iei ) have a statistically significant positive impact (p < . ), e.g., obstruction to the formal education system, and the potentiality of a huge number of people becoming infected may contribute to the fear development of the covid- outbreak in this country. there was also a positive significant association between the chance of community transmission of covid- for immediate emerging issues (iei ) with fear of the covid- outbreak (p < . ). results from the regression analysis further showed eight variables have a significant statistical association with the governance and political capacity to deal with the covid- outbreak in bangladesh (gpi ). a significant positive association was found among the governance and political issues (gpi with gpi and gpi ) and socioeconomic issues (sei ) (p < . ), implying that the government's decision to lockdown activities was at the proper time and has enhanced the people's perception of the capacity of government to deal with the covid- outbreak ( table ). however, the negative association between governance and political issues (gpi ) and the healthcare system of bangladesh (hsb ) (p < . ) shows that a perceived lack of budget created a gap in the response to covid- ( table ) . moreover, a negative association of governance and political issues (gpi ) with the healthcare system of bangladesh (hsb ) and socioeconomic issues (sei ) (p < . ) shows a perceived lack of trained doctors and healthcare professionals, and that a hampering of formal and informal business activities are reducing the government's capacity to deal with the covid- outbreak. nevertheless, a positive association of governance and political issues gpi with socioeconomic issues sei (p < . ) and governance and political issues gpi (p < . ) shows that there is a perceived possibility of social conflict due to this outbreak if not managed properly, and that the bangladesh government will need support from developed nations and allied forces to deal with this outbreak. it should be mentioned here that containment, risk mitigation, and suppression plans must be as inclusive as possible or risk undermining response efforts. the regression analysis showed that, among the variables, nine showed a significant statistical association with the future impacts of implementing lockdown and social-distancing activities (sei ). a significant positive association of socioeconomic issues (sei ) with governance and political issues (gpi ) and socioeconomic issues (sei ) (p < . ) shows that the government took the right decision by shutting down regular activities and implementing the social distancing approach ( table ) . but due to this initiative, the formal and informal business sectors and the economy will be hampered. again, a positive association of socioeconomic issues (sei ) with mental health (mh ) and healthcare services (hsb ) (p < . ) reveals that this decision of shutting down normal activities was imposed due to the fear of losing lives due to covid- and having a lack of healthcare facilities. however, a positive association of socioeconomic issues sei with sei , sei , sei , and enduring emerging issues eei (p < . ) shows that due to this shut down poor people will be severely affected, the price of the basic products will increase, the formal education system will be hampered, and the possibility of severe socio-economic and health crises will increase. in the regression analysis, eight variables are statistically associated with the possibility of community transmission of covid- (iei ). a significant positive association between mental health variables (mh , mh ), healthcare system variables (hsb , hsb ), socioeconomic variables (sei , sei ), and immediate emerging issues (iei , iei ) (p < . ) reveals that community transmission will increase the number of infected people which will create further fear and mental pressure of others of losing their lives due to covid- infection ( table ) . the fragile healthcare system of bangladesh will be unable to detect most of the infected patients due to a lack of health facilities, which leads to undermining the actual infected cases. as of the last day of the survey for this study on march , the testing rate of covid- was at its lowest in bangladesh compared to the other similar countries ( people/ million). however, as the laboratories increased, the number of testing has increased along with this, with people/ million. this is still inadequate compared to the population density. also, the inadequate disposal method of covid- hospital bio-medical waste management and associated facilities could increase community transmission. subsequently, due to the community transmission of covid- , many people will lose their lives and livelihoods, which might lead to creating social conflict, as a worst-case scenario. the regression analysis further identified nine variables that are significantly associated with the possibility of climate-induced extreme natural events (flood, cyclone, landslides, etc.) occurring during/after the covid- pandemic. the pandemic along with natural disasters may create a double burden to the country due to enduring emerging issues (eei ). the positive association between eei , sei , iei , eei , eei , and eei (p < . ) shows that there is a perceived possibility of a climate-change-induced disaster after the covid- situation which would create severe food insecurity ( table ) . poor people will suffer most from food and nutritional deficiency and the country will face enormous economic loss. also, after the covid- situation, a lack of bio-medical and solid waste management will add more problems. moreover, a positive association between eei , hsb , and eei reveals that, after the covid- emergency, existing poverty will create further socio-economic and health crises. overall relationship assessment among the variables from ctt, pca, and ca ctt and pca revealed a confidence level of controlling factors in bangladesh during the covid- outbreak and how these components are correlated to the psychosocial, socio-economic, and environmental crisis components (tables , ) . cluster analysis (ca) further detected the total status of regional variations, and how socio-economic and environmental crises influences psychosocial development (figure ) . from the ctt analysis, according to the corrected interitem correlation analysis, among variables, four variables have low corrected item-total correlations (i.e., the ability of the government to deal the outbreak, − . ; seriousness of the government, − . ; government is taking a proper decision, − . ; and other sectoral involvement to covid- , − . ). the remaining variables in the scale had an acceptable corrected item-total correlation ( . to . ) and the cronbach's alpha ( . ) was acceptable. from pca, nine principal components (pcs) were originally based on standard eigenvalues (surpassed ) that extracted . % of the total variance as displayed in table . the scree plot was adopted to detect the number of pcs to be retained to provide insight into the underlying variable internal structure (figure ) . the loading scores were demarcated into three groups of weak ( . - . ), moderate ( . - . ), and strong (> . ) ( ) ( ) ( ) . the pc (first) showed . % of variance as it encompassed a confidence level of weak positive loading of the healthcare system in bangladesh (hsb - : . - . ); with results being moderate positively loaded for the healthcare system in bangladesh (hsb - : . - . ). the pc (second) indicated . % of the variance and was loaded with moderate positive loading for socio-economic issues (sei - : . - . and sei : . ) and weak positively loaded for socio-economic issues (sei - : . - . and sei : . ). the pc (third) showed . % of the variance and was moderate positively loaded for immediate emerging issues iei - ( . - . ). the pc (four) indicated . % of the variance, and was loaded with a significant level of strong positive loadings for immediate emerging issues iei ( . ); results were moderate positively loaded for immediate emerging issues iei - ( . - . ) and immediate emerging issues iei - : . - . ), and were weak positively loaded for immediate emerging issues iei ( . ). the pc (five) and pc (six) indicated . and . % of the total variances, and loaded a significant level of strong positive loading for mental health issues mhi - ( . - . ) and government and political issues gpi - ( . - . ); results were moderate positively loaded for mental health issues mhi ( . ), mhi ( . ), government and political issues gpi ( . ), and gpi ( . ). results were weak positively loaded for mental health issues mhi ( . ) and government and political issues gpi ( . ). the pc (seven), pc (eight), and pc (nine) showed . , . , and . % of the total variances and were moderate positively loaded for government and political issues gpi - ( . - . ), socioeconomic issues sei ( . ), sei - ( . - . ), and immediate emerging issues (iei : . ); results were weak positively loaded for socio-economic issues sei ( . ), sei - ( . - . ), healthcare sector of bangladesh hsb - in the ca all the parameters were classified into four major groups: cluster- (c ), cluster- (c ), cluster- (c ), and cluster- (c ) (figure ) . c was composed of two sub-clusters of c -a and c -b; c -a was composed of issues surrounding an increase in the number of deaths due to not having proper health facilities, a lack of bio-medical waste management facilities in bangladesh that will create more problems, many people experiencing psychosocial issues due to this outbreak, with a large number of people becoming infected, and there being a chance of not detecting most of the infected patients due to the lack of health facilities leading to undervaluing the actual infected cases (iei - , iei - ). c -b was composed of socioeconomic issues that may lead to poor people suffering from a lack of food, thereby leading to nutritional deficiency (sei - and sei ). c consists of socio-economic issues (sei - ). c consisted of three sub-clusters of c -a, c -b, and c -c. c -a covered governance and political issues gpi - , and socioeconomic issues (sei ). c -b consisted of immediate emerging issues iei - , while c -c was composed of issues related to the healthcare system in bangladesh (hsb - ). cluster- consisted of three sub-clusters of the c -a health system in bangladesh and immediate emerging issues (hbs , iei ), c -b covered mental health issues (mhi - ), and c -c contained governance and political issues (gpi - and gpi ). this perception-based study tried to visualize the psychosocial as well as socioeconomic stresses due to the covid- pandemic in bangladesh. any major epidemic outbreak has negative effects on individuals and society ( ) , and people's fear due to covid- is rational in the sense that the fatality rate of the virus is around % and it can kill healthy adults along with the elderly or those with existing health problems ( ) . it is crucial to assess the covid- pandemic independently based on its attributes and not on past epidemics like sars or mers ( ) . more than covid- symptom-like deaths were reported from leading newspapers and electronic media from th of march to th of april . the reported case numbers certainly underestimate the actual number of infected persons given the limited number of urban testing centers, the shortage of test kits, and the long waiting times for tests and test results ( ) . the covid- outbreak caused other critical care and infectious disease patients to be deprived of basic healthcare facilities. patient-management decisions, early diagnosis, rapid testing, and detection are urgently needed ( , ) . the decentralization of testing and treatment facilities is required for the healthcare system to combat the pandemic. the government needs to aid in implementing testing facilities in both public and private clinical laboratories all over bangladesh. for a developing country, resources need to be assembled appropriately and promptly. with limited screening and testing of covid- in bangladesh, and the presence of only laboratories mostly located in urban areas, it is difficult to predict when transmission of the disease will peak and when the curve will flatten ( ) . predictably, community transmission in the country is happening and people are being infected and infecting their community, in some cases even without showing symptoms. it is further predicted that covid- and dengue together is a deadly combination. as the monsoon season approaches, the risk of dengue infection is on the rise. it is a timely step taken by the dghs to conduct dengue tests on suspected covid- patients, as both diseases share common symptoms (reported on may , by dghs in a daily press briefing on covid- ). successful governance is only possible with a competent early warning system, efficient analysis of the situation, and the interpretation, sharing, and use of relevant knowledge and information ( ) . public health instructions should be established based on scientific evidence to reduce the anxiety and distress caused by misinformation and rumors. epidemiological outcomes need to be informed on in time so that they can be accurately evaluated and explained ( ) . societies where underserved communities exist strongly fear government information and politics. public risk communications are therefore needed to prevent misinformation from social media and electronic media. the psychosocial risk (mental health impacts) for children in this situation are apparent, as they are out of touch with schools, classmates, and playmates, and deprived of physical activities and social activities; these issues need to be addressed. moreover, the isolation and quarantine of parent/s can mentally traumatize them and result in negligence, mistreatment, and abuse in the absence of parents/caregivers frontiers in public health | www.frontiersin.org ( ) . in addition, due to lockdown and the required maintenance of family hygiene, the burden of these activities is increased for women, considering the patriarchal nature of the country (where predominantly all household activities are performed by women). moreover, increased levels of violence against women and girls are experienced, as in the lockdown it is almost impossible for victims to escape those family members who are the perpetrators ( ) . furthermore, in the rohingya refugee camps, it will have catastrophic outcomes ( ) . these kinds of risks, awareness, and prevention methods should be effectively communicated to the public. as the pandemic continues, each new day brings in new conversations on social media and alarming developments of misinformation and propaganda, resulting in unnecessary psychological trauma and anxiety ( ) . moreover, religious tension, personal tension, job insecurity, financial loss, and social insecurity could leave some people feeling particularly vulnerable and mentally unstable ( ) . honest, transparent communication is vital for risk communication about the pandemic, while confusing or contradictory health messaging engenders mistrust and leads people to seek information from unreliable alternative sources and thus proliferates rumors ( ) . the fear of becoming infected or fear for vulnerable family members has amplified along with the administrative procedures of testing and reluctance of other private clinics and hospitals to admit patients. at the bbginning of this pandemic, bangladesh had only icu beds in five dedicated hospitals in dhaka for the treatment of covid- patients. there were no icu beds in hospitals outside dhaka ( ) . this is a sign of weak governance in the healthcare system of bangladesh. in this scenario, other critical care patients are denied admittance, experience negligence, and are often left to die without treatment. moreover, the administrative procedure for the covid- deceased, whether that be burial or cremation, has created more confusion and religious fear in the minds of the common people. often, family members of the deceased have denied claiming the body due to fear of infection. in those cases, government authorities have intervened. moreover, there is a rumor that the victims of covid- are buried without the muslim funeral procedures of bathing, which has created further religious tensions among people. it is, therefore, imperative that the government manages people's fear and anxiety. proper information should be circulated to reduce confusion. the bangladeshi electronic and print media is not acting responsibly to disseminate truthful information and are instead reporting misguided stories on social media. since the th of march, the government of bangladesh formed a division to monitor media to eradicate rumors or incorrect information being disseminated on social media platforms and in the mainstream media to protect the mental health of the people. the bangladesh meteorological department (bmd) had forecasted heavy rainfall events and intermittent nor'westers and cyclones at many places across the country during april and may ( ) . heavy rainfall and nor'westers related to high windspeed causes tremendous disasters by destroying standing crops and properties and cause death to people and livestock. fair and equitable sharing of health resources could mitigate further risks to public health by meeting community health needs and generating all-important trust and resilience ( ) during further climatic disasters. the development of resilience is significant to combat any disasters, even a pandemic. subsequently, to develop resilience in the healthcare systems and to tackle any pandemic, good governance is crucial, along with good coordination. in addition, it also requires financing, service delivery, medicines and equipment for health workers, and information ( ) . moreover, governments, institutions, healthcare facilities, and the general public all hold a social and ethical responsibility to assess and mitigate risks for the most vulnerable communities, including homeless people, people without adequate insurance or employment, indigenous communities, immigrant communities, people with disabilities, and certain frontline healthcare workers and emergency responders. prisons, nursing homes, orphanages, old care homes, homeless shelters, and refugee camps can become focuses for disease outbreaks as these settings often have inadequate access to basic healthcare facilities that increases the disease burden ( ) . the government should prepare policies and decisions on early recovery plans which should be inclusive to all ethnic groups, religious groups, minorities, and the wide range of vulnerable populations. april and may are the months of natural disasters like tropical cyclones, tornados, and early flooding in bangladesh, which may be evident within the coming days. therefore, utilization of the health-emergency disaster risk management (health-edrm) framework is important to implement. health-edrm refers to the "systematic analysis and management of health risks, posed by emergencies and disasters, through a combination of ( ) hazard and vulnerability reduction to prevent and mitigate risks, ( ) preparedness, ( ) response and ( ) recovery measures" ( ) . health-edrm is an umbrella term which the who uses to refer to the broad intersection of health and disaster risk management (drm). as the patients of other seasonal diseases such as dengue are rising, and the possibility of a natural disaster remains, the healthcare system should be coping with the changing scenario of the covid- outbreak in bangladesh, where resilience is very important. the hotspot areas of the disasters have already been identified in the bangladesh delta plan ( ) . vulnerable areas should be given special emphasis in the coming months for the protection of crops, risk reduction, relief preparation, and rehabilitation. biomedical waste should be disposed of following national and international guidelines on the disposal of infectious biological hazardous materials ( ) . when an exponentially rapid spread of a disease or infection breaks out, the generation of biomedical waste and other related healthcare hazards may be considerably increased within a noticeably short period. if improperly treated, this waste may accelerate the spread of disease and pose a significant risk to medical staff, patients, and waste management unit personnel. a complex short-term decision-making problem is required by the authorities to deal with the fast accumulation and transportation mode of the medical waste. healthcare centers can either directly transport the waste to the treatment centers or they can transfer and consolidate via a temporary transit center ( ) . the use of ppe should be distinguished by different risk factors to adopt different epidemic prevention measures and reduce the waste of personal protective equipment, as these resources are already in short supply ( ) . moreover, repeated use of disposable masks and not washing cloth masks could create further risk of infection that needs to be dealt with through proper information to the public ( ) . as the country does not have proper incineration facilities, the government should think of setting up mobile incinerator plants rapidly to responsibly manage bio-medical waste. as we have analyzed the scenario over the past months of partial, a loss of billion bdt a day to gdp is incurring. more than million people are becoming further marginalized due to the loss of wages and jobs ( ) . the dilemma of life vs. livelihoods has put people at high risk of community transmission in the industrial districts after the ready-made-garment (rmg) manufacturers trade organization bgmea decided to open the factories even before the end of lockdown. it was predicted that the government would not get support from the allied forces. weak governance and policy put emergency responders, such as medical doctors and healthcare staff, police, security forces, and army personnel, at risk of infection. already, thousands of doctors and members of the police force have been infected and died during this time. the socio-economic fall-out from this pandemic is already high, particularly for the disadvantaged poor communities, day laborers, wage earners, rmg-sector workers, and small and medium business start-ups. already the country's rmg sector has lost many global orders due to the pandemic, and the remittance flow is at its lowest. job insecurity and financial insecurity is foreseeable, and concerns of a global depression will affect the local market as well as investors. the prime minister of bangladesh already declared a stimulus package of , crore bdt, of which , crore bdt has been announced for the rmg sector, other large industries, and the service sector in an attempt to defeat the economic losses due to the coronavirus situation ( ) . however, on prioritybasis the financial incentives should be given to the povertystricken disadvantaged communities first, as well as insurance for healthcare professionals at the frontline, emergency responders, and caregivers responsible for emergency handling. purchasing intensive care unit (icu) beds, protective equipment, diagnostic test kits, mechanical ventilators, and additional supports is required for these mentally and physically affected persons who have survived covid- . it is also imperative to continue taking precautions, including screening, isolation of suspected cases, and social distancing, even after the pandemic is over. finally, combating the global pandemic is not easy. the statements that we have included in this analysis aid in identifying the associations among the psychosocial, socioeconomic, and possible environmental crisis based on public perception in bangladesh. risk mitigation measures concerning the psychosocial, socio-economic, and environmental components of the public are necessary to combat a global pandemic. therefore, with great advancements in the speed and power of science, international collaborations are required to provide knowledge about the virus and disease recovery. moreover, it is highly recommended by who and other stakeholders from the national level to raise the testing speed and facilities in bangladesh. multi-sectoral involvement and proper relief facilities for unprivileged populations must be ensured. without ensuring fundamental needs would be met, the lockdown due to covid- has imposed mental stress on the public. the weak governance in the healthcare systems and limited healthcare facilities exacerbated the general public's fear and anxiety. the centralized covid- testing facility and limitations of dedicated hospital units for covid- patients hampered other critical patients from receiving healthcare services. as a country vulnerable to climate change, there might be some additional risk factors of occurring natural disasters, such as a tropical cyclone, which may add further pressure on the country. the closure of all educational institutions may increase the number of mentally depressed young people. as the business centres (except for groceries, pharmacies, and other daily necessities) are closed, it has put further stress on the country's economy. an infectious outbreak of dengue might be on the way that may have a cumulative/synergistic negative impact with covid- on public health in bangladesh. however, numerous factors that can be considered in the context of the current covid- outbreak in bangladesh are as follows: risk of community transmission, healthcare capacity, governance coordination, relief for the low-income population, biomedical waste management, and preparation for possible natural disasters. the recommendations collected in the perception study can be summarized as a need to increase covid-testing rates and increase medical facilities. the decentralization of the covid- medical facilities is particularly important due to the forced migration of more than million people from dhaka city to districts of bangladesh after the announcement of partial lockdown. in addition, proper risk assessment and dependable risk communication, a multisectoral management taskforce development, care of biomedical waste, ensuring basic support to vulnerable people, and good governance was suggested to reduce the psychosocial and socioeconomic impact of the covid- outbreak in bangladesh. finally, this assessment process could help the government and policymakers to judge the public perceptions to deal with the covid- pandemic in densely populated lower-middleincome countries like bangladesh. covid- ) situation reports how will country-based mitigation measures influence the course of the covid- epidemic? managing covid- in low-and middleincome countries countries test tactics in 'war' against covid- covid- containment: china provides important lessons for global response covid- : surge in cases in italy and south korea makes pandemic look more likely the fear of covid- scale: development and initial validation mitigate the effects of home confinement on children during the covid- outbreak available online at available online at doctors at private hospitals left vulnerable. the daily star editorial ( ) hatred and stigmatization grip bangladesh amid covid- outbreak student suicide risk and gender: a retrospective study from bangladeshi press reports psychological interventions for people affected by the covid- epidemic choosing a method to reduce selection bi-as: a tool for researchers simultaneous comparison of modified-integrated water quality and entropy weighted indices: implication for safe drinking water in the coastal region of bangladesh scale development: theory and applications application of factor analysis in the assessment of groundwater quality in a blackfoot disease area in taiwan characterization of groundwater quality using water evaluation indices, multivariate statistics and geostatistics in central bangladesh characterizing groundwater quality ranks for drinking purposes in sylhet district, bangladesh, using entropy method, spatial autocorrelation index, and geostatistics responding to covid- -a once-in-a-century pandemic? a midpoint perspective on the covid- pandemic covid- and community mitigation strategies in a pandemic emergence of a novel coronavirus disease (covid- ) and the importance of diagnostic testing: why partnership between clinical laboratories, public health agencies, and industry is essential to control the outbreak to withdraw or not to withdraw? tbs news ( ) crippled community governance and suppressed scientific/professional communities: a critical assessment of failed early warning for the covid- outbreak in china taking the right measures to control covid- covid- : children at heightened risk of abuse, neglect, exploitation and violence amidst intensifying containment measures covid- and violence against women: what the health sector/system can do the covid- pandemic: making sense of rumor and fear covid- : control measures must be equitable and inclusive bangladesh has only icu beds to fight coronavirus! the business standard nor'wester likely this week. the daily star ( ) the resilience of the spanish health system against the covid- pandemic building resilience against biological hazards and pandemics: covid- and its implications for the sendai framework general economics division (ged) planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases reverse logistics network design for effective management of medical waste in epidemic outbreaks: insights from the coronavirus disease (covid- ) outbreak in wuhan (china) rational use of face masks in the covid- pandemic to open or not to open: lockdown exit strategies can help how will the covid- stimulus package be implemented? the daily star ( ) available online at all datasets presented in this study are included in the article/supplementary material. the studies involving human participants were reviewed and approved by department of public health and informatics, jahangirnagar university, bangladesh. the patients/participants provided their written informed consent to participate in this study. mb-d, ms, and mr planned the studies and developed the questionnaire. informatics and data analysis and interpretation were maintained by mb-d, ai, ms, and mr. mb and lb revised and improved the manuscript as suggested by the reviewers. all authors reviewed and read the manuscript before final submission. the authors would like to acknowledge all the frontline doctors fighting this pandemic and all the researchers cited in the references. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fpubh. . /full#supplementary-material the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © bodrud-doza, shammi, bahlman, islam and rahman. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -vo bemg authors: ryan, jeffrey r. title: case studies date: - - journal: biosecurity and bioterrorism doi: . /b - - - - . - sha: doc_id: cord_uid: vo bemg chapter presents six case studies that should provoke the reader to delve more into the particulars of each incident. specifically, the chapter provides details on the sverdlovsk anthrax incident ( ); the rajneeshee salmonella incident ( ); the surat, india pneumonic plague outbreak ( ); the fallen angel ricin incidents ( – ); amerithrax ( ); and the outbreak of ebola virus in west africa ( – ). each of these incidents help illustrate the difference between an unusual natural outbreak and one due to an intentional act. in addition, each case study presented herein shows how confounding these outbreaks can be to public health officials and how fear, panic, and social disruption may ensue. the six case studies presented within this chapter should be viewed as drawing attention to weaknesses in a system of detection first, followed perhaps by issues in containment and mitigation as a result. in looking at these events from a system perspective, we should be aware that the point at which a system fails is often a weakness due to failure in other parts of the system. a system is defined as "a dynamic order of parts and processes standing in mutual interaction with each other" (von bertallanfy, ) . therefore it is necessary for all professionals reading this text to examine all of the parts and processes, especially the interactions among the parts. the manner in which the case studies are presented in this chapter runs the risk of being categorized as anecdotal and, as such, dismissed by some purists. it is not practical for us to completely recreate or chronicle the accounts for the case studies presented here, and more elaborate and definitive references are easily retrieved from open sources. as such, references and websites are provided at the end of the chapter to allow additional, in-depth exploration of the described events. early detection of biologic events requires an innate ability to make sense of seemingly subtle and random events, often lacking scientific explanation. the practice of medicine is an example of the need to combine science, experience, and instinct in the development of a plan of action. rarely do patients themselves progress in clinical presentation and disease etiology as the pages in a textbook might suggest. in , sacks wrote that we need, in addition to conventional medicine, a medicine of a far profounder sort, based on the profoundest understanding of the organism and of the life. empirical science is the key to one form of knowledge, the generalized knowledge that gives us power over nature; the key to wisdom however, is the knowledge of particulars. we anticipate that the reader will filter and interpret this material within the context of his or her chosen vocation. applying some of these lessons may allow future generations, regardless of their particular vocational path, to detect early on the emergence of a biologic event and conceivably achieve improved outcomes. herd health and wellbeing may take precedence over individual rights and outcomes. no doubt this is a hard pill for some to swallow. however, improved outcomes portend a decrease in morbidity and mortality, minimization of social or economic impact, or perhaps even decreased international interest. in april an unusual epidemic of anthrax occurred in sverdlovsk, a city of . million people km east of moscow in the former soviet union (meselson et al., ) . shortly after the cases emerged, soviet officials explained that the source of the outbreak was related to the ingestion of contaminated meat. according to their report, contaminated animals and meat from an anthrax epizootic south of sverdlovsk caused cases of human anthrax (meselson, ) . of these cases, were cutaneous anthrax and were gastrointestinal anthrax. of the cases, of the gastrointestinal anthrax cases were fatal. at the time, there was great debate among officials from other nations as they tried to determine if the outbreak may have actually been due to covert soviet bioweapons production. the following report comes from a recently declassified defense intelligence agency's intelligence information report dated march , : a fourth source reports in late april , the population was awakened by a large explosion that was attributed to a jet aircraft. four days later, seven or eight persons from the military installation were admitted to hospital number in the suburbs where the military installation is located. their symptoms were high fever ( °), blue ears and lips, choking, and difficulty breathing. they died within - h, and autopsies revealed severe pulmonary edema plus symptoms of a serious toxemia. about days after the illness first appeared, the source and other doctors from various hospitals were called together by the district epidemiologist. the number of fatalities had risen sharply, and the source estimated deaths by this time at . the epidemiologist announced the outbreak of an anthrax epidemic and gave a lecture on the disease. he claimed the epidemic was caused by an illegally slaughtered cow suffering from anthrax in a town about km northeast of sverdlovsk. he said the beef had been sold in the suburb where the fatalities were occurring. this explanation was not accepted by the doctors in attendance because the fatalities were caused by pulmonary anthrax as opposed to gastric or skin anthrax, which would be more likely if anthraxcontaminated beef were eaten or handled. as more reports emerged, us intelligence reviewed satellite imagery and signal intercepts from the spring of and found corroborative signs of a serious accident. this included roadblocks and decontamination trucks around what was then known as compound , a military installation in sverdlovsk. in addition, officials learned that the soviet defense minister had visited the city shortly after the incident. the anthrax explanation also seemed plausible given the long-standing history of soviet efforts to mass produce bacillus anthracis into a biological weapon (wampler and blanton, ) . us intelligence agency officials believed that the incident had to be due to inhalation of spores that were released from a secret bioweapons plant in the city. victims presented with severe respiratory distress and died within a few days of the onset of symptoms. this belief came from epidemiological data showing that most victims lived or worked in a narrow zone extending from the bioproduction facility to the southern city limit. furthermore, livestock downwind from the point of release died of anthrax along the same zone's extended axis. the zone paralleled the northerly wind that prevailed shortly before the outbreak (meselson et al., ) . other scientists harbored doubts about the official us accusation, noting that an accidental release of anthrax spores could have been in connection with a defensive biological warfare research program, which was allowed under the convention. it was later concluded that the escape of an aerosol of anthrax pathogen at the military facility caused the outbreak. the reports of a possible anthrax outbreak in sverdlovsk, linked to an incident at a suspected soviet biological warfare facility, served to further deepen already worsening us-soviet relations, which were heading back toward a new cold war in the wake of the soviet invasion of afghanistan. in the s during the reagan administration, sverdlovsk would become one of the major points in the us indictment of the soviet union to build the case that the soviets were violating the ban on the use of biological weapons imposed by the biological warfare convention, which both the united states and the soviet union had signed. despite the proof that western scientists had, the soviets (see fig. . ) refused to discuss the incident and maintained their position that they did not have a program in bioweapons development and production. in fact, the strain of anthrax produced in military compound near sverdlovsk was believed by experts to be the most powerful in the soviet arsenal ("anthrax "). could there be legitimate national security reasons for not disclosing the source of such an outbreak? if there are reasons, what are the potential ramifications for recognition, containment, and mitigation of the danger from the organism? the final breakthrough did not come until after the soviet union had ceased to exist, at the end of , and boris yeltsin came to power as the new head of the russian government. yeltsin had a personal connection to the sverdlovsk issue because he had been communist party chief in the region at the time of the anthrax outbreak, and he believed the kgb and military had lied to him about the true explanation. at a summit meeting with president george h. w. bush in february , yeltsin told bush that he agreed with us accusations regarding soviet violation of the biological weapons convention and that the sverdlovsk incident was the result of an accident at a soviet biological warfare installation, and he promised to clean up this problem. in a may interview yeltsin publicly revealed what he had told bush in private: we have now circumscribed the time of common exposure to anthrax. the number of red dots we can plot on our spot map places nearly all of the victims within a narrow plume that stretches southeast from compound to the neighborhood past the ceramics factory…. we have clarified the relation of the timing of animal and human deaths and believe the exposure for both was nearly simultaneous. all the data-from interviews, documents, lists, autopsies, and wind reports-now fit, like pieces of a puzzle. what we know proves a lethal plume of anthrax came from compound . the sverdlovsk incident represents one of the leading examples of how an unknowing population can be affected by the release of formulated biological agents. it seems pretty clear at this point that the release was accidental. however, questions remain unanswered as to exactly how much b. anthracis was released, how far down range did it travel, and how many people were affected by the release. on september , , a man was admitted to the county's only hospital complaining of intense stomach cramps, nausea, and high fever. two friends were also ill. all three had eaten at a local restaurant earlier that day. in the following week, employees and dozens of customers of the restaurant became violently ill. many called and threatened to sue. within h after the first patient presented to medical professionals, a pathologist at mid-columbia medical center had determined the cause was food poisoning from salmonella bacteria. however, it was a full week before the first complaint of this foodborne outbreak was reported to the county health department. by september , reports of new cases had subsided; the state laboratory had identified the strain of salmonella used. that is when the second wave struck. two days later every bed in the local hospital was filled with salmonella victims. almost one-third of the town's restaurants were implicated ( in all). this was enough to basically shut down the economy of the dalles; many of these restaurants would close forever. on september the local health department called in assistance from the centers for disease control (cdc). by the time the first cdc officers began to arrive, the county health department had already confirmed cases of salmonella enterica serotype typhimurium from the outbreak. they had also found the main epidemiologic connection: most of the sick people had eaten from salad bars. by the time the cdc arrived in force the county health department had already done the main work involved in stopping the outbreak. • the local public health office began immediately tracking patients through passive surveillance. three-day food histories were completed for each patient. these interviews quickly showed that most of the ill people had eaten at a salad bar at one of the affected restaurants. restaurants were asked to close their salad bars; all restaurants in the county immediately complied. • colleagues were interviewing and inspecting restaurants in the county. however, they found nothing that would indicate how restaurants had created a single outbreak using the exact same pathogen. • they found that the affected restaurants used several distinct suppliers, and no supplier served more than restaurants. in addition, the epidemiologic investigation found that various foods were risk factors at various times. the first wave of illness centered on items such as potato salad; the second wave on blue cheese dressing. no major violations were found in the distributors or suppliers. • samples were taken from both water systems that served the area restaurants, from the restaurants themselves and at the municipal level. these samples were negative for any form of bacteria, and all had acceptable color and chlorine levels. despite the suspicions of the community and the lack of any other explanation, an epidemiologic investigation failed to demonstrate that the outbreak was deliberately caused. the state did not want to be considered backward or insensitive to the rajneeshees, and the investigation may have been influenced by such political pressure and would hold to a theory of multiple coincidental cross-contaminations throughout the county. the rajneeshees incident occurred in . however, had this event occurred after the anthrax attacks, do you think investigators would be so quick to discount an intentional attack? many years have passed since the attacks; do you think our vigilance has a shelf life? in all, cases of salmonellosis were confirmed from more than patients; approximately % of the community became ill. although the illness struck simultaneously in restaurants dispersed throughout the county, the state health department's epidemiologic investigation concluded that the outbreak was caused by unsanitary hand-washing practices at the restaurants involved. an initial criminal investigation agreed with the health department's conclusion. one year later a representative of the bhagwan shree rajneesh sect, which had a ranch in the county, announced that members of that sect had poisoned local salad bars with salmonella bacteria in a test run for a plan to influence local election results in the sect's favor ( fig. . ). a subsequent criminal investigation found that the sect had ordered the exact strain of salmonella used by mail from a licensed commercial laboratory company. when the cdc analyzed the data, things looked much different. employees generally had symptoms at the same time as customers, and the strain of salmonella encountered was not at all the same as any other area cases in recent years. the outbreak occurred in two distinct waves that flew in the face of a single-exposure event. in this case the initial state health report denied local law enforcement the probable cause they needed to open an investigation. even in the face of strong evidence suggesting a deliberate attack, investigators initially discounted this theory, giving several reasons why they reached this conclusion. among the reasons were these: there was no apparent motive, no one claimed responsibility, and nothing like this had ever occurred before. these points reinforce the need to maintain a high index of suspicion and follow epidemiological clues to reach a plausible explanation of any unusual outbreak. early involvement of law enforcement personnel may enable investigators to remain subjective in their determination and cognizance of evidentiary matters should a reasonable index of suspicion be warranted. had investigators used more aggressive surveillance techniques to gather more information (ie, surveying doctor's offices for symptomatic persons), they may have received additional information for the investigation and might have produced enough evidence to change the investigator's position on whether the outbreak was accidental or intentional. accounts from community members support the position that numerous patients did not report to the medical community and chose to stay home and treat themselves (personal communication, j. glarum). the population of surat, in the western state of gujarat, boomed shortly after world war ii. surat's population grew from , to approximately . million residents. the city divided into two parts, the "old city," or city center, remained the most heavily populated area, accounting for % of the total population. the newer settled, outer portions of the city were characterized by their universal lack of planning. incorporating a mix of industry and lower class residences, these areas were largely devoid of proper sewage facilities and only % of total daily garbage produced was regularly collected (shah, ) . less than half of the city had access to treated drinking water. the unhygienic conditions and poor working conditions within surat were commonly identified by public health officials as the causes for regular epidemic outbreaks within the city of malaria, gastroenteritis, pneumonia, and diarrhea. in september an earthquake occurred, which killed an estimated , people, and because of the poverty of the area, many of the dead were not properly buried. floods in august created an unbelievable mix of human waste, refuse, and human and animal remains left behind. these events, in addition to the poor refuse disposal and sewer services, created an abundant food supply for rats and other vermin. some reports point to a possible precursor event, which involved the die-off of rats in mamala village to such an extent that they were "falling off rafters, dead, in great numbers" (john, ) . by mid-september, despite the available epidemiological clues, % of the village population was ill with bubonic plague. the indian government initially appeared unable or unwilling to mitigate the spread of the disease created by a series of events in and outside of the country. poor crisis communication regarding the outbreak caused the population to take measures to keep themselves safe in the areas affected and chose to leave, potentially carrying disease with them to unaffected areas. contact tracing was not initially accomplished, once more leading to spread of disease. once the disease became obvious and there was little being done by the government to contain it, panic ensued and more people fled, carrying the disease. it has been estimated that % of the . million people fled the area. a cordon sanitaire (a french term that translates to "sanitary cord." it is used to denote an extreme use of quarantine in which public health authorities implement large-scale quarantine measures to contain the spread of disease. in this case, a small section of the city would have been under quarantine order. as one might imagine, this would be difficult to implement and enforce) may have proven useful in plague containment; however, it would have affected india's diamond-cutting and silk-production center in the area of the slums. sealing off this area from the rest of the city would have prevented workers getting to the factory, cutting off their income, as well as slowing production (see fig. . ). in addition, the encroachment of the holiday season with the associated visitors and large conferences with international guests drawing thousands of international tourists were planned, and tourism is one of india's major financial businesses. this is a similar situation to china's dilemma on dealing with the outbreak of severe acute respiratory syndrome. several countries put restrictions on travelers from india, with moscow imposing a -day quarantine for all visitors from india and banning all travel to the country. estimates for business losses for the city of surat alone were over $ million. it has been estimated that india lost more than $ billion in export earnings and - % of its anticipated tourism (steinberg, ) . several million people lost income when they were unable to work, locally or internationally; many more millions suffered panic, fear, or dislocation. thousands of squatters had their dwellings inspected and condemned. as a nation, india found its modernity, its efficiency, its health administration, and its local governance called into question. locally, agricultural exporters saw their share prices tumble as some foreign countries not only refused indian exports but closed their borders. the united arab emirates was reported to have cut off postal links with india out of fear that the plague would spread via mail. given the economic upheaval, it is interesting to note that approximately people fell ill, with the total death toll only . this is the point: fear and panic due to poor risk communication and appropriate containment measures caused the bigger problems for the financial markets and economy than the actual disease. control of this disease outbreak would have had to include selective quarantine, contact tracing, treatment, and prophylaxis as well as elimination of potential vectors and animal hosts. in hindsight, investigators identified a -year-old man on september as the first case. he had been admitted to a hospital days earlier with respiratory symptoms and fever (shah, ) . over the next week or so, through september , approximately individuals were admitted to various hospitals, mostly to be diagnosed with and treated for malaria. not until september did the presumption of plague surface. public health authorities were alerted, word began to spread through the medical community, and the one hospital was designated for new suspected plague admissions. shops began closing in the most heavily affected region of the city, medical practitioners began to leave the city, and local pharmacies sold out of available tetracycline. hospital admissions continued to grow and public health authorities were barely able to locate sufficient antibiotics to treat the ill and their care providers. within weeks the case-fatality rate had dropped from % to below %. until adequate government supplies of tetracycline begin to arrive, approximately % of surat's population fled, businesses closed, and public facilities (schools, swimming pools) shut down. by the end of september, adequate supplies, plans, and personnel had the epidemic under control (shah, ) . modern public health and medicine are capable of intervening effectively in outbreaks of bacterial diseases, such as plague, through combinations of medical screening, immunization, antibiotic treatment, and supportive care. even in the absence of effective medical intervention, proper behavior, such as contact avoidance, can profoundly alter the disease progression cycle. if any measure is overlooked or botched in its implementation, it is easy to see how containment can be slow or nonexistent. in late september an avid outdoorsman whose pastimes were gardening and fishing left for a short vacation in north carolina. his job as a photo editor required that most of his work time was spent reviewing photographs submitted by mail or over the internet, so no doubt he looked forward to this trip. soon after arriving in north carolina, the first symptoms of illness developed; these included muscle aches, nausea, and fever. the symptoms waxed and waned for the duration of the three-day trip. the day after he returned home he was taken to the hospital for medical evaluation at the emergency department of a florida medical center after he awoke from sleep with fever, emesis, and confusion. because he was disoriented at the time of his presentation at the hospital, he was unable to provide further relevant information. treatment with intravenous cefotaxime and vancomycin was initiated for presumed bacterial meningitis while the patient awaited a lumbar puncture (malecki et al., ) . on physical examination he was found to be lethargic and disoriented. his temperature was °c ( . °f), blood pressure was / mmhg, pulse was , and respirations were . no respiratory distress was noted; his arterial hemoglobin saturation, as indicated by pulse oximetry while he was breathing ambient air, was %. examination of the ear, nose, and throat detected no discharge or signs of inflammation. chest examination revealed rhonchi without rales (bush et al., ) . the initial chest radiograph was interpreted as showing basilar infiltrates and a widened mediastinum (see fig. . ). the results of a computed tomography scan of the head were normal. a spinal tap was performed under fluoroscopic guidance within hours after presentation at the hospital and yielded cloudy cerebrospinal fluid. the patient was admitted to the hospital with a diagnosis of meningitis. after a single dose of cefotaxime (a broad-spectrum cephalosporin) he was started on multiple antibiotics. a short time later he had generalized seizures and was intubated for airway protection. the next day a new array of antibiotics was initiated, replacing those previously prescribed. he remained febrile and became unresponsive to deep stimuli. his condition progressively deteriorated, with hypotension and worsening kidney function. the patient died on october . autopsy findings included hemorrhagic inflammation of lymph nodes in the chest as well as disseminated b. anthracis in multiple organs (bush et al., ) . gram staining of cerebrospinal fluid revealed many polymorphonuclear white cells and many large gram-positive bacilli, both singly and in chains. on the basis of the cerebrospinal fluid appearance, a diagnosis of anthrax was considered, and high-dose intravenous penicillin g was added to the antibiotic regimen. within h after plating on sheep blood agar the cultures of cerebrospinal fluid yielded colonies of gram-positive bacilli. the clinical laboratory of the medical center presumptively identified the organism as b. anthracis within h after plating; this identification was confirmed by the florida department of health laboratory on the following day. it was evident that making a diagnosis of anthrax would have serious ramifications. although the case was reported to local public health authorities when anthrax was first suspected, final laboratory confirmation of the diagnosis was awaited before a public announcement was made. extensive environmental samples from the patient's home and travel destinations were negative for anthrax. moreover, the finding of b. anthracis in regional and local postal centers that served the work site implicates one or more mailed letters or packages as the probable source of exposure (see fig. . ). coworkers report that the patient had closely examined a suspicious letter containing powder on september , approximately days before the onset of illness. this index case highlights the importance of physicians' ability to recognize potential cases in the identification and treatment of diseases associated with biologic terrorism. on the basis of your knowledge of inhalation anthrax, how does the clinical presentation from the index case measure up with the incubation period and final outcome? in summary, officials believe that there were a total of five letters mailed, four of which were recovered. there were two known mailing dates, september and october , . the letter to the ami building in florida (see fig. . ), where the index case originated, was not recovered. the september letters went to the offices of nbc studios and the new york post in new york city. the october letters were mailed to senators daschle and leahy of the us senate. the amount of formulated anthrax spores in these letters was estimated to be - g. the letter to senator leahy (which was unopened at the time it was discovered) contained approximately g of highly weaponized anthrax spores. outbreaks of the disease were concentrated in six locations: florida; new york; new jersey; capitol hill in washington, dc; the washington, dc regional area, including maryland and virginia; and connecticut. the anthrax incidents caused illness in people: with the cutaneous (skin) form of the disease and with the inhalational (respiratory) form, of who died. demands on public health resources reached far beyond the six outbreaks of disease. once officials realized that mail processed at contaminated postal facilities could be cross-contaminated and end up anywhere in the country, residents brought samples of suspicious powders to officials for testing and worried about the safety of their daily mail. in dealing with this crisis, there were deficiencies in the local public health response and the federal government's ability to manage it. public health officials did not fully appreciate the extent of communication, coordination, and cooperation needed among responders. there were difficulties in reaching clinicians to provide them with guidance. the federal bureau of investigation (fbi) reached a conclusion in that the sole perpetrator was dr. bruce ivins, an army biodefense research scientist assigned to the us army research institute of infectious diseases, fort detrick, md. the conclusion of the fbi's investigation has been viewed by some experts as being technically flawed; therefore it is controversial. in october a suspicious letter addressed to the us department of transportation was intercepted by us postal inspectors. upon examination of the letter's contents postal inspectors recovered a warning: a metal vial containing ricin and a note threatening more attacks if laws restricting the activities of commercial truck drivers were not amended (see fig. . ). in february ricin was discovered in senator william frist's office in the dirksen office building. after the toxin was discovered in a letter-opening machine in the senator's office, federal investigators examined some , pieces of mail, hoping to find the source of the ricin, but turned up nothing to lead them to a suspect. they were unable to determine whether the ricin had been there for hours, weeks, or even months before it was discovered by an intern in the office. conflicting reports on the handling of the response emerged. some senate employees described the hours after the toxin was found as confused and chaotic. some employees near dr. frist's office went home with no medical screening after the substance was found, and others went about their activities without being advised to seek decontamination. the authorities said the substance was first seen about : pm on monday when a hazardous materials team was dispatched to dr. frist's offices in the dirksen senate office building. after preliminary tests proved negative, an all-clear was given. such an occurrence is not unusual for congressional offices, which frequently receive suspect mail that turns out to be harmless. what is the risk to overreacting and carrying out containment activities every time a suspect item is discovered at government offices? when follow-up tests detected the presence of ricin, the capitol police returned and began evacuating people to another area of the dirksen building. by that time, staff members who were present said that many people had left for the day. those who had been in the vicinity and remained in the building were directed to shower at a decontamination tent erected in a hallway between the dirksen building and the adjacent hart senate office building. there they were interviewed by the police and allowed to go home. investigators have found nothing to explain how the potentially deadly powder wound up in the offices of the senate majority leader. the investigation focused on a mysterious "fallen angel," who threatened to use ricin as a weapon unless new trucking regulations were rolled back. no obvious direct connection between the frist case and the letters signed by fallen angel has been found (see fig. . ) . those letters were discovered in mail facilities that serve the greenville-spartanburg international airport in south carolina and the white house. in early the world was introduced to the largest outbreak of ebola virus disease (evd) ever known. according to researchers, the index case for this outbreak came from a -year-old boy in the small village of meliandou (guéckédou province), in the west african nation of guinea. the researchers learned that children in meliandou had been playing near the hollow of a large, dead tree. the tree had a colony of bats. the bats were believed to be infected with ebola virus (marí-saéz et al., ) . this has relevance because of what is currently believed to be the role of bats in the epizootic transmission cycle of ebola virus (see fig. . ). we also know that the -year-old boy mentioned previously died from a mysterious febrile illness, which spread throughout his family, to other villagers and then outside his village. on march , , the world health organization (who) was notified of an outbreak of evd in guinea. by that time it had spread to neighboring african countries (liberia, nigeria, senegal, and sierra leone). limited public health resources (see fig. . ) and volunteer medical groups worked to quell the quickly spreading epidemic, but they were overwhelmed by the number of patients and patient contacts. it was not until august , , that the who declared the epidemic to be a public health emergency of international concern (who report, ). this begs the obvious question, "why did it take nearly months to make such a declaration?" on september , , a liberian national, thomas eric duncan, made his way from liberia to houston, texas. before getting on the plane in liberia, mr. duncan assisted an ill pregnant woman by helping her out of a taxi and into a hospital. it is believed the woman was an evd patient, but he was not aware of this. regardless of what he knew, mr. duncan arrived in houston feeling well with no fever or other symptoms. six days later mr. duncan felt very ill, which prompted him to seek medical attention at a hospital in houston, texas. his travel history was not discussed at that time, so he was discharged from the emergency room (er) with some antibiotics for what was believed to be a routine illness. he went back to the apartment, and a few days later his condition was so severe that he reported to the er at texas health presbyterian hospital in dallas where it became apparent that he was a suspect evd patient. he was admitted to the intensive care unit and ended up in an isolation ward. his condition worsened and he later died. unfortunately, infection prevention standards at the hospital were not entirely adequate. this resulted in two nurses (nina pham and amber vinson) being infected with ebola virus. they were both treated successfully and fully recovered weeks later. the media and public reaction to the three cases in the united states (duncan, pham, and vinson) was pronounced. numerous politicians took a stance on mandatory quarantine procedures at the state and federal level. national and local media providers sought to hold the public's constant attention on the serious nature of "the deadly ebola virus." it is safe to say that there was fear and some panic because of the politicization and dramatization of this limited outbreak. meanwhile, state and local officials in texas had an incident on their hands. emergency management and public health agencies had to work together to ensure that the apartment where duncan had been staying did not become the cause of more infections. all of mr. duncan's contacts had to be identified, placed under strict quarantine, and monitored. after their quarantine period the apartment became a hot zone that required thorough decontamination by a commercial hazmat clean-up group, cleaning guys, llc (refer to fig. . ) . none of mr. duncan's contacts outside of the hospital became infected and the apartment he resided in and all its contents were rendered safe using technical decontamination procedures. what has the - evd outbreak taught us about a few cases of viral hemorrhagic fever getting into the united states or any other developed country? consider applying the criteria for category a agents. at the time of the preparation of this chapter, the outbreak had not been completely contained. as of august there have been a total of , confirmed cases with , fatalities (who sitrep ebola summary; august , ). currently, the outbreak is confined to just one country in west africa: the putative source of the outbreak, guinea. the fear is that evd is now endemic in this region, with case numbers fluctuating with the seasons, but always there. the evd outbreak in west africa was unprecedented in its scale and impact. out of this human catastrophe has come renewed attention to global health security-its definition, meaning, and the practical implications for programs and policy. for example, how does a government begin to strengthen its core public health capacities as demanded by the international health regulations? what counts as a global health security concern? in the context of the governance of global health, including who reform, it will be important to distil lessons learned from the ebola outbreak. the lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. their contributions describe some of the major threats to individual and collective human health as well as the values and recommendations that should be considered to counteract such threats in the future. many different perspectives are proposed. their common goal is a more sustainable and resilient society for human health and well-being (heymann et al., ) . what will make for an interesting postoutbreak study are the geopolitical implications of a largescale outbreak of a category a agent, such as ebola hemorrhagic fever. remember that we will always be one simple border crossing or international flight away from the beginning of the next outbreak. the six case studies briefly presented here should provoke the reader to delve more into the particulars of each incident. the sverdlovsk anthrax incident illustrates the danger posed by bioweapons production. a seemingly simple accident involving the release of a small amount of formulated agent can have a dramatic effect. imagine if the same thing occurred in the united states or europe in the information age of which we are all part today. the rajneeshee incident involving the intentional contamination of food with bacteria was the largest act of bioterrorism to occur in the united states. acquisition of the agent, the ease of production, and the covert and simple nature of the attack emphasizes the indiscriminate and insidious nature of biological terrorism. despite the best efforts of many people, it took more than a year and a confession of guilt from the perpetrators to convince officials that the incident was intentional. the outbreak of pneumonic plague that took place in surat, india, is a testimony to the importance of fast and decisive action to contain a natural outbreak of a highly contagious and deadly disease. had this been related to an intentional act there would have been more index cases or victims initially to facilitate widespread disease. this emphasizes the importance of early detection and standard procedures for containment. the amerithrax incident of showed us how vulnerable a nation is to a small amount of formulated biological material. looking back on that time, the events, as they unfolded, seemed surreal. it was hard to believe that we were under attack and no one really knew for some time how widespread it was or when it would end. many have criticized public officials for how they handled or mishandled the event. however, we believe that public health officials moved quickly to disseminate information and increase the awareness of the public (potential victims) and the vigilance of healthcare providers (alert guardians). because of numerous evil documents circulated on the internet, ricin production, possession, and dissemination now fits nicely into the toolbox of every amateur bioterrorist. keeping things in perspective, ricin, in its crudest forms, is not a formidable threat, but it is deadly if delivered to the potential victim in the right way. its production, possession, and dissemination are illegal and deserving of a rapid and formidable response. persons that break these laws should be prosecuted to the fullest extent of the law. the massive evd outbreak of points out just how vulnerable underresourced countries are to hemorrhagic fever viruses. once the genie is out of the bottle, so to speak, it is hard to put him back in. lessons learned from this incident will point to the importance of global surveillance and health security. the "international community" will have to act more quickly to resource and assemble the teams of experts needed to quell the next outbreak in its early stages. once a viral hemorrhagic fever leaves a small village and moves into a large metropolitan area, public health control measures become extremely difficult, if not impossible. our hope is that evd does not remain endemic in west africa. those countries affected will take years to recover economically from the outbreak. • cluster. a grouping of health-related events that are related temporally and in proximity. typically, when clusters are recognized they are reported to public health departments in the local area. • cordon sanitaire. a french term that translates to "sanitary cord." it is used to denote an extreme use of quarantine in which public health authorities implement large-scale quarantine measures to contain the spread of disease. in this case, a small section of the city would have been under quarantine order. as one might imagine, this would be difficult to implement and enforce in a modern setting. • fomite. any inanimate object that can mechanically transmit infectious agents from one host to another. • does it seem to matter if an outbreak is derived from a natural, accidental, or intentional event? in what ways are they equivocal? in what ways are they different? • with reference to the initial response, does it matter whether an outbreak is natural, accidental, or intentional? if yes, how does it matter and to whom? if not, why not? • would automated biosensor programs increase, decrease, or have no effect on the vigilance of medical practitioners presented with unusual disease outbreaks? anthrax at sverdlovsk lessons learned from a full scale bio-terrorism exercise indian "plague" epidemic: unanswered questions and key lessons in their own words: lessons learned from those exposed to anthrax index case of fatal inhalational anthrax due to bioterrorism in the united states general system theory possible bw accident near sverdlovsk global health security: the wider lessons from the west african ebola virus disease epidemic learning from plague in india update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy investigating the zoonotic origin of the west african ebola epidemic the sverdlovsk anthrax outbreak of the biological weapons convention and the sverdlovsk anthrax outbreak of federation of american scientists public interest public health and urban development: the plague in surat indian cities after the plague-what next? intelligence on the deadliest modern outbreak. national security archive electronic briefing book no. world health organization ebola virus disease in west africa -the first months of the epidemic and forward projections key: cord- -dhfl et authors: srivastava, s.; shetty, n. title: healthcare-associated infections in neonatal units: lessons from contrasting worlds date: - - journal: j hosp infect doi: . /j.jhin. . . sha: doc_id: cord_uid: dhfl et neonatal intensive care units are vulnerable to outbreaks and sporadic incidents of healthcare-associated infections (hais). the incidence and outcome of these infections are determined by the degree of immaturity of the neonatal immune system, invasive procedures involved, the aetiological agent and its antimicrobial susceptibility pattern and, above all, infection control policies practised by the unit. it is important to raise awareness of infection control practices in resource-limited settings, since overdependence upon antimicrobial agents and co-existing lack of awareness of infection control is encouraging the emergence of multi-drug-resistant nosocomial pathogens. we reviewed articles regarding hais from both advanced and resource-limited neonatal units in order to study risk factors, aetiological agents, antimicrobial susceptibility patterns and reported successes in infection control interventions. the articles include surveillance studies, outbreaks and sporadic incidents. gram-positive cocci, viruses and fungi predominate in reports from the advanced units, while gram-negative enteric rods, non-fermenters and fungi are commonly reported from resource-limited settings. antimicrobial susceptibility patterns from surveillance studies determined the empirical therapy used in each neonatal unit. most outbreaks, irrespective of the technical facilities available, were traced to specific lack of infection control practices. we discuss infection control interventions, with special emphasis on their applicability in resource-limited settings. cost-effective measures for implementing these interventions, with particular reference to the recognition of the role of the microbiologist, the infection control team and antibiotic policies are presented. summary neonatal intensive care units are vulnerable to outbreaks and sporadic incidents of healthcare-associated infections (hais). the incidence and outcome of these infections are determined by the degree of immaturity of the neonatal immune system, invasive procedures involved, the aetiological agent and its antimicrobial susceptibility pattern and, above all, infection control policies practised by the unit. it is important to raise awareness of infection control practices in resource-limited settings, since overdependence upon antimicrobial agents and co-existing lack of awareness of infection control is encouraging the emergence of multi-drug-resistant nosocomial pathogens. we reviewed articles regarding hais from both advanced and resource-limited neonatal units in order to study risk factors, aetiological agents, antimicrobial susceptibility patterns and reported successes in infection control interventions. the articles include surveillance studies, outbreaks and sporadic incidents. gram-positive cocci, viruses and fungi predominate in reports from the advanced units, while gram-negative enteric rods, non-fermenters and fungi are commonly reported from resource-limited settings. antimicrobial susceptibility patterns from surveillance studies determined the empirical therapy used in each neonatal unit. most outbreaks, irrespective of the technical facilities available, were traced to specific lack of infection control practices. we discuss infection control interventions, with special emphasis on their applicability in resource-limited settings. cost-effective measures for implementing these interventions, with particular reference to the recognition of the role of the microbiologist, the infection control team and antibiotic policies are presented. ª the hospital infection society. published by elsevier ltd. all rights reserved. the neonatal intensive care unit is an ideal situation to incorporate good infection control policy and practice, since it lends itself not only to the spread of severe infections but also to successful interventions. a collaborative effort between neonatologists and clinical microbiologists who take on the role of infection control can successfully mount a defence against healthcare-associated infections (hais) . clinical liaison between microbiologist and clinician is well established in developed countries, whereas in the developing countries such practices are yet to be widely recognized. one reason could be that microbiology results are often delayed in less technologically advanced laboratories, thus forcing the clinician to make empirical treatment decisions without consulting or depending on the microbiologist. however, technical advancement is not a prerequisite for appropriate selection of empirical antimicrobial agents, infection control practices or formulating antibiotic policies. in an environment where resources are scarce, it only requires determination and professional cooperation for suitable interventions to work. this review on healthcare-associated neonatal infections studies the definitions, associated risk factors and the aetiological agents involved with their antimicrobial susceptibility patterns in two contrasting worlds. we discuss the microbiological and infection control intervention strategies that might help, even in resource-limited settings, to prevent the morbidity and mortality associated with hai. levels of neonatal care may be classified as shown in box . a large proportion of neonates in developing countries ( %) and in rural india ( %) are born at home, with poor facilities for safe and clean delivery by unskilled 'dais' or village health workers. , even larger hospitals with a high delivery rate do not have access to level ii neonatal care. no sick newborn care unit (scnu), government or private, is available at district level in many provinces. the equipment and infrastructure are often limited and doctors are forced to select which babies will be admitted and offered facilities such as ventilators. few state-owned centres are equipped with neonatal intensive care units (nicus) and these are scattered across the country. thus, in developing countries we are dealing with neonates with completely different demographic characteristics. whereas the minimum gestational age of live-born babies managed in a nicu in developed countries is weeks with birthweights as low as g, the average gestational age of live-born babies in developing countries is ! weeks with birthweights ! g. in a study on anthropometry and body composition of south indian babies at birth, the mean ae standard deviation (sd) birthweight of all newborns was . ae . kg. financial constraints in developing countries limit the use of technical interventions, due to which very few neonates undergo invasive medical or surgical procedures, unlike reports from developed countries. the available microbiological diagnostic facilities also vary from centre to centre. semiautomated and automated culture systems are available only in a handful of tertiary care centres. the cost of providing these services to patients is borne by the family and is often prohibitive; most clinicians treat patients empirically. microbiological results are particularly important in neonates as signs of sepsis are often non-specific. hence, while financial constraints are difficult to resolve, we still have the option to utilize cost-effective, alternative interventions such as infection control, which by reducing the incidence of infection will decrease the overall morbidity and mortality in sick neonates. successful field trials for home-based neonatal care have already been reported. we need to extend these achievements to healthcare settings. we searched for articles on the pubmed database, using the index terms 'hospital acquired infection', 'neonate', 'nosocomial infection neonate', 'neonatal care level', 'neonatal care india'. reference lists of all articles retrieved were searched to obtain literature for the review. the articles were scrutinized to obtain a comparable and standard definition of nosocomial infection in neonates, inclusion and exclusion criteria used, aetiological agents involved, antimicrobial susceptibility patterns and infection control interventions. within these search results, we reviewed articles mentioning infection control and antibiotic policies, with special reference to neonatal units in developing countries. full text articles were scrutinized for a majority of english language papers; for a small number of articles we relied only on the published abstract. for foreign language studies we were able to quote only from the abstract published in english. the foetus is exposed to a sterile environment in utero, provided no invasive procedures have been carried out on the mother, the membranes are intact until the onset of labour and there is no prolonged rupture of membranes. during the process of delivery, the neonate is exposed to several sources of microbes. these include the maternal genital tract followed by ambient air or water depending on the type of delivery, handling by healthcare personnel and the instruments used at resuscitation. rotimi and duerden studied the development of bacterial flora of neonates during the first week of life. the predominant organisms in the gut, by the end of the first week, were anaerobes. bifidobacteria were isolated from all the neonates. bacteroides and clostridia were isolated from . %. enterococci were isolated from all neonates, enterobacteria from . %, anaerobic cocci from . %. staphylococcus aureus was the predominant species isolated from the umbilicus; it was isolated from . % of neonates on the first day rising to % by the sixth day and represented % of isolates from this site. viridans streptococci ( . % of isolates) were the commonest species recovered from the mouth. they were present from h after birth. the authors also studied the development of microbial flora of preterm neonates. the numbers of infants studied were too small to draw any firm conclusions; their flora predominantly reflected the maternal genital tract. in contrast, preterm and full-term babies born by caesarean section were slow to acquire colonizing flora as compared to those born vaginally. the skin of infants born by caesarean section is sterile soon after birth compared to neonates born by vaginal delivery. bowel colonization of infants born by caesarean delivery is also delayed. colonization with bifidobacterium-like bacteria and lactobacillus-like bacteria reached levels similar to vaginally delivered infants at month and days, respectively. many hais result directly or indirectly from patient colonization; studies have shown that hospitalized patients are colonized rapidly with hospital flora. colonizing flora such as candida albicans in the gastrointestinal tract, vagina or perineal area, can precede infection when normal body defences are impaired through underlying disease, immunomodulating therapy, the use of invasive devices, or when the delicate balance of the normal flora is altered through antimicrobial therapy. however, antimicrobial therapy to eradicate colonizing micro-organisms such as pseudomonas aeruginosa is not beneficial and can propagate drug-resistant pathogens. immune status of the neonate a newborn infant, particularly the preterm infant and to some extent the low birthweight infant, does not have a mature immune system and is often unable to mount an effective immune response. natural barriers, such as the acidity of the stomach or the production of pepsin and trypsin that maintain sterility of the small intestine, are not fully developed until e weeks after birth. membrane protective iga is missing from the respiratory and urinary tracts, and unless the newborn is breast-fed, is absent from the gastrointestinal tract as well. on a cellular level, there is decreased ability of leukocytes to concentrate where necessary. these leukocytes are less bactericidal and phagocytic. at the humoral level, the newborn has low or non-existent levels of the immunoglobulin antibodies igm, ige and iga. the neonate is born with igg antibodies acquired from the mother. however, it is important to note that passive transfer of maternal antibodies does not take place till weeks of gestation. this has implications for preterm infants born e weeks of gestation; they are susceptible to infection despite the mother's antibody status. there is a slow rise of immunoglobulin levels after months of age to levels of older children. before embarking on a review of nosocomial infections, we reviewed the definitions of nosocomial infections used in various studies. at the outset, the national nosocomial infections surveillance system (nnis) of the centers for disease control and prevention (cdc), usa defines nosocomial infection as a localized or systemic condition ( ) that results from adverse reaction to the presence of an infectious agent(s) or its toxin(s) and ( ) that was not present or incubating at the time of admission to the hospital. limitations encountered during the review process in the neonate, the definition of an hai is complicated by the fact that neonates can acquire infection from the maternal genital tract during birth. for this reason, neonatal infections are often classified as early onset (usually e days after birth) and late onset (> days after birth). some authors also classify them as h after birth and > h after birth. it is interesting to note that the cdc includes infections acquired from the maternal genital tract in their surveillance of nosocomial neonatal infection. several investigators have found these criteria unsatisfactory. for the purposes of this review, we have considered only those studies that have excluded infections acquired directly from the maternal genital tract; we found that the definition of nosocomial infections varied between studies and were often related to time of acquisition. the dutch group have modified the cdc criteria to include infections occurring in the neonatal unit e h after admission. in some studies, infections which manifested after the patient was in the hospital for ! h and those infections which developed within a period of days after discharge from the hospital were considered nosocomial. e in other studies, all neonates residing for ! days in a hospital unit were included. e nosocomial transmission of candida in neonates was considered if the neonate showed negative surveillance cultures at birth and positive cultures from one week later, until death or discharge. shankar et al. also recommend using surveillance cultures to differentiate endogenous colonization from nosocomial acquisition. we believe that a consistent and universally accepted case definition of hai in the neonate is important because it offers uniformity of data across centres and facilitates a standardized measurement of outcomes. many studies that we reviewed did not have clear-cut case definitions with clearly stated inclusion and exclusion criteria; when they did, they varied from centre to centre. other common limitations were inadequate sample size, , , e or variability of denominator data wherein some authors reported number of infections per patients (attack rate) or the number of infections per patient-days (incidence density). , annual incidence per live births and per nicu discharges have also been used. absence of robust statistical analysis and the inclusion of anecdotal case reports were also limitations. , e some authors acknowledge the lack of technical equipment to report viral, fungal and parasitic causes of hais. neonates present with their own unique risk factors that predispose them to acquisition of hai. the vulnerability of the neonate, particularly the preterm neonate, is directly linked to an immature immune system. this is the single most important host-related factor that predisposes them to infection. neonatal age itself is a risk factor for hai [odds ratio (or) . ; % confidence interval (ci): . e . ; p < . ]. in another study, admission to the neonatal unit, rather than age at admission, was associated with increased risk of hai (p < . ). the overall nosocomial infection rate was positively correlated with average length of stay in high-risk nurseries (r ¼ . , p < . ). preterm gestational age (< weeks) was a risk factor in e % neonates with bacterial, viral and fungal hai. , e the percentage of neonates with low birthweight ( . e . kg) and with very low birthweight ( . e . kg) who acquired hai was . and . to . % respectively. , infection, including hai, was the most common cause of death in extremely low birthweight (< . kg) neonates and septicaemia (bacterial and fungal) was the most common presentation ( . %). , male sex was a predisposing factor for nosocomial infections (p < . ). , the male predominance in neonatal sepsis has suggested the possibility of an x-linked factor in host susceptibility. , underlying medical conditions such as chronic lung disease, gastro-oesophageal reflux, history of neonatal respiratory distress, maternal infection and congenital heart disease predisposed to hais in . e . % of neonates. e a high complexity score, which categorizes procedures by severity of illness and technical complexity, was associated with increased incidence of hai in neonates after cardiac surgery (or: . ; % ci: . e . ; p < . ). prism (pediatric risk of mortality) score of > was also related to neonatal hai (crude or: . ; % ci: . e . ; p < . ). the clinical risk index for babies (crib) score shows that nosocomial bacteraemia is independently associated with low birthweight and preterm neonates. lack of maternal antibodies was a risk factor for infection with unusual rotavirus strains. factors relating to healthcare personnel, practices and the environment are often overlooked, and yet remain the most obvious and inexpensive area of intervention. indeed, the most common route of spread of nosocomial pathogens is personto-person transmission within the unit and during transfer of patients between units. such incidents have been linked with outbreaks of bacterial and viral infection in the nicu. , e the most common iatrogenic factor contributing to neonatal hais is hands of healthcare workers. , , , e intervention in the form of simple handwashing procedures and infection control practices has prevented outbreaks, as reported in many studies. , , , e , , during the process of delivery, the neonate is exposed to several sources of microbes. medical devices such as umbilical catheters, central venous catheters, urinary catheters and endotracheal tubes are commonly used in the nicu. , , , , , central venous catheters contributed to . % of hais in one study and was a significant risk factor (p < . ) in others. , , , the nosocomial infection rate was higher in neonates subjected to device use (r ¼ . , p < . ). about . % of catheterized patients developed hospital-acquired urinary tract infection (uti). the duration of ventilation was also related to the acquisition of hai. reuse of single-use items, a common though unsound practice in many units, has led to outbreaks of hai. endotracheal tubes and mucous extraction suction catheters soaked in hibitane were associated with hai in the labour room and the special care baby unit. baby placement services, resuscitation equipment and cleansing solutions have also been implicated in hai. an environmental risk factor often overlooked is related to the seasonal variation in the incidence of neonatal hai. factors such as warm climate have been associated with a rise in colonization rates with enterobacter spp. increased humidity and increased environmental dew point at the time of use of nursery air conditioners propagates airborne dissemination of acinetobacter spp. and has been associated with acinetobacter-related bloodstream infections. bacteria in ambient air have been reported to colonize the conjunctiva in neonates. agent factors contributing to hai relate to the aetiological agents implicated in infection. infection with drug-resistant organisms plays a significant role in the outcome of hai in all patients, irrespective of their gestational age and underlying condition. hospitalization leads to colonization of the skin and gastrointestinal tract with resistant flora found in hospitals and subsequent bloodstream infection, when the skin or mucosa is abraded. studies have reported that administration of prophylactic antibiotics to neonates can increase the incidence of hai with drug-resistant pathogenic micro-organisms. about . e % of neonates presenting with hai had received prior broadspectrum antibiotics. , , clinical presentation of hais in neonates a summary of the most commonly reported neonatal hai is described in table i . , , , , , , , , , , , a review of the findings of these studies is hampered by the variation and sometimes lack of denominator data. the reader is advised to study these reports with caution, taking into consideration the limitations mentioned earlier. healthcare-associated infections in the neonatal unit cover the entire spectrum of organisms: bacterial, fungal, viral and rarely parasitic. a review of healthcare-associated bacterial (table ii) , , , , , , , , , , , e fungal (table iii) , , , , , e and viral (table iv) , , , , , , e infections is summarized in the relevant tables. fortunately parasitic nosocomial infections are rare. there have been isolated reports of babesiosis transmitted by blood transfusion in neonates. among four neonates transfused with blood from asymptomatic babesia-infected donors, two ( %) became parasitaemic, of whom only one developed symptoms of babesiosis. it is interesting to note that gram-negative fermenters (e. coli, klebsiella spp.) and nonfermenting gram-negative rods such as acinetobacter spp. and pseudomonas spp. have established themselves as predominant causes of serious neonatal infections in the indian subcontinent (table ii) . in contrast, the predominant organisms isolated from invasive neonatal infections in technologically advanced countries are gram-positive cocci (coagulase-negative staphylococci, group b streptococcus). the reason for this difference is probably multifactorial and could be due to gestational age of the babies involved, the use of invasive devices (central vascular catheters and shunts), ambient moisture, humidity and the prevalent flora in the unit. evidence supporting these risk factors has been discussed elsewhere in the review and probably merits further evaluation. of all the fungal infections reported in neonatal patients, candida spp. cause significant mortality and morbidity in the neonatal unit (table iii) and will be discussed in some detail here. although the source of c. albicans infection in the nicu is often considered to be endogenous, molecular typing studies have shown that nosocomial transmission of c. albicans is the predominant mode of acquisition. , the nosocomial acquisition of c. albicans is related to cross-contamination via the hands of healthcare workers or parents and the use of contaminated equipment. , in one study, retrograde medication syringe fluids were significantly more likely to be contaminated with candida than other fluids being administered to the infants (p < . ). candidaemia was significantly associated with total parenteral nutrition (p ¼ . ) and retrograde medication administration (p ¼ . ). central vascular catheters, steroid administration, endotracheal intubation and h -blockers have also been reported as risk factors for systemic fungal infections in neonates. , other risk factors include prematurity, low birthweight and use of broad-spectrum antibiotics. complications of candidaemia such as endocarditis and uveitis have been reported in neonates. the onset of endocarditis was related to persistant candidaemia. fungal endocarditis was present in . % neonates with persistent disease (> days of candidaemia) and . % patients with non-persistent disease (or: . ), while uveitis developed in . % patients. mortality in neonates with persistent disease was comparable to the mortality in neonates with non-persistent disease. viruses account for about % of infections in hospitalized neonates. the most common viral infections are due to enterovirus/parechovirus (table iv) . enteroviruses were responsible for the highest mortality and development of serious sequelae. respiratory syncytial virus (rsv) is the second most common virus causing infections in hospitalized neonates ( e %). , , , e respiratory viruses were diagnosed in . % of neonates on mechanical ventilators; the most frequent was rsv ( . %), followed by influenza a virus ( . %). in another study, nosocomially acquired rsv infection was present in % of neonates, . % had an underlying condition predisposing to severe disease and % died. human parainfluenza type is the most common cause of bronchiolitis and pneumonia after respiratory syncytial virus. parainfluenza type virus was isolated in six of neonates cultured (five symptomatic patients and one asymptomatic patient). eighteen of nursing personnel had been ill during the previous week, concomitantly with cough and nasal congestion. nosocomial transmission of rotavirus in neonates has been reported. , , the onset of acute diarrhoea due to rotavirus in two neonates was followed by five neonates developing gastroenteritis with the same strain of rotavirus. in another study, in % of inpatients with nosocomial gastroenteritis, the causative agent was rotavirus and % of those were premature neonates. hais and resistance to antimicrobial agents compared to community-acquired infections, hais are often caused by multi-drug-resistant pathogens. in this section we concentrate on reports from the subcontinent and other resource-poor settings. in a retrospective study of bacterial isolates from cases of neonatal septicaemia over a period of years, there was a significant rise in the incidence of drugresistant acinetobacter spp. and p. aeruginosa. the incidence rate of acinetobacter septicaemia in another study was . / live births. other studies have also documented acinetobacter spp. as emerging neonatal pathogens. , , susceptibility tests showed that acinetobacter isolates were resistant to two or more antibiotics, most notably to ampicillin ( . %), cephalexin ( . %), gentamicin ( . %) and cefotaxime ( . %). most isolates were susceptible to amikacin ( . %), ciprofloxacin ( . %) and piperacillin ( . %). only about % of bacterial aetiological agents of neonatal hai would be covered by an empirical regimen of ampicillin and gentamicin. gramnegative organisms causing hai in neonates were cause of candidaemia, endophthalmitis, endocarditis, meningitis, peritonitis. source of infection was central venous catheter. rhodotorula mucilaginosa outbreak (n ¼ ) of indwelling catheter-related septicaemia in nicu. related to birthweight, gestational age, duration of parenteral nutrition, antibiotic therapy and prophylactic fluconazole. rhizopus microsporus outbreak of cutaneous infection in preterm neonates (n ¼ ) . source traced to wooden tongue depressors used in the nursery as splints for intravenous and arterial cannulation site. the combination of warm, humid conditions in neonatal incubators, particularly in association with occlusive dressings, also favours cutaneous fungal infections. nicu, neonatal intensive care unit. a non-albicans candida spp. included c. parapsilosis, c. tropicalis, c. lusitaniae, c. glabrata, c. krusei, c. guillermondii. less susceptible to the commonly used antibiotics, such as ampicillin ( . %), amoxicillin ( . %), gentamicin ( . %), ceftazidime ( . %) and cefotaxime ( . %). these organisms were more susceptible to imipinem ( . %), amikacin ( . %), ofloxacin and ciprofloxacin ( . %). , other workers found third-generation cephalosporins and aminoglycosides such as netilmicin to be effective in the treatment of neonatal sepsis. at the same time, studies have also shown that administration of antimicrobial prophylaxis, presumed to prevent hais, can be a putative risk factor in itself for hai. , , single-centre studies have shown that probiotics containing anaerobic bacteria may reduce the rate and severity of necrotizing enterocolitis. antifungal agents fluconazole has been recommended as prophylaxis against systemic fungal infections in preterm low birthweight infants. , however, other workers have found no resurgence of fungal infection after cessation of prophylactic fluconazole use. there is also concern about emergence of resistance to fluconazole. in an investigation into the resurgence of bloodstream infections due to c. parapsilosis in one unit, after the institution of fluconazole prophylaxis, primary resistance to fluconazole was not detected. others propose a twice weekly dosing of prophylactic fluconazole to decrease candida colonization, invasive infection, cost and patient exposure in high-risk preterm infants weighing < g at birth; the lower and less frequent dosing may even delay or prevent the emergence of antifungal resistance. there are reports of c. albicans resistance to fluconazole ( . %) and amphotericin-b ( %) in studies from india. newer antifungal agents, including voriconazole and caspofungin, show promise in the treatment of potentially fatal fungal infections in neonates and additional controlled studies are indicated to evaluate their role. the existing evidence base for infection control practices specifically for the neonatal unit is described in table v . , , , , , e , , , , , , e important lessons in infection control can be learnt from published accounts of specific outbreaks. in addition to the outbreaks documented in tables iii and iv , we have selected other outbreak reports that we believe reinforce the infection control message (table vi) . , , , , , , e environmental surveillance is not routinely recommended since pathogens present in the inanimate nicu environment, e.g. floors, walls, sink-drains or furniture are not associated with , , , e nosocomially acquired infection among / neonates with rsv. infection control measures successful. rotavirus , , , , , nosocomial transmission of rotavirus in / neonates with diarrhoea. winter peak. high morbidity. among patients with nosocomial rotavirus diarrhoea, % were preterm neonates. cytomegalovirus (cmv) , transfusion-acquired cmv in / neonates. adenovirus gastroenteritis was the main clinical presentation in preterm infants. parainfluenza, type , outbreak in nicu (n ¼ ). linked to hcw. controlled by glove, gown and cohorting. herpes simplex virus, rhinovirus, rubellavirus infections reported in the nicu. influenza a virus neonates on mechanical ventilation were nosocomially infected with influenza a virus. human coronaviruses patient-to-staff and staff-to-patient transmission in nicu. universal precaution with surface disinfection and handwashing prevent spread of infection. echovirus type coxsackie b nosocomial outbreak (n ¼ ) in special care nursery. transmission by staff. nicu, neonatal intensive care unit; hcw, healthcare worker. hais. only three nicu sites, namely baby placements, resuscitation equipment and various cleansing solutions, were found to be significantly associated with hais (p < . ) in one study. the relative risk of infection was greatest if baby placement sites were colonized (odds ratio ¼ . ; p < . ). this reinforces the need for scrupulous cleaning regimens rather than adopting a policy of routine environmental surveillance. however, environmental cultures may play a role in specific outbreak situations. outbreak strains of salmonella worthington were isolated from the baby warmer mattress, baby cot, suction machine bottle and wall of the refrigerator. the role of surveillance cultures to predict the onset of nosocomial infections in neonates undergoing invasive procedures, such as exchange transfusion, has been studied. the authors found that except for staphylococci, the flora from umbilical stump and umbilical vein blood in asymptomatic neonates was similar to the flora from infected neonates. 'intensive care' need not be synonymous with 'invasive care'. in the presence of constraints such as lack of trained staff, intermittent power supply or lack of disinfection between their use, incubators and other medical devices can be a risk factor for hai. in these situations kangaroo care provided by the mother has emerged as a cost-effective and widely accepted style of caring for an infant in hospital. in a study from india, there was significant improvement among the kangaroo care group compared with the conventional group, in terms of hypothermia ( / vs / , p < . ), higher oxygen saturations ( . vs . %, p < . ) and decrease in respiratory rates ( . vs . , p < . ). however, there was no statistically significant difference in the incidence of hyperthermia, sepsis, apnoea, onset of breastfeeding and hospital stay in the two groups. further studies are needed to evaluate the role of kangaroo care and the incidence of hai in neonates. the role of microbiology in the detection, epidemiological analyses and prevention of hais cannot be overemphasized, whether the unit is one that benefits from being resource rich or resource poor. in a setting where most physicians are reluctant to use first-line agents, due to misleading or lack of sufficient susceptibility data, a qualified microbiologist is indispensable. communication between microbiologist and neonatologist helps in deciding the most probable pathogen and in initiating the most appropriate antimicrobial therapy. the formulation of a mutually agreed antibiotic policy at community, institutional and national levels is imperative. an infection control team (ict) comprising an infection control nurse or an infection control trained link nurse in the nicu, a neonatologist/ physician and a microbiologist must actively participate in outbreak management and infection control policy issues. in turn, it is mandatory that microbiologists balance their focus equally on diagnostic as well as clinical microbiology. microbiological influence and involvement can be enhanced if the microbiologist joins regular clinical ward rounds and helps to raise awareness among healthcare professionals regarding all aspects of infectious disease management. education and training is an important remit of the ict. besides training of healthcare staff we believe it is important to provide training to empower the mother. as the main carer in the family her education is vital; if she can be made aware of the rationale behind the microbiologist or neonatologist's advice, she will be in a stronger position to participate in the wellbeing of herself and the baby. even as huge efforts are underway to halt the misuse of antimicrobial agents, issues regarding antimicrobial resistance in pathogens are less important to the lay public. as long as these essential drugs are available over-the-counter in many countries, all efforts in any other part of the world toward preventing their misuse will be undermined. in addition, a number of privately funded laboratories have sprung up in several cities and towns in developing countries. they lack quality assurance and the personnel who work in identifying pathogens and reporting susceptibility are not trained adequately in quality control methods. in resource-limited settings, as in technologically advanced units, advising that we wash our hands and use the most appropriate antimicrobial agent may be more valuable than suggesting expensive tools for molecular testing. we provide a simple, resource-efficient template for the instigation and maintenance of infection control in the clinical setting (box ). in the present era of global information sharing, professionals working in the area of infection control need not feel isolated. there are several useful web tools that provide practical information and guidance; our own outbreak investigation klebsiella spp. outbreak of septic arthritis (n ¼ ) linked to contaminated cover sheets. epidemiological evidence of an association between acquiring p. aeruginosa bloodstream infection in neonates and exposure to nurses with long and artificial fingernails. short natural fingernails is a policy that is essential to reduce the incidence of hai in neonates. an outbreak of invasive s. marcescens in the nicu (n ¼ ) . molecular tests showed that a vast majority of clinical and environmental isolates (from hands of nurse, handwashes and disinfectants) belonged to the same clonal type. cohorting of non-infected neonates, isolation of colonized and infected neonates, glove use and handwashing controlled the outbreak. outbreak (n ¼ ) of s. marcescens in the nicu. epidemic strain isolated from handwashes and doors of incubators. strict handwashing, disinfection of incubators, cohorting and isolating patients controlled further transmission. acinetobacter spp. during an outbreak, isolates with similar antibiogram were recovered from intravenous catheter and washbasin. , neonatal cross-infection due to contaminated equipment resulted in sepsis and central nervous system disease. outbreak of seven cases, six fatalities. equipment and environment were the source of outbreak. outbreak was controlled through cleaning and fumigation. transmission among nursery staff. enterotoxigenic e. coli (etec) outbreak involved preterm neonates (n ¼ ); surveillance cultures of swabs from the utensils used to prepare milk feed, culture of the formula feed and all items handled by one particular cook were undertaken. the cook's hand swabs and faecal sample yielded growth of etec. the outbreak was controlled by appropriate therapy and institution of proper measures of hygiene. enterobacter spp. outbreak (n ¼ and n ¼ ) of enterobacter cloacae septicaemia traced to preceding bladder catheterization and/or parenteral nutrition solution, respectively. , policy is available free of charge at www.infectioncontrolservices.co.uk/. . ensure a strict protocol for hygienic handwashing and provision of clinical handwash basins or sinks . involve the microbiologist in the planning stages or when refurbishing the unit; advice on physical setting of the unit and general layout of cots, bays, sinks will impact on infection control . provision of side rooms and bays for the isolation of infected babies or protection of healthy neonates . provide training and advice regarding environmental cleaning; ensuring that all surfaces are maintained clean and dry . create an infection control policy document and a rational antibiotic policy that is constantly reviewed . appoint an infection control team (ict) comprising a microbiologist, neonatologist, infection control nurse/liaison nurse trained in infection control . support the ict in the management of infectious diseases and in promoting infection control practices . provide education and training of unit staff in infection control . take the lead in outbreak investigation and control . install a laboratory surveillance system for alert organisms (i.e. 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nosocomial infections in bahrami children hospital repeated prevalence surveys of paediatric hospitalacquired infection nosocomial infections among neonates in high-risk nurseries in the united states. national nosocomial infections surveillance system neonatal gram-negative bacteremia the use of palivizumab monoclonal antibody to control an outbreak of respiratory syncytial virus infection in a special care baby unit occurrence and impact of community-acquired and nosocomial rotavirus infections e a hospital-based study over epidemiological characteristics of nosocomial infection in a newborn intensive care unit (nicu), south korea pattern of neonatal septicemia in a malaysian maternity hospital trends in neonatal septicemia: emergence of non-albicans candida six year trend of neonatal septicaemia in a large malaysian maternity hospital outcome of very low birthweight neonates in a developing country: experience from a large malaysian maternity hospital causes of death in the extremely low birth weight infant evaluation of bacteriological research data and laboratory symptoms of infection in the diagnosis of congenital and acquired infections sex differences in susceptibility to infections epidemiology and clinical presentation of respiratory syncytial virus infection in a tunisian neonatal unit from risk factors for hospital-acquired infections in the neonatal intensive care unit enterobacter bacteremia in pediatric patients a hospital outbreak of extended-spectrum beta-lactamase-producing klebsiella pneumoniae investigated by rapd typing and analysis of the genetics and mechanisms of resistance the relationship between pediatric risk of mortality (prism) score and nosocomial infections in neonatal intensive care unit lack of maternal antibodies to p serotypes may predispose neonates to infections with unusual rotavirus strains use of pulsed-field gel electrophoresis to investigate an outbreak of serratia marcescens infection in a neonatal intensive care unit shigellosis occurring in newborn nursery staff prevention of nosocomial transmission of respiratory syncytial virus in a newborn nursery molecular epidemiology of gram-negative bacilli from infected neonates and health care workers' hands in neonatal intensive care units hospital-acquired infections in the neonatal intensive care unit e klebsiella pneumoniae nosocomial infections due to human coronaviruses in the newborn fingerprinting with the polymerase chain reaction: confirmation of an enterobacter cloacae epidemic in a neonatal intensive care unit nosocomial infections of ocular conjunctiva in newborns delivered by cesarian section serious fungal infections in neonates and children outbreak of acinetobacter spp. bloodstream infections in a nursery associated with contaminated aerosols and air conditioners sadler rd je. hospital-acquired urinary tract infection a -year study of bloodstream infections in an english children's hospital hospitalacquired urinary tract infections in the pediatric patient: a prospective study risk factors associated with candidaemia in the neonatal intensive care unit: a caseecontrol study role of bacteriological monitoring of the hospital environment and medical equipment in a neonatal intensive care unit association between climate and enterobacter colonization in swedish neonatal units epidemiology and diagnosis of hospital-acquired conjunctivitis among neonatal intensive care unit patients sepsis in the newborn study on antimicrobial susceptibility of bacteria causing neonatal infections: a year study ( e ) neonatal nosocomial sepsis in a level-iii nicu: evaluation of the causative agents and antimicrobial susceptibilities prospective surveillance of vancomycin-resistant enterococci in a neonatal intensive care unit neonatal group b streptococcal bacteraemia in india: ten years' experience incidence and antifungal susceptibility of candida species in neonatal septicemia duration and outcome of persistent candidaemia in newborn infants recurrent candidaemia in a neonate with hirschsprung's disease: fluconazole resistance and genetic relatedness of eight candida tropicalis isolates rhodotorula mucilaginosa outbreak in neonatal intensive care unit: microbiological features, clinical presentation, and analysis of related variables nosocomial infection with rhizopus microsporus in preterm infants: association with wooden tongue depressors clinical and epidemiologic characteristics of viral infections in a neonatal intensive care unit during a -year period nosocomial respiratory syncytial virus infection in a newborn nursery hospital-acquired viral pathogens in the neonatal intensive care unit incidence of respiratory viruses in preterm infants submitted to mechanical ventilation outbreak of respiratory syncytial virus infection in a neonatal intensive care unit neonatal rotavirus infection in belem, northern brazil: nosocomial transmission of a p[ ] g strain rotaviruses as a cause of nosocomial, infantile diarrhoea in northern brazil: pilot study morbidity from acquired cytomegalovirus infection in a neonatal intensive care unit outbreak of parainfluenza virus type in a neonatal nursery diagnosis of horizontal enterovirus infections in neonates by nested pcr and direct sequence analysis enterobacter cloacae: a predominant pathogen in neonatal septicaeima systemic fungal infections in neonates use of dna fingerprinting and biotyping methods to study a candida albicans outbreak in a neonatal intensive care unit outbreak of candida bloodstream infections associated with retrograde medication administration in a neonatal intensive care unit antimicrobial susceptibility of isolates from neonatal septicemia acinetobacter sepsis in newborns neonatal septicaemia among inborn and outborn babies in a referral hospital hospital-acquired neonatal infections in developing countries neonatal sepsis in hospitalborn babies neonatal sepsis in hospital born babies probiotics and neonatal intestinal infection fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a singlecenter, -year, retrospective cohort study effects of cessation of a policy of neonatal fluconazole prophylaxis on fungal resurgence emergence of fluconazole resistance in a candida parapsilosis strain that caused infections in a neonatal intensive care unit twice weekly fluconazole prophylaxis for prevention of invasive candida infection in high-risk infants of < grams birth weight neonatal cutaneous fungal infections varicella exposure in a neonatal intensive care unit: case report andcontrol measures a prolonged outbreak of pseudomonas aeruginosa in a neonatal intensive care unit: did staff fingernails play a role in disease transmission? outbreak of salmonella worthington meningitis & septicaemia in a hospital at chandigarh (north india) listeriosis e a review of eighty-four cases the bacterial flora of neonates in intensive care-monitoring and manipulation computerized detection of nosocomial infections in newborns neonatal sepsis: the antibiotic crisis molecular epidemiology of an outbreak of serratia marcescens in a neonatal intensive care unit outbreak of acinetobacter spp septicemia in a neonatal icu neonatal crossinfection with listeria monocytogenes nosocomial outbreak of diarrhoea by enterotoxigenic escherichia coli among preterm neonates in a tertiary care hospital in india: pitfalls in healthcare risk factors for enterobacter septicemia in a neonatal unit: caseecontrol study enterobacter cloacae sepsis outbreak in a newborn unit caused by contaminated total parenteral nutrition solution feasibility of kangaroo mother care in mumbai key: cord- -k imddzr authors: siegel, jane d.; rhinehart, emily; jackson, marguerite; chiarello, linda title: guideline for isolation precautions: preventing transmission of infectious agents in health care settings date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: k imddzr nan . clinical syndromes or conditions warranting additional empiric transmission-based precautions pending confirmation of diagnosis table . infection control considerations for highpriority (cdc category a) diseases that may result from bioterrorist attacks or are considered bioterrorist threats table . recommendations for application of standard precautions for the care of all patients in all health care settings table . components of a protective environment . the transition of health care delivery from primarily acute care hospitals to other health care settings (eg, home care, ambulatory care, freestanding specialty care sites, long-term care) created a need for recommendations that can be applied in all health care settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. accordingly, the revised guideline addresses the spectrum of health care delivery settings. furthermore, the term ''nosocomial infections'' is replaced by ''health care-associated infections'' (hais), to reflect the changing patterns in health care delivery and difficulty in determining the geographic site of exposure to an infectious agent and/ or acquisition of infection. . the emergence of new pathogens (eg, severe acute respiratory syndrome coronavirus [sars-cov] associated with sars avian influenza in humans), renewed concern for evolving known pathogens (eg, clostridium difficile, noroviruses, communityassociated methicillin-resistant staphylococcus aureus [ca-mrsa]), development of new therapies (eg, gene therapy), and increasing concern for the threat of bioweapons attacks, necessitates addressing a broader scope of issues than in previous isolation guidelines. . the successful experience with standard precautions, first recommended in the guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all health care settings. new additions to the recommendations for standard precautions are respiratory hygiene/cough etiquette and safe injection practices, including the use of a mask when performing certain highrisk, prolonged procedures involving spinal canal punctures (eg, myelography, epidural anesthesia). the need for a recommendation for respiratory hygiene/cough etiquette grew out of observations during the sars outbreaks, when failure to implement simple source control measures with patients, visitors, and health care workers (hcws) with respiratory symptoms may have contributed to sars-cov transmission. the recommended practices have a strong evidence base. the continued occurrence of outbreaks of hepatitis b and hepatitis c viruses in ambulatory settings indicated a need to reiterate safe injection practice recommendations as part of standard precautions. the addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. . the accumulated evidence that environmental controls decrease the risk of life-threatening fungal infections in the most severely immunocompromised patients (ie, those undergoing allogeneic hematopoietic stem cell transplantation [hsct] ) led to the update on the components of the protective environment (pe). . evidence that organizational characteristics (eg, nurse staffing levels and composition, establishment of a safety culture) influence hcws' adherence to recommended infection control practices, and thus are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. . continued increase in the incidence of hais caused by multidrug-resistant organisms (mdros) in all health care settings and the expanded body of knowledge concerning prevention of transmission of mdros created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of health care settings. this document is intended for use by infection control staff, health care epidemiologists, health care administrators, nurses, other health care providers, and persons responsible for developing, implementing, and evaluating infection control programs for health care settings across the continuum of care. the reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems. part i reviews the relevant scientific literature that supports the recommended prevention and control practices. as in the guideline, the modes and factors that influence transmission risks are described in detail. new to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. this became a concern during the sars outbreaks of , when transmission associated with aerosol-generating procedures was observed. also new is a definition of ''epidemiologically important organisms'' that was developed to assist in the identification of clusters of infections that require investigation (ie multidrug-resistant organisms, c difficile). several other pathogens of special infection control interest (ie, norovirus, sars, centers for disease control and prevention [cdc] category a bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed, to present new information and infection control lessons learned from experience with these agents. this section of the guideline also presents information on infection risks associated with specific health care settings and patient populations. part ii updates information on the basic principles of hand hygiene, barrier precautions, safe work practices, and isolation practices that were included in previous guidelines. however, new to this guideline is important information on health care system components that influence transmission risks, including those components under the influence of health care administrators. an important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the complex modern health care system. evidence presented also demonstrates another administrative concern: the importance of nurse staffing levels, including ensuring numbers of appropriately trained nurses in intensive care units (icus) for preventing hais. the role of the clinical microbiology laboratory in supporting infection control is described, to emphasize the need for this service in health care facilities. other factors that influence transmission risks are discussed, including the adherence of hcws to recommended infection control practices, organizational safety culture or climate, and education and training. discussed for the first time in an isolation guideline is surveillance of health care-associated infections. the information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of hai rates. part iii describes each of the categories of precautions developed by the health care infection control practices advisory committee (hicpac) and the cdc and provides guidance for their application in various health care settings. the categories of transmission-based precautions are unchanged from those in the guideline: contact, droplet, and airborne. one important change is the recommendation to don the indicated personal protective equipment (ppe-gowns, gloves, mask) on entry into the patient's room for patients who are on contact and/or droplet precautions, because the nature of the interaction with the patient cannot be predicted with certainty, and contaminated environmental surfaces are important sources for transmission of pathogens. in addition, the pe for patients undergoing allogeneic hsct, described in previous guidelines, has been updated. five tables summarize important information. table provides a summary of the evolution of this document. table gives guidance on using empiric isolation precautions according to a clinical syndrome. table summarizes infection control recommendations for cdc category a agents of bioterrorism. table lists the components of standard precautions and recommendations for their application, and table lists components of the pe. a glossary of definitions used in this guideline also is provided. new to this edition of the guideline is a figure showing the recommended sequence for donning and removing ppe used for isolation precautions to optimize safety and prevent self-contamination during removal. appendix a provides an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. a preamble to the appendix provides a rationale for recommending the use of or more transmission-based precautions in addition to standard precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in health care settings. the type and duration of recommended precautions are presented, with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. relevant citations are included. new to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of mdros. this portion of the guideline was published electronically in october and updated in november (siegel jd, rhinehart e, jackson m, chiarello l and hicpac. management of multidrug-resistant organisms in health care settings, ; available from http://www.cdc.gov/ ncidod/dhqp/pdf/ar/mdroguideline .pdf), and is considered a part of the guideline for isolation precautions. this section provides a detailed review of the complex topic of mdro control in health care settings and is intended to provide a context for evaluation of mdro at individual health care settings. a rationale and institutional requirements for developing an effective mdro control program are summarized. although the focus of this guideline is on measures to prevent transmission of mdros in health care settings, information concerning the judicious use of antimicrobial agents also is presented, because such practices are intricately related to the size of the reservoir of mdros, which in turn influences transmission (eg, colonization pressure). two tables summarize recommended prevention and control practices using categories of interventions to control mdros: administrative measures, education of hcws, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. recommendations for each category apply to and are adapted for the various health care settings. with the increasing incidence and prevalence of mdros, all health care facilities must prioritize effective control of mdro transmission. facilities should identify prevalent mdros at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing mdro rates. a set of intensified mdro prevention interventions is to be added if the incidence of transmission of a target mdro is not decreasing despite implementation of basic mdro infection control measures, and when the first case of an epidemiologically important mdro is identified within a health care facility. this updated guideline responds to changes in health care delivery and addresses new concerns about transmission of infectious agents to patients and hcws in the united states and infection control. the primary objective of the guideline is to improve the safety of the nation's health care delivery system by reducing the rates of hais. instruct symptomatic persons to cover mouth/nose when sneezing/ coughing; use tissues and dispose in no-touch receptacle; observe hand hygiene after soiling of hands with respiratory secretions; wear surgical mask if tolerated or maintain spatial separation, . feet if possible. *during aerosol-generating procedures on patients with suspected or proven infections transmitted by respiratory aerosols (eg, severe acute respiratory syndrome), wear a fittested n or higher respirator in addition to gloves, gown, and face/eye protection. -proper construction of windows, doors, and intake and exhaust ports -ceilings: smooth, free of fissures, open joints, crevices -walls sealed above and below the ceiling -if leakage detected, locate source and make necessary repairs d ventilation to maintain $ air changes/hour d directed air flow; air supply and exhaust grills located so that clean, filtered air enters from one side of the room, flows across the patient's bed, and exits on opposite side of the room d positive room air pressure in relation to the corridor; pressure differential of . . pa ( . -inch water gauge) d air flow patterns monitored and recorded daily using visual methods (eg, flutter strips, smoke tubes) or a hand-held pressure gauge d self-closing door on all room exits d back-up ventilation equipment (eg, portable units for fans or filters) maintained for emergency provision of ventilation requirements for pe areas, with immediate steps taken to restore the fixed ventilation system d for patients who require both a pe and an airborne infection isolation room (aiir), use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside, or place a hepa filter in the exhaust duct. ( ) reaffirm standard precautions as the foundation for preventing transmission during patient care in all health care settings; ( ) reaffirm the importance of implementing transmission-based precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined ( table ) ; and ( ) provide epidemiologically sound and, whenever possible, evidence-based recommendations. this guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other health care settings. the information also will be useful for other hcws, health care administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. commonly used abbreviations are provided, and terms used in the guideline are defined in the glossary. medline and pubmed were used to search for relevant studies published in english, focusing on those published since . much of the evidence cited for preventing transmission of infectious agents in health care settings is derived from studies that used ''quasiexperimental designs,'' also referred to as nonrandomized preintervention and postintervention study designs. although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. these include: difficulties in controlling for important confounding variables, the use of multiple interventions during an outbreak, and results that are explained by the statistical principle of regression to the mean (eg, improvement over time without any intervention). observational studies remain relevant and have been used to evaluate infection control interventions. , the quality of studies, consistency of results, and correlation with results from randomized controlled trials, when available, were considered during the literature review and assignment of evidencebased categories (see part iv: recommendations) to the recommendations in this guideline. several authors have summarized properties to consider when evaluating studies for the purpose of determining whether the results should change practice or in designing new studies. , , this guideline contains changes in terminology from the guideline: . the term ''nosocomial infection'' is retained to refer only to infections acquired in hospitals. the term ''health care-associated infection'' (hai) is used to refer to infections associated with health care delivery in any setting (eg, hospitals, long-term care facilities, ambulatory settings, home care). this term reflects the inability to determine with certainty where the pathogen was acquired, because patients may be colonized with or exposed to potential pathogens outside of the health care setting before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of health care. in addition, patients frequently move among the various settings within the health care system. of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. this section describes the interrelationship of these elements in the epidemiology of hais. i.b. . sources of infectious agents. infectious agents transmitted during health care derive primarily from human sources but inanimate environmental sources also are implicated in transmission. human reservoirs include patients, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] hcws, , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and household members and other visitors. [ ] [ ] [ ] [ ] [ ] [ ] such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. other sources of hais are the endogenous flora of patients (eg, bacteria residing in the respiratory or gastrointestinal tract). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] i.b. . susceptible hosts. infection is the result of a complex interrelationship between a potential host and an infectious agent. most of the factors that influence infection and the occurrence and severity of disease are related to the host. however, characteristics of the host-agent interaction as it relates to pathogenicity, virulence, and antigenicity also are important, as are the infectious dose, mechanisms of disease production, and route of exposure. there is a spectrum of possible outcomes after exposure to an infectious agent. some persons exposed to pathogenic microorganisms never develop symptomatic disease, whereas others become severely ill and even die. some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. still others progress from colonization to symptomatic disease either immediately after exposure or after a period of asymptomatic colonization. the immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individual's outcome. host factors such as extremes of age and underlying disease (eg, diabetes , , human immunodeficiency virus/acquired immune deficiency syndrome [hiv/ aids], , malignancy, and transplantation , , ) can increase susceptibility to infection, as can various medications that alter the normal flora (eg, antimicrobial agents, gastric acid suppressors, corticosteroids, antirejection drugs, antineoplastic agents, immunosuppressive drugs). surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. indwelling devices, such as urinary catheters, endotracheal tubes, central venous and arterial catheters, [ ] [ ] [ ] and synthetic implants, facilitate development of hais by allowing potential pathogens to bypass local defenses that ordinarily would impede their invasion and by providing surfaces for development of biofilms that may facilitate adherence of microorganisms and protect from antimicrobial activity. some infections associated with invasive procedures result from transmission within the health care facility; others arise from the patient's endogenous flora. clothing, uniforms, laboratory coats, or isolation gowns used as ppe may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (eg, mrsa, vancomycin-resistant enterococci [vre], and c difficile ). although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients. i.b. .b. droplet transmission. droplet transmission is technically a form of contact transmission; some infectious agents transmitted by the droplet route also may be transmitted by direct and indirect contact routes. however, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. respiratory droplets are generated when an infected person coughs, sneezes, or talks , or during such procedures as suctioning, endotracheal intubation, [ ] [ ] [ ] [ ] cough induction by chest physiotherapy, and cardiopulmonary resuscitation. , evidence for droplet transmission comes from epidemiologic studies of disease outbreaks, [ ] [ ] [ ] [ ] from experimental studies, and from information on aerosol dynamics. , studies have shown that the nasal mucosa, conjunctivae, and, less frequently, the mouth are susceptible portals of entry for respiratory viruses. the maximum distance for droplet transmission is currently unresolved; pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. historically, the area of defined risk has been a distance of , feet around the patient, based on epidemiologic and simulated studies of selected infections. , using this distance for donning masks has been effective in preventing transmission of infectious agents through the droplet route. however, experimental studies with smallpox , and investigations during the global sars outbreaks of suggest that droplets from patients with these infections could reach persons located feet or more from their source. it is likely that the distance that droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors (eg, temperature, humidity), and the pathogen's ability to maintain infectivity over that distance. thus, a distance of , feet around the patient is best considered an example of what is meant by ''a short distance from a patient'' and should not be used as the sole criterion for determining when a mask should be donned to protect from droplet exposure. based on these considerations, it may be prudent to don a mask when within to feet of the patient or on entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. more studies are needed to gain more insight into droplet transmission under various circumstances. droplet size is another variable under investigation. droplets traditionally have been defined as being . mm in size. droplet nuclei (ie, particles arising from desiccation of suspended droplets) have been associated with airborne transmission and defined as , mm in size, a reflection of the pathogenesis of pulmonary tuberculosis that is not generalizeable to other organisms. observations of particle dynamics have demonstrated that a range of droplet sizes, including those of diameter $ mm, can remain suspended in the air. the behavior of droplets and droplet nuclei affect recommendations for preventing transmission. whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring aiir to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances and thus do not require special air handling and ventilation. examples of infectious agents transmitted through the droplet route include b pertussis, influenza virus, adenovirus, rhinovirus, mycoplasma pneumoniae, sars-cov, , , group a streptococcus, and neisseria meningitides. , , although rsv may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to standard precautions plus contact precautions prevents transmission in health care settings. , , rarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. for example, although s aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of s aureus from the nose into the air for a distance of feet under both outbreak and experimental conditions; this is known as the ''cloud baby'' and ''cloud adult'' phenomenon. [ ] [ ] [ ] i.b. .c. airborne transmission. airborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (eg, spores of aspergillus spp and m tuberculosis). microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or even been in the same room with) the infectious individual. [ ] [ ] [ ] [ ] preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (eg, aiirs) to contain and then safely remove the infectious agent. , infectious agents to which this applies include m tuberculosis, - rubeola virus (measles), and varicella-zoster virus (chickenpox). in addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances, and aiirs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox. , , in addition to aiirs, respiratory protection with a national institute for occupational safety and health (niosh)-certified n or higher-level respirator is recommended for hcws entering the aiir, to prevent acquisition of airborne infectious agents such as m tuberculosis. for certain other respiratory infectious agents, such as influenza , and rhinovirus, and even some gastrointestinal viruses (eg, norovirus and rotavirus ) , there is some evidence that the pathogen may be transmitted through small-particle aerosols under natural and experimental conditions. such transmission has occurred over distances . feet but within a defined air space (eg, patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. aiirs are not routinely required to prevent transmission of these agents. additional issues concerning small-particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below. although sars-cov is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (eg, within a room) has been suggested, although not proven. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] this is true of other infectious agents as well, such as influenza virus and noroviruses. , , influenza viruses are transmitted primarily by close contact with respiratory droplets, , and acquisition by hcws has been prevented by droplet precautions, even when positive-pressure rooms were used in one center. however, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of an aircraft. observations of a protective effect of ultraviolet light in preventing influenza among patients with tuberculosis during the influenza pandemic of - have been used to suggest airborne transmission. , in contrast to the strict interpretation of an airborne route for transmission (ie, long distances beyond the patient room environment), short-distance transmission by small-particle aerosols generated under specific circumstances (eg, during endotracheal intubation) to persons in the immediate area near the patient also has been demonstrated. aerosolized particles , mm in diameter can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles. sars-cov transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardiopulmonary resuscitation. , , , , although the most frequent routes of transmission of noroviruses are contact and foodborne and waterborne routes, several reports suggest that noroviruses also may be transmitted through aerosolization of infectious particles from vomitus or fecal material. , , , it is hypothesized that the aerosolized particles are inhaled and subsequently swallowed. roy this conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (eg, smallpox, sars, influenza, noroviruses). concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in the adoption of overextreme prevention strategies, and recommended precautions may change as the epidemiology of an emerging infection becomes more well defined and controversial issues are resolved. i.b. .d.ii. transmission from the environment. some airborne infectious agents are derived from the environment and do not usually involve person-to-person transmission; for example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract. , spores of environmental fungi (eg, aspergillus spp) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized spores (through, eg, construction dust). , as a rule, neither of these organisms is subsequently transmitted from infected patients; however, there is well-documented report of person-to-person transmission of aspergillus sp in the icu setting that was most likely due to the aerosolization of spores during wound debridement. the pe involves isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic hsct patients. , , , [ ] [ ] [ ] [ ] environmental sources of respiratory pathogens (eg, legionella) transmitted to humans through a common aerosol source is distinct from direct patient-to-patient transmission. i.b. .e. other sources of infection. sources of infection transmission other than infectious individuals include those associated with common environmental sources or vehicles (eg, contaminated food, water, or medications, such as intravenous fluids). although aspergillus spp have been recovered from hospital water systems, the role of water as a reservoir for immunosuppressed patients remains unclear. vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in health care settings. prevention of vectorborne transmission is not addressed in this document. this section discusses several infectious agents with important infection control implications that either were not discussed extensively in previous isolation s vol. no. supplement guidelines or have emerged only recently. included are epidemiologically important organisms (eg, c difficile), agents of bioterrorism, prions, sars-cov, monkeypox, noroviruses, and the hemorrhagic fever viruses (hfvs). experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. these agents are included for information purposes and, for some (ie, sars-cov, monkeypox), to highlight the lessons that have been learned about preparedness planning and responding effectively to new infectious agents. i.c. . epidemiologically important organisms. under defined conditions, any infectious agent transmitted in a health care setting may become targeted for control because it is epidemiologically important. c difficile is specifically discussed below because of its current prevalence and seriousness in us health care facilities. in determining what constitutes an ''epidemiologically important organism,'' the following criteria apply: d a propensity for transmission within health care facilities based on published reports and the occurrence of temporal or geographic clusters of more than patients, (eg, c difficile, norovirus, rsv, influenza, rotavirus, enterobacter spp, serratia spp, group a streptococcus). a single case of health care-associated invasive disease caused by certain pathogens (eg, group a streptococcus postoperatively, in a burn unit, or in a ltcf; legionella spp, , aspergillus spp ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and the severity of illness associated with these infections. i.c. .a. clostridium difficile. c difficile is a sporeforming gram-positive anaerobic bacillus that was first isolated from stools of neonates in and identified as the most frequent causative agent of antibioticassociated diarrhea and pseudomembranous colitis in . this pathogen is a major cause of health care-associated diarrhea and has been responsible for many large outbreaks in health care settings that have proven extremely difficult to control. important factors contributing to health care-associated outbreaks include environmental contamination, persistence of spores for prolonged periods, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by hcws to other patients, and exposure of patients to frequent courses of antimicrobial agents. antimicrobials most frequently associated with increased risk of c difficile include third-generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones. since , outbreaks and sporadic cases of c difficile with increased morbidity and mortality have occurred in several us states, canada, england, and the netherlands. [ ] [ ] [ ] [ ] [ ] the same strain of c difficile has been implicated in all of these outbreaks; this strain, toxinotype iii, north american pulsedfield gel electrophoresis (pfge) type , and polymerase chain reaction (pcr)-ribotype (nap / ), has been found to hyperproduce toxin a (a -fold increase) and toxin b (a -fold increase) compared with isolates from other pfge types. a recent survey of us infectious disease physicians found that % of the respondents perceived recent increases in the incidence and severity of c difficile disease. standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals. it is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins a and b, increasing the severity of diarrhea and producing more environmental contamination. considering the greater morbidity, mortality, length of stay, and costs associated with c difficile disease in both acute care and long-term care facilities, control of this pathogen is becoming increasingly important. prevention of transmission focuses on syndromic application of contact precautions for patients with diarrhea, accurate identification of affected patients, environmental measures (eg, rigorous cleaning of patient rooms), and consistent hand hygiene. using soap and water rather than alcohol-based handrubs for mechanical removal of spores from hands and using a bleachcontaining disinfectant ( ppm) for environmental disinfection may be valuable in cases of transmission in health care facilities. appendix a provides for recommendations. i.c. .b. multidrug-resistant organisms. in general, mdros are defined as microorganisms-predominantly bacteria-that are resistant to or more classes of antimicrobial agents. although the names of certain mdros suggest resistance to only a single agent (eg, mrsa, vre), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. this latter feature defines mdros that are considered to be epidemiologically important and deserve special attention in health care facilities. other mdros of current concern include multidrug-resistant streptococcus pneumoniae, which is resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones, multidrug-resistant gram-negative bacilli (mdr-gnb), especially those producing esbls; and strains of s aureus that are intermediate or resistant to vancomycin (ie, visa and vrsa). mdros are transmitted by the same routes as antimicrobial susceptible infectious agents. patient-to-patient transmission in health care settings, usually via hands of hcws, has been a major factor accounting for the increase in mdro incidence and prevalence, especially for mrsa and vre in acute care facilities. [ ] [ ] [ ] preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (eg, nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other hcws, judicious antibiotic use, comprehensive surveillance for targeted mdros, application of infection control precautions during patient care, environmental measures (eg, cleaning and disinfection of the patient care environment and equipment, dedicated single-patient use of noncritical equipment), and decolonization therapy when appropriate. the prevention and control of mdros is a national priority, one that requires that all health care facilities and agencies assume responsibility and participate in community-wide control programs. , a detailed discussion of this topic and recommendations for prevention published in is available at http:// www.cdc.gov/ncidod/dhqp/pdf/ar/mdroguideline . pdf. i.c. . agents of bioterrorism. the cdc has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as category a (high priority), because these agents can be easily disseminated environmentally and/or transmitted from person to person, can cause high mortality and have the potential for major public health impact, might cause public panic and social disruption, and necessitate special action for public health preparedness. general information relevant to infection control in health care settings for category a agents of bioterrorism is summarized in table . (see http:// www.bt.cdc.gov for additional, updated category a agent information as well as information concerning category b and c agents of bioterrorism and updates.) category b and c agents are important but are not as readily disseminated and cause less morbidity and mortality than category a agents. health care facilities confront a different set of issues when dealing with a suspected bioterrorism event compared with other communicable diseases. an understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that specify an approach and relevant websites and other resources for disease-specific guidance to health care, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. infection control issues to be addressed include ( ) identifying persons who may be exposed or infected; ( ) preventing transmission among patients, hcws, and visitors; ( ) providing treatment, chemoprophylaxis, or vaccine to potentially large numbers of people; ( ) protecting the environment, including the logistical aspects of securing sufficient numbers of aiirs or designating areas for patient cohorts when an insufficient number of aiirs is available; ( ) providing adequate quantities of appropriate ppe; and ( ) identifying appropriate staff to care for potentially infectious patients (eg, vaccinated hcws for care of patients with smallpox). the response is likely to differ for exposures resulting from an intentional release compared with a naturally occurring disease because of the large number of persons that can be exposed at the same time and possible differences in pathogenicity. various sources offer guidance for the management of persons exposed to the most likely agents of bioterrorism. federal agency websites (eg, http://www. usamriid.army.mil/publications/index.html and http:// www.bt.cdc.gov) and state and county health department websites should be consulted for the most upto-date information. sources of information on specific agents include anthrax, smallpox, [ ] [ ] [ ] plague, , botulinum toxin, tularemia, and hemorrhagic fever viruses. , i.c. .a. pre-event administration of smallpox (vaccinia) vaccine to health care workers. vaccination of hcwsl in preparation for a possible smallpox exposure has important infection control implications. [ ] [ ] [ ] these include the need for meticulous screening for vaccine contraindications in persons at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the health care setting and at home; and management of patients with vaccinia-related adverse events. , the pre-event us smallpox vaccination program of is an example of the effectiveness of carefully developed recommendations for both screening potential vaccinees for contraindications and vaccination site care and monitoring. between december and february , approximately , individuals were vaccinated in the department of defense and , in the civilian or public health populations, including approximately , who worked in health care settings. no cases of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or contact transfer of vaccinia were reported in health care settings or in military workplaces. , outside the health care setting, there were cases of contact transfer from military vaccinees to close personal contacts (eg, bed partners or contacts during participation in sports such as wrestling ). all contact transfers were from individuals who were not following recommendations to cover their vaccination sites. vaccinia virus was confirmed by culture or pcr in cases, of which resulted from tertiary transfer. all recipients, including breast-fed infant, recovered without complications. subsequent studies using viral culture and pcr techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia. [ ] [ ] [ ] [ ] this experience emphasizes the importance of ensuring that newly vaccinated hcws adhere to recommended vaccination site care, especially those caring for high-risk patients. recommendations for pre-event smallpox vaccination of hcws and vacciniarelated infection control recommendations are published in the morbidity and mortality weekly report, , with updates posted on the cdc's bioterrorism website. i.c. . prions. creutzfeldt-jakob disease (cjd) is a rapidly progressive, degenerative neurologic disorder of humans, with an incidence in the united states of approximately person/million population/year. , cjd is believed to be caused by a transmissible proteinaceous infectious agent known as a prion. infectious prions are isoforms of a host-encoded glycoprotein known as the prion protein. the incubation period (ie, time between exposure and and onset of symptoms) varies from years to many decades. however, death typically occurs within year of the onset of symptoms. approximately % of cjd cases occur sporadically with no known environmental source of infection, and % of cases are familial. iatrogenic transmission has occurred, with most cases resulting from treatment with human cadaver pituitary-derived growth hormone or gonadotropin, , from implantation of contaminated human dura mater grafts, or from corneal transplants. transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes. [ ] [ ] [ ] [ ] prion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (bse, or ''mad cow disease'') in cattle, and chronic wasting disease in deer and elk. bse, first recognized in the united kingdom in , was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal. the possible transmission of bse to humans causing variant cjd (vcjd) was first described in and was subsequently found to be associated with consumption of bse-contaminated cattle products primarily in the united kingdom. there is strong epidemiologic and laboratory evidence for a causal association between the causative agent of bse and vcjd. although most cases of vcjd have been reported from the united kingdom, a few cases also have been reported from europe, japan, canada, and the united states. most persons affected with vcjd worldwide lived in or visited the united kingdom during the years of a large outbreak of bse ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) and may have consumed contaminated cattle products during that time (see http://www.cdc.gov/ncidod/ diseases/cjd/cjd.htm). although there has been no indigenously acquired vcjd in the united states, the sporadic occurrence of bse in cattle in north america has heightened awareness of the possibility that such infections could occur and have led to increased surveillance activities. updated information may be found at http://www.cdc.gov/ncidod/diseases/cjd/cjd.htm. the public health impact of prion diseases has been reviewed previously. vcjd in humans has different clinical and pathologic characteristics than sporadic or classic cjd, including ( ) younger median age at death ( [range, to ] vs years), ( ) longer median duration of illness ( months vs to months), ( ) increased frequency of sensory symptoms and early psychiatric symptoms with delayed onset of frank neurologic signs; and ( ) detection of prions in tonsillar and other lymphoid tissues, not present in sporadic cjd. similar to sporadic cjd, there have been no reported cases of direct human-tohuman transmission of vcjd by casual or environmental contact, droplet, or airborne routes. ongoing blood safety surveillance in the united states has not detected sporadic cjd transmission through blood transfusion; - however, bloodborne transmission of vcjd is believed to have occurred in patients in the uited kingdom. , the following fda websites provide information on steps currently being taken in the united states to protect the blood supply from cjd and vcjd: http://www.fda.gov/cber/gdlns/cjdvcjd.htm and http:// www.fda.gov/cber/gdlns/cjdvcjdq&a.htm. standard precautions are used when caring for patients with suspected or confirmed cjd or vcjd. however, special precautions are recommended for tissue handling in the histology laboratory and for conducting an autopsy, embalming, and coming into contact with a body that has undergone autopsy. recommendations for reprocessing surgical instruments to prevent transmission of cjd in health care settings have been published by the world health organization (who) and are currently under review at the cdc. questions may arise concerning notification of patients potentially exposed to cjd or vcjd through contaminated instruments and blood products from patients with cjd or vcjd or at risk of having vcjd. the risk of transmission associated with such exposures is believed to be extremely low but may vary based on the specific circumstance. therefore, consultation on appropriate options is advised. the united kingdom has developed several documents that clinicians and patients in the united states may find useful (see http://www.hpa.org.uk/infections/topics_az/cjd/ information_documents.htm). i.c. . severe acute respiratory syndrome. sars is a newly discovered respiratory disease that emerged in china late in and spread to several countries. , in particular, mainland china, hong kong, hanoi, singapore, and toronto have been significantly affected. sars is caused by sars-cov, a previously unrecognized member of the coronavirus family. , the incubation period from exposure to the onset of symptoms is typically to days, but can be as long as days and in rare cases even longer. the illness is initially difficult to distinguish from other common respiratory infections. signs and symptoms usually include fever above . c and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. a radiographic profile of atypical pneumonia is an important clinical indicator of possible sars. compared with adults, children are affected less frequently, have milder disease, and are less likely to transmit sars-cov. , [ ] [ ] [ ] the overall case fatality rate is approximately %; underlying disease and advanced age increase the risk of mortality (see http://www.who.int/csr/sarsarchive/ _ _ a/en/). outbreaks in health care settings, with transmission to large numbers of hcws and patients, haa been a striking feature of sars; undiagnosed infectious patients and visitors have been important initiators of these outbreaks. , [ ] [ ] [ ] the relative contribution of potential modes of transmission is not known precisely. there is ample evidence for droplet and contact transmission; , , however, opportunistic airborne transmission cannot be excluded. , [ ] [ ] [ ] [ ] [ ] , for example, exposure to aerosol-generating procedures (eg, endotracheal intubation, suctioning) has been associated with transmission of infection to large numbers of hcws outside of the united states. , , , , therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multibed room or shared airspace. a review of the infection control literature generated from the sars outbreaks of concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, and do not consistently use ppe, and that n or higher-level respirators may offer additional protection to those exposed to aerosol-generating procedures and high-risk activities. , organizational and individual factors that affect adherence to infection control practices for sars also were identified. control of sars requires a coordinated, dynamic response by multiple disciplines in a health care setting. early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with sars patients, followed by implementation of respiratory hygiene/cough etiquette (ie, placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas. the precise combination of precautions to protect hcws has not yet been determined. at the time of this publication, the cdc recommends standard precautions, with emphasis on the use of hand hygiene; contact precautions, with emphasis on environmental cleaning due to the detection of sars-cov rna by pcr on surfaces in rooms occupied by sars patients; , , and airborne precautions, including use of fit-tested niosh-approved n or higher-level respirators and eye protection. in hong kong, the use of droplet and contact precautions, including the use of a mask but not a respirator, was effective in protecting hcws. however, in toronto, consistent use of an n respirator was found to be slightly more protective than a mask. it is noteworthy that no transmission of sars-cov to public hospital workers occurred in vietnam despite inconsistent use of infection control measures, including use of ppe, which suggests other factors (eg, severity of disease, frequency of high-risk procedures or events, environmental features) may influence opportunities for transmission. sars-cov also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. research laboratories in which sars-cov was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of . lessons learned from the sars outbreaks are useful in devising plans to respond to future public health crises, such as pandemic influenza and bioterrorism events. surveillance for cases among patients and hcws, ensuring availability of adequate supplies and staffing, and limiting access to health care facilities were important factors in the response to sars. guidance for infection control precautions in various settings is available at http://www.cdc.gov/ncidod/sars. i.c. . monkeypox. monkeypox is a rare viral disease found mostly in the rain forest countries of central and west africa. the disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. the only recognized outbreak of human monkeypox in the united states was detected in june , after several people became ill after contact with sick pet prairie dogs. infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from africa, including giant gambian rats. this outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology, as well as the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure. only limited data on transmission of monkeypox are available. transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (eg, during administration of nebulized medications to ill prairie dogs ). in humans, instances of monkeypox transmission in hospitals have been reported in africa among children, usually related to sharing the same ward or bed. , additional recent literature documents transmission of congo basin monkeypox in a hospital compound for an extended number of generations. there has been no evidence of airborne or any other person-to-person transmission of monkeypox in the united states, and no new cases of monkeypox have been identified since the outbreak in june . the outbreak strain is a clade of monkeypox distinct from the congo basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the congo basin; this awaits further study. smallpox vaccine is % protective against congo basin monkeypox. because there is an associated case fatality rate of , %, administration of smallpox vaccine within days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable policy. for the most current information on monkeypox, see http://www.cdc.gov/ncidod/mon keypox/clinicians.htm. i.c. . noroviruses. noroviruses, formerly referred to as norwalk-like viruses, are members of the caliciviridae family. these agents are transmitted via contaminated food or water and from person to person, causing explosive outbreaks of gastrointestinal disease. environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks. , although noroviruses cannot be propagated in cell culture, dna detection by molecular diagnostic techniques has brought a greater appreciation of their role in outbreaks of gastrointestinal disease. reported outbreaks in hospitals, and large crowded shelters established for hurricane evacuees has demonstrated their highly contagious nature, their potentially disruptive impact in health care facilities and the community, and the difficulty of controlling outbreaks in settings in which people share common facilites and space. of note, there is nearly a -fold increase in the risk to patients in outbreaks when a patient is the index case compared with exposure of patients during outbreaks when a staff member is the index case. the average incubation period for gastroenteritis caused by noroviruses is to hours, and the clinical course lasts to hours. illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. the disease is largely self-limited; rarely, death due to severe dehydration can occur, particularly in elderly persons with debilitating health conditions. the epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally contaminated food or water, secondary and tertiary cases often result from person-to-person transmission facilitated by contamination of fomites , and dissemination of infectious particles, especially during the process of vomiting. , , , , , , , widespread, persistent, and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control. , , these clinical observations and the detection of norovirus dna on horizontal surfaces feet above the level that might be touched normally suggest that under certain circumstances, aerosolized particles may travel distances beyond feet. it is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. in addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. development of disease and transmission may be facilitated by the low infectious dose (ie, , viral particles) and the resistance of these viruses to the usual cleaning and disinfection agents (ie, they may survive , ppm chlorine). [ ] [ ] [ ] an alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak. , there are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled. absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the b histo-blood group antigen. consultation on outbreaks of gastroenteritis is available through the cdc's division of viral and rickettsial diseases. i.c. . hemorrhagic fever viruses. hfv is a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and, in some cases, high mortality; the resulting disease is referred to as viral hemorrhagic fever (vhf). among the more commonly known hfvs are ebola and marburg viruses (filoviridae), lassa virus (arenaviridae), crimean-congo hemorrhagic fever and rift valley fever virus (bunyaviridae), and dengue and yellow fever viruses (flaviviridae). , these viruses are transmitted to humans through contact with infected animals or via arthropod vectors. although none of these viruses is endemic in the united states, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. furthermore, there is a concern that some of these agents could be used as bioweapons. person-to-person transmission has been documented for ebola, marburg, lassa, and crimean-congo hfvs. in resource-limited health care settings, transmission of these agents to hcws, patients, and visitors has been described and in some outbreaks has accounted for a large proportion of cases. [ ] [ ] [ ] transmission within households also has been documented in individuals who had direct contact with ill persons or their body fluids, but not in those who did not have such contact. evidence concerning the transmission of hfvs has been summarized previously. , person-to-person transmission is associated primarily with direct blood and body fluid contact. percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality. , the finding of large numbers of ebola viral particles in the skin and the lumina of sweat glands has raised concerns that transmission could occur from direct contact with intact skin, although epidemiologic evidence to support this is lacking. postmortem handling of infected bodies is an important risk for transmission. , , in rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact have led to speculation that airborne transmission could have occurred. however, airborne transmission of naturally occurring hfvs in humans has not been documented. a study of airplane passengers exposed to an in-flight index case of lassa fever found no transmission to any passengers. in the laboratory setting, animals have been infected experimentally with marburg or ebola virus through direct inoculation of the nose, mouth, and/or conjunctiva , and by using mechanically generated viruscontaining aerosols. , transmission of ebola virus among laboratory primates in an animal facility has been described. the secondarily infected animals were in individual cages separated by approximately meters. although the possibility of airborne transmission was suggested, the investigators were not able to exclude droplet or indirect contact transmission in this incidental observation. guidance on infection control precautions for hvfs transmitted person-to-person have been published by the cdc , and by the johns hopkins center for civilian biodefense strategies. the most recent recommendations at the time of publication of this document were posted on the cdc website on may , . inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in us hospitals. in less developed countries, outbreaks of hfvs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices. , the preponderance of evidence on hfv transmission indicates that standard, contact, and droplet precautions with eye protection are effective in protecting hcws and visitors coming in contact with an infected patient. single gloves are adequate for routine patient care; doublegloving is advised during invasive procedures (eg, surgery) that pose an increased risk of blood exposure. routine eye protection (ie goggles or face shield) is particularly important. fluid-resistant gowns should be worn for all patient contact. airborne precautions are not required for routine patient care; however, use of aiirs is prudent when procedures that could generate infectious aerosols are performed (eg, endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). n or higher-level respirators may provide added protection for individuals in a room during aerosol-generating procedures ( table , appendix a). when a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated on presentation and then modified as more information is obtained ( table ) . patients with hemorrhagic fever syndrome in the setting of a suspected bioweapons attack should be managed using airborne precautions, including aiirs, because the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable. numerous factors influence differences in transmission risks among the various health care settings. these factors include the population characteristics (eg, increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with hcws. these factors, as well as organizational priorities, goals, and resources, influence how different health care settings adapt transmission prevention guidelines to meet their specific needs. , infection control management decisions are informed by data regarding institutional experience/epidemiology; trends in community and institutional hais; local, regional, and national epidemiology; and emerging infectious disease threats. i.d. . hospitals. infection transmission risks are present in all hospital settings. however, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. these are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital. i.d. .a. intensive care units. intensive care units (icus) serve patients who are immunocompromised by disease state and/or by treatment modalities, as well as patients with major trauma, respiratory failure, and other life-threatening conditions (eg, myocardial infarction, congestive heart failure, overdose, stroke, gastrointestinal bleeding, renal failure, hepatic failure, multiorgan system failure, and extremes of age). although icus account for a relatively small proportion of hospitalized patients, infections acquired in these units account for . % of all hais. in the national nosocomial infection surveillance (nnis) system, . % of hais were reported from icu and high-risk nursery (neonatal icu [nicu]) patients in (nnis, unpublished data). this patient population has increased susceptibility to colonization and infection, especially with mdros and candida spp, , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (eg central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation, hemodialysis/filtration, pacemakers, implantable left-ventricular assist devices), the frequency of contact with hcws, prolonged lengths of stay, and prolonged exposure to antimicrobial agents. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality. outbreaks associated with various bacterial, fungal, and viral pathogens due to common-source and person-to-person transmissions are frequent in adult icus and pediatric icus (picus). , [ ] [ ] [ ] [ ] [ ] [ ] i.d. .b. burn units. burn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality. , , the risk of invasive burn wound infection is particularly high in patients with a burn injury involving . % of the total body surface area (tbsa). , infections occurring in patients with burn injuries involving , % of the tbsa are usually associated with the use of invasive devices. mssa, mrsa, enterococci (including vre), gram-negative bacteria, and candida spp are prevalent pathogens in burn infections, , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and outbreaks of these organisms have been reported. [ ] [ ] [ ] [ ] shifts over time in the predominance of pathogens causing infections in burn patients often lead to changes in burn care practices. , [ ] [ ] [ ] [ ] burn wound infections caused by aspergillus spp or other environmental molds may result from exposure to supplies contaminated during construction or to dust generated during construction or other environmental disruption. hydrotherapy equipment is an important environmental reservoir of gram-negative organisms. its use in burn care is discouraged based on demonstrated associations between the use of contaminated hydrotherapy equipment and infections. burn wound infections and colonization, as well as bloodstream infections, caused by multidrug-resistant p aeruginosa, acinetobacter baumannii, and mrsa have been associated with hydrotherapy; thus, excision of burn wounds in operating rooms is the preferred approach. advances in burn care (specifically, early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding) have led to decreased infectious complications. other advances have included prophylactic antimicrobial use, selective digestive decontamination, and use of antimicrobial-coated catheters; however, few epidemiologic studies and no efficacy studies have been performed to investigate the relative benefit of these measures. there is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (eg, single-bed rooms, laminar flow, and high-efficiency particulate air [hepa] filtration, or maintaining burn patients in a separate unit with no exposure to patients or equipment from other units ). there also is controversy regarding the need for and type of barrier precautions in the routine care of burn patients. one retrospective study demonstrated the efficacy and cost-effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks, and impermeable plastic aprons (rather than isolation gowns) for direct patient contact. however, to date no studies have determined the most effective combination of infection control precautions for use in burn settings. prospective studies in this area are needed. i.d. .c. pediatrics. studies of the epidemiology of hais in children have identified unique infection control issues in this population. , , [ ] [ ] [ ] [ ] [ ] pediatric icu patients and the lowest birth weight babies in the nicu monitored in the nnis system have had high rates of central venous catheter-associated bloodstream infections. , ) . close physical contact between hcws and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. such practices and behaviors as congregation of children in play areas where toys and bodily secretions are easily shared and rooming-in of family members with pediatric patients can further increase the risk of transmission. pathogenic bacteria have been recovered from toys used by hospitalized patients; contaminated bath toys were implicated in an outbreak of multidrug-resistant p. aeruginosa on a pediatric oncology unit. in addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in health care settings (eg, immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in nicus and picus). there are theoretical concerns that infection risk will increase in association with innovative practices used in the nicu for the purpose of improving developmental outcomes, such factors include cobedding and kangaroo care, which may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although the risk of infection actually may be reduced among infants receiving kangaroo care. children who attend child care centers , and pediatric rehabilitation units may increase the overall burden of antimicrobial resistance by contributing to the reservoir of ca-mrsa. [ ] [ ] [ ] [ ] [ ] [ ] patients in chronic care facilities may have increased rates of colonization with resistant garm-negative bacilli and may be sources of introduction of resistant organisms to acute care settings. i.d. . nonacute health care settings. health care is provided in various settings outside of hospitals, including long-term care facilities (ltcfs) (eg nursing homes), homes for the developmentally disabled, behavioral health service settings, rehabilitation centers, and hospices. in addition, health care may be provided in non-health care settings, such as workplaces with occupational health clinics, adult day care centers, assisted-living facilities, homeless shelters, jails and prisons, school clinics, and infirmaries. each of these settings has unique circumstances and population risks that must be considered when designing and implementing an infection control program. several of the most common settings and their particular challenges are discussed below. although this guideline does not address each setting, the principles and strategies provided herein may be adapted and applied as appropriate. i.d. .a. long-term care. the designation ltcf applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic care facilities. [ ] [ ] [ ] nursing homes for the elderly predominate numerically and frequently represent longterm care as a group of facilities. approximately . million americans reside in the nation's , nursing homes. estimates of hai rates of . to . per resident-care days have been reported, with a range of to per resident-care days in the more rigorous studies. [ ] [ ] [ ] [ ] [ ] the infrastructure described in the department of veterans affairs' nursing home care units is a promising example for the development of a nationwide hai surveillance system for ltcfs. lctfs are different from other health care settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods; for most residents, it is their home. an atmosphere of community is fostered, and residents share common eating and living areas and participate in various facility-sponsored activities. , because able residents interact freely with each other, controlling infection transmission in this setting can be challenging. a residents who is colonized or infected with certain microorganisms are in some cases restricted to his or her room. however, because of the psychosocial risks associated with such restriction, balancing psychosocial needs with infection control needs is important in the ltcf setting. , , , ) and bacteria, including group a streptococcus, , b pertussis, nonsusceptible s pneumoniae, , other mdros, and c difficile ). these pathogens can lead to substantial morbidity and mortality, as well as increased medical costs; prompt detection and implementation of effective control measures are needed. risk factors for infection are prevalent among ltcf residents. , , age-related declines in immunity may affect the response to immunizations for influenza and other infectious agents and increase the susceptibility to tuberculosis. immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory, and cutaneous and soft tissue infections, whereas malnutrition can impair wound healing. [ ] [ ] [ ] [ ] [ ] medications (eg, drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (eg, urinary catheters and feeding tubes) heighten the susceptibility to infection and colonization in ltcf residents. [ ] [ ] [ ] finally, limited functional status and total dependence on hcws for activities of daily living have been identified as independent risk factors for infection , , and for colonization with mrsa , and esbl-producing klebsiella pneumoniae. several position papers and review articles provide guidance on various aspects of infection control and antimicrobial resistance in ltcfs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the centers for medicare and medicaid services has established regulations for the prevention of infection in ltcfs. because residents of ltcfs are hospitalized frequently, they can transfer pathogens between ltcfs and health care facilities in which they receive care. , [ ] [ ] [ ] [ ] this also is true for pediatric long-term care populations. pediatric chronic care facilities have been associated with the importation of extendedspectrum cephalosporin-resistant, gram-negative bacilli into a picu. children from pediatric rehabilitation units may contribute to the reservoir of community-associated mrsa. , [ ] [ ] [ ] i.d. .b. ambulatory care. over the past decade, health care delivery in the united states has shifted from the acute, inpatient hospital to various ambulatory and community-based settings, including the home. ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physicians' offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and other setting. in , there were million visits to hospital outpatient clinics and more than million visits to physicians' offices; ambulatory care now accounts for most patient encounters with the health care system. adapting transmission prevention guidelines to these settings is challenging, because patients remain in common areas for prolonged periods waiting to be seen by a health care provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. furthermore, immunocompromised patients often receive chemotherapy in infusion rooms, where they stay for extended periods along with other types of patients. little data exist on the risk of hais in ambulatory care settings, with the exception of hemodialysis centers. , , transmission of infections in outpatient settings has been reviewed in studies. [ ] [ ] [ ] goodman and solomon summarized clusters of infections associated with the outpatient setting between and . overall, clusters were associated with common source transmission from contaminated solutions or equipment, were associated with person-to-person transmission from or involving hcws, and were associated with airborne or droplet transmission among patients and health care workers. transmission of bloodborne pathogens (ie, hbv, hcv, and, rarely, hiv) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. these outbreaks often are related to common source exposures, usually a contaminated medical device, multidose vial, or intravenous solution. , [ ] [ ] [ ] [ ] [ ] in all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique. this subject has been reviewed, and recommended infection control and safe injection practices have been summarized. airborne transmission of m tuberculosis and measles in ambulatory settings, most often emergency departments, has been reported. , , , , [ ] [ ] [ ] measles virus was transmitted in physicians' offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly. , , rubella has been transmitted in the outpatient obstetric setting; there are no published reports of varicella transmission in the outpatient setting. in the ophthalmology setting, adenovirus type epidemic keratoconjunctivitis has been transmitted through incompletely disinfected ophthalmology equipment and/or from hcws to patients, presumably by contaminated hands. , , , [ ] [ ] [ ] [ ] preventing transmission in outpatient settings necessitates screening for potentially infectious symptomatic and asymptomatic individuals, especially those at possible risk for transmitting airborne infectious agents (eg, m tuberculosis, varicella-zoster virus, rubeola [measles]), at the start of the initial patient encounter. on identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (eg, respiratory hygiene/cough etiquette and transmission-based precautions) can decrease transmission risks. , transmission of mrsa and vre in outpatient settings has not been reported, but the association of ca-mrsa in hcws working in an outpatient hiv clinic with environmental ca-mrsa contamination in that clinic suggests the possibility of transmission in that setting. patient-to-patient transmission of burkholderia spp and p aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed. , i.d. .c. home care. home care in the united states is delivered by more than , provider agencies, including home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. home care is provided to patients of all ages with both acute and chronic conditions. the scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis. the incidence of infection in home care patients, other than that associated with infusion therapy, has not been well studied. [ ] [ ] [ ] [ ] [ ] [ ] however, data collection and calculation of infection rates have been done for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy [ ] [ ] [ ] [ ] [ ] and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting. draft definitions for home care-associated infections have been developed. transmission risks during home care are presumed to be minimal. the main transmission risks to home care patients are from an infectious home care provider or contaminated equipment; a provider also can be exposed to an infectious patient during home visits. because home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. infections of home care providers that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (eg, chickenpox, tuberculosis, influenza), skin infestations (eg, scabies and lice), and infections transmitted by direct or indirect contact (eg, impetigo). there are no published data on indirect transmission of mdros from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. of note, investigations of the first case of visa in home care and the first reported cases of vrsa , , , found no evidence of transmission of visa or vrsa to other home care recipients. home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found that % of recipients did not receive prescribed antibiotics according to recommended guidelines. although most home care agencies implement policies and procedures aimed at preventing transmission of organisms, the current approach is based on the adaptation of the guideline for isolation precautions in hospitals, as well as other professional guidance. , this issue has proven very challenging to the home care industry, and practice has been inconsistent and frequently not evidence-based. for example, many home health agencies continue to observe ''nursing bag technique,'' a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home. although the home environment may not always appear clean, the use of barriers between noncritical surfaces has been questioned. , opportunites exist to conduct research in home care related to infection transmission risks. i.d. .d. other sites of health care delivery. facilities that are not primarily health care settings but in which health care is delivered include clinics in correctional facilities and shelters. both of these settings can have suboptimal features, such as crowded conditions and poor ventilation. economically disadvantaged individuals who may have chronic illnesses and health care problems related to alcoholism, injected drug use, poor nutrition, and/or inadequate shelter often receive their primary health care at such sites. infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (eg, n meningitides, s pneumoniae), sexually transmitted and bloodborne diseases (eg, hiv, hbv, hcv, syphilis, gonorrhea), hepatitis a virus, diarrheal agents such as norovirus, and foodborne diseases. , [ ] [ ] [ ] [ ] a high index of suspicion for tuberculosis and ca-mrsa in these populations is needed; outbreaks in these settings or among the populations they serve have been reported. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for m tuberculosis infection, along with diagnosing and treating acute illnesses. recommended infection control measures in these nontraditional areas designated for health care delivery are the same as for other ambulatory care settings. therefore, these settings must be equipped to observe standard precautions and, when indicated, transmission-based precautions. as new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations must be addressed. i.e. . immunocompromised patients. patients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving health care; these patients may be located throughout the health care facility. the specific immune system defects determine the types of infections most likely to be acquired (eg, viral infections are associated with t cell defects, and fungal and bacterial infections occur in patients who are neutropenic). as a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections, such as influenza and other respiratory viruses. , the use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups. , with the application of newer and more intense immunosuppressive therapies for various medical conditions (eg, rheumatologic disease, , inflammatory bowel disease ), immunosuppressed patients are likely to be more widely distributed throughout a health care facility rather than localized to single patient units (eg, hematologyoncology). guidelines for preventing infections in certain groups of immunocompromised patients have been published previously. , , published data provide evidence to support placing patients undergoing allogeneic hsct in a pe. , , in addition, guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a pe for the prevention of infections caused by aspergillus spp and other environmental fungi. , , as more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional days. i.e. . cystic fibrosis patients. patients with cystic fibrosis (cf) require special consideration when developing infection control guidelines. compared with other patients, cf patients require additional protection to prevent transmission from contaminated respiratory therapy equipment. [ ] [ ] [ ] [ ] [ ] such infectious agents as b cepacia complex and p aeruginosa. , , , have unique clinical and prognostic significance. in cf patients, b cepacia infection has been associated with increased morbidity and mortality, [ ] [ ] [ ] whereas delayed acquisition of chronic p aeruginosa infection may be associated with an improved long-term clinical outcome. , person-to-person transmission of b cepacia complex has been demonstrated among children and adults with cf in health care settings , and from various social contacts, most notably attendance at camps for patients with cf and among siblings with cf. successful infection control measures used to prevent transmission of respiratory secretions include segregation of cf patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of cf camps. , the cystic fibrosis foundation has published a consensus document with evidence-based recommendations for infection control practices in cf patients. i.f. new therapies associated with potentially transmissible infectious agents i.f. . gene therapy. gene therapy has has been attempted using various viral vectors, including nonreplicating retroviruses, adenoviruses, adeno-associated viruses, and replication-competent strains of poxviruses. unexpected adverse events have restricted the prevalence of gene therapy protocols. the infectious hazards of gene therapy are theoretical at this time but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. the greatest concern attends the use of replication-competent viruses, especially vaccinia. to date, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published. [ ] [ ] [ ] i.f. . infections transmitted through blood, organs, and other tissues. the potential hazard of transmitting infectious pathogens through biologic products is a small but ever-present risk, despite donor screening. reported infections transmitted by transfusion or transplantation include west nile virus infection, cytomegalovirus infection, cjd, hepatitis c, infections with clostridium spp and group a streptococcus, malaria, babesiosis, chagas disease, lymphocytic choriomeningitis, and rabies. , therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection. i.f. . xenotransplantation. transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. transmission of known zoonotic infections (eg, trichinosis from porcine tissue) is of concern. also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. potential infections that potentially could accompany transplantation of porcine organs have been described previously. guidelines from the us public health service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation; policies and procedures that explain how standard precautions and transmission-based precautions are applied, including systems used to identify and communicate information on patients with potentially transmissible infectious agents, are essential to ensure the success of these measures. these policies and procedures may vary according to the characteristics of the organization. a key administrative measure is the provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. specific components include bedside nurse and infection prevention and control professional (icp) staffing levels, inclusion of icps in facility construction and design decisions, clinical microbiology laboratory support, , adequate supplies and equipment including facility ventilation systems, adherence monitoring, assessment and correction of system failures that contribute to transmission, , and provision of feedback to hcws and senior administrators. , , , the positive influence of institutional leadership has been demonstrated repeatedly in studies of hcws' adherence to recommended hand hygiene practices. , , , , , [ ] [ ] [ ] [ ] [ ] [ ] health care administrators' involvement in the infection control processes can improve their awareness of the rationale and resource requirements for following recommended infection control practices. several administrative factors may affect the transmission of infectious agents in health care settings, including the institutional culture, individual hcw behavior, and the work environment. each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals. , , , ii.a. .a. scope of work and staffing needs for infection control professionals. the effectiveness of infection surveillance and control programs in preventing nosocomial infections in ust hospitals was assessed by the cdc through the study on the efficacy of nosocomial infection control (senic project) conducted between and . in a representative sample of us general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program and at least infection control nurse per beds were associated with a % lower rate of the infections studied (cvc-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections). since the publication of that landmark study, responsibilities of icps have expanded commensurate with the growing complexity of the health care system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of health care settings. the scope of work of icps was first assessed in - by the certification board of infection control, and has been reassessed every years since that time. , [ ] [ ] [ ] the findings of these analyses have been used to develop and update the infection control certification examination, which was first offered in . with each new survey, it becomes increasingly apparent that the role of the icp is growing in complexity and scope beyond traditional infection control activities in acute care hospitals. activities currently assigned to icps in response to emerging challenges include ( ) surveillance and infection prevention at facilities other than acute care hospitals (eg, ambulatory clinics, day surgery centers, ltcfs, rehabilitation centers, home care); ( ) oversight of employee health services related to infection prevention (eg, assessment of risk and administration of recommended treatment after exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in ); ( ) preparedness planning for annual influenza outbreaks, pandemic influenza, sars, and bioweapons attacks; ( ) adherence monitoring for selected infection control practices; ( ) oversight of risk assessment and implementation of prevention measures associated with construction and renovation; ( ) prevention of transmission of mdros; ( ) evaluation of new medical products that could be associated with increased infection risk (eg, intravenous infusion materials); ( ) communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and ( ) participation in local and multicenter research projects. , , , , , none of the certification board of infection control job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the survey included the number of icps assigned to the responding facilities. there is agreement in the literature that a ratio of icp per acute care beds is no longer adequate to meet current infection control needs; a delphi project that assessed staffing needs of infection control programs in the st century concluded that a ratio of . to . icp per occupied acute care beds is an appropriate staffing level. a survey of participants in the nnis system found an average daily patient census of per icp. results of other studies have been similar: per beds for large acute care hospitals, per to beds in ltcfs, and . per in small rural hospitals. , the foregoing demonstrates that infection control staffing no longer can be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the health care system, tools available to assist personnel to perform essential tasks (eg, electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community. furthermore, appropriate training is required to optimize the quality of work performed. , , ii.a. .a.i. infection control nurse liaison. designating a bedside nurse on a patient care unit as an infection control liaison or ''link nurse'' is reported to be an effective adjunct to enhance infection control at the unit level. [ ] [ ] [ ] [ ] [ ] [ ] such individuals receive training in basic infection control and have frequent communication with icps, but maintain their primary role as bedside caregiver on their units. the infection control nurse liaison increases the awareness of infection control at the unit level. he or she is especially effective in implementating new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. this position is an adjunct to, not a replacement for, fully trained icps. furthermore, the infection control liaison nurses should not be counted when considering icp staffing. there is increasing evidence that the level of bedside nurse staffing influences the quality of patient care. , adequate nursing staff makes it more likely that infection control practices, including hand hygiene, standard precautions, and transmission-based precautions, will be given appropriate attention and applied correctly and consistently. a national multicenter study reported strong and consistent inverse relationships between nurse staffing and adverse outcomes in medical patients, of which were hais (urinary tract infections and pneumonia). the association of nursing staff shortages with increased rates of hai has been demonstrated in several outbreaks in hospitals and ltcfs, and with increased transmission of hepatitis c virus in dialysis units. , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in most cases, when staffing was improved as part of a comprehensive control intervention, the outbreak ended or the hai rate declined. in studies, , the composition of the nursing staff (''pool'' or ''float'' vs regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and that of pool nurses increased. ii.a. .c. clinical microbiology laboratory support. the critical role of the clinical microbiology laboratory in infection control and health care epidemiology has been well described , , [ ] [ ] [ ] and is supported by the infectious disease society of america's policy statement on the consolidation of clinical microbiology laboratories published in . the clinical microbiology laboratory contributes to preventing transmission of infectious diseases in health care settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assessing the effectiveness of recommended precautions to limit transmission during outbreaks. outbreaks of infections may be recognized first by laboratorians. health care organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (eg, providers of clinical care, infection control staff, health care epidemiologists, and infectious disease consultants). as concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory assumes ever-greater importance. for health care organizations that outsource microbiology laboratory services (eg, ambulatory care, home care, ltcfs, smaller acute care hospitals), it is important to specify by contract the types of services (eg, periodic institution-specific aggregate susceptibility reports) required to support infection control. several key functions of the clinical microbiology laboratory are relevant to this guideline: ii.a. . institutional safety culture and organizational characteristics. safety culture (or safety climate) refers to a work environment in which a shared commitment to safety on the part of management and the workforce is understood and maintained. , , the authors of the institute of medicine's report titled to err is human acknowledged that causes of medical error are multifaceted but emphasized the pivotal role of system failures and the benefits of a safety culture. a safety culture is created through ( ) the actions that management takes to improve patient and worker safety, ( ) worker participation in safety planning, ( ) the availability of appropriate ppe, ( ) the influence of group norms regarding acceptable safety practices, and ( ) the organization's socialization process for new personnel. safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units, as demonstrated by studies of surgical icus. , each of these factors has a direct bearing on adherence to transmission prevention recommendations. measurement of an institution's culture of safety is useful in designing improvements in health care. , several hospitalbased studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids. [ ] [ ] [ ] [ ] [ ] [ ] [ ] one study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture. several hospitals that are part of the veterans administration health care system have taken specific steps toward improving the safety culture, including error-reporting mechanisms, root cause analyses of identified problems, safety incentives, and employee education. [ ] [ ] [ ] ii.a. . adherence of health care workers to recommended guidelines. hcws' adherence to recommended infection control practices decreases the transmission of infectious agents in health care settings. , , [ ] [ ] [ ] [ ] [ ] several observational studies have shown limited adherence to recommended practices by hcws. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] observed adherence to universal precautions ranged from % to %. , , , , the degree of adherence often depended on the specific practice that was assessed and, for glove use, the circumstance in which the practice was applied. observed rates of appropriate glove use has ranged from a low of % to a high of %. however, % and % adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures in which considerable blood contact may occur. , differences in observed adherence have been reported among occupational groups in the same health care facility and between experienced and nonexperienced professionals. in surveys of hcws, self-reported adherence was generally higher than actual adherence found in observational studies. furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence. among nurses and physicians, increasing years of experience is a negative predictor of adherence. , education to improve adherence is the primary intervention that has been studied. whereas positive changes in knowledge and attitude have been demonstrated, , no or only limited accompanying changes in behavior often have been found. , self-reported adherence is higher in groups that received an educational intervention. , in one study, educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the study period, but the long-term effect of such interventions is not known. the use of videotaping also served to identify system problems (eg, communication and access to ppe) that otherwise may not have been recognized. interest is growing in the use of engineering controls and facility design concepts for improving adherence. whereas the introduction of automated sinks was found to have a negative impact on consistent adherence to handwashing in one study, the use of electronic monitoring and voice prompts to remind hcws to perform hand hygiene and improving accessibility to hand hygiene products increased adherence and contributed to a decrease in hais in another study. more information is needed regarding ways in which technology might improve adherence. improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment. , using several behavioral theories, kretzer and larson concluded that a single intervention (eg, a handwashing campaign or putting up new posters about transmission precautions) likely would be ineffective in improving hcws adherence. improvement requires the organizational leadership to make prevention an institutional priority and integrate infection control practices into the organization's safety culture. a recent review of the literature concluded that variations in organizational factors (eg, safety climate, policies and procedures, education and training) and individual factors (eg, knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against sars and other respiratory pathogens. surveillance is an essential tool for case finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (eg, susceptible bacteria such as s aureus, s pyogenes [group a streptococcus] or enterobacter-klebsiella spp; mrsa, vre, and other mdros; c difficile; rsv; influenza virus) for which transmission-based precautions may be required. surveillance is defined as the ongoing systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health. the work of ignaz semmelweis delineating the role of person-toperson transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents. surveillance of both process measures and the infection rates to which they are linked is important in evaluating the effectiveness of infection prevention efforts and identifying indications for change. , [ ] [ ] [ ] [ ] the study on the efficacy of nosocomial infection control (senic) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals; however, surveillance was the only component essential for reducing all types of hais. although a similar study has not been conducted in other health care settings, a role for surveillance and the need for novel strategies in ltcfs , , , and in home care [ ] [ ] [ ] [ ] have been described. the essential elements of a surveillance system are ( ) standardized definitions, ( ) identification of patient populations at risk for infection, ( ) statistical analysis (eg, risk adjustment, calculation of rates using appropriate denominators, trend analysis using such methods as statistical process control charts), and ( ) feedback of results to the primary caregivers. [ ] [ ] [ ] [ ] [ ] [ ] data gathered through surveillance of high-risk populations, device use, procedures, and facility locations (eg, icus) are useful in detecting transmission trends. [ ] [ ] [ ] identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time and to guide implementation of interventions and evaluation of the effectiveness of those interventions. targeted surveillance based on the highest-risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources. , however, for certain epidemiologically important organisms, surveillance may need to be facility-wide. surveillance methods will continue to evolve as health care delivery systems change , and user-friendly electronic tools for electronic tracking and trend analysis become more widely available. , , individuals with experience in health care epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis, to ensure that the need for efficient and accurate hai surveillance will be met. effective surveillance is increasingly important as legislation requiring public reporting of hai rates is passed and states work to develop effective systems to support such legislation. the education and training of hcws is a prerequisite for ensuring that policies and procedures for standard and transmission-based precautions are understood and practiced. understanding the scientific rationale for the precautions will allow hcws to apply procedures correctly, as well as to safely modify precautions based on changing requirements, resources, or health care settings. , , - one study found that the likelihood of hcws developing sars was strongly associated with less than hours of infection control training and poor understanding of infection control procedures. education regarding the important role of vaccines (eg, influenza, measles, varicella, pertussis, pneumococcal) in protecting hcws, their patients, and family members can help improve vaccination rates. [ ] [ ] [ ] [ ] education on the principles and practices for preventing transmission of infectious agents should begin during training in the health professions and be provided to anyone who has an opportunity for contact with patients or medical equipment (eg, nursing and medical staff; therapists and technicians, including respiratory, physical, occupational, radiology, and cardiology personnel; phlebotomists; housekeeping and maintenance staff; and students). in health care facilities, education and training on standard and transmission-based precautions are typically provided at the time of orientation and should be repeated as necessary to maintain competency; updated education and training are necessary when policies and procedures are revised or when a special circumstance occurs, such as an outbreak that requires modification of current practice or adoption of new recommendations. education and training materials and methods appropriate to the hcw's level of responsibility, individual learning habits, and language needs can improve the learning experience. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] education programs for hcws have been associated with sustained improvement in adherence to best practices and a related decrease in device-associated hais in teaching and nonteaching settings , and in medical and surgical icus (coopersmith, # ) . several studies have shown that in addition to targeted education to improve specific practices, periodic assessment and feedback of the hcw's knowledge and adherence to recommended practices are necessary to achieve the desired changes and identify continuing education needs. , [ ] [ ] [ ] [ ] [ ] the effectiveness of this approach for isolation practices has been demonstrated in the control of rsv. , patients, family members, and visitors can be partners in preventing transmission of infections in health care settings. , , - information on standard precautions, especially hand hygiene, respiratory hygiene/cough etiquette, vaccination (especially against influenza), and other routine infection prevention strategies, may be incorporated into patient information materials provided on admission to the health care facility. additional information on transmission-based precautions is best provided when these precautions are initiated. fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for transmission-based precautions purposes, explanation of the use of ppe by hcws, and directions for use of such equipment by family members and visitors. such information may be particularly helpful in the home environment, where household members often have the primary responsibility for adherence to recommended infection control practices. hcws must be available and prepared to explain this material and answer questions as needed. hand hygiene has been frequently cited as the single most important practice to reduce the transmission of infectious agents in health care settings , , and is an essential element of standard precautions. the term ''hand hygiene'' includes both handwashing with either plain or antiseptic-containing soap and water and the use of alcohol-based products (gels, rinses, foams) that do not require water. in the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience. have been associated with a sustained decrease in the incidence of mrsa and vre infections primarily in icus. , , [ ] [ ] [ ] [ ] the scientific rationale, indications, methods, and products for hand hygiene have been summarized in previous publications. , the effectiveness of hand hygiene can be reduced by the type and length of fingernails. , , individuals wearing artificial nails have been shown to harbor more pathogenic organisms, especially gram-negative bacilli and yeasts, on the nails and in the subungual area compared with individuals with native nails. , in , the cdc/hicpac recommended (category ia) that artificial fingernails and extenders not be worn by hcws who have contact with high-risk patients (eg, those in icus and operating rooms), due to the association with outbreaks of gram-negative bacillus and candidal infections as confirmed by molecular typing of isolates. , , , [ ] [ ] [ ] [ ] the need to restrict the wearing of artificial fingernails by all hcws who provide direct patient care and those who have contact with other high-risk groups (eg, oncology and cystic fibrosis patients) has not been studied but has been recommended by some experts. currently, such decisions are at the discretion of an individual facility's infection control program. there is less evidence indicating that jewelry affects the quality of hand hygiene. although hand contamination with potential pathogens is increased with ring-wearing, , no studies have related this practice to hcw-to-patient transmission of pathogens. ppe refers to various barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. the choice of ppe is based on the nature of the patient interaction and/or the likely mode(s) of transmission. specific guidance on the use of ppe is provided in part iii of this guideline. a suggested procedure for donning and removing ppe aimed at preventing skin or clothing contamination is presented in figure . designated containers for used disposable or reusable ppe should be placed in a location convenient to the site of removal, to facilitate disposal and containment of contaminated materials. hand hygiene is always the final step after removing and disposing of ppe. the following sections highlight the primary uses of and criteria for selecting this equipment. ii.e. . gloves. gloves are used to prevent contamination of hcw hands when ( ) anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; ( ) having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route (eg, vre, mrsa, rsv , , ); or ( ) handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces. , , gloves can protect both patients and hcws from exposure to infectious material that may be carried on hands. the extent to which gloves will protect hcws from transmission of bloodborne pathogens (eg, hiv, hbv, hcv) after a needlestick or other puncture that penetrates the glove barrier has not yet been determined. although gloves may reduce the volume of blood on the external surface of a sharp by % to %, the residual blood in the lumen of a hollow-bore needle would not be affected; therefore, the effect on transmission risk is unknown. gloves manufactured for health care purposes are subject to fda evaluation and clearance. nonsterile disposable medical gloves made of various materials (eg, latex, vinyl, nitrile) are available for routine patient care. the selection of glove type for nonsurgical use is based on various factors, including the task to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment. , [ ] [ ] [ ] for contact with blood and body fluids during nonsurgical patient care, a single pair of gloves generally provides adequate barrier protection. however, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness. whereas there is little difference in the barrier properties of unused intact gloves, studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions. , [ ] [ ] [ ] [ ] for this reason, either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity or will involve more than brief patient contact. a facility may need to stock gloves in several sizes. heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces. , , during patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from ''clean'' to ''dirty'' and confining or limiting contamination to those surfaces directly needed for patient care. it may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites. , it also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment transported from room to room. discarding gloves between patients is necessary to prevent transmission of infectious material. gloves must not be washed for subsequent reuse, because microorganisms cannot be removed reliably from glove surfaces, and continued glove integrity cannot be ensured. furthermore, glove reuse has been associated with transmission of mrsa and gram-negative bacilli. [ ] [ ] [ ] when gloves are worn in combination with other ppe, they are put on last. gloves that fit snugly around the wrist are preferred for use with an isolation gown, because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. proper glove removal will prevent hand contamination (fig ) . hand hygiene after glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could have contaminated the hands during glove removal. , , ii.e. . isolation gowns. isolation gowns are used as specified by standard and transmission-based precautions to protect the hcw's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material. , , , [ ] [ ] [ ] the need for and the type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. the wearing of isolation gowns and other protective apparel is mandated by the occupational safety and health administration's (osha) bloodborne pathogens standard. clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered ppe. when applying standard precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. however, when contact precautions are used (ie, to prevent transmission of an infectious agent that is not interrupted by standard precautions alone and is associated with environmental contamination), donning of both gown and gloves on room entry is indicated, to prevent unintentional contact with contaminated environmental surfaces. , , , the routine donning of isolation gowns on entry into an icu or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas, however. , [ ] [ ] [ ] [ ] isolation gowns are always worn in combination with gloves, and with other ppe when indicated. gowns are usually the first piece of ppe to be donned. full coverage of the arms and body front, from neck to the mid-thigh or below, will ensure protection of clothing and exposed upper body areas. several gown sizes should be available in a health care facility to ensure appropriate coverage for staff members. isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. isolation gowns should be removed in a manner that prevents contamination of clothing or skin (fig ) ; the outer, ''contaminated'' side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination. ii.e. . face protection: masks, goggles, and face shields. ii.e. .a. masks. masks are used for primary purposes in health care settings: ( ) placed on hcws to protect them from contact with infectious material from patients (eg, respiratory secretions and sprays of blood or body fluids), consistent with standard precautions and droplet precautions; ( ) placed on hcws engaged in procedures requiring sterile technique, to protect patients from exposure to infectious agents carried in the hcw's mouth or nose; and ( ) placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (ie, respiratory hygiene/cough etiquette). masks may be used in combination with goggles to protect the mouth, nose, and eyes, or, alternatively, a face shield may be used instead of a mask and goggles to provide more complete protection for the face, as discussed below. masks should not be confused with particulate respirators used to prevent inhalation of small particles that may contain infectious agents transmitted through the airborne route, as described below. the mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents; other skin surfaces also may be portals if skin integrity is compromised (by, eg, acne, dermatitis). , [ ] [ ] [ ] [ ] therefore, use of ppe to protect these body sites is an important component of standard precautions. the protective effect of masks for exposed hcws has been demonstrated previously. , , , procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (eg, endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or a mask and goggles. [ ] [ ] [ ] [ ] , , , , the wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposure is likely is mandated by osha's bloodborne pathogens standard. appropriate ppe should be selected based on the anticipated level of exposure. two mask types are available for use in health care settings: surgical masks that are cleared by the fda and required to have fluid-resistant properties, and procedure or isolation masks. ,# to date, no studies comparing mask types to determine whether one mask type provides better protection than another have been published. because procedure/isolation masks are not regulated by the fda, they may be more variable in terms of quality and performance than surgical masks. masks come in various shapes (eg, molded and nonmolded), sizes, filtration efficiency, and method of attachment (eg, ties, elastic, ear loops). health care facilities may find that different types of masks are needed to meet individual hcw needs. ii.e. .b. goggles and face shields. guidance on eye protection for infection control has been published. the eye protection chosen for specific work situations (eg, goggles or face shield) depends on the circumstances of exposure, other ppe used, and personal vision needs. personal eyeglasses and contact lenses are not considered adequate eye protection (see http://www.cdc.gov/ niosh/topics/eye/eye-infectious.html). niosh guidelines specify that eye protection must be comfortable, allow for sufficient peripheral vision, and adjustable to ensure a secure fit. a health care facility may need to provide several different types, styles, and sizes of eye protection equipment. indirectly vented goggles with a manufacturer's antifog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. many styles of goggles fit adequately over prescription glasses with minimal gaps. although effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. the role of goggles in addition to a mask in preventing exposure to infectious agents transmitted through respiratory droplets has been studied only for rsv. reports published in the mid- s demonstrated that eye protection reduced occupational transmission of rsv. , whether this was due to the prevention hand-eye contact or the prevention of respiratory droplet-eye contact has not been determined. however, subsequent studies demonstrated that rsv transmission is effectively prevented by adherence to standard precautions plus contact precautions and that routine use of goggles is not necessary for this virus. , , , , it is important to remind hcws that even if droplet precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose, and mouth using a mask and goggles or a face shield alone is necessary when a splash or spray of any respiratory secretions or other body fluids is likely to occur, as defined in standard precautions. disposable or nondisposable face shields may be used as an alternative to goggles. compared with goggles, a face shield can provide protection to other facial areas besides the eyes. face shields extending from the chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. removal of a face shield, goggles, and mask can be performed safely after gloves have been removed and hand hygiene performed. the ties, earpieces, and/or headband used to secure the equipment to the head are considered ''clean'' and thus safe to touch with bare hands. the front of a mask, goggles, and face shield are considered contaminated (fig ) . ii.e. . respiratory protection. the subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit testing is under scientific review and was the subject of a cdc workshop. respiratory protection currently requires the use of a respirator with n or higher-level filtration to prevent inhalation of infectious particles. information about respirators and respiratory protection programs is summarized in the guideline for preventing transmission of mycobacterium tuberculosis in health care settings. respiratory protection is broadly regulated by osha under the general industry standard for respiratory protection ( cfr . ), which requires that us employers in all employment settings implement a program to protect employees from inhalation of toxic materials. osha program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested niosh-certified n and higher-level particulate filtering respirators; education on respirator use, and periodic reevaluation of the respiratory protection program. when selecting particulate respirators, models with inherently good fit characteristics (ie, those expected to provide protection factors of $ % to % of wearers) are preferred and theoretically could preclude the need for fit testing. , issues pertaining to respiratory protection remain the subject of ongoing debate. information on various types of respirators is available at http://www.cdc.gov/niosh/ npptl/respirators/respsars.html and in several previously published studies. , , a user-seal check (formerly called a ''fit check'') should be performed by the wearer of a respirator each time that the respirator is donned, to minimize air leakage around the face piece. the optimal frequency of fit testing has not been determined; retesting may be indicated if there is a change in wearer's facial features, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the respirator that was initially assigned. respiratory protection was first recommended for protection of us hcws from exposure to m tuberculosis in . that recommendation has been maintained in successive revisions of the guidelines for prevention of transmission of tuberculosis in hospitals and other health care settings. , the incremental benefit from respirator use, in addition to administrative and engineering controls (ie, aiirs, early recognition of patients likely to have tuberculosis and prompt placement in an aiir, and maintenance of a patient with suspected tuberculosis in an aiir until no longer infectious), for preventing transmission of airborne infectious agents (eg, m tuberculosis) remains undetermined. although some studies have demonstrated effective prevention of m tuberculosis transmission in hospitals in which surgical masks instead of respirators were used in conjunction with other administrative and engineering controls. , , the cdc currently recommends n or higher-level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. currently, this recommendation also holds for other diseases that could be transmitted through the airborne route, including sars and smallpox, , , until inhalational transmission is better defined or health care-specific ppe more suitable for preventing infection is developed. wearing of respirators is also currently recommended during the performance of aerosol-generating procedures (eg, intubation, bronchoscopy, suctioning) in patients with sars-cov infection, avian influenza, and pandemic influenza (see appendix a). although airborne precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, no data are available on which to base a recommendation for respiratory protection to protect susceptible personnel against these infections. transmission of varicella-zoster virus has been prevented among pediatric patients using negativepressure isolation alone. whether respiratory protection (ie, wearing a particulate respirator) will enhance protection from these viruses has not yet been studied. because most hcws have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections. [ ] [ ] [ ] [ ] although there is no evidence suggesting that masks are not adequate to protect hcws in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all aiirs, regardless of the specific infectious agent present. procedures for safe removal of respirators are provided in figure . in some health care settings, particulate respirators used to provide care for patients with m tuberculosis are reused by the same hcw. this is an acceptable practice providing that the respirator is not damaged or soiled, the fit is not compromised by a change in shape, and the respirator has not been contaminated with blood or body fluids. no data are available on which to base a recommendation regarding the length of time that a respirator may be safely reused. sharps-related injuries. injuries due to needles and other sharps have been associated with transmission of hbv, hcv, and hiv to hcws. , the prevention of sharps injuries has always been an essential element of universal precautions and is now an aspect of standard precautions. , these include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. these measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures addressed elsewhere. [ ] [ ] [ ] [ ] [ ] since , when osha first issued its bloodborne pathogens standard to protect hcws from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. this has included focusing attention on removing sharps hazards through the development and use of engineering controls. the federal needlestick safety and prevention act, signed into law in november , authorized osha's revision of its bloodborne pathogens standard to more explicitly require the use of safety-engineered sharps devices. the cdc has provided guidance on sharps injury prevention, , including guidelines for the design, implementation and evaluation of a comprehensive sharps injury prevention program. ii.f. . prevention of mucous membrane contact. exposure of mucous membranes of the eyes, nose, and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to hcws. , , , the prevention of mucous membrane exposures has always been an element of universal precautions and is now an element of standard precautions for routine patient care , and is subject to osha bloodborne pathogen regulations. safe work practices, in addition to wearing ppe, are designed to protect mucous membranes and nonintact skin from contact with potentially infectious material. these include keeping contaminated gloved and ungloved hands from touching the mouth, nose, eyes, or face and positioning patients to direct sprays and splatter away from the caregiver's face. careful placement of ppe before patient contact will help avoid the need to make adjustments to ppe and prevent possible face or mucous membrane contamination during use. in areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with -way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure. ii.f. .a. precautions during aerosol-generating procedures. the performance of procedures that can generate small-particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to hcws, including m tuberculosis, sars-cov, , , and n meningitidis. protection of the eyes, nose, and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with standard precautions. the use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain m tuberculosis, sars-cov, or avian or pandemic influenza viruses. ii.g. . hospitals and long-term care facilities. options for patient placement include single-patient rooms, -patient rooms, and multibed wards. of these, single-patient rooms are preferred when transmission of an infectious agent is of concern. although some studies have failed to demonstrate the efficacy of single-patient rooms in preventing hais, other published studies, including one commissioned by the aia and the facility guidelines institute, have documented a beneficial relationship between private rooms and reduced infectious and noninfectious adverse patient outcomes. , the aia notes that private rooms are the trend in hospital planning and design. however, most hospitals and ltcfs have multibed rooms and must consider many competing priorities when determining the appropriate room placement for patients (eg, reason for admission; patient characteristics, such as age, gender, and mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). in the absence of obvious infectious diseases that require specified airborne infection isolation rooms (eg, tuberculosis, sars, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. when only a limited number of single-patient rooms is available, it is prudent to prioritize room assignments for those patients with conditions that facilitate transmission of infectious material to other patients (eg, draining wounds, stool incontinence, uncontained secretions) and those at increased risk of acquisition and adverse outcomes resulting from hais (due to, eg, immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on hcws for activities of daily living). , , , , , single-patient rooms are always indicated for patients placed on airborne precautions in a pe and are preferred for patients requiring contact or droplet precautions. , , , , , during a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, the use of single-patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits or fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (eg, infants, children, and patients with altered mental status or developmental delay). in the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and standard precautions (especially hand hygiene and appropriate environmental cleaning) are maintained. assignment of a dedicated commode to a patient, and cleaning and disinfecting fixtures and equipment that may have fecal contamination (eg, bathrooms, commodes, scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room cannot be assigned, because environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients. , the results of several studies that investigated the benefit of a single-patient room in preventing transmission of c difficile were inconclusive. , [ ] [ ] [ ] some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission; , - however, for children, the risk of health care-associated diarrhea is increased with the increased number of patients per room. these findings demonstrate that patient factors are important determinants of infection transmission risks. the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to a single area and prevent contact with other patients. cohorts are created based on clinical diagnosis, microbiologic confirmation (when available), epidemiology, and mode of transmission of the infectious agent. avoiding placing severely immunosuppressed patients in rooms with other patients is generally preferred. cohorting has been extensively used for managing outbreaks of mdros, including mrsa, rotavirus, and sars. modeling studies provide additional support for cohorting patients to control outbreaks; - however, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. assigning or cohorting hcws to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients, , but is difficult to achieve in the face of current staffing shortages in hospitals and residential health care sites. [ ] [ ] [ ] however, cohorting of hcws may be beneficial when transmission continues after implementing routine infection control measures and creating patient cohorts. during periods when rsv, human metapneumovirus, parainfluenza, influenza, other respiratory viruses, and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children. for example, during the respiratory virus season, infants may be cohorted based solely on the clinical diagnosis of bronchiolitis, due to the logistical difficulties and costs associated with requiring microbiologic confirmation before room placement and the predominance of rsv during most of the season. however, when available, single-patient rooms are always preferred, because a common clinical presentation (eg, bronchiolitis), can be caused by more than infectious agent. , , furthermore, the inability of infants and children to contain body fluids, and the close physical contact associated with their care, increases the risk of infection transmission for patients and personnel in this setting. , ii.g. . ambulatory care settings. patients actively infected with or incubating transmissible infectious diseases are frequently seen in ambulatory settings (eg, outpatient clinics, physicians' offices, emergency departments) and potentially expose hcws and other patients, family members, and visitors. , , , , , in response to the global outbreak of sars in and in preparation for pandemic influenza, hcws working in outpatient settings are urged to implement source containment measures (eg, asking coughing patients to wear a surgical mask or cover coughing with tissues) to prevent transmission of respiratory infections, beginning at the initial patient encounter, , , as described in section iii.a. .a. signs can be posted at the facility's entrance or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist of any symptoms of respiratory infection (eg, cough, flulike illness, increased production of respiratory secretions). the presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (eg, measles, pertussis, chickenpox, tuberculosis) also could be added. prompt placement of a potentially infectious patient in an examination room limits the number of exposed individuals in the common waiting area. in waiting areas, maintaining a distance between symptomatic and nonsymptomatic patients (eg, . feet), in addition to source control measures, may limit exposures. however, infections transmitted through the airborne route (eg, m tuberculosis, measles, chickenpox) require additional precautions. , , patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room (preferably an aiir) as soon as possible. if this is not possible, then having the patient wear a mask and segregating the patient from other patients in the waiting area will reduce the risk of exposing others. because the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may be extended to these persons if they are symptomatic. , , family members accompanying children admitted with suspected m tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic. , patients with underlying conditions that increase their susceptibility to infection (eg, immunocompromised status , or cystic fibrosis ) require special efforts to protect them from exposure to infected patients in common waiting areas. informing the receptionist of their infection risk on arrival allows appropriate steps to further protect these patients from infection. in some cystic fibrosis clinics, to avoid exposure to other patients who could be colonized with b cepacia, patients have been given beepers on registration so that they may leave the area and receive notification to return when an examination room becomes available. ii.g. . home care. in home care, patient placement concerns focus on protecting others in the home from exposure to an infectious household member. for individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. for example, in a situation where a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (age under years) and immunocompromised persons who have not yet been infected should be removed or excluded from the household. during the sars outbreak of , segregation of infected persons during the communicable phase of the illness was found to be beneficial in preventing household transmission. , several principles guide the transport of patients requiring transmission-based precautions. in the inpatient and residential settings, these include the following: . limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room. . when transport is necessary, applying appropriate barriers on the patient (eg, mask, gown, wrapping in sheets or use of impervious dressings to cover the affected areas) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission. . notifying hcws in the receiving area of the patient's impending arrival and of the necessary precautions to prevent transmission. . for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of transmission-based precautions being used. for tuberculosis, additional precautions may be needed in a small shared air space, such as in an ambulance. cleaning and disinfecting noncritical surfaces in patient care areas is an aspect of standard precautions. in general, these procedures do not need to be changed for patients on transmission-based precautions. the cleaning and disinfection of all patient care areas is important for frequently touched surfaces, especially those closest to the patient, which are most likely to be contaminated (eg, bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient). , , , the frequency or intensity of cleaning may need to be changed, based on the patient's level of hygiene and the degree of environmental contamination and for certain infectious agents with reservoirs in the intestinal tract. this may be particularly important in ltcfs and pediatric facilities, where patients with stool and urine incontinence are encountered more frequently. in addition, increased frequency of cleaning may be needed in a pe to minimize dust accumulation. special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published previously. in all health care settings, administrative, staffing, and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. during a suspected or proven outbreak in which an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. adherence should be monitored and reinforced to promote consistent and correct cleaning. us environmental protection agency-registered disinfectants or detergents/disinfectants that best meet the overall needs of the health care facility for routine cleaning and disinfection should be selected. , in general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. this includes those pathogens that are resistant to multiple classes of antimicrobial agents (eg, c difficile, vre, mrsa, mdr-gnb , , , , , , ). most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection, rather than to the specific cleaning and disinfectant agents used. [ ] [ ] [ ] [ ] certain pathogens (eg, rotavirus, noroviruses, c difficile) may be resistant to some routinely used hospital disinfectants. , , [ ] [ ] [ ] [ ] [ ] [ ] the role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally. also, because c difficile may display increased levels of spore production when exposed to non-chlorine-based cleaning agents, and because these spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a : dilution of . % sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with c difficile when there is continued transmission. , one study found an association between the use of a hypochlorite solution and decreased rates of c difficile infections. the need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee. , , detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the guidelines for environmental infection control in health care facilities and in the guideline for disinfection and sterilization. medical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents. , , , cleaning to remove organic material always must precede highlevel disinfection and sterilization of critical and semicritical instruments and devices, because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes. , noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before being used on another patient. all such equipment and devices should be handled in a manner that will prevent hcw and environmental contact with potentially infectious material. it is important to include computers and personal digital assistants used in patient care in policies for cleaning and disinfection of noncritical items. the literature on contamination of computers with pathogens has been summarized, and reports have linked computer contamination to colonization and infections in patients. , although keyboard covers and washable keyboards that can be easily disinfected are available, the infection control benefit of these items and their optimal management have not yet been determined. in all health care settings, providing patients who are on transmission-based precautions with dedicated noncritical medical equipment (eg, stethoscope, blood pressure cuff, electronic thermometer) has proven beneficial for preventing transmission. , , , , when this is not possible, disinfection of this equipment after each use is recommended. other previously published guidelines should be consulted for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances. , , , , , , in home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. equipment can be cleaned onsite using a detergent/disinfectant and, when possible, should be placed in a plastic bag for transport to the reprocessing location. , although soiled textiles, including bedding, towels, and patient or resident clothing, may be contaminated with pathogenic microorganisms, the risk of disease transmission is negligible if these textiles are handled, transported, and laundered in a safe manner. , , key principles for handling soiled laundry are ( ) avoiding shaking the items or handling them in any way that may aerosolize infectious agents, ( ) avoiding contact of one's body and personal clothing with the soiled items being handled, and ( ) containing soiled items in a laundry bag or designated bin. if a laundry chute is used, it must be maintained to minimize dispersion of aerosols from contaminated items. methods of handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations; guidance is provided in the guidelines for environmental infection control in health care facilities. rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended. , when laundering is done outside of a health care facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that pose a risk for immunocompromised patients. institutions are required to launder garments used as ppe and uniforms visibly soiled with blood or infective material. little data exist on the safety of home laundering of hcw uniforms, but no increase in infection rates was observed in the one published study, and no pathogens were recovered from home-or hospital-laundered scrubs in another study. in the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering and may be washed with warm water and detergent. , , the management of solid waste emanating from the health care environment is subject to federal and state regulations for medical and nonmedical waste. , no additional precautions are needed for nonmedical solid waste removed from rooms of patients on transmission-based precautions. solid waste may be contained in a single bag of sufficient strength. the combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. therefore, no special precautions are needed for dishware (eg, dishes, glasses, cups) or eating utensils. reusable dishware and utensils may be used for patients requiring transmission-based precautions. in the home and other communal settings, eating utensils and drinking vessels should not be shared, consistent with principles of good personal hygiene and to help prevent transmission of respiratory viruses, herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (eg, hepatitis a virus, noroviruses). if adequate resources for cleaning utensils and dishes are not available, then disposable products may be used. important adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents but nonetheless improve the effectiveness of such programs include ( ) antimicrobial management programs, ( ) postexposure chemoprophylaxis with antiviral or antibacterial agents, ( ) vaccines used both for pre-exposure and postexposure prevention, and ( ) screening and restricting visitors with signs of transmissible infections. detailed discussion of judicious use of antimicrobial agents is beyond the scope of this document; however, this topic has been addressed in a previous cdc guideline (http://www.cdc.gov/ncidod/dhqp/pdf/ar/ mdroguideline .pdf). ii.n. . chemoprophylaxis. antimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. infections for which postexposure chemoprophylaxis is recommended under defined conditions include b pertussis, , n meningitides, b anthracis after environmental exposure to aeosolizable material, influenza virus, hiv, and group a streptococcus. orally administered antimicrobials also may be used under defined circumstances for mrsa decolonization of patients or hcws. another form of chemoprophylaxis involves the use of topical antiseptic agents. for example, triple dye is routinely used on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by s aureus, including mrsa, and group a streptococcus. , extension of the use of triple dye to low birth weight infants in a nicu was one component of a program that controlled a long-standing mrsa outbreak. topical antiseptics (eg, mupirocin) also are used for decolonization of hcws or selected patients colonized with mrsa, as discussed in the mdro guideline , [ ] [ ] [ ] [ ] ii.n. . immunoprophylaxis. certain immunizations recommended for susceptible hcws have decreased the risk of infection and the potential for transmission in health care facilities. , the osha mandate requiring employers to offer hbv vaccination to hcws has played a substantial role in the sharp decline in incidence of occupational hbv infection. , the routine administration of varicella vaccine to hcws has decreased the need to place susceptible hcws on administrative leave after exposure to patients with varicella. in addition, reports of health care-associated transmission of rubella in obstetric clinics , and measles in acute care settings demonstrate the importance of immunization of susceptible hcws against childhood diseases. many states have requirements for vaccination of hcws for measles and rubella in the absence of evidence of immunity. annual influenza vaccine campaigns targeted at patients and hcws in ltcfs and acute care settings have been instrumental in preventing or limiting institutional outbreaks; consequently, increasing attention is being directed toward improving influenza vaccination rates in hcws. , , , [ ] [ ] [ ] transmission of b pertussis in health care facilities has been associated with large and costly outbreaks that include both hcws and patients. , , , , , , , hcws in close contact with infants with pertussis are at particularly high risk because of waning immunity and, until , the absence of a vaccine appropriate for adults. but acellular pertussis vaccines were licensed in the united states in , for use in individuals age to years and the other for use in those age to years. current advisory committee on immunization practices provisional recommendations include immunization of adolescents and adults, especially those in contact with infants under age months and hcws with direct patient contact. , immunization of children and adults will help prevent the introduction of vaccine-preventable diseases into health care settings. the recommended immunization schedule for children is published annually in the january issues of the morbidity and mortality weekly report, with interim updates as needed. , an adult immunization schedule also is available for healthy adults and those with special immunization needs due to high-risk medical conditions. some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella, influenza, hepatitis b, and smallpox vaccines. , in the future, administration of a newly developed s aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing health care-associated s aureus (including mrsa) infections in high-risk groups (eg, hemodialysis patients and candidates for selected surgical procedures). , immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (eg, varicella-zoster virus, hbv, rabies, measles and hepatitis a virus , , ). the rsv monoclonal antibody preparation palivizumab may have contributed to controlling a nosocomial outbreak of rsv in one nicu, but there is insufficient evidence to support a routine recommendation for its use in this setting. ii.n. , , , and sars , [ ] [ ] [ ] . effective methods for visitor screening in health care settings have not yet been studied, however. visitor screening is especially important during community outbreaks of infectious diseases and for high-risk patient units. sibling visits are often encouraged in birthing centers, postpartum rooms, pediatric inpatient units, picus, and residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections. screening may be passive, through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. more active screening may include the completion of a screening tool or questionnaire to elicit information related to recent exposures or current symptoms. this information is reviewed by the facility staff, after which the visitor is either permitted to visit or is excluded. family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure, as well as signs and symptoms of current infection. potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. if exclusion is not considered to be in the best interest of the patient or family (ie, primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the health care facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. visitor screening is used consistently on hsct units. , however, considering the experience during the sars outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial. education concerning respiratory hygiene/cough etiquette is a useful adjunct to visitor screening. ii.n. .b. use of barrier precautions by visitors. the use of gowns, gloves, and masks by visitors in health care settings has not been addressed specifically in the scientific literature. some studies included the use of gowns and gloves by visitors in the control of mdros but did not perform a separate analysis to determine whether their use by visitors had a measurable impact. [ ] [ ] [ ] family members or visitors who are providing care to or otherwise are in very close contact with the patient (eg, feeding, holding) may also have contact with other patients and could contribute to transmission in the absence of effective barrier precautions. specific recommendations may vary by facility or by unit and should be determined by the specific level of interaction. there are tiers of hicpac/cdc precautions to prevent transmission of infectious agents, standard precautions and transmission-based precautions. standard precautions are intended to be applied to the care of all patients in all health care settings, regardless of the suspected or confirmed presence of an infectious agent. implementation of standard precautions constitutes the primary strategy for the prevention of health care-associated transmission of infectious agents among patients and hcws. transmission-based precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. because the infecting agent often is not known at the time of admission to a health care facility, transmission-based precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. examples of this syndromic approach are presented in table . the hicpac/cdc guidelines also include recommendations for creating a protective environment for allogeneic hsct patients. the specific elements of standard and transmission-based precautions are discussed in part ii of this guideline. in part iii, the circumstances in which standard precautions, transmission-based precautions, and a protective environment are applied are discussed. tables and summarize the key elements of these sets of precautions standard precautions combine the major features of universal precautions , and body substance isolation and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which health care is delivered (table ). these include hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). the application of standard precautions during patient care is determined by the nature of the hcw-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. for some interactions (eg, performing venipuncture), only gloves may be needed; during other interactions (eg, intubation), use of gloves, gown, and face shield or mask and goggles is necessary. education and training on the principles and rationale for recommended practices are critical elements of standard precautions because they facilitate appropriate decision-making and promote adherence when hcws are faced with new circumstances. , [ ] [ ] [ ] [ ] [ ] [ ] an example of the importance of the use of standard precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (eg, sars-cov, n meningitides). the application of standard precautions is described below and summarized in table . guidance on donning and removing gloves, gowns and other ppe is presented in figure . standard precautions are also intended to protect patients by ensuring that hcws do not carry infectious agents to patients on their hands or via equipment used during patient care. , , the strategy proposed has been termed respiratory hygiene/cough etiquette , and is intended to be incorporated into infection control practices as a new component of standard precautions. the strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a health care facility. , , the term cough etiquette is derived from recommended source control measures for m tuberculosis. , the elements of respiratory hygiene/cough etiquette include ( ) education of health care facility staff, patients, and visitors; ( ) posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; ( ) source control measures (eg, covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); ( ) hand hygiene after contact with respiratory secretions; and ( ) spatial separation, ideally . feet, of persons with respiratory infections in common waiting areas when possible. covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air. , , , masking may be difficult in some settings, (eg, pediatrics), in which case the emphasis by necessity may be on cough etiquette. physical proximity of , feet has been associated with an increased risk for transmission of infections through the droplet route (eg, n meningitidis and group a streptococcus ) and thus supports the practice of distancing infected persons from others who are not infected. the effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside [ ] [ ] [ ] health care settings is summarized in several reviews. , , these measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (eg, influenza virus, adenovirus, b pertussis, and m pneumoniae ). although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. therefore, the absence of fever does not always exclude a respiratory infection. patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. although these patients often are not infectious, cough etiquette measures are prudent. hcws are advised to observe droplet precautions (ie, wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. hcws who have a respiratory infection are advised to avoid direct patient contact, especially with high-risk patients. if this is not possible, then a mask should be worn while providing patient care. iii.a. .b. safe injection practices. the investigation of large outbreaks of hbv and hcv among patients in ambulatory care facilities in the united states identified a need to define and reinforce safe injection practices. the outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. the primary breaches in infection control practice that contributed to these outbreaks were reinsertion of used needles into a multiple-dose vial or solution container (eg, saline bag) and use of a single needle/syringe to administer intravenous medication to multiple patients. in of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. these and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications. , these include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication. whenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. outbreaks related to unsafe injection practices indicate that some hcws are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. a survey of us health care workers who provide medication through injection found that % to % reused the same needle and/or syringe on multiple patients. among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow up on reported breaches in infection control practices in ambulatory settings. therefore, to ensure that all hcws understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence. iii.a. .c. infection control practices for special lumbar puncture procedures. in , the cdc investigated cases of postmyelography meningitis that either were reported to the cdc or identified through a survey of the emerging infections network of the infectious disease society of america. blood and/or cerebrospinal fluid of all cases yielded streptococcal species consistent with oropharyngeal flora and there were changes in the csf indices and clinical status indicative of bacterial meningitis. equipment and products used during these procedures (eg, contrast media) were excluded as probable sources of contamination. procedural details available for cases determined that antiseptic skin preparations and sterile gloves had been used. however, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. bacterial meningitis after myelography and other spinal procedures (eg, lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] as a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (eg, myelography, lumbar puncture, spinal anesthesia) has been debated. , face masks are effective in limiting the dispersal of oropharyngeal droplets and are recommended for the placement of central venous catheters. in october , hicpac reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space. there are categories of transmission-based precautions: contact precautions, droplet precautions, and airborne precautions. transmission-based precautions are used when the route(s) of transmission is (are) not completely interrupted using standard precautions alone. for some diseases that have multiple routes of transmission (eg, sars), more than transmission-based precautions category may be used. when used either singly or in combination, they are always used in addition to standard precautions. see appendix a for recommended precautions for specific infections. when transmission-based precautions are indicated, efforts must be made to counteract possible adverse effects on patients (ie, anxiety, depression and other mood disturbances, - perceptions of stigma, reduced contact with clinical staff, [ ] [ ] [ ] and increases in preventable adverse events ) to improve acceptance by the patients and adherence by hcws. iii.b. . contact precautions. contact precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are spread by direct or indirect contact with the patient or the patient's environment as described in section i.b. .a. the specific agents and circumstance for which contact precautions are indicated are found in appendix a. the application of contact precautions for patients infected or colonized with mdros is described in the hicpac/cdc mdro guideline. contact precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased potential for extensive environmental contamination and risk of transmission. a single-patient room is preferred for patients who require contact precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). in multipatient rooms, $ feet spatial separation between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. hcws caring for patients on contact precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. donning ppe on room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (eg, vre, c difficile, noroviruses and other intestinal tract pathogens, rsv). , , , , , , iii.b. . droplet precautions. droplet precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions as described in section i.b. .b. because these pathogens do not remain infectious over long distances in a health care facility, special air handling and ventilation are not required to prevent droplet transmission. infectious agents for which droplet precautions are indicated are listed in appendix a and include b pertussis, influenza virus, adenovirus, rhinovirus, n meningitides, and group a streptococcus (for the first hours of antimicrobial therapy). a single-patient room is preferred for patients who require droplet precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). spatial separation of $ feet and drawing the curtain between patient beds is especially important for patients in multibed rooms with infections transmitted by the droplet route. hcws wear a mask (a respirator is not necessary) for close contact with infectious patient; the mask is generally donned on room entry. patients on droplet precautions who must be transported outside of the room should wear a mask if tolerated and follow respiratory hygiene/cough etiquette. iii.b. . airborne precautions. airborne precautions prevent transmission of infectious agents that remain infectious over long distances when suspended in the air (eg, rubeola virus [measles], varicella virus [chickenpox], m tuberculosis, and possibly sars-cov), as described in section i.b. .c and appendix a. the preferred placement for patients who require airborne precautions is in an aiir, a single-patient room equipped with special air handling and ventilation capacity that meet the aia/facility guidelines institute standards for aiirs (ie, monitored negative pressure relative to the surrounding area; air exchanges per hour for new construction and renovation and air exchanges per hour for existing facilities; air exhausted directly to the outside or recirculated through hepa filtration before return). , some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with m tuberculosis. a respiratory protection program that includes education about use of respirators, fit testing, and user seal checks is required in any facility with aiirs. in settings where airborne precautions cannot be implemented due to limited engineering resources (eg, physician offices), masking the patient, placing the patient in a private room (eg, office examination room) with the door closed, and providing n or higher-level respirators or masks if respirators are not available for hcws will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an aiir or returned to the home environment, as deemed medically appropriate. hcws caring for patients on airborne precautions wear a mask or respirator, depending on the disease-specific recommendations (see section ii.e. , table , and appendix a), that is donned before room entry. whenever possible, nonimmune hcws should not care for patients with vaccine-preventable airborne diseases (eg, measles, chickenpox, smallpox). diagnosis of many infections requires laboratory confirmation. because laboratory tests, especially those that depend on culture techniques, often require or more days for completion, transmission-based precautions must be implemented while test results are pending, based on the clinical presentation and likely pathogens. use of appropriate transmission-based precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a health care facility for care, reduces transmission opportunities. although it is not possible to identify prospectively all patients needing transmission-based precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (see table ). icps are encouraged to modify or adapt this table according to local conditions. transmission-based precautions remain in effect for limited periods (ie, while the risk for transmission of the infectious agent persists or for the duration of the illness (see appendix a). for most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. for some diseases (eg, pharyngeal or cutaneous diphtheria, rsv), transmission-based precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for rsv, symptomatic disease is resolved. for other diseases (eg, m tuberculosis), state laws and regulations and health care facility policies may dictate the duration of precautions. in immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks. , [ ] [ ] [ ] [ ] [ ] [ ] the duration of contact precautions for patients who are colonized or infected with mdros remains undefined. mrsa is the only mdro for which effective decolonization regimens are available. however, carriers of mrsa who have negative nasal cultures after a course of systemic or topical therapy may resume shedding mrsa in the weeks after therapy. , although early guidelines for vre suggested discontinuation of contact precautions after stool cultures obtained at weekly intervals proved negative, subsequent experiences have indicated that such screening may fail to detect colonization that can persist for . year. , [ ] [ ] [ ] likewise, available data indicate that colonization with vre, mrsa, and possibly mdr-gnb can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. it may be prudent to assume that mdro carriers are colonized permanently and manage them accordingly. alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (eg, or months) before reculturing patients to document clearance of carriage may be used. determination of the best strategy awaits the results of additional studies. see the hicpac/cdc mdro guideline for a discussion of possible criteria to discontinue contact precautions for patients colonized or infected with mdros. although transmission-based precautions generally apply in all health care settings, exceptions exist. for example, in home care, aiirs are not available. furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting hcws would need to use such protection. similarly, management of patients colonized or infected with mdros may necessitate contact precautions in acute care hospitals and in some ltcfs when there is continued transmission, but the risk of transmission in ambulatory care and home care has not been defined. consistent use of standard precautions may suffice in these settings, but more information is needed. a pe is designed for allogeneic hsct patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see table for specifications). , [ ] [ ] [ ] the need for such controls has been demonstrated in studies of aspergillosis outbreaks associated with construction. , , , , as defined by the aia and presented in detail in the cdc's guideline for environmental infection control in health care facilities, , air quality for hsct patients is improved through a combination of environmental controls that include ( ) hepa filtration of incoming air, ( ) directed room air flow, ( ) positive room air pressure relative to the corridor, ( ) well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside, ( ) ventilation to provide $ air changes per hour, ( ) strategies to minimize dust (eg, scrubbable surfaces rather than upholstery and carpet, and routinely cleaning crevices and sprinkler heads), and ( ) prohibiting dried and fresh flowers and potted plants in the rooms of hsct patients. the latter is based on molecular typing studies that have found indistinguishable strains of aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients. [ ] [ ] [ ] the desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow. , to prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health care facility, it has been recommended that severely immunocompromised patients wear a high-efficiency respiratory protection device (eg, an n respirator) when they leave the pe. , , the use of masks or respirators by hsct patients when they are outside of the pe for prevention of environmental fungal infections in the absence of construction has not been evaluated. a pe does not include the use of barrier precautions beyond those indicated for standard precuations and transmission-based precautions. no published reports support the benefit of placing patients undergoing solid organ transplantation or other immunocompromised patients in a pe. these recommendations are designed to prevent transmission of infectious agents among patients and hcws in all settings where health care is delivered. as in other cdc/hicpac guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and, when possible, economic impact. the cdc/hicpac system for categorizing recommendations is as follows: category ia. strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. category ib. strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. category ic. required for implementation, as mandated by federal and/or state regulation or standard. category ii. suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. no recommendation; unresolved issue. practices for which insufficient evidence or no consensus regarding efficacy exists. health care organization administrators should ensure the implementation of recommendations specified in this section. agents into the objectives of the organization's patient and occupational safety programs. assume that every person is potentially infected or colonized with an organism that could be transmitted in the health care setting and apply the following infection control practices during the delivery of health care. iv.a. . during the delivery of health care, avoid unnecessary touching of surfaces in close proximity to the patient to prevent both contamination of clean hands from environmental surfaces and transmission of pathogens from contaminated hands to surfaces. airborne precautions does not need to wear a mask or respirator during transport if the patient is wearing a mask and infectious skin lesions are covered. category ii v.d. . exposure management immunize or provide the appropriate immune globulin to susceptible persons as soon as possible after unprotected contact (ie, exposure) to a patient with measles, varicella, or smallpox: category ia d administer measles vaccine to exposed susceptible persons within hours after the exposure or administer immune globulin within days of the exposure event for high-risk persons in whom vaccine is contraindicated. , - d administer varicella vaccine to exposed susceptible persons within hours after the exposure or administer varicella immune globulin (vzig or an alternative product), when available, within hours for high-risk persons in whom vaccine is contraindicated (eg, immunocompromised patients, pregnant women, newborns whose mother's varicella onset was , days before or within hours after delivery). , - d administer smallpox vaccine to exposed susceptible persons within days after exposure. vi. protective environment (see table airborne infection isolation room (aiir). formerly known as a negative-pressure isolation room, an aiir is a single-occupancy patient care room used to isolate persons with a suspected or confirmed airborne infectious disease. environmental factors are controlled in aiirs to minimize the transmission of infectious agents that are usually transmitted from person to person by droplet nuclei associated with coughing or aerosolization of contaminated fluids. aiirs should provide negative pressure in the room (so that air flows under the door gap into the room), an air flow rate of to air changes per hour (ach) ( ach for existing structures, ach for new construction or renovation), and direct exhaust of air from the room to the outside of the building or recirculation of air through a highefficiency particulate air filter before returning to circulation. ( ambulatory care setting. a facility that provides health care to patients who do not remain overnight; examples include hospital-based outpatient clinics, non-hospital-based clinics and physician offices, urgent care centers, surgicenters, free-standing dialysis centers, public health clinics, imaging centers, ambulatory behavioral health and substance abuse clinics, physical therapy and rehabilitation centers, and dental practices. bioaerosol. an airborne dispersion of particles containing whole or parts of biological entities, including bacteria, viruses, dust mites, fungal hyphae, and fungal spores. such aerosols usually consist of a mixture of monodispersed and aggregate cells, spores, or viruses carried by other materials, such as respiratory secretions and/or inert particles. infectious bioaerosols (ie, those containing biological agents capable of causing an infectious disease) can be generated from human sources (eg, expulsion from the respiratory tract during coughing, sneezing, talking, singing, suctioning, or wound irrigation), wet environmental sources (eg, high-volume air consitioning and cooling tower water with legionella) or dry sources (eg, construction dust with spores produced by aspergillus spp). bioaerosols include large respiratory droplets and small droplet nuclei (cole ec. ajic ; : - ) . caregiver.. any person who is not an employee of an organization, is not paid, and provides or assists in providing health care to a patient (eg, family member, friend) and acquire technical training as needed based on the tasks that must be performed. cohorting. in the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). during outbreaks, health care personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). colonization. proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. the presence of a microorganism within a host may occur with varying durations but may become a source of potential transmission. in many instances, colonization and carriage are synonymous. droplet nuclei. microscopic particles , mm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. these particles can remain suspended in the air for prolonged periods and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. engineering controls. removal or isolation of a workplace hazard through technology. an airborne infection isolation room, a protective environment, engineered sharps injury prevention device, and a sharps container are examples of engineering controls. epidemiologically important pathogen. an infectious agent that has one or more of the following characteristics: ( ) readily transmissible, ( ) a proclivity toward causing outbreaks, ( ) possible association with a severe outcome, and ( ) difficult to treat. examples include acinetobacter spp, aspergillus spp, burkholderia cepacia, clostridium difficile, klebsiella or enterobacter spp, extended-spectrum beta-lactamaseproducing gram-negative bacilli, methicillin-resistant staphylococcus aureus, pseudomonas aeruginosa, vancomycin-resistant enterococci, vancomycin-resistant staphylococcus aureus, influenza virus, respiratory syncytial virus, rotavirus, severe acute respiratory syndrome coronavirus, noroviruses, and the hemorrhagic fever viruses. hand hygiene. a general term that applies to any one of the following: ( ) handwashing with plain (nonantimicrobial) soap and water, ( ) antiseptic handwashing (soap containing antiseptic agents and water), ( ) antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands), or ( ) surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora). health care-associated infection (hai). an infection that develops in a patient who is cared for in any setting where health care is delivered (eg, acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (ie, was not incubating or present at the time health care was provided). in ambulatory and home settings, hai refers to any infection that is associated with a medical or surgical intervention. because the geographic location of infection acquisition is often uncertain, the preferred term is considered to be health care-associated rather than health care-acquired. healthcare epidemiologist. a person whose primary training is medical (md, do) and/or masters-or doctorate-level epidemiology who has received advanced training in health care epidemiology. typically these professionals direct or provide consultation to an infection control program in a hospital, long-term care facility, or health care delivery system (also see infection control professional). health care personnel, health care worker (hcw). any paid or unpaid person who works in a health care setting (eg, any person who has professional or technical training in a health care-related field and provides patient care in a health care setting or any person who provides services that support the delivery of health care such as dietary, housekeeping, engineering, maintenance personnel). hematopoietic stem cell transplantation (hsct). any transplantation of blood-or bone marrow-derived hematopoietic stem cells, regardless of donor type (eg, allogeneic or autologous) or cell source (eg, bone marrow, peripheral blood, or placental/umbilical cord blood), associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (mmwr ; : rr- ). high-efficiency particulate air (hepa) filter. an air filter that removes . . % of particles . . mm (the most penetrating particle size) at a specified flow rate of air. hepa filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (mmwr ; : rr- ). home care. a wide range of medical, nursing, rehabilitation, hospice, and social services delivered to patients in their place of residence (eg, private residence, senior living center, assisted living facility). home health care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. immunocompromised patient. a patient whose immune mechanisms are deficient because of a congenital or acquired immunologic disorder (eg, human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, intensive care unit care, malnutrition, and immunosuppressive therapy of another disease process [eg, radiation, cytotoxic chemotherapy, anti-graft rejection medication, corticosteroids, monoclonal antibodies directed against a specific component of the immune system]). the type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. patients undergoing allogeneic hematopoietic stem cell transplantation and those with chronic graft versus host disease are considered the most vulnerable to health care-associated infections. immunocompromised states also make it more difficult to diagnose certain infections (eg, tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system. infection. the transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues. infection control and prevention professional (icp). a person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired specialized training in infection control. responsibilities may include collection, analysis, and feedback of infection data and trends to health care providers; consultation on infection risk assessment, prevention, and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (eg, to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the health care setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. certification in infection control is available through the certification board of infection control and epidemiology. infection control and prevention program. a multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of health care-associated infections are implemented and followed by health care workers, making the health care setting safe from infection for patients and health care personnel. the joint commission on accreditation of healthcare organizations requires the following components of an infection control program for accreditation: ( ) surveillance: monitoring patients and health care personnel for acquisition of infection and/or colonization; ( ) investigation: identification and analysis of infection problems or undesirable trends; ( ) prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; ( ) control: evaluation and management of outbreaks; and ( ) reporting: provision of information to external agencies as required by state and federal laws and regulations (see http://www.jcaho.org). the infection control program staff has the ultimate authority to determine infection control policies for a health care organization with the approval of the organization's governing body. long-term care facility (ltcf). a residential or outpatient facility designed to meet the biopsychosocial needs of persons with sustained self-care deficits. these include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. mask. a term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (see http://www.fda. gov/cdrh/ode/guidance/ .html# ). multidrug-resistant organism (mdro). in general, a bacterium (excluding mycobacterium tuberculosis) that is resistant to or more classes of antimicrobial agents and usually is resistant to all but or commercially available antimicrobial agents (eg, methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing or intrinsically resistant gram-negative bacilli). nosocomial infection. derived from greek words, ''nosos'' (disease) and ''komeion'' (to take care of), refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. personal protective equipment (ppe). a variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. ppe includes gloves, masks, respirators, goggles, face shields, and gowns. procedure mask. a covering for the nose and mouth that is intended for use in general patient care situations. these masks generally attach to the face with ear loops rather than ties or elastic. unlike surgical masks, procedure masks are not regulated by the food and drug administration. protective environment. a specialized patient care area, usually in a hospital, with a positive air flow relative to the corridor (ie, air flows from the room to the outside adjacent space). the combination of high-efficiency particulate air filtration, high numbers (. ) of air changes per hour, and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (eg, those who have received allogeneic hemopoietic stem cell transplantation) and decrease the risk of exposure to spores produced by environmental fungi. other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants. quasi-experimental study. a study undertaken to evaluate interventions but do not use randomization as part of the study design. these studies are also referred to as nonrandomized, pre-/postintervention study designs. these studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning an attributable benefit obtained through a randomized controlled trial. in hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical, and urgency reasons; therefore, quasi-experimental design studies are commonly used. however, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result. such a study design is used when it is not logistically feasible or ethically possible to conduct a randomized controlled trial, (eg, during outbreaks). within the classification of quasi-experimental study designs, there is a hierarchy of design features that may contribute to validity of results (harris et al. cid : : . residential care setting. a facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for. respirator. a personal protective device worn by health care personnel over the nose and mouth to protect them from acquiring airborne infectious diseases due to inhalation of infectious airborne particles , mm in size. these include infectious droplet nuclei from patients with mycobacterium tuberculosis, variola virus [smallpox], or severe acute respiratory syndrome and dust particles that contain infectious particles, such as spores of environmental fungi (eg, aspergillus spp). the centers for disease control and prevention's national institute for occupational safety and health (niosh) certifies respirators used in health care settings (see http://www.cdc.gov/niosh/topics/respirators/). the n disposable particulate, air-purifying respirator is the type used most commonly by health care personnel. other respirators used include n- and n- particulate respirators, powered air-purifying respirators with high-efficiency filters, and nonpowered fullfacepiece elastomeric negative pressure respirators. a listing of niosh-approved respirators can be found at http://www.cdc.gov/niosh/npptl/respirators/disp_part/ particlist.html. respirators must be used in conjunction with a complete respiratory protection program, as required by the occupational safety and health administration, which includes fit testing, training, proper selection of respirators, medical clearance, and respirator maintenance. respiratory hygiene/cough etiquette. a combination of measures designed to minimize the transmission of respiratory pathogens through droplet or airborne routes in health care settings. the components of respiratory hygiene/cough etiquette are ( ) covering the mouth and nose during coughing and sneezing, ( ) using tissues to contain respiratory secretions with prompt disposal into a no-touch receptacle, ( ) offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and ( ) turning the head away from others and maintaining spatial separation (ideally . feet) when coughing. these measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a health care setting (eg, reception/triage in emergency departments, ambulatory clinics, health care provider offices). (srinivasin a iche ; : ; http://www.cdc.gov/flu/ professionals/infectioncontrol/resphygiene.htm). safety culture. shared perceptions of workers and management regarding the level of safety in the work environment. a hospital safety climate includes the following organizational components: ( ) senior management support for safety programs, ( ) absence of workplace barriers to safe work practices, ( ) cleanliness and orderliness of the worksite, ( ) minimal conflict and good communication among staff members, ( ) frequent safety-related feedback/training by supervisors, and ( ) availability of ppe and engineering controls. source control. the process of containing an infectious agent either at the portal of exit from the body or within a confined space. the term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (eg, a draining wound, vesicular or bullous skin lesions). respiratory hygiene/cough etiquette that encourages individuals to ''cover your cough'' and/or wear a mask is a source control measure. the use of enclosing devices for local exhaust ventilation (eg, booths for sputum induction or administration of aerosolized medication) is another example of source control. standard precautions. a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. standard precautions represents a combination and expansion of universal precautions and body substance isolation. standard precautions are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include hand hygiene and, depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. in addition, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). surgical mask. a device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. surgical masks also are used to protect health care personnel from contact with large infectious droplets (. mm in size). according to draft guidance issued by the food and drug administration on may , , surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability to mitigate the risks to health associated with the use of surgical masks. these specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (http://www.fda.gov/cdrh/ode/guidance/ .html# ). surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents (eg, mycobacterium tuberculosis). other species s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. giardia lamblia s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. noroviruses s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks, because virus can be aerosolized from these body substances; , , ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled. , hypochlorite solutions may be required when there is continued transmission. [ ] [ ] [ ] alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination. cohorting of affected patients to separate airs paces and toilet facilities may help interrupt transmission during outbreaks. rotavirus c di ensure consistent environmental cleaning and disinfection and frequent removal of soiled diapers. prolonged shedding may occur in both immunocompetent and immunocompromised children and the elderly. also for asymptomatic, exposed infants delivered vaginally or by c-section and if mother has active infection and membranes have been ruptured for more than to hours until infant surface cultures obtained at to hours of age negative after hours of incubation. susceptible hcws should not enter room if immune caregivers are available; no recommendation for face protection of immune hcws; no recommendation for type of protection (ie, surgical mask or respirator) for susceptible hcws. in an immunocompromised host with varicella pneumonia, prolong the duration of precautions for duration of illness. postexposure prophylaxis: provide postexposure vaccine as soon as possible but within hours; for susceptible exposed persons for whom vaccine is contraindicated (immunocompromised persons, pregnant women, newborns whose mother's varicella onset is # days before delivery or within hours after delivery) provide vzig, when available, within hours; if unavailable, use ivig. provide airborne precautions for exposed susceptible persons and exclude exposed susceptible health care workers beginning days after first exposure until days after last exposure or if received vzig, regardless of postexposure vaccination. variola (see smallpox) vibrio parahaemolyticus (see gastroenteritis) vincent's angina (trench mouth) s viral hemorrhagic fevers due to lassa, ebola, marburg, crimean-congo fever viruses s, d, c di single-patient room preferred. emphasize: use of sharps safety devices and safe work practices, hand hygiene; barrier protection against blood and body fluids on entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields), and appropriate waste handling. use n or higher-level respirator when performing aerosol-generating procedures. largest viral load in final stages of illness when hemorrhage may occur; additional ppe, including double gloves, leg and shoe coverings may be used, especially in resource-limited settings where options for cleaning and laundry are limited. notify public health officials immediately if ebola is suspected. , , , also see table *type of precautions: a, airborne precautions; c, contact; d, droplet; s, standard; when a, c, and d are specified, also use s. y duration of precautions: cn, until off antimicrobial treatment and culture-negative; di, duration of illness (with wound lesions, di means until wounds stop draining); de, until environment completely decontaminated; u, until time 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recent outbreak of adenovirus type infection in a chronic inpatient facility for the severely handicapped an outbreak of multidrugresistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents human-to-human transmission of rabies virus by corneal transplant human rabies prevention, united states, : recommendations of the advisory committee on immunization practices (acip) rhinovirus and the lower respiratory tract concurrent outbreaks of rhinovirus and respiratory syncytial virus in an intensive care nursery: epidemiology and associated risk factors rhinovirus infection associated with serious lower respiratory illness in patients with bronchopulmonary dysplasia nosocomial ringworm in a neonatal intensive care unit: a nurse and her cat nosocomial transmission of trichophyton tonsurans tinea corporis in a rehabilitation hospital molecular epidemiology of staphylococcal scalded skin syndrome in premature infants an outbreak of fatal nosocomial infections due to group a streptococcus on a medical ward an outbreak of group a streptococcal infection among health care workers clusters of invasive group a streptococcal infections in family, hospital, and nursing home settings isolation techniques for use in hospitals us government printing office rethinking the role of isolation practices in the prevention of nosocomial infections the authors and hicpac gratefully acknowledge dr larry strausbaugh for his many contributions and valued guidance in the preparation of this guideline. the mode(s) and risk of transmission for each specific disease agent listed in this appendix were reviewed. principle sources consulted for the development of disease-specific recommendations for the appendix included infectious disease manuals and textbooks. , , the published literature was searched for evidence of person-to-person transmission in health care and non-health care settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where health care is delivered. the following criteria were used to assign transmission-based precautions categories: d a transmission-based precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in health care or non-health care settings and/or if patient factors (eg, diapered infants, diarrhea, draining wounds) increased the risk of transmission. d transmission-based precautions category assignments reflect the predominant mode(s) of transmission. d if there was no evidence for person-to-person transmission by droplet, contact or airborne routes, then standard precautions were assigned. d if there was a low risk for person-to-person transmission and no evidence of health care-associated transmission, then standard precautions were assigned. d standard precautions were assigned for bloodborne pathogens (eg, hbv, hcv, hiv) in accordance with cdc recommendations for universal precautions issued in . subsequent experience has confirmed the efficacy of standard precautions to prevent exposure to infected blood and body fluid. , , additional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (eg, sars-cov, avian influenza) that have been added to appendix a. the reader may refer to more detailed discussion concerning modes of transmission and emerging pathogens in the background text and for mdro control in the mdro guideline. key: cord- -ceehbhcb authors: eksin, c.; ndeffo-mbah, m.; weitz, j. s. title: reacting to outbreaks at neighboring localities date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ceehbhcb we study the dynamics of epidemics in a networked metapopulation model. in each subpopulation, representing a locality, disease propagates according to a modified susceptible-exposed-infected-recovered (seir) dynamics. we assume that individuals reduce their number of contacts as a function of the weighted sum of cumulative number of cases within the locality and in neighboring localities. the susceptible and exposed (pre-symptomatic and infectious) individuals are allowed to travel between localities undetected. to investigate the combined effects of mobility and contact reduction on disease progression within interconnected localities, we consider a scenario with two localities where disease originates in one and is exported to the neighboring locality via travel of undetected pre-symptomatic individuals. we associate the behavior change at the disease-importing locality due to the outbreak size at the origin with the level of preparedness of the locality. our results show that restricting mobility is valuable if the importing locality is increasing its level of preparedness with respect to the outbreak size at the origin. moreover, increased levels of preparedness can yield lower total outbreak size by further reducing the outbreak size at the importing locality, even when the response at the origin is weak. our results highlight that public health decisions on social distancing at localities with less severe outbreaks should strongly account for potential impact of neighbouring localities with a poor response to the outbreak rather than localities with successful responses. early detection of disease outbreaks at their location of origin provide a chance for local containment and time to prepare in other locations. such preparation may enable locations connected to the origin to become more aware of the outbreak and develop a stronger response to the disease especially when it is not contained. the success of containment strategies is highly dependent on the ability of promptly detecting most infectious individuals in a given location. the recent outbreak of the covid- virus has shown that successful containment efforts are highly challenging when many infectious individuals remain asymptomatic and can travel undetected between locations [ ] . in the ongoing covid- outbreak, localities in the us are beginning to see alarming surges in their number of cases and hospitalized individuals at different times, likely because the introduction times of the disease to the local communities differ [ ] . while reducing mobility between localities can delay the overall epidemic progression, the epidemic trajectory, e.g., the final outbreak size, is not strongly affected by the travel restrictions unless they are combined with a strong reduction in transmission within the locality [ ] [ ] [ ] [ ] . in the us, local authorities are implementing non-pharmaceutical interventions, e.g., declaring emergency or issuing stay at home orders, at different times. community response to these interventions differ across localities [ ] . the premise of this work is to assess-in a generalized model -the combined effects of mobility, local response to disease prevalence, and the level of alertness prior to disease surge in a locality. here, we consider a networked-metapopulation model [ ] [ ] [ ] [ ] where the disease progresses according to susceptibleexposed-infected-recovered (seir) dynamics within each population or locality (similar to [ ] ). within each population, susceptible individuals can become exposed, i.e., pre-symptomatic, by being in contact with individuals in exposed and infected compartments. recent experiments on temporal viral shedding of covid- estimate near half of the secondary cases happen by being in contact with individuals in pre-symptomatic stage [ ] . the difference between pre-symptomatic infected and infected individuals is that pre-symptomatic individuals can travel between localities undetected. in our model, the exposed individuals progress to being infected and then to being recovered. that is, we do not make a distinction between symptomatic and asymptomatic infected individuals; further extensions could incorporate such differences, e.g., [ , ] . our focus is on the role of behavior changes in different localities and the effects of behavior changes on local disease progression. we assume individuals change their behavior and reduce their contacts proportional to disease severity, i.e., the ratio of infected and recovered, in the population [ , ] . in addition, behavior in a locality can be affected by the disease severity in neighboring localities. that is, individuals in a locality take protective measures, e.g., social distancing, based on disease severity in a neighboring locality. in particular, we consider a scenario between two localities in which the disease originates in one, and moves to the other locality by mobility of exposed individuals. in this scenario, we interpret initial behavior changes at the locality neighboring the origin as 'preparedness-based' behavior change. our aim is to quantify the combined effects of inter-locality mobility, preparedness-based behavior change, and behavior changes in response to local disease prevalence. our analysis focuses on delay in peak times between two localities, total outbreak size and the outbreak size at localities neighboring the origin as a function of mobility, preparedness, and population response. we consider a networked meta-population model. at each population, the disease propagates according to seir dynamics, that assumes a homogeneously mixed population. in addition, we assume there is constant travel in and out of each population. at midst of containment efforts, the flow of travelers are only healthy (susceptible), and those that are infectious without symptoms (exposed). the dynamics at locality i is given as follows: where β i is the transmission rate at location i, λ ij is the flow of individuals from location i to neighboring location j, µ denotes transition rate from exposed (pre-symptomatic) to infected (symptomatic), and δ is the recovery rate. we denote the neighboring localities of i with n i . we assume total flow in and out of a location are equal, i.e., λ ij = λ ji . the total mobility flow from i to j include susceptible and exposed individuals proportional to their size in the population. we assume infected individuals cannot move without being detected. the transmission rate at location i depends on the inherent infectivity rate β and social distancing due to disease prevalence, in the social distancing model, individuals reduce their interaction with others proportional to the ratio of cumulative cases, defined as the ratio of infectious and recovered in the population, individuals at locality i and neighboring localities of i. the term inside the parentheses is the awareness at locality i caused by disease prevalence. the weight constant ω ii ∈ [ , ] determines the importance of disease prevalence at locality i versus the importance of disease prevalence at neighboring n i localities, ω ij ∈ [ , ]. we assume the weights sum to one, i.e., j∈ni i ω ij = . the exponent constant α i represents the strength of response to the disease awareness. it determines the overall distancing at locality i based on the awareness. if α i = , there is no distancing response to the awareness at locality i. note that the awareness term inside the parentheses is always less than or equal to . thus, the larger α i is, the larger is the distancing response at locality i to disease prevalence. we refer to the case with α i = as the linear distancing model. in the following, we consider two localities with equal population sizes n = n . the disease starts at locality with . % infected, and spreads over to locality via undetected exposed individuals traveling from to . we set β = , µ = , and δ = based on the rates estimated at [ ] for the covid- outbreak in china. note that we have the standard seir model in both localities when α i = and λ ij = for all localities. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . (right) percentage reduction in outbreak size and ratio of infected at peak with respect to increasing social distancing exponent (αi) at locality . we measure the reduction with respect to the no-distancing case (αi = ). in both cases, we have the mobility per day λ = λ = . % of the population. as a baseline we consider no distancing response, i.e., α i = for all i = { , }-see figure (left). final sizes at localities are almost the same. the difference in peak times of two localities increases from days to days as λ ij decreases from . % to . %. next, we consider the effect of social distancing. for this, we assume localities only put weight on disease prevalence at their own locality, i.e., ω ii = for i ∈ { , }. figure (right) shows the reduction in final outbreak size and peak ratio of infected at locality as localities become more responsive, i.e., as α i increases. when the distancing is linear α i = , the reductions in peak and outbreak size are slightly above %. reduction in both metrics reaches above % when α i = . while both metrics continue to decrease with α i increasing, there does not exist a critical threshold of α i that stops the outbreak from happening [ ] [ ] [ ] . we observe a slight decrease in time of peak from day to day as α i increases from to . the results mentioned above for locality are very similar for locality which observes the outbreak on average days earlier. this similarity is expected when ω = ω = , and α = α . next, we analyze when localities respond differently to the outbreak. we analyze the effect of awareness at locality caused by the outbreak in locality . we denote the weight ω associated with this awareness as the adopted awareness weight. locality , the origin of the outbreak, faces the outbreak first. we assume locality 's awareness is not shaped by the outbreak at locality , i.e., ω = . figure (left) and (right) show the outbreak size at locality with respect to the weight locality puts on the size of the epidemic at locality respectively for weak linear (α = ) and strong (α = ) responses at locality . in each plot, we consider both weak (α = ) and strong (α = ) responses by locality , and low (λ ij = . %) and high (λ ij = . %) mobility rates. in figure (left) and (right), the outbreak size at locality monotonically decreases starting from no adopted awareness case, as adopted awareness w increases irrespective of the strength of response α at locality . the starting point is higher on the left figure since the response to awareness at locality is weak (linear) while the strength of response on the right is strong with α = . in both figures, the decrease of the outbreak size at locality with respect to the adopted awareness constant is faster when the response at locality is weak. the reason for this is that a weaker response at locality results in a higher ratio of cumulative cases, which means higher awareness at locality . indeed, locality is always better off adopting the awareness at locality , as this will lead to an early strong response to the disease. the mobility across localities amplifies the effect of response at locality on the outbreak size at locality . when mobility is low, the difference in time when disease takes-off at locality compared to locality is very large (≈ days), which means the contribution of the ratio of cumulative cases at locality to the awareness at locality is high. this translates to a stronger response at locality . when the response at locality is high, we observe that high awareness caused by the outbreak at locality can suffice in stopping disease transmission at . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . locality -see figure (right) for w > . for low mobility and weak response at locality . we note that the adopted awareness should be interpreted as individuals in locality reducing contacts, i.e., practice social distancing, based on the awareness that the outbreak at locality creates. that is, when the disease starts in one location (locality ) and moves to a neighboring locality (locality ) via travel of exposed or asymptomatic infectious individuals from the origin, the adopted awareness distancing term at locality is a measure of the preparedness at locality . while the above analysis shows that locality can benefit from a heightened awareness due to a weak response at locality , this awareness is a direct result of the lack of control at locality . in figure , we analyze the total outbreak size given the same setting as in figure . in figure (left), we consider a weak (linear) response at locality . in this scenario, for adopted awareness smaller than . (ω < . ), we observe that the total outbreak size is smaller in the cases that locality responds strongly, i.e., α = (shown by blue lines). for adopted awareness larger than . (ω > . ), we see that the total outbreak size is smaller in the cases that locality responds weakly, i.e., α = (shown by black lines). an intuition for this result follows. when the response at locality gets weaker, the outbreak size at locality increases. this increase results in a higher level of preparedness at locality , which yields a smaller outbreak size at locality . figure (left) shows that there exists a level of preparedness (ω ≈ . ) above which the increase in severity of the outbreak at locality is smaller than the reduction in the outbreak size . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . benefit of adopted awareness with respect to mobility. locality shows a strong response α = , while the response at locality is weak α = . the benefit is measured as the reduction in final size with respect to the zero-adopted awareness constant scenario ω = . let f (ω , λ ) denote the final outbreak size at locality with respect to ω and λ . the benefit of alertness is defined as f ( , λ ) − f (ω , λ ). at locality . we note that the critical level of preparedness needed is higher when mobility is high. in contrast, when the response at locality is strong in figure (right), there does not exist an adopted awareness constant value where a weak response at locality can be better in terms of total outbreak size. this is because even a small outbreak at locality triggers a strong level of preparedness at locality because the response constant is α = . comparing figures (left) and (right), the total outbreak size is always lower on the right figure, i.e., when the response at locality is strong. these observations indicate that we obtain the best outcome in terms of total outbreak size when both localities respond strongly, and locality has an adopted awareness constant value near ω ≈ . . recall, ω represents a measure of preparedness at locality . in other words, the best outcome in terms of total outbreak size is when a locality balances its reaction to its own state and that of others. we further demonstrate the effects of mobility rate on the outbreak size at locality in figure . we measure the benefit in outbreak size with respect to the outbreak size when adopted awareness constant is zero, i.e., ω = . as is evident from figure , it is better to have a high adopted awareness constant for all mobility rate values. given positive adopted awareness constant values ω > , the potential benefit of adopted awareness reduces as mobility increases. the intuition for this is that when the mobility increases, the delay in start times of the outbreaks between localities is reduced. this implies the adopted awareness at locality is lower as the full impact of the outbreak at locality is not yet realized. we developed a mathematical model to analyze the impact of social distancing efforts on disease dynamics among interconnected populations. we assumed that social distancing efforts at a given location is a function of both disease prevalence within the population and outbreak dynamics at neighboring localities. our analysis showed that it is beneficial to reduce travel between localities given the inability to detect asymptomatic infectious individuals (consistent with recent findings [ ] ). however, this benefit is contingent on how prepared neighboring localities are for the importation of cases. we used the term adopted awareness to determine the level of preparedness at neighboring localities as an increasing function of the outbreak size at the origin. the increasing function assumption implied that neighboring localities increase their levels of preparedness as the severity of the disease at the origin increased. that is, as the severity of the outbreak at the origin increases, this triggers increased social distancing efforts at neighboring localities by local authorities making non-pharmaceutical interventions, e.g., declaring state of emergency, or issuing stay at home orders. our analysis showed that slow mobility will provide the lead time for increased alertness levels and will result in higher levels of preparedness. indeed, low mobility reduces the critical level of preparedness needed to stop the outbreak from becoming a pandemic at a neighboring locality (figure ) . it is not surprising that increased levels of preparedness reduces the outbreak size at localities neighboring the origin. however, the level of preparedness is contingent on the outbreak size at the origin. thus, in order for the level of preparedness to increase at a locality, its neighbor should incur a larger outbreak size. in order to assess . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . https://doi.org/ . / . . . doi: medrxiv preprint whether the level of preparedness, and thus, reduction in outbreak size at neighboring localities can make up for the increased outbreak size at the origin, we looked at the total outbreak size as a function of strength of response to local disease prevalence. our results show that increased levels of preparedness at neighboring localities can yield lower total outbreak sizes even when the response at the origin is weak (figure (left) ). these findings imply that if there are multiple localities with outbreaks, the jurisdictions with less severe outbreaks should be looking at their worse-off neighbor rather than their best-off neighbor, and implementing social distancing measures accordingly. given the continuing threat of covid- , the present study provides additional support for viewing pandemics in a connected, rather than isolated, context. substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov ) probability of current covid- outbreaks in all us counties. medrxiv the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak impact of international travel and border control measures on the global spread of the novel coronavirus outbreak risk for transportation of novel coronavirus disease from wuhan to other cities in china. emerging infectious diseases the effect of human mobility and control measures on the covid- epidemic in china assessing changes in commuting and individual mobility in major metropolitan areas in the united states during the covid- outbreak multiscale, resurgent epidemics in a hierarchical metapopulation model dynamics and control of diseases in networks with community structure covid- healthcare demand projections: texas cities invasion threshold in heterogeneous metapopulation networks. physical review letters nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study temporal dynamics in viral shedding and transmissibility of covid- . medrxiv the time scale of asymptomatic transmission affects estimates of epidemic potential in the covid- outbreak. medrxiv networked sis epidemics with awareness systematic biases in disease forecasting-the role of behavior change the spread of awareness and its impact on epidemic outbreaks jsw was supported, in part, by a grant from the army research office (w nf ). the code is available at https://github.com/ceyhuneksin/reacting_outbreaks_neighboring_localities. key: cord- -p ld tun authors: bonadonna, lucia; la rosa, giuseppina title: a review and update on waterborne viral diseases associated with swimming pools date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: p ld tun infectious agents, including bacteria, viruses, protozoa, and molds, may threaten the health of swimming pool bathers. viruses are a major cause of recreationally-associated waterborne diseases linked to pools, lakes, ponds, thermal pools/spas, rivers, and hot springs. they can make their way into waters through the accidental release of fecal matter, body fluids (saliva, mucus), or skin flakes by symptomatic or asymptomatic carriers. we present an updated overview of epidemiological data on viral outbreaks, a project motivated, among other things, by the availability of improved viral detection methodologies. special attention is paid to outbreak investigations (source of the outbreak, pathways of transmission, chlorination/disinfection). epidemiological studies on incidents of viral contamination of swimming pools under non-epidemic conditions are also reviewed. swimming pools have been implicated in the transmission of infections. the risk of infection has mainly been linked to fecal contamination of the water, generally due to feces released by bathers or to contaminated source water. failure in disinfection has been recorded as the main cause of many of the outbreaks associated with swimming pools. the majority of reported swimming pool-related outbreaks have been caused by enteric viruses [ , ] . sinclair and collaborators reported that % of viral outbreaks occur in swimming pools, % in lakes or ponds, and the remaining % in fountains, hot springs, and rivers ( % each) [ ] . viruses cannot replicate outside their host's tissues and cannot multiply in the environment. therefore, the presence of viruses in a swimming pool is the result of direct contamination by bathers, who may shed viruses through unintentional fecal release, or through the release of body fluids such as saliva, mucus, or vomitus [ ] . evidence suggests that skin may also be a potential source of pathogenic viruses. we carried out a comprehensive literature review aimed at investigating waterborne viral outbreaks linked to swimming pools, to explore the etiological agents implicated, pathways of transmission, associations between indicator organisms and disease, and key issues related to chlorination/disinfection procedures. viral outbreaks are summarized in table . the presence of enteric viruses in swimming pools under non-epidemic conditions was also reviewed. different databases (scopus, pubmed, and google scholar) were accessed using the terms norovirus, norwalk virus, adenovirus, enterovirus, echovirus, coxsackievirus, and hepatitis a, in combination with terms recreation, swimming, pool, and water. switched off, to avoid eye irritation with chlorine. within one week, of the exposed swimmers became ill. children swimming in the afternoon, when chlorination was still working, did not get sick. the infection was shown to spread in families having index cases ( infected contacts). analyses of water were done approximately days after the presumed exposure. for this reason, attempts to isolate the virus from the water failed. an outbreak of acute conjunctivitis due to hadv type occurred in kansas, usa in : cases and one hospitalization were documented [ ] . eye symptoms predominated (red or pink eyes, swollen eyes), but a variety of other signs were also noted (mainly fever, headache, and nausea). a school swimming pool was identified as the source of infection. chlorine concentration was low due to an equipment failure. the epidemic was easily controlled by raising the pool's chlorine level. unfortunately, tests for viruses and bacterial indicators were carried out after super-chlorination and consequently results were negative. in , two outbreaks associated with swimming pools occurred in georgia, usa. the first, due to hadv type , involved at least cases [ ] , with patients showing different symptoms, including sore throat, fever, headache, anorexia and conjunctivitis. in this case, a private swimming pool was the source of infection. a temporary malfunction in the water filtration system of the pool associated with inadequate chlorine levels was recorded. both waterborne and person-to-person transmission occurred. in the second outbreak, hadv type was recognized as the etiological agent of pharyngoconjunctival fever in persons [ ] . an insufficient amount of chlorine was found in the water of the pool. to stop the spread of infection, the pool was closed during the summer and adequately chlorinated. adenovirus was recovered from the water sampled from the pool. in oklahoma, usa, an outbreak of pharyngitis caused by hadv type a was recorded in among children attending a swimming pool [ ] . symptoms included conjunctivitis, fever, sore throat, headache, and abdominal pain. two cases were hospitalized with dehydration from persistent vomiting. a malfunction of the automatic pool chlorinator was identified as the cause of the outbreak. in fact, during the two weeks preceding the epidemic, its failure forced the pool operator to manually add chlorine to the pool. another outbreak was recorded in , in greece, where athletes under years of age presented with fever, conjunctivitis, sore throat, weakness, and abdominal pain, after swimming in a pool [ ] . seven athletes were hospitalized. virological analyses on clinical samples were not performed and the illness was attributed to hadv on the basis of clinical symptoms alone. water samples from both the pool and the distribution system were tested for hadv, enterovirus, and hepatitis a virus by molecular methods. the water of the pool tested positive for hadv and negative for the other viruses, demonstrating its role as the source of infection. samples from the water system were negative for all viruses tested. chlorine levels were found to be low, probably due to a malfunctioning of the pool chlorination system. five hadv outbreaks associated with swimming were recorded in the s. in the year , an outbreak of pharyngoconjunctival fever occurred in north queensland, australia, where, after a school camp, children aged - , got sick [ ] . in addition to primary cases acquired at the camp (n • = ), nine other cases were acquired within the households. the school camp had a large saltwater swimming pool. adenovirus was isolated from eye and throat swabs. a pcr analysis of water samples for hadv did not yield positive results. it was, however, demonstrated that the pool was not properly maintained, and that the level of residual chlorine was inadequate. an outbreak of pharyngoconjunctival fever affecting children under was recorded in a municipality of northern spain in july [ ] . forty-three cases were recognized as primary cases, all of whom attended a municipal swimming pool. the remaining children were secondary cases, which had been in close contact with a primary case. adenovirus type was detected in pharyngeal swabs. electrical system failures causing the intermittent breakdown of the pool's bromine dosing pumps and the slowing down of water circulation were assumed to have been the cause of the outbreak. swimming was only allowed after the disinfection system was restored and appropriate concentrations of bromine were reached. due to logistic problems, no water samples were taken from the swimming pool for virological analysis. in , children ( - years old) who had attended a swimming training center in eastern china showed symptoms of pharyngoconjunctival fever. adenovirus type was recognized as the etiological agent [ ] . a total of cases were confirmed from among amateur swimmers, with an incidence of . %. fourteen hospital admissions were documented. fever, tonsillitis, sore throat, headache, sneezing, cough, conjunctivitis, fatigue, and diarrhea occurred among the bathers. the low level of residual chlorine in the water, along with excessive crowding in the pool were suggested as having caused the epidemic. in the same year, in a primary school in taiwan, an outbreak of hadv infection occurred among students, with four hospitalizations [ ] . most of the students attended a swimming course in two swimming facilities outside the school and presented with fever and symptoms of upper respiratory tract infection. other symptoms included diarrhea, vomiting, skin eruptions and conjunctivitis. throat swabs of affected students were tested for influenza virus, adenovirus, respiratory syncytial virus, coronavirus, metapneumovirus, parainfluenza types - , and herpes simplex virus. samples were found positive only for hadv type . water samples were not obtained from any of the facilities for virological analysis. in , an outbreak of pharyngoconjunctival fever involved people ( students and six staff) at a university in beijing, china [ ] . fifty patients ( %) attending the same swimming pool two weeks before the onset of symptoms were considered primary cases. the other five subjects ( %) who had not swum in the pool were defined as secondary cases (person-to-person transmission). human adv type was identified from both eye and throat swabs of the patients and from concentrated swimming pool water samples. gene sequences obtained from the water samples exhibited a % match with the sequences obtained from swab samples. control measures included the emptying and closing of the pool, and the disinfection with a high dose of sodium hypochlorite ( mg/l). enterovirus is a genus in the family picornaviridae, consisting of four human enterovirus species. enteroviruses can cause many illnesses, including paralysis, meningitis, and cardiomyopathy, although most infections are asymptomatic or cause less severe conditions, such as colds and fever. a number of reports have described enterovirus infections linked to swimming pools. the first enterovirus swimming pool-related outbreak occurred in , at a municipal pool in colorado, usa. twenty-six children presented with fever along with at least one additional symptom such as malaise, headache, stomachache, nausea, or diarrhea [ ] . it was found that the pool chlorination system was operating improperly, with chlorine levels close to zero. stool specimens collected from the children affected were tested for common enteric bacterial pathogens (salmonella, shigella, aeromonas, and campylobacter), but not for viruses. enterovirus was suggested as a likely etiological agent based on clinical manifestations, course of disease, incubation time, and the exclusion of likely bacterial pathogens. an enterovirus outbreak occurred in ireland in , with cases experiencing vomiting, diarrhea, and headache after attending an outdoor swimming pool in a small seaside village. one subject had vomited into the pool, and echovirus was isolated from this case and from six other cases. chlorine levels were found to comply with health standards, but were inadequate to contain the risk of infection from vomitus [ ] . another echovirus outbreak occurred in rome, italy, in late [ ] . children from two schools showed clinical manifestations after swimming in a pool. twenty children had meningitis-like symptoms (fever, headache, and vomiting), and six of them were hospitalized. other children had respiratory symptoms consistent with enterovirus infection. echovirus was isolated from the cerebrospinal fluid and stools of the hospitalized children. based on the epidemiological characteristics, it was hypothesized that person-to-person transmission occurred both at the swimming pool and in a number of classrooms. data on chlorination at the time of the outbreak were not available. virological analysis of pool water was performed one month after the outbreak, but yielded no positive results. in south africa, an outbreak involving children occurred following a summer camp in [ ] . camp activities included swimming and other aquatic sports. symptoms included mainly headaches, sore eyes, and/or abdominal discomfort, with one case of vomiting. four children were hospitalized for meningitis. echovirus was detected in cerebrospinal fluid and stool samples from symptomatic and asymptomatic children. the presence of viruses in the pool was not investigated. water contamination was confirmed through a total coliform count. in germany, cases of aseptic meningitis were recorded from july to october [ ] . swimming in a public, nature-like pond was identified as a risk factor for disease. up to people visited the pond each day during the summer holidays. echovirus and were detected in cerebrospinal fluid samples taken from some of the patients. an echovirus sequence obtained from one water sample collected from the pond showed a high level of genetic similarity ( % nucleotide homology) with sequences obtained from patient isolates. in august , an outbreak of meningitis occurred among campers staying at a campground in connecticut, usa [ ] . a total of cases of aseptic meningitis, four hospitalized patients and cases of enterovirus-like illness with symptoms such as headache, neck stiffness, photophobia, sore throat, chills, or exanthema were identified. echovirus serotype was detected in cerebrospinal fluid samples from three of the patients. the spread of the virus was associated with swimming in a crowded pool, which had low chlorine levels. as a result, the pool water was intermittently contaminated with enterovirus. hepatitis a is a virus causing mild to severe liver disease. globally, there are an estimated . million cases of hepatitis a every year. the virus is transmitted mainly via the fecal/oral route through the ingestion of contaminated food and water, or through direct contact with an infected subject. there is evidence to suggest that hepatitis a can be acquired by swimming in contaminated water. in september , an outbreak of hepatitis a affecting children ( - years old) and causing hospitalizations was recorded in hungary [ ] . all of the children swam in a pool at a summer camp. the pool was a non-chlorinated thermal pool/spa, which was overcrowded during the month of august. it was concluded that crowding and poor hygienic conditions, with a suspected accidental fecal release, contributed to the outbreak. another outbreak of hepatitis a was described in the usa during . it involved cases, probably associated with a public swimming pool [ ] . it was hypothesized that a cross-connection between a sewage line and the pool water intake line may have been the cause of the outbreak. according to another hypothesis, it was a swimmer who contaminated the water in the pool. however, disinfectant levels in the pools met local standards. seven hepatitis a cases among children from six families were documented in australia in [ ] . the children had attended an outdoor spa pool treated with hydrogen peroxide solution. it was hypothesized that hepatitis a virus was shed by the index case in the spa pool, and subsequently ingested by the others, who became secondary cases. virological analyses of water samples were not performed. noroviruses (novs), formerly known as norwalk-like viruses, are small viruses within the family caliciviridae, subdivided into at least seven genogroups (gi-vii), with gi, gii, and giv infecting humans. they are recognized as a major cause of sporadic and epidemic gastroenteritis in both industrialized and non-industrialized countries. outbreaks have been associated with a variety of settings including childcare centers, hospitals, nursing homes, cruise ships and restaurants. noroviruses are mainly transmitted via the fecal-oral route through contaminated food or water. norovirus-contaminated water-both recreational and drinking water-can thus lead to waterborne infections. a number of nov swimming-pool related outbreaks have been described. in , an outbreak of acute gastroenteritis with the typical symptoms of vomiting, cramping, nausea and diarrhea was documented among students and teachers at a primary school in ohio, usa [ ] . serologic studies suggested infection by norwalk virus to be the cause of the outbreak. the first cases recorded were caused by swimming in a contaminated pool, and a person-to-person transmission followed. the water of the pool tested negative for both bacterial and viral pathogens. water contamination was linked to both the pool chlorinator, which was accidentally turned off at the time of the school visits, and a leak in the water supply pipes. a large outbreak of gastroenteritis due to novs was recorded in july in helsinki. it involved people (children and adults) after bathing in an outdoor wading pool [ ] . norovirus and astrovirus were detected in both patient stool samples and pool water, with identical nucleotide sequences. the pool was found to be heavily contaminated with human fecal material carried from public toilets. the pool water had been manually chlorinated three times per week, thus not continuously. to control the outbreak, the pool was emptied, refilled, and the water was heavily chlorinated (up to mg/l of free chlorine). for the subsequent swimming season, the pool was equipped with both a continuous chlorination system and a water filtration system. in , a nov outbreak associated with a swimming pool was reported in minnesota, usa. thirty-six persons of three different youth sports teams became ill after swimming in a hotel pool and spa [ ] . unfortunately, there is no other information available on this epidemic. in , an acute gastroenteritis epidemic affected people who had swum in a pool in vermont, usa. vomiting and/or diarrhea occurred within h of attending a private indoor pool. specimens tested positive for nov. at the time of the inspection, no equipment failures or irregularities were identified. nevertheless, deficiencies in pool operation and maintenance, including poorly trained operators, inadequate maintenance checks, failure to alert management, and insufficient record keeping were reported [ ] . finally, yoder and coworkers documented a nov outbreak linked to a hotel pool in wisconsin, usa in , with persons exhibiting symptoms of gastroenteritis, related to inadequate disinfection and continued use by ill swimmers [ ] . hadv spain not tested [ ] hadv china not tested [ ] hadv taiwan not tested [ ] yes. gene sequences obtained from the water samples were % identical to the sequences obtained from the swab samples. [ ] to date, a limited number of studies examined the extent of viral contamination in swimming pools under non-epidemic conditions. the first isolation of viruses from urban wading pools was documented in albany, ny, usa in [ ] . two enteroviruses (echovirus and echovirus ) were identified from two chlorinated pools, both filled with water from the municipal supply. the same echovirus strains were found to be present in raw sewage sampled at the albany treatment plant, reflecting widespread infection in the community. in toronto, canada, coxsackievirus b was isolated from children with pleurodynia, myalgia, and primary peritonitis during . examination for the virus content of a gauze swab, which was placed daily in a wading pool with high bather load located in a congested city area, revealed the presence of the same coxsackievirus type [ ] . in in israel, swimming pool samples were found positive for enterovirus: three for echovirus , two for coxsackievirus b , and one for echovirus [ ] . viruses were isolated from water samples with no detectable fecal or total coliform bacteria. different enteroviruses were detected in swimming pools and wading pools equipped with gas chlorine and sand/gravel filters in texas, usa, in [ ] . after virus concentration from water, samples were assayed on cell culture and plaque assays. enteroviruses were found in / ( %) of the examined samples. coxsackieviruses b and b , poliovirus , and echovirus were isolated in pool waters. no correlation was found with total coliform bacteria, as six among the positive virus samples were negative for coliforms. in three samples, viruses were detected in the presence of free chlorine exceeding . ppm and in the absence of coliforms, indicating that viruses can survive low levels of biocides in actively used pools. cell cultures used in the study were suited for the isolation of enteroviruses, but it is likely that other viruses, not capable of growing on those cell lines, could also have been present in the water. three years later, in , enteroviruses were detected in . % of water samples [ ] collected from three outdoor swimming pools. a direct correlation was established between viral and microbial contamination, and the low exchange of water in the pools. in , van heerden and coworkers detected hadv in of samples ( . %) from an indoor swimming pool and in three of samples ( . %) from an outdoor swimming pool [ ] . quantitative data were also obtained by real-time pcr. application of these results in an exponential risk assessment model, assuming a daily ingestion of ml of water during swimming, indicated a daily risk of infection ranging from . × − to . × − . no acceptable microbial risk has thus far been established for swimming pool water. however, pool water quality is generally considered comparable to drinking water quality (absence of fecal indicators and pathogens). for this reason, a maximum of one infection per , consumers per year has been recommended as an acceptable level of microbial risk for swimming pools. the risk of hadv infections calculated for the swimming pool water in the study exceeded this acceptable risk. more recently, in in cyprus, hadvs and enteroviruses were detected in public swimming pools complying with bacteriological standards (such as fecal coliforms and enterococci) [ ] . the investigation was performed over a period of months, from april to december . a total of samples were obtained from swimming pools located in five major cities. bacteriological marker analysis showed that % of pools complied with the national regulations. enteroviruses were identified in four swimming pools, one containing echovirus , two containing echovirus and one containing poliovirus sabin . in four swimming pools, hadvs were detected, all characterized as type . in - , a study investigated the presence of human enteric viruses (adenovirus, norovirus, and enterovirus) in indoor and outdoor swimming pool waters in rome. bacteriological parameters (fecal indicator bacteria, heterotrophic plate count, pseudomonas aeruginosa, and staphylococcus aureus) were also investigated [ ] . moreover, the study was the first to examine the occurrence of non-enteric viruses in swimming pool waters: human papillomavirus (hpv) and human polyomavirus (hpyv). interestingly, enteric viruses were not detected, while both hpvs and hpyvs were identified in / swimming pool water samples, by means of molecular methods. neither of these viruses had previously been recognized as potential recreational waterborne pathogens, although the who guidelines for safe recreational water environments do include hpvs among non-fecally-derived viruses as viruses associated with plantar warts [ ] . a variety of hpvs and hpyvs were found in another study investigating spa/pool waters in rome [ ] . recently, disinfected water from sixteen pools and spa collected in rome between and were examined for the presence of human enteric viruses (adenovirus, norovirus and enterovirus. viruses were detected in % of the analyzed samples by molecular methods: two samples were positive for adenovirus (type ) and three samples for norovirus gii (type gii. ) (bonadonna et al., unpublished data). starting with the first hadv outbreak recorded in , we reviewed all of the reports concerning swimming-pool related viral illness. the data collected here confirm the involvement of viruses in cases and outbreaks associated with swimming pool attendance. a number of considerations emerge: • the paper reviews viral outbreaks due to adenovirus, enterovirus, hepatitis a virus, and norovirus, accounting for more than cases. nevertheless, there are likely to have been many other undetected cases and outbreaks. in fact, waterborne diseases are difficult to record because of their wide variety, the difficulty associating symptoms with water use/contact, and the limitations of pathogen detection methods. in the studies described, viruses responsible for reported cases were detected in pool waters only in % of the outbreaks, and were found to match with viruses of clinical origin. currently, better and more rapid methods for the detection of viruses in water samples are available than in the past, resulting in better studies and improved reporting of viral recreational outbreaks worldwide. this allows researchers to identify the causes of outbreaks and possible contributing factors for them. an excellent model to follow is the us-waterborne disease and outbreak surveillance system (wbdoss) that has been collecting and reporting data related to occurrences and causes of waterborne disease outbreaks associated with drinking and recreational waters since . • some of the studies found that waters meeting state or local water quality requirements contained enteric viruses and were the source of disease outbreaks, confirming that bacterial indicators are unreliable indicators of the presence of viruses and that enteric viruses are important hazardous waterborne pathogens. indeed, despite the relatively low concentration of viruses in water, they may nevertheless pose health risks due to their low infectious doses ( - virions). the human illnesses associated with enteric viruses in the reviewed studies were diverse: the most commonly reported symptoms were gastroenteritis, respiratory symptoms, and conjunctivitis. more severe symptoms were also documented, however, including hepatitis and central nervous system infections (aseptic meningitis). the majority of the outbreaks described involved mainly children and young people less than years of age. this may be attributable to differences in behaviors, susceptibility and/or immune defenses between children and adults. children are known to experience more severe symptoms than adults. • low concentrations of disinfectant/disinfection malfunction in swimming pools were reported in the vast majority of the outbreaks. only in one case the concentration of biocide was considered high. in 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and adenovirus presence in swimming pools in cyprus from first detection of papillomaviruses and polyomaviruses in swimming pool waters: unrecognized recreational water-related pathogens? detection of oncogenic viruses in water environments by a luminex-based multiplex platform for high throughput screening of infectious agents author contributions: l.b. and g.l.r. conceived and wrote the paper, and approved the submitted version.funding: this research received no external funding. the authors declare no conflict of interest. key: cord- -nu pn q authors: ardabili, s. f.; mosavi, a.; ghamisi, p.; ferdinand, f.; varkonyi-koczy, a. r.; reuter, u.; rabczuk, t.; atkinson, p. m. title: covid- outbreak prediction with machine learning date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: nu pn q several outbreak prediction models for covid- are being used by officials around the world to make informed-decisions and enforce relevant control measures. among the standard models for covid- global pandemic prediction, simple epidemiological and statistical models have received more attention by authorities, and they are popular in the media. due to a high level of uncertainty and lack of essential data, standard models have shown low accuracy for long-term prediction. although the literature includes several attempts to address this issue, the essential generalization and robustness abilities of existing models needs to be improved. this paper presents a comparative analysis of machine learning and soft computing models to predict the covid- outbreak. among a wide range of machine learning models investigated, two models showed promising results (i.e., multi-layered perceptron, mlp, and adaptive network-based fuzzy inference system, anfis). based on the results reported here, and due to the highly complex nature of the covid- outbreak and variation in its behavior from nation-to-nation, this study suggests machine learning as an effective tool to model the outbreak. access to accurate outbreak prediction models is essential to obtain insights into the likely spread and consequences of infectious diseases. governments and other legislative bodies rely on insights from prediction models to suggest new policies and to assess the effectiveness of the enforced policies [ ] . the novel coronavirus disease (covid - ) has been reported to infect more than million people, with more than , confirmed deaths worldwide. the recent global covid- pandemic has exhibited a nonlinear and complex nature [ ] . in addition, the outbreak has differences with other recent outbreaks, which brings into question the ability of standard models to deliver accurate results [ ] . besides the numerous known and unknown variables involved in the spread, the complexity of population-wide behavior in various geopolitical areas and differences in containment strategies had dramatically increased model uncertainty [ ] . consequently, standard epidemiological models face new challenges to deliver more reliable results. to overcome this challenge, many novel models have emerged which introduce several assumptions to modeling (e.g., adding social distancing in the form of curfews, quarantines, etc.) [ ] [ ] [ ] . to elaborate on the effectiveness of enforcing such assumptions understanding standard dynamic epidemiological (e.g., susceptible-infected-recovered, sir) models is essential [ ] . the modeling strategy is formed around the assumption of transmitting the infectious disease through contacts, considering three different classes of well-mixed populations; susceptible to infection (class s), infected (class i), and the removed population (class r is devoted to those who have recovered, developed immunity, been isolated or passed away). it is further assumed that the class i transmits the infection to class s where the number of probable transmissions is proportional to the total number of contacts [ ] [ ] [ ] . the number of individuals in the class s progresses as a time-series, often computed using a basic differential equation as follows: where is the infected population, and is the susceptible population both as fractions. represents the daily reproduction rate of the differential equation, regulating the number of susceptible infectious contacts. the value of in the time-series produced by the differential equation gradually declines. initially, it is assumed that at the early stage of the outbreak ≈ while the number of individuals in class i is negligible. thus, the increment becomes linear and the class i eventually can be computed as follows: where regulates the daily rate of new infections by quantifying the number of infected individuals competent in the transmission. furthermore, the class r, representing individuals excluded from the spread of infection, is computed as follows: under the unconstrained conditions of the excluded group, eq. , the outbreak exponential growth can be computed as follows: the outbreaks of a wide range of infectious diseases have been modeled using eq. . however, for the covid- outbreak prediction, due to the strict measures enforced by authorities, the susceptibility to infection has been manipulated dramatically. for example, in china, italy, france, hungary and spain the sir model cannot present promising results, as individuals committed voluntarily to quarantine and limited their social interaction. however, for countries where containment measures were delayed (e.g., united states) the model has shown relative accuracy [ ] . figure. shows the inaccuracy of conventional models applied to the outbreak in italy by comparing the actual number of confirmed infections and epidemiological model predictions . the seir models through considering the significant incubation period during which individuals have been infected showed progress in improving the model accuracy for varicella and zika outbreak [ , ] . seir models assume that the incubation period is a random variable and similarly to the sir model, there would be a disease-free-equilibrium [ , ] . it is worth mentioning that seir model will not work well where the parameters are non-stationary through time [ ] . a key cause of non-stationarity is where the social mixing (which determines the contact network) changes through time. social mixing determines the reproductive number which is the number of susceptible individuals that an infected person will infect. where is less than the epidemic will die out. where it is greater than it will spread. for covid- prior to lockdown was estimated as a massive presenting a pandemic. it is expected that lockdown measures should bring down to less than . the key reason why seir models are difficult to fit for covid- is non-stationarity of mixing, caused by nudging (step-by-step) intervention measures. one can calculate that standard epidemiological models can be effective and reliable only if (a) the social interactions are stationary through time (i.e., no changes in interventions or control measures), or (b) there exists a great deal of knowledge of class r with which to compute eq. . often to acquire information on class r, several novel models included data from social media or call data records (cdr), which showed promising results [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, observation of the behavior of covid- in several countries demonstrates a high degree of uncertainty and complexity [ ] . thus, for epidemiological models to be able to deliver reliable results, they must be adapted to the local situation with an insight into susceptibility to infection [ ] . this imposes a huge limit on the generalization ability and robustness of conventional models. advancing accurate models with a great generalization ability to be scalable to model both the regional and global pandemic is, thus, essential [ ] . a further drawback of conventional epidemiological models is the short lead-time. to evaluate the performance of the models, the median success of the outbreak prediction presents useful information. the median prediction factor can be calculated as follows: as the lead-time increases, the accuracy of the model declines. for instance, for the covid- outbreak in italy, the accuracy of the model for more than -days-in-the-future reduces from = for the first five days to = . for day [ ] . due to the complexity and the large-scale nature of the problem in developing epidemiological models, machine learning (ml) has recently gained attention for building outbreak prediction models. ml approaches aim at developing models with higher generalization ability and greater prediction reliability for longer lead-times [ ] [ ] [ ] [ ] [ ] . although ml methods were used in modeling former pandemics (e.g., ebola, cholera, swine fever, h n influenza, dengue fever, zika, oyster norovirus [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ), there is a gap in the literature for peer-reviewed papers dedicated to covid- . table represents notable ml methods used for outbreak prediction. these ml methods are limited to the basic methods of random forest, neural networks, bayesian networks, naïve bayes, genetic programming and classification and regression tree (cart). although ml has long been established as a standard tool for modeling natural disasters and weather forecasting [ , ] , its application in modeling outbreak is still in the early stages. more sophisticated ml methods (e.g., hybrids, ensembles) are yet to be explored. consequently, the contribution of this paper is to explore the application of ml for modeling the covid- pandemic. this paper aims to investigate the generalization ability of the proposed ml models and the accuracy of the proposed models for different lead-times. the rest of this paper is organized as follows. section two describes the methods and materials. the results are given in section three. sections four and five present the discussion and the conclusions, respectively. data were collected from https://www.worldometers.info/coronavirus/country for five countries, including italy, germany, iran, usa, and china on total cases over days. figure presents the total case number (cumulative statistic) for the considered countries. currently, to contain the outbreak, the governments have implemented various measures to reduce transmission through inhibiting people's movements and social activities. although for advancing the epidemiological models information on changes in social distancing is essential, for modeling with machine learning no assumption is required. as can be seen in figure , the growth rate in china is greater than that for italy, iran, germany and the usa in the early weeks of the disease. the next step is to find the best model for the estimation of the time-series data. logistic, linear, logarithmic, quadratic, cubic, compound, power and exponential equations (table ) are employed to develop the desired model. a, b, c, µ, and l are parameters (constants) that characterize the above-mentioned functions. these constants need to be estimated to develop an accurate estimation model. one of the goals of this study was to model time-series data based on the logistic microbial growth model. for this purpose, the modified equation of logistic regression was used to estimate and predict the prevalence (i.e., i/population at a given time point) of disease as a function of time. estimation of the parameters was performed using evolutionary algorithms like ga, particle swarm optimizer, and the grey wolf optimizer. these algorithms are discussed in the following. evolutionary algorithms (ea) are powerful tools for solving optimization problems through intelligent methods. these algorithms are often inspired by natural processes to search for all possible answers as an optimization problem [ ] [ ] [ ] . in the present study, the frequently used algorithms, (i.e., genetic algorithm (ga), particle swarm optimizer (pso) and grey wolf optimizer (gwo)) are employed to estimate the parameters by solving a cost function. genetic algorithm (ga) gas are considered a subset of "computational models" inspired by the concept of evolution [ ] . these algorithms use "potential solutions" or "candidate solutions" or "possible hypotheses" for a specific problem in a "chromosome-like" data structure. ga maintains vital information stored in these chromosome data structures by applying "recombination operators" to chromosome-like data structures [ ] [ ] [ ] [ ] . in many cases, gas are employed as "function optimizer" algorithms, which are algorithms used to optimize "objective functions." of course, the range of applications that use the ga to solve problems is very wide [ , ] . the implementation of the ga usually begins with the production of a population of chromosomes generated randomly and bound up and down by the variables of the problem. in the next step, the generated data structures (chromosomes) are evaluated, and chromosomes that can better display the optimal solution of the problem are more likely to be used to produce new chromosomes. the degree of "goodness" of an answer is usually measured by the population of the current candidate's answers [ ] [ ] [ ] [ ] [ ] . the main algorithm of a ga process is demonstrated in figure . in the present study, ga [ ] was employed for estimation of the parameters of eq. to . the population number was selected to be and the maximum generation (as iteration number) was determined to be according to different trial and error processes to reduce the cost function value. the cost function was defined as the mean square error between the target and estimated values according to eq. : where, es refer to estimated values, t refers to the target values and n refers to the number of data. in , kennedy and eberhart [ ] introduced the pso as an uncertain search method for optimization purposes. the algorithm was inspired by the mass movement of birds looking for food. a group of birds accidentally looked for food in a space. there is only one piece of food in the search space. each solution in pso is called a particle, which is equivalent to a bird in the bird's mass movement algorithm. each particle has a value that is calculated by a competency function which increases as the particle in the search space approaches the target (food in the bird's movement model). each particle also has a velocity that guides the motion of the particle. each particle continues to move in the problem space by tracking the optimal particles in the current state [ ] [ ] [ ] . the pso method is rooted in reynolds' work, which is an early simulation of the social behavior of birds. the mass of particles in nature represents collective intelligence. consider the collective movement of fish in water or birds during migration. all members move in perfect harmony with each other, hunt together if they are to be hunted, and escape from the clutches of a predator by moving another prey if they are to be preyed upon [ ] [ ] [ ] . particle properties in this algorithm include [ ] [ ] [ ] : • each particle independently looks for the optimal point. • each particle moves at the same speed at each step. each particle remembers its best position in the space. the particles work together to inform each other of the places they are looking for. each particle is in contact with its neighboring particles. every particle is aware of the particles that are in the neighborhood. every particle is known as one of the best particles in its neighborhood. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . the pso implementation steps can be summarized as: the first step establishes and evaluates the primary population. the second step determines the best personal memories and the best collective memories. the third step updates the speed and position. if the conditions for stopping are not met, the cycle will go to the second step. the pso algorithm is a population-based algorithm [ , ] . this property makes it less likely to be trapped in a local minimum. this algorithm operates according to possible rules, not definite rules. therefore, pso is a random optimization algorithm that can search for unspecified and complex areas. this makes pso more flexible and durable than conventional methods. pso deals with nondifferential target functions because the pso uses the information result (performance index or target function to guide the search in the problem area). the quality of the proposed route response does not depend on the initial population. starting from anywhere in the search space, the algorithm ultimately converges on the optimal answer. pso has great flexibility to control the balance between the local and overall search space. this unique pso property overcomes the problem of improper convergence and increases the search capacity. all of these features make pso different from the ga and other innovative algorithms [ , , ] . in the present study, pso was employed for estimation of the parameters of eq. to . the population number was selected to be and the iteration number was determined to be according to different trial and error processes to reduce the cost function value. the cost function was defined as the mean square error between the target and estimated values according to eq. . one recently developed smart optimization algorithm that has attracted the attention of many researchers is the grey wolf algorithm. like most other intelligent algorithms, gwo is inspired by nature. the main idea of the grey wolf algorithm is based on the leadership hierarchy in wolf groups and how they hunt [ ] . in general, there are four categories of wolves among the herd of grey wolves, alpha, beta, delta and omega. alpha wolves are at the top of the herd's leadership pyramid, and the rest of the wolves take orders from the alpha group and follow them (usually there is only one wolf as an alpha wolf in each herd). beta wolves are in the lower tier, but their superiority over delta and omega wolves allows them to provide advice and help to alpha wolves. beta wolves are responsible for regulating and orienting the herd based on alpha movement. delta wolves, which are next in line for the power pyramid in the wolf herd, are usually made up of guards, elderly population, caregivers of damaged wolves, and so on. omega wolves are also the weakest in the power hierarchy [ ] . eq. to are used to model the hunting tool: where t is represents repetition of the algorithm. and are vectors of the prey site and the vectors represent the locations of the grey wolves. is linearly reduced from to during the repetition. ⃗⃗⃗ and ⃗⃗⃗ are random vectors where each element can take on realizations in the range [ . ]. the gwo algorithm flowchart is shown in figure . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . in the present study, gwo [ ] was employed for estimation of the parameters of eq. to . the population number was selected to be and the iteration number was determined to be according to different trial and error processes to reduce the cost function value. the cost function was defined as the mean square error between the target and estimated values according to eq. . ml is regarded as a subset of ai. using ml techniques, the computer learns to use patterns or "training samples" in data (processed information) to predict or make intelligent decisions without overt planning [ , ] . in other words, ml is the scientific study of algorithms and statistical models used by computer systems that use patterns and inference to perform tasks instead of using explicit instructions [ , ] . time-series are data sequences collected over a period of time [ ] , which can be used as inputs to ml algorithms. this type of data reflects the changes that a phenomenon has undergone over time. let x t be a time-series vector, in which xt is the outbreak at time point t and t is the set of all equidistant time points. to train ml methods effectively, we defined two scenarios, listed in table . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . table , scenario employs data for three weeks to predict the outbreak on day t and scenario employs outbreak data for five days to predict the outbreak for day t. both of these scenarios were employed for fitting the ml methods. in the present research, two frequently used ml methods, the multi-layered perceptron (mlp) and adaptive network-based fuzzy inference system (anfis) are employed for the prediction of the outbreak in the five countries. ann is an idea inspired by the biological nervous system, which processes information like the brain. the key element of this idea is the new structure of the information processing system [ ] [ ] [ ] . the system is made up of several highly interconnected processing elements called neurons that work together to solve a problem [ , ] . anns, like humans, learn by example. the neural network is set up during a learning process to perform specific tasks, such as identifying patterns and categorizing information. in biological systems, learning is regulated by the synaptic connections between nerves. this method is also used in neural networks [ ] . by processing experimental data, anns transfer knowledge or a law behind the data to the network structure, which is called learning. basically, learning ability is the most important feature of such a smart system. a learning system is more flexible and easier to plan, so it can better respond to new issues and changes in processes [ ] . in anns, with the help of programming knowledge, a data structure is designed that can act like a neuron. this data structure is called a node [ , ] . in this structure, the network between these nodes is trained by applying an educational algorithm to it. in this memory or neural network, the nodes have two active states (on or off) and one inactive state (off or ), and each edge (synapse or connection between nodes) has a weight. positive weights stimulate or activate the next inactive node, and negative weights inactivate or inhibit the next connected node (if active) [ , ] . in the ann architecture, for the neural cell c, the input bp enters the cell from the previous cell p. wpc is the weight of the input bp with respect to cell c and ac is the sum of the multiplications of the inputs and their weights [ ] : a non-linear function Өc is applied to ac. accordingly, bc can be calculated as eq. [ ] : similarly, wcn is the weight of the bcn which is the output of c to n. w is the collection of all the weights of the neural network in a set. for input x and output y, hw(x) is the output of the neural network. the main goal is to learn these weights for reducing the error values between y and hw(x). that is, the goal is to minimize the cost function q(w), eq. [ ] : in the present research, one of the frequently used types of ann called the mlp [ ] was employed to predict the outbreak. mlp was trained using a dataset related to both scenarios (according to table ). for the training of the network, , , and inner neurons were tried to achieve the best response. results were evaluated by rmse and correlation coefficient to reduce the cost function value. figure presents the architecture of the mlp. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . an adaptive neuro fuzzy inference system is a type of ann based on the takagi-sugeno fuzzy system [ ] . this approach was developed in the early s. since this system integrates the concepts of neural networks and fuzzy logic, it can take advantage of both capabilities in a unified framework. this technique is one of the most frequently used and robust hybrid ml techniques. it is consistent with a set of fuzzy if-then rules that can be learned to approximate nonlinear functions [ , ] . hence, anfis was proposed as a universal estimator. an important element of fuzzy systems is the fuzzy partition of the input space [ , ] . for input k, the fuzzy rules in the input space make a k faces fuzzy cube. achieving a flexible partition for nonlinear inversion is non-trivial. the idea of this model is to build a neural network whose outputs are a degree of the input that belongs to each class [ ] [ ] [ ] . the membership functions (mfs) of this model can be nonlinear, multidimensional and, thus, different to conventional fuzzy systems [ ] [ ] [ ] . in anfis, neural networks are used to increase the efficiency of fuzzy systems. the method used to design neural networks is to employ fuzzy systems or fuzzy-based structures. this model is a kind of division and conquest method. instead of using one neural network for all the input and output data, several networks are created in this model: • a fuzzy separator to cluster input-output data within multiple classes. • a neural network for each class. training neural networks with output input data in the corresponding classes. figure presents a simple architecture for anfis. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . input n output figure . anfis architecture in the present study, anfis is developed to tackle two scenarios described in table . each input included by two mfs with the tri. shape; trap. shape and gauss. shape mfs. the output mf type was selected to be linear with a hybrid optimizer type. evaluation was conducted using the root mean square error (rmse) and correlation coefficient. these statistics compare the target and output values and calculate a score as an index for the performance and accuracy of the developed methods [ , ] . table presents the evaluation criteria equations. where, n is the number of data, p and a are, respectively, the predicted (output) and desired (target) values. tables to present the results of the accuracy statistics for the logistic, linear, logarithmic, quadratic, cubic, compound, power and exponential equations, respectively. the coefficients of each equation were calculated by the three ml optimizers; ga, pso and gwo. the table contains country name, model name, population size, number of iterations, processing time, rmse and correlation coefficient. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . according to tables to , gwo provided the highest accuracy (smallest rmse and largest correlation coefficient) and smallest processing time compared to pso and ga for fitting the logistic, linear, logarithmic, quadratic, cubic, power, compound, and exponential-based equations for all five countries. it can be suggested that gwo is a sustainable optimizer due to its acceptable processing time compared with pso and ga. therefore, gwo was selected as the best optimizer by providing the highest accuracy values compared with pso and ga. in general, it can be claimed that gwo, by suggesting the best parameter values for the functions presented in table , increases outbreak prediction accuracy for covid- in comparison with pso and ga. therefore, the functions derived by gwo were selected as the best predictors for this research. tables to present the description and coefficients of the linear, logarithmic, quadratic, cubic, compound, power, exponential and logistic equations estimated by gwo. tables to also present the rmse and r-square values for each equation fitted to data for china, italy, iran, germany and usa, respectively. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , as is clear from tables to , in general, the logistic equation followed by the quadratic and cubic equations provided the smallest rmse and the largest r-square values for the prediction of covid- outbreak. the claim can also be considered from figure to , which presents the capability and trend of each model derived by gwo in the prediction of covid- cases for china, italy, iran, germany, and the usa, respectively. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . figure . set of models for usa fitted by gwo figures to illustrate the fit of the models investigated in this paper. the best fit for the prediction of covid- cases was achieved for the logistic model followed by cubic and quadratic models for china (figure ) , logistic followed by cubic models for italy (figure ) , cubic followed by logistic and quadratic models for iran (figure ), the logistic model for germany (figure ), and logistic model for the usa (figure ). this section presents the results for the training stage of ml methods. mlp and anfis were employed as single and hybrid ml methods, respectively. ml methods were trained using two datasets related to scenario and scenario . table presents the results of the training phase. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . according to table , the dataset related to scenarios and have different performance values. accordingly, for italy, the mlp with neurons provided the highest accuracy for scenario and anfis with tri. mf provided the highest accuracy for scenario . by considering the average values of the rmse and correlation coefficient, it can be concluded that scenario is more suitable for modeling outbreak cases in italy, as it provides a higher accuracy (the smallest rmse and the largest correlation coefficient) than scenario . for the dataset related to china, for both scenarios, mlp with and neurons, respectively for scenarios and , provided the highest accuracy compared with the anfis model. by considering the average values of rmse and correlation coefficient, it can be concluded that scenario with a larger average correlation coefficient and smaller average rmse than scenario is more suitable for modeling the outbreak in china. for the dataset of iran, mlp with neurons in the hidden layer for scenario and anfis with gaussian mf type for scenario provided the best performance for the prediction of the outbreak. by considering the average values of the rmse and correlation coefficient, it can be concluded that scenario provided better performance than scenario . also, in general, the mlp has higher prediction accuracy compared with the anfis method. in germany, mlp with neurons in its hidden layer provided the highest accuracy (smallest rmse and largest correlation coefficient). by considering the average values of the rmse and correlation coefficient, it can be concluded that scenario is more suitable for the prediction of the outbreak in germany than scenario . in the usa, the mlp with and neurons, respectively, for scenarios and , provided higher accuracy (the smallest rmse and the largest correlation coefficient values) than the anfis model. by considering the average values of the rmse and correlation coefficient values, it can be concluded that scenario is more suitable than scenario , and mlp is more suitable than anfis for outbreak prediction. figures to present the model fits for italy, china, iran, germany, and the usa, respectively. by comparing figure to with figures to , it can be concluded that the mlp and the logistic model fitted by gwo provided a better fit than the other models. in addition, the ml methods provided better performance compared with other models. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted april , . . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted april , . . the parameters of several simple mathematical models (i.e., logistic, linear, logarithmic, quadratic, cubic, compound, power and exponential) were fitted using ga, pso, and gwo. the logistic model outperformed other methods and showed promising results on training for days. extrapolation of the prediction beyond the original observation range of -days should not be expected to be realistic considering the new statistics. the fitted models generally showed low accuracy and also weak generalization ability for the five countries. although the prediction for china was promising, the model was insufficient for extrapolation, as expected. in turn, the logistic gwo outperformed the pso and ga and the computational cost for gwo was reported as satisfactory. consequently, for further assessment of the ml models, the logistic model fitted with gwo was used for comparative analysis. in the next step, for introducing the machine learning methods for time-series prediction, two scenarios were proposed. scenario considered four data samples from the progress of the infection from previous days, as reported in table . the sampling for data processing was done weekly for scenario . however, scenario was devoted to daily sampling for all previous consecutive days. providing these two scenarios expanded the scope of this study. training and test results for the two machine learning models (mlp and anfis) were considered for the two scenarios. a detailed investigation was also carried out to explore the most suitable number of neurons. for the mlp, the performances of using , and neurons were analyzed throughout the study. for the anfis, the membership function (mf) types of tri, trap, and gauss were analyzed throughout the study. the five counties of italy, china, iran, germany, and usa were considered. the performance of both ml models for these countries varied amongst the two different scenarios. given the observed results, it is not possible to select the most suitable scenario. therefore, both daily and weekly sampling can be used in machine learning modeling. comparison between analytical and machine learning models using the deviation from the target value (figures to ) indicated that the mlp in both scenarios delivered the most accurate results. extrapolation for long-term prediction of up to days using the ml models was tested. the actual prediction of mlp and anfis for the five countries was reported which showed the progression of the outbreak. the global pandemic of the severe acute respiratory syndrome coronavirus (sars-cov- ) has become the primary national security issue of many nations. advancement of accurate prediction models for the outbreak is essential to provide insights into the spread and consequences of this infectious disease. due to the high level of uncertainty and lack of crucial data, standard epidemiological models have shown low accuracy for long-term prediction. this paper presents a comparative analysis of ml and soft computing models to predict the covid- outbreak. the results of two ml models (mlp and anfis) reported a high generalization ability for long-term prediction. with respect to the results reported in this paper and due to the highly complex nature of the covid- outbreak and differences from nation-to-nation, this study suggests ml as an effective tool to model the outbreak. for the advancement of higher performance models for long-term prediction, future research should be devoted to comparative studies on various ml models for individual countries. due to the fundamental differences between the outbreak in various countries, advancement of global models with generalization ability would not be feasible. as observed and reported in many studies, it is unlikely that an individual outbreak will be replicated elsewhere [ ] . although the most difficult prediction is to estimate the 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using artificial neural networks and adaptive neuro-fuzzy inference system techniques an adaptive neuro-fuzzy inference system (anfis) model for wire-edm ahlawat, a. modeling and analysis of significant key: cord- - iqjugcx authors: bédubourg, gabriel; le strat, yann title: evaluation and comparison of statistical methods for early temporal detection of outbreaks: a simulation-based study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: iqjugcx the objective of this paper is to evaluate a panel of statistical algorithms for temporal outbreak detection. based on a large dataset of simulated weekly surveillance time series, we performed a systematic assessment of statistical algorithms, implemented in the r package surveillance and two other methods. we estimated false positive rate (fpr), probability of detection (pod), probability of detection during the first week, sensitivity, specificity, negative and positive predictive values and f( )-measure for each detection method. then, to identify the factors associated with these performance measures, we ran multivariate poisson regression models adjusted for the characteristics of the simulated time series (trend, seasonality, dispersion, outbreak sizes, etc.). the fpr ranged from . % to . % and the pod from . % to . %. some methods had a very high specificity, up to . %, but a low sensitivity. methods with a high sensitivity (up to . %) had a low specificity. all methods had a high negative predictive value, over %, while positive predictive values ranged from . % to . %. multivariate poisson regression models showed that performance measures were strongly influenced by the characteristics of time series. past or current outbreak size and duration strongly influenced detection performances. public health surveillance is the ongoing, systematic collection, analysis, interpretation, and dissemination of data for use in public health action to reduce morbidity and mortality of health-related events and to improve health [ ] . one of the objectives of health surveillance is outbreak detection, which is crucial to enabling rapid investigation and implementation of control measures [ ] . the threat of bioterrorism has stimulated interest in improving health surveillance systems for early detection of outbreaks [ , ] reemergence of infectious diseases such as middle east respiratory syndrome due to new coronavirus (mers-cov) in [ ] or ebola in west africa in [ ] . nowadays, a large number of surveillance systems are computer-supported. the computer support and statistical alarms are intended to improve outbreak detection for traditional or syndromic surveillance [ , ] . these systems routinely monitor a large amount of data, recorded as time series of counts in a given geographic area for a given population. they produce statistical alarms that need to be confirmed by an epidemiologist, who determines if further investigation is needed. one limitation of these detection systems is an occasional lack of specificity, leading to false alarms that can overwhelm the epidemiologist with verification tasks [ , ] . it is thus important to implement statistical methods that offer a good balance between sensitivity and specificity in order to detect a large majority of outbreaks without generating too many false positive alarms. in the literature, a broad range of statistical methods has been proposed to detect outbreaks from surveillance data. the main statistical approaches have been reviewed by shmueli et al. [ ] and unkel et al. [ ] . by restricting these reviews to the methods that allow temporal detection of outbreaks without integrating the spatial distribution of cases, the general principle is to identify a time interval in which the observed number of cases of an event under surveillance (i.e. the number of reported cases) is significantly higher than expected. this identification is mainly based on a two-step process: first, an expected number of cases of the event of interest for the current time unit (generally a week or a day) is estimated and then compared to the observed value by a statistical test. a statistical alarm is triggered if the observed value is significantly different from the expected value. the main difference between statistical methods lies in how the expected value is estimated, which is most often done using statistical process control or regression techniques or combination of both [ ] . a major constraint to the practical implementation of these methods is their capacity to be run on an increasing number of time series, provided by multiple sources of information, and centralized in large databases [ , , ] . monitoring a large number of polymorphic time series requires flexible statistical methods to deal with several well-known characteristics observed in time series: the frequency and variance of the number of cases, secular trend and one or more seasonality terms [ ] . even if some authors proposed to classify time series into a small number of categories and sought suitable algorithms for each category, in this automated and prospective framework, statistical methods cannot easily be fine tuned by choosing the most appropriate parameters adapted to each time series in an operational way, as explained by farrington et al. [ ] . a key question for public health practitioners is what method(s) can be adopted to detect the effects of unusual events on the data. some authors have proposed a systematic assessment of the performances of certain methods in order to choose one reference algorithm [ ] [ ] [ ] [ ] [ ] . they assessed these methods on a real dataset [ , ] , a simulated dataset [ - , , ] or on real time series for which simulated outbreaks were added [ , ] . simulating data offers the advantage of knowing the exact occurrence of the simulated outbreaks and their characteristics (amplitude, etc.). for example, lotze et al. developed a simulated dataset of time series and outbreak signatures [ ] . in the same way, noufaily et al. [ ] proposed a thorough simulation study to improve the farrington algorithm [ ] . guillou et al. [ ] compared the performance of their own algorithm to that of the improved farrington, using the same simulated dataset. this dataset was also used by salmon et al. to assess their method [ ] . to our knowledge, no study has been proposed to thoroughly evaluate and compare the performance of a broad range of methods on a large simulated dataset. the objective of this paper is to evaluate the performance of statistical methods applied to large simulated datasets for outbreak detection in weekly health surveillance. the simulated dataset is presented in section . the evaluated methods and performance measures are described in section . evaluations and comparisons are presented in section . a discussion follows in the last section. we simulated data following the approach proposed by noufaily et al. [ ] . first, simulated baseline data (i.e. time series of counts in the absence of outbreaks) were generated from a negative binomial model of mean μ and variance ϕμ, ϕ being the dispersion parameter ! . the mean at time t, μ(t), depends on a trend and seasonality modeled using fourier terms: time series were simulated from parameter combinations (called scenarios and presented in table in [ ] ) with different values taken by θ, β, γ , γ , m and ϕ, respectively associated with the baseline frequency of counts, trend, seasonality (no seasonality: m = , annual seasonality: m = , biannual seasonality: m = ) and the dispersion parameter. for each scenario, replicates of the baseline data (time series with weeks) were generated. we thus obtained × = simulated time series. the last weeks of each time series were named current weeks. the evaluated algorithms were run on these most recent weeks. performance measures described below were computed based on detection during these weeks. secondly, for each time series, five outbreaks were simulated. four outbreaks were generated in baseline weeks. each outbreak started at a randomly drawn week and we generated the outbreak size (i.e. the number of outbreak cases) as poisson with mean equal to a constant k times the standard deviation of the counts observed at the starting week. the fifth outbreak was generated in the current weeks in the same manner, using another constant noted k . we chose the values of k to be , , , and in baseline weeks and k from to in current weeks as in [ ] . finally, outbreak cases were randomly distributed according to a lognormal distribution with mean and standard deviation . . a total of , time series were generated from the scenarios: , time series during the first step of simulation process ( × duplicates × values for k ), and , time series during the second step of simulation process ( , × values for k ), leading to a large simulated dataset including a great variety of time series, as observed in real surveillance data. at the end of the simulation process, , , current weeks were generated, among which . % were classified as outbreak weeks as they were included in an outbreak. we studied statistical methods, of which were implemented in the r package surveillance [ , ] : • cusum variants: original cusum [ , ] , a rossi approximate cusum [ ] , a cusum algorithm for which the expected values are estimated by a glm model [ ] , a mixed rossi approximate cusum glm algorithm [ ] , • the original farrington algorithm [ ] and the improved farrington algorithm [ ] , • a count data regression chart (glrnb) [ , ] and a poisson regression chart (glr poisson) [ , ] , • the outbreakp method [ ] , • ears c , c and c algorithms [ , ] for all simulated time series, we used the tuning parameters recommended by their authors for each algorithm when available and proposed by default in the package surveillance. the commands used from the r package surveillance and the control tuning parameters chosen for these algorithms are presented in table . we also proposed two additional methods not implemented in the package surveillance: • a periodic poisson regression where μ(t) is defined as in eq ( ). the threshold is the − α quantile of a poisson distribution with mean equal to the predicted value at week t. • a periodic negative binomial regression, also defined as in eq ( ), where the threshold is the − α quantile of a negative binomial distribution with mean equal to the predicted value at week t and a dispersion parameter estimated by the model. rki algo.rki () - [ ] glr negative binomial algo.glrnb() arl = , dir = "inc" [ , ] glr poisson algo.glrpois() arl = , dir = "inc" [ , ] ears c earsc() method = "c ", α [ , ] ears c earsc() method = "c ", α [ , ] ears c earsc() method = "c ", α [ , ] outbreakp algo.outbreakp() k = , ret = c("value") [ ] these last two models were run on all the historical data. an alarm was triggered if the observed number of cases was greater than the upper limit of the prediction interval. these two methods are basic periodic regressions. the r code of these two algorithms is presented in the s appendix. we evaluated the performances of the methods with three different α values: α = . , α = . and α = . . we considered eight measures to assess the performance of the methods: • measure is false positive rate (fpr). for each method and each scenario, we calculated the fpr defined as the proportion of weeks corresponding to an alarm in the absence of an outbreak, as in [ ] . nominal fprs were . for analyses with α = . , . for analyses with α = . or . for analyses with α = . . • measure is probability of detection (pod). for each scenario and for each current week period, if an alarm is generated at least once between the start and the end of an outbreak, the outbreak is considered to be detected [ ] . pod is an event-based sensitivity (i.e. the entire outbreak interval is counted as a single observation for the sensitivity measurement) and is thus the proportion of outbreaks detected in replicates. • measure is probability of detection during the first week (pod week), which makes it possible to evaluate the methods' ability to enable early control measures. • measure is observation-based sensitivity (se): outbreak weeks associated with an alarm were defined as true positive (tp), non-outbreak weeks without alarm as true negative (tn), outbreak weeks without alarm as false negative (fn) and non-outbreak weeks with alarm as false positive (fp). thus, se = tp/(tp+fn). • measure is specificity (sp) defined as sp = tn/(tn+fp). unlike fpr which was calculated on current weeks without any simulated outbreak, specificity was calculated on the entire number of current weeks out of the time series including current outbreaks. • measure is positive predictive value (ppv) defined as: ppv = tp/(tp+fp). • measure is negative predictive value (npv) defined as: npv = tn/(tn+fn). • measure is f -measure defined as the harmonic mean of the sensitivity and the ppv: in the result section, we proposed to calculate averaged performance measures, i.e. to calculate fpr on the overall , time series without outbreak during the current weeks, and to calculate the other performance measures on the overall , time series with simulated outbreaks during the current weeks. fpr was estimated prior to the simulation of current outbreaks, i.e. among the current weeks for , ( × , ) time series. other indicators (pod, pod week, se, sp, ppv, npv) were estimated once outbreaks had been simulated, i.e. on the current weeks of all the time series ( , time series). for each α value, we proposed roc curve-like representation of these results with four plots representing sensitivity according to -specificity, pod and pod week as functions of fpr, and sensitivity according to ppv. to identify the factors associated with the performance measures for α = . and assess the strength of associations, multivariate poisson regression models [ ] were run, as in barboza et al. [ ] or buckeridge et al. [ ] . a set of covariates corresponding to the characteristics of the simulated time series was included: trend (yes/no), seasonality (no/annual/biannual), the baseline frequency coefficient θ, the dispersion coefficient ϕ and k representing the amplitude and duration of past outbreaks. the last three covariates and k were treated as continuous and modeled using fractional polynomials. the statistical methods were introduced as covariates to estimate performance ratios, i.e. the ratios of performances of two methods, adjusted for the characteristics of the time series represented by the other covariates. adjusted fpr, pod, pod week, sensitivity, and specificity ratios were estimated with the improved farrington algorithm as reference. % confidence intervals were calculated with robust estimation of standard errors. for each continuous covariate modeled by fractional polynomials, ratios were presented for each value [ ] . the simulation study, the implementation of the detection methods, and the estimations of performance were carried out using r (version . . ), in particular using the package surveillance. poisson regression models used to identify the factors associated with the performance measures and to assess the strength of associations were run using stata . in this section, we present the averaged performances of each evaluated method, i.e. the performances irrespective of the scenario and of the characteristics of the time series. table presents averaged fpr, specificity, pod, pod week, sensitivity, negative predictive value, positive predictive value and f -measure for all scenarios and all past and current outbreak amplitude and duration and for α = . . overall, fpr ranged from . % to . % and pod from . % to . %. methods with the highest specificity, such as the improved farrington method or the periodic negative binomial regression, presented a pod lower than % and a sensitivity lower than %. averaged measures for α = . and α = . are presented in s table and s table. rki - , glr negative binomial, glr poisson, bayes - and outbreakp algorithms' performances do not vary with α values (see table ). their performances are only reported in table . for each method, a radar chart presenting the measures - for α = . is proposed in the s appendix. . two groups stand out from the rest. the first group consists of bayes , and . these methods present the best pod (around . ) and pod week with a fpr around %. the second group consists of the cusum methods: cusum, cusum rossi, cusum glm, and cusum glm rossi. for α = . , these methods present the best sensitivity (around . ) but the lowest specificity ( . ) and the highest fpr ( . ). note that while of the algorithm test statistics are based on the likelihood of single-week observations independent of recent ones, cusums are not, and they may be important for applications where detection of gradual events rather than one-week spikes is especially critical. the outbreakp method had the lowest specificity without having a better pod or pod week than the first two groups. finally, a third group consists of the other methods that had good specificity (over . ) but a lower sensitivity, pod and pod week than the first two groups. all methods presented a high negative predictive value, greater than %. the ppv of outbreakp is very low ( . %), while the periodic negative binomial glm method had the highest ppv ( . %). a first attempt to visualize certain differences is to plot pod and fpr according to the scenario and the k or k values. to illustrate this, fig shows the performances of the cdc method. the first row represents fpr for an increasing past outbreak constant k = , , , and according to the scenarios. the second row shows pod according to k for the scenarios (each curve corresponds to a simulated scenario) for an increasing past outbreak constant k = , , , and . it clearly shows that performance depends on the scenario. the same plots with tables presenting numerical values for each method and different α values are presented in the s appendix to s appendix. to better compare the methods, we presented on a single display in the s appendix, their fpr according to the scenarios and their pod according to the k values for k = and α = . . to better understand which characteristics are associated with each performance and to compare each method with the improved farrington method, we present the results obtained from the multivariate poisson regression models in the next section. adjusted performance ratios and associated factors table presents the adjusted performance ratios for performance measures to as described in the methods' section (α = . for improved farrington, original farrington, periodic poisson glm and neg binomial glm, cdc and ears c -c . α = . for bayes - ). evaluation and comparison of statistical methods for early temporal detection of outbreaks • adjusted fpr ratios decreased when the amplitude and duration (driven by k in eq ( )) of past outbreaks increased. it is indeed more difficult to detect an outbreak when past outbreaks have occurred, especially when these outbreaks are large and when the method does not under-weight their influence to estimate the expected number of cases. adjusted fpr ratio was . times higher for time series with a secular trend than for the others. as we simulated time series with a non-negative trend (β ! in eq ( )), it was expected that fpr would decrease with a trend, especially for methods which do not integrate a trend in the estimation of the expected number of cases. in the same way, annual seasonality-and biannual seasonality to an even greater extent-and overdispersion increased fpr. we observed a nonlinear relation between fpr and baseline frequency: fpr ratio increased from the lowest frequencies to cases per week, then decreased for the highest frequencies, with no clear explanation. only periodic negative binomial glm presented a fpr lower than improved farrington fpr (fpr ratio = . ). adjusted fpr ratios of outbreakp and all cusum variants were higher than . another group of methods all presented fpr ratios below : cdc, rki variants, ears methods, periodic poisson glm, original farrington, bayes and glr negative binomial. fpr ratios for other methods (bayes and , and glr poisson) were between and . • adjusted specificity ratios were almost all equal to as the amplitude and duration of past outbreaks had little influence on specificity. they were significantly lower for time series with a secular trend (adjusted specificity ratio = . ) or with annual or biannual seasonality (respective ratios: . and . ). specificity decreased when dispersion increased but increased when the baseline frequency (θ in eq ( )) increased. only the periodic negative binomial glm presented a specificity as good as that of the improved farrington method (specificity ratio = . ). • the adjusted pod ratios significantly decreased when past outbreak amplitude and duration (k ) increased, which is logical. they increased when current outbreak amplitude and duration (k ) increased, which is also normal. pod was higher for time series with secular trends which can be explained by the positive trend. pod decreased when there was an annual or a biannual seasonality (respective pod ratio = . and . ). only the highest dispersion value (θ = ) had an influence on pod (adjusted pod ratio = . ). bayes , and , cusum variants and the glr poisson method presented the highest pod ratios, from . (glr poisson) to . (cusum glm). any method was less able to detect an outbreak than the improved farrington algorithm. • pod week presented results that were similar to those of pod. adjusted pod week ratios were significantly lower than those of pod for ears c ( . versus . ), for cdc ( . versus . ) and for glr negative binomial ( . versus . ). other methods presented ratios for pod week that were similar to or greater than those of pod. • finally, similar results were observed for sensitivity and for pod. bayes and methods, outbreakp, rki , cusum variants and the glr poisson method presented the highest sensitivity ratios, from . (rki ) to . (cusum glm). as observed in the pod model, any method was less able to detect an outbreak than the improved farrington algorithm. estimation from the multivariate regression models to explain ppv and npv are presented in s table. we presented a systematic assessment of the performance of outbreak detection algorithms using a simulated dataset. one advantage of a simulation study for outbreak detection methods benchmarking is the a priori knowledge of the occurrence of outbreaks, which enables the developpment of a real "gold standard". some authors have already proposed that simulation studies be used to assess outbreak detection methods [ , , ] , and others have suggested adding simulated outbreaks to real surveillance data baselines [ , , ] , but without proposing a systematic assessment of the performance of a broad range of outbreak detection methods. choi et al. [ ] proposed such a study design based on the daily simulation method proposed by hutwagner et al. [ ] but do not study the influence of past outbreaks or time series characteristics (frequency, variance, secular trends, seasonalities, etc.), on methods performance. the simulated dataset we used to perform our study is large enough to include the considerable diversity of time series observed in real surveillance systems. we also simulated a high diversity of outbreaks in terms of amplitude and duration. in our opinion, this simulated dataset presents a high representativeness of real weekly surveillance data. to extend our results to daily surveillance data, it should be necessary to perform a similar study with daily surveillance data. these characteristics of the simulated dataset enabled us to propose simple intrinsic performance indicator estimations such as fpr and pod and sensitivity and specificity to compare the performance of the evaluated methods. furthermore, this allows us to compare our results to other studies based on the same dataset. negative predictive value and positive predictive value are proposed as operational indicators for decision making when an alarm is triggered, or not triggered, by an algorithm. a benefit of the addition of outbreaks to the baseline weeks is that outlier removal strategies considered by many authors may be objectively tested and evaluated. one limitation in the simulation process was the fact that only increasing secular trends were used. increasing secular trends would facilitate outbreak detection, while decreasing trends would hamper it. furthermore, our study was designed based on weekly surveillance, while syndromic surveillance systems are most often daily systems. in daily surveillance time series, other seasonalities such as the "day of the week" effect need to be taken into account, which is not the case in our study. the performance of the evaluated methods was only considered from a general perspective, in order to detect outbreaks in a large number of polymorphic weekly-based time series. in a pragmatic approach, it seems very difficult to adapt the tuning parameters of these methods for every time series. in france, public health agencies, such as the french national public health agency (santé publique france), the french agency for food, environmental and occupational health safety (anses) and the french armed forces center for epidemiology and public health (cespa) have deployed computer-supported outbreak detection systems in traditional or syndromic surveillance contexts [ ] [ ] [ ] [ ] . they monitor a broad range of time series on a daily or weekly basis without, however, having rigorously evaluated the algorithms implemented. in the same way, the performance of the methods varied according to different baseline profiles depending on trend, seasonality, baseline frequency and overdispersion. even if similar meta-models were already proposed by buckeridge et al. for example [ ] , an original approach was to compare performance indicators adjusted for these parameters in a regression model. as expected, the adjusted performance of the methods was penalized by increasing amplitude and duration in past outbreaks and by annual or biannual seasonality. conversely, performance was better for increasing amplitude and duration in current outbreaks to be detected. more generally, the methods' performance was highly dependent on simulation tuning parameters. we proposed various measures to monitor the performance of outbreak detection methods. false positive rate (fpr) and probability of detection (pod) were proposed by noufaily et al. [ ] . we proposed an observation-based sensitivity measure and an event based sensitivity (pod). the concept of sensitivity based on alerting in each observation period is not applicable in some applications because signals of interest are intermittent and multimodal and may even be interpreted as multiple events. many of the algorithms are based on the likelihood of single-week observations independent of recent ones, but cusums are not, and the large sensitivity advantage in the cusums methods, diminished for pod and pod week, may be a result of the way the outbreak effects are modeled. by contrast, the implementation of the pod measure is uniformly applicable. public health response to an outbreak depends on its early detection. in the pod definition, an outbreak was considered to be detected even if the first statistical alarm was issued during its last week. with the aim of estimating early detection performance, we also proposed pod during the first week, which cannot be considered alone, because even if it is done belatedly, an outbreak needs to be detected by the methods. while pod week was an indicator of a method's ability to detect an outbreak early, we did not propose any measure of timeliness like salmon et al. [ ] or jiang et al. [ ] . this topic could be further explored in another study. to give some insight on the speed of detection, we calculated it for the improved farrington algorithm and the cusum glm rossi algorithm. on average, on the overall dataset, it took . weeks for the improved farrincton method to detect an outbreak or . weeks for the cusum glm rossi method. no method presented outbreak detection performances sufficient enough to provide reliable monitoring for a large surveillance system. methods which provide high specificity or fpr, such as the improved farrington or cdc algorithms, are not sensitive enough to detect the majority of outbreaks. these two algorithms could be implemented in systems that monitor health events to detect the largest outbreaks with the highest specificity. conversely, methods with the highest sensitivity and able to detect the majority of outbreaks-bayes or cusum glm rossi for example-produced an excessive number of false alarms, which could saturate a surveillance system and overhelm an epidemiologist in charge of outbreak investigations. as a screening test in clinical activity, the aim of an early outbreak detection method is to identify the largest possible number of outbreaks without producing too many false alarms. the performances presented in this paper should be interpreted with caution as they depend both on tuning parameters and on the current implementation of the methods in the r packages. packages evolve with time and their default parameters may also change. so this work based on r available packages, may be viewed as a starting point for researchers to enhance the comparison of methods and/or to optimize the tuning according to their data. since no single algorithm presented sufficient performance for all scenarios, combinations of methods must be investigated to achieve predefined minimum performance. other performance criteria should be proposed in order to improve the choice of algorithms to be implemented in surveillance systems. therefore, we suggest that a study of the detection period between the first week of an outbreak and the first triggered alarm be conducted. table. fpr, specificity, pod, pod week, sensitivity, negative predictive value, positive predictive value and f -measure for evaluated methods and α = . (for past outbreak constant k = , , , , and current outbreak k = to for pod and sensitivity). (pdf) s table. fpr, specificity, pod, pod week, sensitivity, negative predictive value, positive predictive value and f -measure for evaluated methods and α = . (for past outbreak constant k = , , , , and current outbreak k = to for pod and sensitivity). (pdf) s table. other performance ratios, adjusted on past and current outbreak duration and amplitude, trend, seasonality, dispersion and baseline frequency (α = . for improved framework for evaluating public health surveillance systems for early detection of outbreaks: recommendations from the cdc working group. mmwr recommendations and reports: morbidity and mortality weekly report recommendations and reports / centers for disease control the emerging science of very early detection of disease outbreaks statistical issues and challenges associated with rapid detection of bio-terrorist attacks outbreak detection through automated surveillance: a review of the determinants of detection isolation of a novel coronavirus from a man with pneumonia in saudi arabia the next epidemic-lessons from ebola practical usage of computer-supported outbreak detection in five european countries a system for automated outbreak detection of communicable diseases in germany an improved algorithm for outbreak detection in multiple surveillance systems public health monitoring tools for multiple data streams. mmwr morbidity and mortality weekly report statistical challenges facing early outbreak detection in biosurveillance statistical methods for the prospective detection of infectious disease outbreaks: a review automated biosurveillance data from england and wales a statistical algorithm for the early detection of outbreaks of infectious disease an evaluation and comparison of three commonly used statistical models for automatic detection of outbreaks in epidemiological data of communicable diseases assessing surveillance using sensitivity, specificity and timeliness comparing aberration detection methods with simulated data comparing syndromic surveillance detection methods: ears' versus a cusum-based methodology comparison of various statistical methods for detecting disease outbreaks statistical algorithms for early detection of the annual influenza peak season in hong kong using sentinel surveillance data a simulation model for assessing aberration detection methods used in public health surveillance for systems with limited baselines evaluation of a method for detecting aberrations in public health surveillance data comparing early outbreak detection algorithms based on their optimized parameter values a simulation study comparing aberration detection algorithms for syndromic surveillance. bmc medical informatics and decision making yahav i simulating multivariate syndromic time series and outbreak signatures, social science research network an extreme value theory approach for the early detection of time clusters. a simulation-based assessment and an illustration to the surveillance of salmonella bayesian outbreak detection in the presence of reporting delays surveillance: an r package for the monitoring of infectious diseases surveillance: temporal and spatio-temporal modeling and monitoring of epidemic phenomena detection of aberrations in the occurrence of notifiable diseases surveillance data an approximate cusum procedure for surveillance of health events count data regression charts for the monitoring of surveillance time series discussion paper // sonderforschungsbereich der ludwig-maximilians-universität münchen robust outbreak surveillance of epidemics in sweden the bioterrorism preparedness and response early aberration reporting system (ears) agreement, the f-measure, and reliability in information retrieval a modified poisson regression approach to prospective studies with binary data factors influencing performance of internet-based biosurveillance systems used in epidemic intelligence for early detection of infectious diseases outbreaks predicting outbreak detection in public health surveillance: quantitative analysis to enable evidence-based method selection the use of fractional polynomials to model continuous risk variables in epidemiology automated early warning system for the surveillance of salmonella isolated in the agro-food chain in france ten years experience of syndromic surveillance for civil and military public health value of syndromic surveillance within the armed forces for early warning during a dengue fever outbreak in french guiana in . bmc medical informatics and decision making generalized amoc curves for evaluation and improvement of event surveillance the authors would like to thank angela noufaily and paddy farrington for providing them with simulated datasets and an r code to simulate outbreaks. conceptualization: gabriel bédubourg, yann le strat. key: cord- -yntcwq t authors: li, xuelian; lin, panpan; lin, jyh-horng title: covid- , insurer board utility, and capital regulation date: - - journal: financ res lett doi: . /j.frl. . sha: doc_id: cord_uid: yntcwq t this paper develops a down-and-out call option model by introducing a structural break in volatility to capture the coronavirus (covid- ) outbreak. the life insurer's equity and its board's utility are evaluated at the optimal guaranteed rate in the equity maximization. results suggest that the seriousness degree of the covid- outbreak and capital regulation enhance the optimal guaranteed rate and the board's utility. increased the board's utility by increasing liabilities costs insurer profitability. conflicts of incentives can arise during the covid- outbreak. there are two reports related to the coronavirus (covid- ) outbreak paving the way for this paper since the outbreak has caused a crisis for the global markets. brodzicki ( ) reports that the significantly increased global volatility due to the covid- outbreak can adversely affect the prospects for a global recovery. mao and zhang ( ) report that the immediate impact of the covid- outbreak on the global economy is inevitable. however, this covid- outbreak does not harm all of the business opportunities. the life insurance business is a new business opportunity since people's awareness of life and health has been enhanced and then stimulate demand for life and health insurance. we extend the reports by examining the impacts of the covid- and capital regulation on the insurer's optimal guaranteed rate and the board's utility, which imply possible interest conflicts between the insurer and its board. we focus on the covid- for reasons. first, the outbreak of the covid- is now the most significant black swan of (brodzicki, ) . zhang et al. ( ) point out that the covid- outbreak has significant impacts on the global financial markets and creates substantial volatility. second, the risks the insurer faces are more evenly spread between the two sides of the balance sheet. thus, asset-liability matching under capital regulation is a crucial issue from the standpoint of insurance stability (insurance europe, ) . third, we consider the effects of the covid- outbreak and capital regulation on the optimal guaranteed rate-setting behavior and the board utility, possibly revealing conflicts of incentives. the recent literature remains silent on this issue. in this paper, a model exploring the covid- outbreak is proposed. for that purpose, a form of a structural break in volatility is introduced to evaluate the insurer's equity value in a contingent claim model. the model also formulates the board utility to study the issue of interest conflicts. moreover, deriving the comparative statics presents intuition and application in the paper. consider the insurer who makes all financial decisions during a period horizon, [ , ] t  . this model applies briys and de varenne ( ) , and more importantly, the covid- outbreak is introduced to investigate the asset-liability matching management. the liability is specified as a profit-sharing policy including a guaranteed interest rate and participation in the terminal surplus. insurer investment is core to the provision of profit-sharing policies. accordingly, risks faced by insurers include investment risk, underwriting risk, and mismatch risk, which provide crucial information about the default probability that concerns insurers and regulators. we argue that the accounting approach does not take into account the risk information above. insurance europe ( ) further indicates that insurance liabilities are generally illiquid such as annuities entail predictable payments to policyholders; thus, insurance liabilities are a contingent rather than an unconditional claim. this is the reason why we develop a contingent claim model to evaluate the market value of the insurer's equity. toward that end, we apply briys and de varenne ( ) , and more importantly, the covid- outbreak is introduced to investigate the asset-liability matching management. technically speaking, the volatility of the underlying assets of the insurer reveals information about the equity risk in the call option valuation that we focus on. we suppose that , where a r is the risky asset-market rate, is the asset value with the expected return   , and the structural break in volatility [ ( ( / ))] vv  + +  in the spirit of kholodilin and yao ( ) where  is the expected volatility without the covid- occurrence, v is the initial occurrence of the covid- outbreak and  is the degree of influencing the insurer. the parameter ( ( / )) vv  + is an impact factor of the covid- outbreak, which, for simplicity, creates only a positive impact on the expected volatility. this form also measures the seriousness degree  of the covid- to influence the insurer.  is a standard wiener process. in the profit-sharing policy, we denote by ( ) r ae where r is the guaranteed interest rate set by the insurer (polborn, ) . the book value of the liabilities plays as a strike price of the call option since the market value of the insurer's equity can be thought of as a call option on  . the market value of the equity ( , )   will then be given by the formula of briys and de varenne ( ) for the call options:  with the strike price  and a short call offsetting exactly the bouns call of the policyholders. next, we apply hermalin ( ) by assuming the board's preference as a utility function that positively weights equity but negatively wights equity risk: ( ) eq. ( ) consists of the weight-average net positive equity ( ) p  − and the weight-average net negative equity risk () p   − where p is the default probability (vassalou and xing, ) and   is the equity risk, that is the instantaneous standard deviations of the return on  (ronn and verma, ). the first term can be interpreted as the board's like captured by the net real equity return and the second term can be interpreted as the board's dislike captured by the net real equity risk due to the default probability is explicitly expressed in the board utility function. differentiating eq. ( ) with respect to r , the first-order condition is where the optimal r is determined. the second-order besides, differentiation of eq. ( ) evaluated at the optimal r with respect to i is given by: where the first-term is the direct effect, which is the effect of the parameter i on u , holding the optimal r constant. the second term is the indirect effect, which is for specifications of p and   , see appendix the effect of the parameter i on u through the adjustments of the optimal r . to investigate eqs. ( ) and ( ), we adopt a numerical approach to provide intuition. numerical analyses are based on the following reasonable parameter baselines. the parameter values, unless stated otherwise, are assumed as follows. (i) the shaded areas represent the values evaluated at the optimal . % r = . table shows that an increase in the degree of the covid- outbreak increases the life insurance policy businesses at an increased optimal guaranteed rate. intuitively, as the seriousness of the covid- has a significant impact on the investment risk, the insurer must now provide a return to a higher risk base. one way the insurer may attempt to augment its total returns is by increasing life insurance policies at an increased optimal guarantee rate for the asset-liability matching management purpose. our result is in large supported by mao and zhang ( ) although who remain silent on the optimal guaranteed rate determination. the shaded areas represent the values evaluated at the optimal . % r = . table presents that an increase in capital regulation increases the life insurance policies at an increased optimal guaranteed rate. an increase in capital regulation implies a decrease in the insurer's leverage, leading to investment funds decreased. to keep sufficient funds for investment, the insurer will conduct its guaranteed rate-setting strategy to increase its life insurance contracts. thus, policyholder protection increases at the cost of the decreased optimal insurer interest margin due to an increase in the guaranteed rate. thereby, stringent capital regulation helps policyholder protection but harms the insurer's interest margin, contributing to insurance stability during the covid- outbreak period. alpert ( ) reports that the bank of england rolls out stimulus measures on march , , mainly lowering capital requirements for u.k. financial institutions, which is money kept in reserve to increase institutions' resistance to global covid- shocks. this bailout allows nearly $ billion in new lending investment. however, our result is different because the insurer can use its pricing strategy by increasing the optimal guaranteed rate to attract insurance businesses and thus funds available for investment are increased. therefore, our result further complements and provides choices for the financial authorities: capital regulation to the insurer reaching the goal of policyholder protection and capital deregulation to the insurer achieving the goal of the profit maximization when the covid- outbreak is considered. table demonstrates that capital regulation enhances insurance businesses. the enhancement is reinforced when the covid- outbreak becomes more serious. the serious covid- harms the insurer's investment return. for the asset-liability matching management, the insurer will increase its optimal guaranteed rate to attract more policies to substitute the increased capital reserves. thus, stringent capital regulation helps policyholder protection, thereby contributing to insurance stability. in table , we show that the more serious covid- outbreak directly enhances the board's utility, holding the optimal guaranteed rate constant, since the increased equity risk is insufficient to offset the increased equity return. moreover, an increase in the covid- indirectly increases the board's utility through optimal guaranteed-rate adjustments. the positive direct effect is mainly from the explicit consideration of equity return and risk, while the positive indirect effect considers the optimal guaranteed-rate adjustments. the indirect effect reinforces the direct effect, leading to a positive effect on the board's utility. in the setting of the board utility, conflicts of incentives between the manager and the board disappear. accordingly, our result in large consistent with the argument of mao and zhang ( ) : the life insurance business is one of the new opportunities during the covid- period, implicitly implying that the board's utility is increased. in table , we show that capital regulation enhances the board's utility due to the safety net provided to the insurer and thus its board's utility can be improved by requiring the insurer to operate with more capital during the covid- outbreak. the result thereby contributes to insurance stability since insurer capital serves directly for policyholder protection (insurance europe, ). as reported by daniels trading ( ) , the covid- outbreak has been a primary driver of recent market volatility. insurance is considered a transfer of risks from the insured to the insurer. it must have a level of capital, which enables it to absorb unfavorable risks and to be solvent (araichi et al., ) . our result encompasses the suggestion of araichi et al. ( ) since the guaranteed rate-setting behavior during the covid- outbreak period is explicitly considered. in table , we describe that stringent capital regulation reduces the positive effect of the covid- outbreak on the board's utility. as the insurer is increasingly forced to increase its capital relative to the life insurance policy, it must increasingly provide a return to a larger equity base, yielding the board's utility increasingly. our result is in large consistent with zhang et al. ( ) : policy responses may create further uncertainty in financial [insurance] markets. this paper proposes to explore the effects of the covid- outbreak and capital regulation on the insurer's interest margin and its board utility. results suggest that the covid- outbreak and capital regulation increase insurance businesses at increased optimal guaranteed rates and enhance the board's utility. one immediate application reveals the conflicts of incentives between the insurer and its board since an increase in the board utility at the cost of the insurer's liabilities from the standpoint of insurer profitability. the model presented here is relatively fairly and should open at least one further avenue of research. an immediate outgrowth of the model is to introduce reinsurance options, particularly during the unexpected period of the covid- outbreak. this is because the covid- event has been a primary driver of market volatility. in conclusion, it is shown that guaranteed rate-setting behavior mode and capital regulation are intimately relevant to the covid- outbreak. appendix : we support that the policyholders whose premium payments at t = is denoted by   , and the equity holders whose equity capital at t = is denoted by ea  = . ( ) government stimulus efforts to fight the covid- crisis solvency capital requirement for temporal dependent losses in insurance life insurance in a contingent claim framework: pricing and regulatory implications impact of covid- on the chinese and global economy using futures to hedge against coronavirus (covid- ) risks. daniels trading trends in corporate governance why insurers differ from banks. insurance europe modelling the structural break in volatility new business opportunities emerging in china under the covid- outbreak. china briefing a model of an oligopoly in an insurance market pricing risk-adjusted deposit insurance: an option-based model default risk in equity returns financial markets under the global pandemic of covid- key: cord- -tp ckb r authors: robillard, r.; saad, m.; edwards, j. d.; solomonova, e.; pennestri, m.-h.; daros, a.; veissiere, s. p. l.; quilty, l.; dion, k.; nixon, a.; phillips, j. l.; bhatla, r.; spilg, e.; godbout, r.; yazji, b.; rushton, c. h.; gifford, w.; gautam, m.; boafo, a.; kendzerska, t. title: social, financial and psychological stress during an emerging pandemic: observations from a population web-based survey in the acute phase of the covid- pandemic date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: tp ckb r background understanding the multifaceted impacts of the coronavirus- (covid- ) outbreak as it unfolds is crucial to identify the most critical needs and to inform targeted interventions. methods this population survey study presents cohort characteristics and baseline observations linked to the acute-mid phase of the covid- outbreak in terms of perceived threats and concerns, occupational and financial impacts, social impacts and stress as measured by the cohen's perceived stress scale (pss) collected cross-sectionally between april and may , . a multivariate linear regression model was used to identify factors associated with stress changes relative to pre-outbreak estimates. results , / , ( . %) participants filled out at least / of the survey and were included in the analyses. on average, pss scores increased from . + . before the outbreak to . + . during the outbreak (p< . ). the independent factors associated with stress worsening were: having a mental disorder, female sex, having underage children, heavier alcohol consumption, working with the general public, shorter sleep duration, younger age, less time elapsed since the start of the outbreak, lower stress before the outbreak, worse symptoms that could be linked to covid- , lower coping skills, worse obsessive-compulsive symptoms related to germs and contamination, personalities loading on extraversion, conscientiousness and neuroticism, left-wing political views, worse family relationships, and spending less time exercising and doing artistic activities. interpretation cross-sectional analyses showed a significant increase from average low to moderate stress during the covid- outbreak. identified modifiable factors associated with an increase in stress may be informative for intervention development. an outbreak of coronavirus disease (covid- ) , a cluster of acute febrile respiratory illness, was first reported in wuhan, china, in december . the world health organization declared a pandemic on march , , after infections were reported in countries and territories. as of june , covid- had spread to countries and territories, infected , , individuals, and caused , deaths worldwide. this pandemic has created profound economic and social disruption, with the potential for widespread psychological impacts. early covid- studies from china, india, brazil, paraguay, and the united states indicated high levels of stress with associated sleep problems, poor life satisfaction, and mental illness. [ ] [ ] [ ] [ ] [ ] as the consequences of this pandemic are likely to be influenced by a range of demographic, occupational, and physical/mental health factors, , , there is a need for comprehensive investigations to identify potential factors modulating psychological responses to this complex situation. furthermore, most studies to date adopted a broad, representational sampling of adults, but increased efforts to reach individuals at elevated risk for negative outcomes and a lifespan perspective incorporating younger to older age ranges holds particular benefits in informing both prevention and intervention initiatives. the current manuscript presents the cohort characteristics and baseline observations from an ongoing longitudinal survey launched during the acute phase of the covid- pandemic. perceived threats and concerns, occupational, financial and social impacts, as well as psychological stress changes relative to retrospective pre-outbreak estimates are reported. a comprehensive longitudinal online survey was distributed via websites, social media, and multiple organizations and hospitals across canada. this recruitment strategy (see supplementary section for details) was used to target three core groups: people with chronic mental or physical illnesses, healthcare providers, and the general population. while subsequent reports will focus on specific subgroups, the current report introduces the full cohort. the sole inclusion criterion was to be years of age and older. the survey was available in english and french, nested in a secured access online platform (www.qualtrics.com) and designed on a decisional tree structure. it included a set of validated questionnaires and custom-built questions pertaining to the pandemic (see supplementary section). themes covered in the current report include: factors linked to the pandemic (e.g., testing, perceived threat and . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint concerns); occupational and financial life; social life, and psychological stress. retrospective questions were used to estimate temporal changes from "before the outbreak" (i.e. in the last month before the outbreak) to "during the outbreak" (i.e. in the seven days prior to filling out the survey). the survey was developed and conducted following guidelines from the checklist for reporting results of internet e-surveys. additional information about the survey and the psychometric properties of validated scales included are outlined in supplemental material. electronic informed consent was obtained from each participant. this study was approved by the clinical trials ontario -qualified research ethics board via the ottawa health science network (protocol # ) and registered at clinicaltrials.gov (nct ). respondents retrospectively assessed their stress levels on the cohen's perceived stress scale (pss) before and during the outbreak. pss scores were analyzed continuously (i.e. scale of to , estimated minimal clinically important relative change: %) and categorically based on established thresholds: to (low stress), to (moderate stress), and to (high stress). factors hypothesized a priori to be associated with stress changes were: pre-outbreak stress level, time elapsed since the pandemic declaration by the who, age, sex, education level, total family income, employment status, working with the general public, political views, having underage children, having travelled abroad in the past days, index reflective of the number and severity of potential covid- symptoms, the dimensional obsessive-compulsive scale (docs) contamination subscale, big personality subscales, brief resilient coping scale (brcs), having a mental disorder, alcohol and drugs use, having a physical condition at risk for covid- , sleep duration, quality of family relationships, and amount of time spent outdoors, interacting with other people, following the news on covid- , and engaging in physical and artistic activities. descriptive statistics were used to characterize survey respondents. to assess changes before and during the outbreak, chi-squared analyses, paired t-tests/wilcoxon tests, and mcnemar-bowker tests were used. a repeated measures anova was used to assess the unadjusted cross-sectional temporal evolution of pss change scores. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint multivariate linear regression was used to identify factors independently associated with pss changes scores using the "enter" pairwise approach with the predictors listed above. to improve sample homogeneity, this model was run solely on the subgroup of canadian respondents. a series of multivariate linear models were also run to assess the relation between changes in stress and each independent variable separately while accounting for pre-outbreak pss scores. analyses were done using the statistical package for social sciences (ibm spss statistics for windows, version · . armonk, usa). details on data cleaning procedures are provided in the supplementary material. between april rd and may th (i.e. to days after the pandemic declaration by the who), , individuals consented to take part in this study and answered the first survey question. all , respondents who filled out the minimally sufficient portion of the survey ( · % of those who answered the first question; see details in supplement) were included in the current report. · % ( , / , ) respondents completed the entire survey. sample characteristics are presented in table . respondents ranged between and years old. most respondents were middle-aged, female, canadian (mostly from ontario or quebec), caucasian, highly educated, lived in an urban residential area, had children, and were employed with a total yearly family income above $ , . ( , / , ) for their country. figure shows the degree of concerns related to different secondary effects of the . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint outbreak. overall, the highest concerns pertained to one's children or relatives not coping well with the situation, closely followed by being unable to access medications or medical services. on average, when comparing pre-outbreak estimates and current states: sleep duration shortened (z=- · , p< · , r= · ), family relationships deteriorated (z=- · , p< · , r= · ), and weekly alcohol and cannabis consumption increased (z=- · , p< · , r= · and z=- · , p< · , r= · ). specifically, · % ( / , ) of the sample over years of age increased their weekly alcohol consumption by five drinks or more. of the student respondents (table ) , · % ( / ) reported that their school closed because of the outbreak. within actively working respondents, · % ( , / , ) were working from home, · % ( / , ) had increased work hours because of the outbreak, and · % ( / , ) had decreased work hours. · % ( / , ) underwent a salary decrease due to the outbreak, with an overall median salary reduction of % (iqr= ). of all respondents who were working in the month preceding the outbreak, · % ( / , ) saw their employment terminated because of the outbreak. rates of employment termination due to the outbreak or salary loss exceeding % were higher in those with a family income below $ k ( · %, / ) compared to those with higher family income ( · %, / , , χ = · , p< · ), in people without a university degree ( · %, / ) compared to in those with a university degree ( · %; / , ; χ = · , p< · ), and in people with a diagnosis of a mental disorder ( · %, / ) compared to those without ( · %, / , ; χ = · , p= · ). rates of employment termination/salary decrease were similar in females versus males (χ = · , p= · ), caucasians versus other ethnicities (χ = · , p= · ), and people with or without physical illnesses (χ = · , p= · ). across the entire sample, · % ( , / , ) reported that their expenses had decreased since the start of the outbreak and · % ( / , ) reported an increase, with a mean estimated rise in health-related expenses of · + · %, compared to · + · % for food-related expenses. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint family and other relationships half of parents with underage children ( · %, / ) said that they or their partner were homeschooling. most respondents estimated that the outbreak was being somewhat disruptive for the management of their work/study and family life (mean rating on a scale from " -very disruptive" to " -not different from usual" and " -easier than usual": · + · ). the proportion of respondents interacting with their family more frequently since the start of the outbreak was significantly higher than the proportion of those who were interacting less frequently (p< · ). the reverse pattern was found for interactions with friends (p< · ). · % ( , / , ) of respondents reported feeling more connected to their family during compared to before the outbreak, while · % ( , / , ) felt less connected. this pattern was reversed for connectedness to friends, with · ( , / , ) reporting feeling less connected and · % ( , / , ) feeling more connected. on average, relationships ratings with both family and friends during the outbreak significantly deteriorated compared to pre-outbreak estimates (z=- · , p< · and z=- · , p< · ). social distancing · % ( , / , ) of respondents were following at least one social distancing guideline at the time of filling out the survey, with · % ( , / , ) maintaining a meters distance from others, · % ( , / , ) avoiding gatherings in person, · % ( , / , ) not using public transport, · % ( , / , ) not attending public areas, · % ( , / , ) not going out of the home unless they had no choice (e.g. to go to a medical appointment), · % ( , / , ) wearing a mask when leaving home, and · % ( / , ) having food/supplies delivered to their homes. a statistically significant proportion of individuals (between · to · %) disengaged from some of the social distancing practices that they had initially followed since the start of the outbreak (all p< · ). scores on the ucla loneliness scale were significantly higher in individuals who were avoiding going out of their home (z=- · , p= · ), living alone (z=- · , p< · ), younger than years of age (z=- · , p< · ), diagnosed with a mental disorder (z=- · , p< · ), or unemployed (chi-squared= · , p< · ). there was no significant difference in loneliness based on other social distancing practice, sex or whether one worked from home (p> · ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint psychological stress pss scores globally increased from · + · before the outbreak to · + · during the outbreak (z=- · , p< · , r= · ), which reflects a transition from low to moderate stress. rates of individuals with pss score in the high stress range increased from · % ( / , ) before the outbreak to · % ( / , ) during the outbreak (figure ) . a clinically meaningful increase in stress was noted in · % of respondents, while · % had a clinically meaningful reduction in stress. over the course of the survey period, there was an overall attenuation of stress worsening on pss change scores (f ( , ) = · , p< · , figure ). there was a non-significant reduction in stress worsening between april rd and th, followed by a plateau which persisted until may th, after which there was a significant drop (p≤ · ), compared to all preceding time periods. the following variables were found to be significant independent factors linked to stress worsening in the multivariable linear regression model ( table ) : shorter time elapsed since the start of the outbreak, younger age, female sex, having left wing political views, work involving in-person contact with the general public, having underage children, worse covid- symptoms index, shorter sleep duration, lower pss scores before the outbreak, higher scores on the docs -contamination subscale and on the extraversion, conscientiousness and neuroticism scales of the big , lower brcs scores, having a mental disorder diagnosis, having had more than five alcoholic drinks in the past week, worse family relationships, and spending less time exercising and doing artistic activities. baseline data from our longitudinal survey in , respondents suggests that the financial, social and psychological correlates of the covid- outbreak may interact in a complex manner, and that they vary considerably across individuals. while some of our findings echo previous observations, we propose a more comprehensive integrated model of independent factors associated with worse stress responses to this pandemic. in line with previous polls reporting that many people perceived the covid- pandemic as a greater threat to the economy than to their health, we observed higher sense of threat related to external/global as opposed to more personal matters. our observation of concerns about access to medical services are aligned with high rates of potential covid- symptoms with low reported access to testing for covid- , a combination which may increase stress. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint consistent with canadian rates of employment which plummeted by about % from february to april , but lower than the % worldwide job losses anticipated by the un labor agency, % of our respondents lost their job because of the outbreak and an additional % underwent salary cuts, with a non-trivial median reduction in salary of %. low income and the lack of a university degree were found to be major risk factors for adverse work and salary outcomes, a phenomenon that may further widen economic disparities. similarly, reports in the us showed that % of people earning $ k or less lost their jobs due to the covid- outbreak and that most of those who kept their job had a university degree. importantly, the current study is to our knowledge the first one to identify having a mental disorder as a risk factor for employment termination during the outbreak. the psychological impacts of unemployment are likely to further worsen mental health in these individuals, and they may be at higher risks for subsequent unemployment. therefore, this subgroup may face additional challenges not only to cope with the occupational and financial consequences of the pandemic, but also to find work after de-confinement, which highlights potential needs for targeted governmental relief packages and supporting programs to find work. in line with early covid- reports from china describing major reductions in social contacts beyond the household, we observed increased interactions with family and decreased interactions with friends, which probably reflect social distancing. this change was accompanied by consistent changes in feelings of connectedness and, paradoxically, by a worsening in relationships quality. together with previous observations of increased family violence during the pandemic, this stresses the need to better understand how close proximity in the context of confinement may create family tensions. only % of respondents were following at least one social distancing guideline, a percentage similar to previously reported rates in a previous canadian poll. although the state of emergency still prevailed at the time of the survey, about - % of respondents had been phasing out their social distancing practices. this raises considerable concerns since even a % increase in adherence to social distancing can contribute to slow the spread of covid- . we found a significant increase in stress co-occurring with the outbreak, with % of individuals undergoing clinically meaningful stress worsening. this is consistent with rates of moderate to severe stress reaching to % in asia, europe, and australia. , , [ ] [ ] [ ] [ ] as anticipated, more acute stress reactions were observed in the earlier phases of the outbreak, with a sharp drop shortly after the mortality peak in canada was announced. these preliminary observations suggest that although the degree of stress worsening during the outbreak may be phasing out for many individuals, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint two months after the pandemic declaration, stress levels were not fully back to pre-outbreak levels. this supports the need for the development/promotion of self-help tools for stress management. having a current diagnosis of a mental disorder was found to be the strongest independent factor linked to stress worsening, a finding consistent with previous observations about pre-existing psychiatric conditions. , , [ ] [ ] [ ] [ ] this stresses the importance of further investigation in this group who may require more intensive stress management resources. poorer coping skills and personality traits loading heavily on extraversion, conscientiousness, and neuroticism were also associated with worse increases in stress. high neuroticism has previously been linked to maladaptive stress coping strategies. while personalities loading on conscientiousness are usually well-organized, goal-directed and more effective in dealing with stress, the uncertainty associated with this unprecedented outbreak may prevent them from relying on their usual coping strategies, leading to heightened stress. since extraversion is characterized by a tendency to be active and sociable, social distancing measures probably contributed to worse stress responses in extraverted individuals. accordingly, a brazilian covid- survey showed that higher extraversion was associated with lower engagement in social distancing practices, likely reflecting how challenging it is for extraverted individuals to reduce their social proximity. in line with our finding of an association between left-wing views and stress worsening, a recent gallup poll in the us found that liberals (as compared to conservatives) were more likely to worry about worst-case outcomes of the pandemic. the politicization of the crisis and associated media bias (with risk-preventive, pro-lockdown perspectives in the liberal media, and the conservative media appearing to take the crisis less seriously) is one possible explanation for worse pandemic-related distress in liberals. our results confirm that several factors previously linked to stress, such as female sex, younger age, having children, and having symptoms that could be linked to covid- , , independently contribute to stress worsening. while previous reports highlighted increased risks in healthcare workers, our findings suggest that this extends to other types of workers physically interacting with the public. importantly, the current study also identified some modifiable factors that were associated with lower stress responses. for instance, protecting a sufficient period for sleep, minimizing alcohol consumption, promoting better family relationships, exercising, and doing artistic activities may be helpful. since sleep is thought to contribute to emotional regulation, attenuating the adverse effects of the pandemic on sleep may enable better coping resources. about minutes of moderate-intensity aerobic exercise three times weekly may also boost mood, reduce psychological distress and decrease symptoms of depression and anxiety. planning family activities that may help alleviate tensions and foster more positive relations, as well as creating some . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint time and space for individuals to offset the challenges posed by sustained family proximity may also be relevant to manage stress. appropriate home-schooling support, as well as better work adaptation for parents may also be required. increased access to testing is likely to have the collateral effect of attenuating stress levels. the study has several important limitations. first, generalizability is limited by the dissemination strategy and volunteer bias; although our demographic characteristics are consistent with other published surveys. the length and online nature of the survey may have prevented some individuals from completing it. recall bias may have affected retrospective estimates of pre-outbreak metrics. although our multivariate model corrected for this, data collection spanned over a month, a period during which we did observe dynamic changes in stress responses. this study also has several strengths, such as a relatively large sample size, the comprehensive set of factors assessed, and its launch in the early/mid phase of the outbreak. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we wish to thank all the participants who gave their time to fill out this extensive survey during this period of turmoil. we also extend our gratitude to the ethics boards who rapidly and diligently provided insights on this project to enable a timely launch, the organizations who helped circulate the survey in their networks, and niva inc, for their advice on distribution strategies. we thank the clinical investigation unit at the ottawa hospital research institute for assistance with participant recruitment. all co-authors were involved in the following: study conception and design, interpretation of data, revising the manuscript critically for the accuracy and important intellectual content, and final approval of the version to be published. all co-authors are accountable for all aspect of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. rr, tk, and je were additionally involved in the participants' recruitment as site primary investigators. rr, ms, an and tk were additionally involved in the following: analyses of data and drafting of the manuscript. all authors declare that no competing interests exist. proposals to access data from this study can be submitted to the corresponding author and may be made available upon data sharing agreement. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint figure . transitions across stress levels relative to before the outbreak levels lasagna plot of the percentages (%) of respondents endorsing low, moderate and high stress levels (as per established severity threshold for the cohen's perceived stress scale (pss)) in the retrospective assessment of their stress levels in the month prior to the start of the pandemic (before the outbreak) and in the past days before filling out the survey (i.e. during the outbreak). dashed lines indicate the transition points between the stress severity ranges. as compared to before the outbreak, · % ( , / , ) of respondents had progressed to a higher stress range during the outbreak, and · % (n= / , ) of respondents moved to a lower stress range . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint april th april th april th may st may th average change in pss score relative to pre-outbreak levels ** . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . who coronavirus disease (covid- ) outbreak situation covid- ) outbreak situation the impact of covid- epidemic declaration on psychological consequences: a study on active weibo users the emotional impact of coronavirus -ncov (new coronavirus disease) rapid assessment of psychological and epidemiological predictors of covid- concern, financial strain, and health-related behavior change in a large online sample a nationwide survey of psychological distress among chinese people in the covid- epidemic: implications and policy recommendations immediate psychological responses and associated factors during the initial stage of the coronavirus disease (covid- ) epidemic among the general population in china anxiety, worry and perceived stress in the world due to the covid- pandemic acute mental health responses during the covid- pandemic in australia. medrxiv improving the quality of web surveys: the checklist for reporting results of a global measure of perceived stress cross-cultural adaptation and validation of the danish consensus version of the -item perceived stress scale. scand j work environ heal public divided on whether isolation, travel bans prevent covid- spread; border closures become more acceptable. ipsos un labour agency. nearly half of global workforce at risk as job losses increase due to covid- : un labour agency board of governors of the federal reserve system mental health affects future employment as job loss affects mental health: findings from a longitudinal population study changes in contact patterns shape the dynamics of the covid- outbreak in china. science ( -) increased risk for family violence during the covid- the enemy who sealed the world: effects quarantine due to the covid- on sleep quality, anxiety, and psychological distress in the italian population a nationwide survey of psychological associated factors pandemic on adults and their children in italy protective elements of mental health status during the covid- outbreak in the portuguese population. medrxiv the interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression personality differences and covid- : are extroversion and conscientiousness personality traits associated with engagement with containment measures? trends psychiatry psychother the interplay between sleep and emotion regulation: conceptual framework empirical evidence and future directions exercise reduces depression and inflammation but key: cord- -ibli rq authors: to, kelvin k.w.; chan, jasper f.w.; tsang, alan k.l.; cheng, vincent c.c.; yuen, kwok-yung title: ebola virus disease: a highly fatal infectious disease reemerging in west africa date: - - journal: microbes infect doi: . /j.micinf. . . sha: doc_id: cord_uid: ibli rq ebolavirus can cause a highly fatal and panic-generating human disease which may jump from bats to other mammals and human. high viral loads in body fluids allow efficient transmission by contact. lack of effective antivirals, vaccines and public health infrastructures in parts of africa make it difficult to health workers to contain the outbreak. ebolavirus has been known to cause outbreaks of severe hemorrhagic fever with high fatality in africa since [ ] . however, ebolavirus has been out of the spotlight of the clinical and scientific community because it mainly affects remote villages involving at most few hundred people, and these outbreaks often stopped spontaneously. in , a large ebolavirus outbreak occurred in west africa. this outbreak was first reported from guinea in march , although epidemiological investigation suggested that the first fatal case had occurred in december [ ] . the outbreak then spread to liberia, sierra leone, nigeria, senegal, and mali in africa. the first case diagnosed outside africa was reported from usa on september , [ ] . in october , three nurses acquired ebolavirus locally in the united states and spain which has generated huge media attention and public panic. the west africa ebolavirus outbreak is unprecedented in many ways. firstly, this is the largest ebolavirus outbreak recorded in history, with over , cases and a mortality rate of . % [ ] . secondly, the outbreak involved major cities, including conakry in guinea, free-town in sierra leone, monrovia in liberia, and lagos in nigeria [ , ] . the involvement of major cities increases the risk of rapid local dissemination, spread to neighboring countries, and transcontinental spread by air travel, and therefore presenting a major health threat to the entire world [ ] . here, we review the basic science, epidemiology and clinical aspects of ebolavirus which are relevant for the control of the current outbreak. ebolavirus, together with marburgvirus and cuevavirus, are the three genera belonging to the family filoviridae in the order mononegavirales [ ] . four species within the ebolavirus genus can cause fatal human disease, including sudan gabon, which are located in central and east africa. zaire and sudan ebolavirus are responsible for most outbreaks, and these species are associated with highest case-fatality rates, ranging from e % and e %, respectively. taï forest ebolavirus caused illness in an ethnologist who performed a necropsy on an infected chimpanzee in in cote d'ivoire of west africa [ ] . bundibugyo ebolavirus has only been associated with two outbreaks since , with relatively low case-fatality rate [ ] . reston ebolavirus can cause disease in pigs and be fatal in monkeys [ ] , but has not been definitively associated with any human disease, although asymptomatic infection, diagnosed with serological test, was identified in persons with contacts with infected monkeys and pigs [ , ] . in addition to clinically apparent evd outbreaks, seroepidemiology studies showed that there is a high prevalence seropositive individuals, suggesting that asymptomatic or mild infection can occur [ ] . in a study testing blood samples collected from individuals from randomly selected village in gabon between and , . % of samples were found have ebolavirus-specific antibodies using elisa [ ] . ebolavirus-specific antibodies can also be found in individuals from areas without apparent evd outbreak. for example, ebolavirus-specific antibodies, detected using indirect immunofluorescence slide test, were found in . % of healthy individuals from a rainforest area of liberia in the early s [ ] . though these serological test results have not been confirmed by neutralization antibody study, it is highly likely that asymptomatic and mildly symptomatic infections are much more common than severely symptomatic and fatal illness. the current west africa evd outbreak started in december , when cases first appeared in meliandou village, gu eck edou of guinea (table ) [ ] . the index patient was a -year-old child with fever, black stool, and vomiting, with symptom onset on december , , and died days later. the disease then spread to other villages of the gu eck edou district, and also macenta and kissidougou district. the first peak occurred in march when patients were diagnosed with evd in liberia. the second peak occurred in may and june , coinciding with the first report of cases from sierra leone. contact tracing found that the initial cases in sierra leone attended a funeral of a highly respected "traditional healer", who has treated patients with evd in guinea [ , ] . there was a large increase in cases since july . the first case in nigeria was a traveler from liberia, who has caused an outbreak involving laboratoryconfirmed cases from july to september [ ] . senegal and mali reported the first imported cases on august and october , , respectively [ ] . the first case of evd diagnosed outside africa was confirmed on september , [ ] . the patient, from liberia, arrived in usa on september , and developed symptoms on september . a separate evd outbreak, also caused by zaire ebolavirus, has occurred in drc since july [ ] . as of october , , the drc outbreak has involved cases with deaths [ ] . together with these epidemiological data, viral genomic data has provided important information on the origin and the transmission dynamics of the west africa ebolavirus strain. phylogenetic analysis using the whole genome sequences of ebolavirus strains from patients revealed that the west africa evd outbreak is caused by a zaire ebolavirus lineage that is most closely related to the one causing the evd outbreak in drc [ ] . molecular dating suggested that this west african lineage likely diverged from the central african lineage in [ ] . analysis of the ebolavirus strains from guinea and sierra leone showed that they are highly similar, which is in agreement with the findings from contact tracing (fig. ) . however, there are two distinct lineages of ebolavirus in sierra leone which were estimated to have diverged in april . this finding suggests that the virus has further mutated either in guinea or in sierra leone [ ] . on the other hand, the ebolavirus strain causing the drc evd outbreak in july is another zaire strain most closely related to drc outbreak zaire strain [ ] , confirming that this is a separate outbreak. before , the largest evd outbreak affected less than people. however, in the current outbreak, there are already , cases and deaths as of october , [ ] . further studies must be undertaken to understand the viral and environmental factors that contribute to the unprecedented scale of this outbreak. it is still uncertain at this stage whether the virus has become more transmissible in human or has increased environmental stability. it is unclear why zaire ebolavirus suddenly appear in west africa. the only human case of ebolavirus infection in west africa before the outbreak occurred years ago. epidemiological investigation suggested that the first patient was a -year-old child in meliandou village, gu eck edou. one postulation is the spread of the virus by fruit bats from central africa [ ] , but this will require confirmation by further field studies. humans can acquire the infection from infected animals or infected persons. the index patients of evd outbreaks are usually persons working in forests, caves or mines. many of these index patients are bushmeat hunters with direct contact with animals. in the natural setting, transmission from animals usually involves direct contact with the animal or handling of the carcasses. however, most humans acquire the infection through direct person-to-person transmission that can occur via direct contact with body fluids. many clusters occurred when people attended the funeral of an infected patient [ , ] . a caseecontrol study showed that household contacts with direct physical contact with the ill patient or cadaver and exposure to body fluids were risk factors for acquiring infections [ ] . ebolavirus can be transmitted directly through broken skin or mucous membranes from the blood, body fluid, and secretions of the infected person, as the virus could be detected in blood, urine, saliva, seminal fluid, breast milk, tears, stool, skin, and swabs from vagina, rectum and conjunctiva [ ] . virus shedding can be prolonged. reverse-transcriptase polymerase chain reaction (rt-pcr) remained positive in the blood for up to days, in the vaginal, rectal and conjunctival swab for up to days, and in the seminal fluid for up to days [ ] . live virus could be isolated from a patient's seminal fluid days after symptom onset. transmission through environmental surfaces is possible. it was shown that live ebolavirus can survive on dried glass or plastic surface for up to days [ ] . studies have shown that lower temperature and higher absolute humidity are associated with evd outbreaks [ ] . animal studies showed that other routes may be possible. reston ebolavirus can be transmitted from pigs to cynomolgus macaques without direct contact, suggesting that ebolavirus can be transmitted from animal reservoirs to humans without direct contact [ ] . studies in rhesus macaques showed that ebolavirus given orally can cause fatal infections [ ] . aerosol transmission in macaques has been documented [ ] , but this route of transmission has not been documented in humans. almost all cases in the current outbreak are related to person-to-person transmission. the effective reproduction numbers for the outbreak were estimated to be . for guinea, . for liberia, . for nigeria, and . for sierra leone [ ] . hospital-acquired infections are common. during the evd outbreak, the index case had transmitted the virus to healthcare workers and hospitalized patients with at least generations of person-to-person transmission [ ] . during the current outbreak, at least healthcare workers were infected, with at least deaths [ ] . in addition, ebolavirus is also transmitted indirectly when the broken skin or mucous membranes come into contact with the contaminated environment or items such as soiled clothing, bed linen, or used needles. unsterilized syringe was associated with the outbreak in zaire [ ] . in one study, the virus could also be found on the doctor's blood-stained glove and the bloody intravenous insertion site, but was not found on the patient's surrounding environment [ ] . laboratory-acquired infections from accidental puncture while handling infected materials have been reported [ , ] . in a detailed analysis of confirmed and probable ebolavirus cases in guinea, liberia, nigeria and sierra leone from december , to september , , the median age was years with an interquartile range from to years. the male to female ratio was : [ ] . the incubation period is usually e days, but can be as short as days and as long as days [ ] . in the current outbreak, the mean incubation period was . days, with % of patients had symptom onset within days. ebolavirus has been found in several animals, including bats, primates (chimpanzee, gorilla), rodents (rats, mice, shrews), duikers (cephalophus species), and pigs [ ] . although ebolavirus-specific antibody can be detected in up to . % of serum samples from dogs in ebolavirus endemic areas [ ] , there have not been any reports on the isolation of ebolavirus or detection of ebolavirus nucleic acid from dog's samples. in some animals, ebolavirus causes epidemic fatal disease. it was estimated that after the ebolavirus outbreak in the drc between and , there were %, % and % reductions in the chimpanzee, gorilla and duiker populations, respectively [ ] . bats have been proposed to be the source of ebolavirus. bats have been known to be the source of several human viruses including severe acute respiratory syndrome-related coronavirus (sars-cov), hendra virus, nipah virus, menangle virus, rabies virus and lyssaviruses [ , ] . ebolavirus was first reported to be found in the fruit bat species hypsignathus monstrosus, epomops franqueti and myonycteris torquata, which were captured during the and outbreak in gabon and the drc [ ] . during the investigation of the outbreak in drc, it was found that the affected area has a large palm plantation where migratory fruit bats settled for food between april and may, and that the first human case ate a freshly killed bat which was bought from a hunter in may [ ] . ebolavirus is not limited to africa. serological study showed that antibodies against zaire and reston ebolavirus could be detected in fruit bats from bangladesh [ ] , while reston ebolavirus could be detected in fruit bats from the philippines [ ] . a study in china showed that up to . % of bats were seropositive for ebolavirus [ ] . the most common bats species with ebolavirus identified in china include rousettus leschenaultia, hipposideros pomona, miniopterus schreibersii, pipistrellus pipistrellus, myotis ricketti, in which other novel viruses have also been identified [ e ]. reston ebolavirus have been found in domestic pigs in the philippines and china [ , ] . antibodies specific against all ebolavirus species have been found in apes of indonesia [ ] . like all filoviruses, ebolavirus is a filamentous enveloped virus with a negative-sense, non-segmented single-stranded genome of about kb, measuring nm in diameter and up to nm in length [ ] . the end of the viral genome consists of a non-coding region, followed by genes (nucleoprotein [ , and then a non-coding region at the end. each gene encodes one protein, except for the gp gene, which encodes three glycoproteins. the full-length gp is produced by rna editing, in which the two reading frames are joined together by slippage of viral polymerase at an editing site, generating an mrna transcript that allows read-through translation of gp. gp contains gp subunit for host cell receptor binding and the gp subunit for cell-virion membrane fusion. the soluble gp (sgp) is generated by an unedited transcript, which is much more abundant than gp [ ] . a third protein, called small soluble gp (ssgp), is produced via rna editing [ ] . gp, vp and vp are associated with membrane, while np, vp , vp , and l protein bind to the viral genome, which are required for viral genome replication and transcription. vp is also required for the assembly of nucleocapsid. the viral life cycle starts when gp attaches to cell surface receptors [ , ] . although ebolavirus can bind to host cell surface dendritic cell (dc)-specific icam -grabbing nonintegrin (sign) (dc-sign), liver and lymph node sign (l-sign) and t cell immunoglobulin and mucin domaincontaining (tim ), it is currently unclear which cell surface receptor is most important. after attachment, viral entry occurs via macropinocytosis and clathrin-mediated endocytosis [ ] . after entry, the virus is then trafficked into endosome. inside the endosome, several factors are required for the fusion of the viral and endosomal membrane to occur, including acidification of the endosome, and priming and triggering of the gp. priming of gp occurs when gp , which is bound to gp , is cleaved into the kda gp by cathepsin l and then to kda by cathepsin b. triggering occurs when the kda gp undergoes conformational change to expose the fusion loop [ ] . another important event in the fusion step is the binding of the endosomal membrane protein, niemann-pick c (npc ), to cleaved gp [ ] . viral genome replication and transcription then take place in the cytoplasm, which require the viral polymerase l protein, vp , vp and np. vp is required for nucleocapsid formation and assembly. viral transcription is also regulated by vp [ ] . the gp, after modification in the golgi, is trafficked to the plasma membrane, where it is associated with other proteins. virus budding and release then occur, and require the matrix protein vp . in addition to the viral life cycle, these viral proteins are also involved in the pathogenesis of the infection. gp can cause destruction of endothelial cells [ , ] . several lines of evidence suggest that the sgp is important in the modulation of host inflammatory response and immune defense. in vitro, sgp can inhibit the neutralizing activity of anti-gp antibody [ ] . sgp also subverts anti-gp immune response by inducing a host antibody that competes for the binding site of anti-gp antibody [ ] . sgp can also interact with neutrophils, although the receptor for this interaction is controversial [ , ] . on the other hand, sgp may limit the virulence of the virus. recombinant ebolavirus without sgp are less cytotoxic than those with sgp [ ] . sgp can protect endothelial cells from tnf-a [ ] . sgp can also bind to gp , but the importance of this finding requires further study [ ] . vp also inhibits the innate immune rig-i signaling, interferon(ifn)-a and ifn-b production, and dendritic cell maturation [ ] . vp is important in the inhibition of ifn signaling [ , ] . it is currently unclear whether the west africa ebolavirus strain possesses unique characteristics that favor its spread among the human populations. one possible reason is the higher mutation rate. it has been shown that the mutation rate in the current outbreak is about twice as high than that in previous outbreaks [ ] . decontamination methods for ebolavirus include heat inactivation at e c for h or at c for min, g-irradiation, chemicals, including formalin and quaternary ammonium ion, and nanoemulsions, which disrupts the membrane [ ] . in most cases, ebolavirus likely enters the body via breaks in the skins or mucous membranes. infection of monocytes, macrophages and dendritic cells helps to disseminate the virus to the lymph nodes via the lymphatics, and to the liver and spleen via the blood. notably, ebolavirus does not infect lymphocytes, although lymphocyte depletion occurs due to apoptosis [ ] . when the infected monocytes, macrophages or dendritic cells move out of the lymph nodes and spleen, the virus can disseminate to other organs [ ] . ebolavirus can also infect endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells. since patients with severe disease have higher viral load in blood, uncontrolled viral replication may play an important role in the pathogenesis of severe evd [ ] . macroscopically, there are hemorrhagic lesions on the skin, mucous membranes, and visceral organs at autopsy. microscopic examination reveals necrosis in many organs, including the liver, spleen, kidneys and gonads [ ] . in the liver, there is also evidence of apoptosis, microvesicular steatosis and kupffer cell hyperplasia. councilman bodies, which are apoptotic liver cells that have dislodged from adjacent hepatocytes, may be present. eosinophilic oval or filamentous cytoplasmic inclusions may be present, and they are aggregates of ebolavirus np. examination of the lung shows hemorrhages and diffuse alveolar damage. infection of the adrenal gland has been documented in humans [ ] . adrenal necrosis may be one possible pathogenic mechanisms leading to hypotension. marked coagulopathy is a hallmark of evd. disseminated intravascular coagulation frequently occurs. it is believed that tissue factors secreted from monocytes/macrophages are related to the coagulopathies in macaques [ ] . the level of protein c is reduced during coagulopathy [ ] . protein c is important in inflammatory response. a study in which rnapc and rhapc-treated rhesus macaque had better outcome, had higher levels of genes transcriptionally regulated by ccaat/ enhancer-binding protein alpha, tumor protein , and megakaryoblastic leukemia and myocardin-like protein [ ] . although the virus can infect endothelial cells, vascular lesions are not seen in postmortem tissues, and therefore the severe bleeding is unlikely to be related to the direct destruction of the blood vessels by the ebolavirus. similar to other causes of severe sepsis, cytokine/chemokine dysregulation occurs in patients with severe disease. fatal cases had high levels of mip- b, il- , il- , and il- [ ] . in one study, asymptomatic patients had elevated levels of il- b, il- , tnfa, mcp- , mip- a and mip- b in the plasma [ ] . however, in one study, gene expression levels of cytokines in peripheral blood mononuclear cells from infected patients were not different from that of non-infected patients. the level of plasma nitric oxide is higher in fatal than that of non-fatal cases [ ] . the high levels of nitric oxide may have contributed to lymphocyte apoptosis, tissue and vascular damage, and may be associated with the hemodynamic instability seen in fatal cases. one of the major innate defense mechanisms against viral infection is the ifn pathway. ifn are produced by cells upon viral infection, and induced several proteins, including the ifn-induced transmembrane proteins (ifitms). it has been shown that the type ifns and the ifitm , and to a lesser extent ifitm , restrict the cell entry of ebolavirus [ ] . as mentioned above, the viral proteins vp and vp interfere with the ifn pathway which may in turn dampen the priming effect on the adaptive immune response, thus allowing the virus to replicate to high titers. the importance of humoral and cell-mediated immune response is illustrated by a study comparing survived and fatal cases [ ] . ebolavirus-specific igm and igg were detected in all survivors during the early course of illness, with positive titer detected as early as days after symptom onset. in contrast, only one third and none of fatal cases had detectable igm and igg response, respectively. activation of cytotoxic t cells, as indicated by the upregulation of fasl and perforin mrna expression, was observed at the time of viral clearance for survivors, and the levels of ifng, soluble fas and soluble fasl were low during the recovery phase, suggestive of a regulated cytotoxic t cell response during the recovery phase. for the fatal cases, the levels of ifng, soluble fas and soluble fasl were elevated and increasing before death, suggestive of massive activation of cytotoxic t cells. after natural infection, neutralizing antibodies are produced in some patients. persistent serum-neutralizing activity and igg immunoreactivity for at least years after infection have been found in some survivors [ ] . monoclonal antibodies against gp have been shown to protect non-human primates from lethal infection as both post-exposure prophylaxis [ e ] and treatment [ , ] . the level of anti-gp igg highly correlated with survival in guinea pigs and cynomolgus macaques which were vaccinated by gp expressed in adenovirus or vesicular stomatitis virus vectors [ ] . antibodies are also critical in conferring protection for cynomolgus macaques after vaccination with recombinant vesicular stomatitis virus expressing gp [ ] . vaccine studies in animals have provided clues to the contribution of cell mediated immunity in conferring protection. mice study showed that virus-like particles induced protective immunity only in wild type mice but not in nk-cell depleted mice, therefore suggesting that nk cells are important in protective immunity [ ] . the role of t cells is controversial. while one study showed that cd þ t cells are required for conferring protection [ ] , another study showed that it is not required [ ] . despite a high case-fatality rate, there are many individuals with asymptomatic infections, as evidenced by a high percentage of seropositive individuals. although many factors may determine whether a patient develops symptomatic disease, host genetic differences likely play an important role, as in other infectious diseases [ , ] . mice with different genetic backgrounds had different susceptibility to ebolavirus infection, and possibly related to the variations in the tek gene responsible for coagulation [ ] . evd typically progresses rapidly with multisystem involvements, and in particular coagulopathy leading to severe hemorrhage. during the early stage of illness, the patients usually exhibit an acute onset of non-specific flu-like symptoms, including fever, chills, myalgia, and headache, followed by gastrointestinal symptoms including abdominal pain, nausea, vomiting and diarrhea [ ] . respiratory symptoms, such as cough and sore throat may also occur. a maculopapular rash typically occurs on day e after symptom onset, and is associated with erythema and desquamation. hemorrhagic phenomenon then appears, which can include petechiae or ecchymoses, uncontrolled oozing from venipuncture sites, and mucosal hemorrhages. however, it should be noted that massive hemorrhage occurs in fewer than half of patients and is seldom the cause of death. in the outbreak, unexplained bleeding was reported in only % of patients [ ] . hypovolemia can develop rapidly. as in other causes of severe sepsis, complications including disseminated intravascular coagulopathy and multi-organ failure can occur. death usually occurs between days and after symptom onset. survivors usually improved on day e , when neutralizing antibodies start to develop. in the convalescent phase, myelitis, recurrent hepatitis, psychosis and uveitis may develop [ ] . for pregnant women, there may be an increased risk of severe illness and death. there is also an increased risk of spontaneous abortion and pregnancy-related hemorrhage. in the outbreak in drc, fetal or neonatal loss occurred in all third trimester pregnancies [ ] . in fact, the first case of evd in sierra leone was a pregnant woman with miscarriage [ ] . blood test may show thrombocytopenia, leukopenia, hepatic dysfunction with elevated levels of aspartate aminotransferase more than that of alanine aminotransferase, amylase and d-dimer. hemolysis is severe especially in the acute stage [ ] . blood film may also show atypical lymphocytes [ ] . renal impairment usually appears by the end of the first week. fatal cases have higher viral load in the blood [ , ] . despite a fatal disease in over % of infected patients, some individuals did not develop symptoms. during the evd outbreaks in gabon in , asymptomatic individuals with direct exposure to infected materials were identified [ ] . eleven of these patients developed specific igm and igg response to ebolavirus. furthermore, rt-pcr for ebolavirus was positive in the peripheral blood mononuclear cell samples from of these seropositive individuals. positive-strand rna, the presence of which suggests active replication, was detected in individuals. since high grade viremia occurs in the acute period, the preferred diagnostic test is rt-pcr of the blood. rt-pcr targeting the np can be performed in the serum, plasma, whole blood, or oral fluid [ , ] . rnaemia can be detected on the day of symptom onset with viral loads of about e logs copies per ml. the viral load increases rapidly and reaches to logs on day of symptom onset. the level of rnaemia peaks on about day after symptom onset, and the level of rnaemia is higher in fatal cases than that in survivors [ ] . antigen-capture elisa can also be used on blood samples, but is less sensitive than rt-pcr [ ] . a rapid immunochromatographic assay for the detection of ebolavirus antigen, which claimed to provide result in min, was recently announced by the france's atomic energy commission [ ] . viral culture from the blood using vero e is usually positive in the acute stage, but should not be performed except in biosafety level facilities. viral particles may be seen in the serum under electron microscope, which was used in the confirmation of the first cases in the current outbreak [ ] . other than blood samples and oral fluids, the virus can also be detected in other body fluids, but these are not usually used for diagnosis. serum igm is useful during the convalescent phase, but is not useful in the acute setting. serum igg is not reliable, as one study showed that out of survivors did not have detectable igg levels at the time when viral antigen was no longer detected [ ] . several biomarkers have been proposed to be associated with adverse outcomes. in addition to elevated cytokine/chemokine levels, levels of thrombomodulin and ferritin are also elevated in patients with poor outcome, while the scd l, a protein produced by platelet responsible for repairing damaged endothelium, is higher in survivors [ ] . currently, the cornerstone in the management of patients with evd is supportive care. although this is taken for granted in developed countries, these supportive measures are usually lacking in the most affected areas with poor healthcare infrastructures. aggressive volume and electrolyte management, oral and intravenous nutrition, medications to control fever and gastrointestinal distress, and medications to treat pain, anxiety and agitation are important measures [ ] . coinfections should be actively sought and treated appropriately [ ] . there are currently no licensed antiviral drugs to treat evd. before the outbreak, specific therapy has been used in humans with some success. during the evd outbreak, a male investigator pricked himself while transferring homogenized liver from an infected guinea pig [ ] . six days after the injury, he developed fever, central abdominal pain and nausea. on the same day, he started to receive a -day course of human ifn million units every h administered intramuscularly. the human ifn was prepared by stimulating peripheral lymphocytes with sendai virus in vitro. on day after the injury, he received ml of convalescent sera which was obtained from infected people from zaire, and the viral load was reduced from . guineapig infective units per ml to - guinea-pig infective units per ml. on day after the injury, he received the nd infusion of convalescent sera. he eventually recovered. subsequently in the ebolavirus outbreak in kikwit, of patients who received blood donated from convalescent patients survived [ ] . both convalescent plasma and ifn-b were later tested in rhesus macaques, but only convalescent plasma was found to improve survival [ , ] . in the evd outbreak, convalescent plasma has been given to several patients, but the efficacy of convalescent plasma remains to be determined. in addition to convalescent plasma and ifn-b, several experimental treatments have been shown to improve survival in non-human primates ( table ). the first strategy employs the antiviral effect of neutralizing antibodies, either through direct administration of the antibodies or through active immunization. monoclonal antibody cocktails targeting different sites of the ebolavirus were shown to protect primates [ , , ] . zmapp, a cocktail of monoclonal antibodies that are originally contained in the preparation mb- (consisting of human or human-mouse chimeric mabs c c , h f and c d ), and zmab (consisting of murine mabs m h , m g and m g targeting gp) have been shown to protect rhesus macaques from lethal challenge when given up to days post infection [ ] . post-exposure vaccine, such as the vesicular stomatitis virus-based vaccine, can elicit anti-gp antibodies and improve the survival of rhesus macaques when given e min post infection [ ] . the second strategy is to inhibit the activity of virus proteins. antisense oligonucleotides target the viral l protein and vp proteins, can also improve survival of infected rhesus macaques [ , ] . the third strategy aims to ameliorate the deleterious host immune response. recombinant nematode anticoagulant protein c and recombinant human activated protein c could alleviate the coagulopathy and improve survival in animal models [ , ] . however, the clinical efficacy of recombinant human activated protein c is questioned because a randomized double-blind placebo-controlled study did not show survival benefit in patients with septic shock [ ] . among these experimental treatments, monoclonal antibody cocktail (zmapp) and small interfering rna (tkm-ebola) have been used in patients during the current outbreak [ , ] . both antibody and rna-based therapy might be limited to a particular species, and may become ineffective if there are mutations affecting the related antigenic epitopes or gene targets. the efficacy of these experimental treatments in humans remains to be determined. several drugs currently undergoing clinical trials have antiviral activity against ebolavirus. one of the most promising is nucleotide analog brincidofovir (cmx- ), which is a lipid-conjugated prodrug of cidofovir that is converted intracellularly to cidofovir. brincidofovir is currently undergoing phase iii clinical trials for adenovirus and cytomegalovirus infection. this drug has in vitro activity against ebolavirus [ ] , and has been used as an experimental treatment in the current outbreak [ ] . repurposing of licensed drugs has been considered for the treatment of evd as in other emerging infectious diseases which have no specific antiviral treatment [ e ] ( table ). the ic of clomiphene, chloroquine and imatinib table experimental post-exposure prophylaxis/treatment after lethal ebolavirus challenge in non-human primates. are above the peak serum level in humans, and therefore these are unlikely useful clinically. both toremifene and favipiravir had peak serum levels above the ic , and both of these drugs have shown to improve survival in mouse models [ , ] . toremifene can achieve plasma concentrations of about mm at a high dose of mg/day that are inhibitory in cell culture (ic e mm in vero cells). however the murine model utilizing a high dose of mg/kg initiated at h post infection can only achieve a % survival [ ] . moreover prolonged qtc changes have been reported at a dose of mg once daily [ ] . thus clinical trials should consider dosage adjustment, cardiac and electrolyte monitoring. favipiravir also appears effective in mice model, and has been administered to a patient in france [ ] . although the efficacy of these drugs in humans is uncertain especially when non-human primate treatment data are not available, they may be considered when better options are not available and the benefit-risk ratio is favorable. since fusion of the viral and cellular membrane in the endosome plays an important role in the viral life cycle, several studies have used chemical libraries to screen for molecules which can inhibit processes in the fusion step. using this strategy, molecules that can inhibit cathepsin-l mediated cleavage of gp [ ] and binding of gp and npc [ ] have been identified. the experience of post-exposure prophylaxis in humans mainly comes from laboratory accidents. in , a scientist from the us army medical research institute of infectious diseases (usamriid) suffered from a needlestick injury while working with mouse-adapted variant of zaire ebolavirus [ ] . as post-exposure prophylaxis, he received a liveattenuated recombinant vesicular stomatitis virus expressing gp of zaire ebolavirus h after the accident. the scientist had fever h after receiving the vaccine, but otherwise remained asymptomatic. three phase- clinical trials have been conducted. the first trial used an adenovirus-based vaccine expressing gp, involving subjects in the vaccine group and subjects in the placebo group [ ] . the vaccine group was further divided into a high dose and a low dose group. specific antibody response developed in % for recipients of high dose vaccine. the vaccine was well-tolerated. two vaccine recipients were complicated by the development of antiphospholipid antibody, and one vaccine recipient developed fever > c. in the second trial, two gp (zaire and sudan) dna vaccines were expressed in a vr- expression vector and produced in escherichia coli [ ] . there were subjects in the vaccine group and subjects in the placebo group. specific antibody responses to at least one of the vaccine antigens developed in all vaccine recipients. this second vaccine is also well-tolerated. in the vaccine group, subject developed raised creatine phosphokinase (associated with vigorous exercise) and subject developed herpes zoster. the third trial (vrc study) evaluated a dna vaccine encoding the wild type gp antigens from zaire and sudan ebolavirus which is produced in e. coli [ ] . ten subjects were enrolled. there were no serious adverse events. the vaccine elicited specific antibodies against both gp antigens. at the time of writing, two other vaccines are undergoing phase i clinical trials [ ] . vaccines against ebolavirus consisting of virus-vectors such as adenovirus type , human parainfluenza virus type , vesicular stomatitis virus; virus-like particles with vp , np and gp, and recombinant ebolavirus have been tested in animal models [ ] . the efficacy of these vaccines in humans awaits further studies. current evidence suggests that ebolavirus is transmitted via contact with contaminated body fluid or the contaminated environment, and therefore the practice of contact precautions with appropriate personal protection equipment (ppe) is of utmost importance when handling suspected or confirmed cases of evd. healthcare workers should preferably work in pairs so as to mutually guard against breaks in infection control measures. they are required to put on the ppe in the following sequence, from n respirator, water repellent cap or hood, full length shoe cover or boot, water resistant gown, face shield, and long nitrile gloves. if the patient has hemorrhagic symptoms, double nitrile gloves should be worn. in table licensed drugs with antiviral activity against ebolavirus. view of the high virulence and mortality, patients suspected to have evd should be isolated in airborne isolation room in the developed countries, although who allows cohorted nursing in the designated areas with dedicated instruments, where access should be restricted in the developing countries with limited isolation facilities [ ] . degowning remains the most critical procedure for the healthcare workers. the most contaminated ppe should be removed first, from long nitrite gloves, water resistant gown, full length shoe cover or boot, face shield, water repellent cap or hood, and finally n respirator. hand hygiene with alcohol-based hand rub should be performed in each step of degowning. when the hand is visibly soiled, it should be washed with soap and water. healthcare workers must be well trained and audited for the proper procedure of gowning and degowning. when the suspected or confirmed case of evd dies, the healthcare and mortuary workers are required to wear ppe as described above. the dead body is placed in double bags with leak-proof characteristic of no less than mm thick. absorbent material should be put under the body and placed in the first bag. the surface of each body bag is wiped with , ppm sodium hypochlorite solution. the bags are sealed and labeled with the indication of highly-infectious material (category ) and moved to the mortuary immediately. viewing in funeral parlor, embalming and hygienic preparation are not allowed. the dead body should not be removed from the body bag and should be sent to cremation as soon as possible. since the outbreak was first reported to who on march , , the situation continues to deteriorate, and the consequences can be catastrophic in terms of lost lives but also severe socioeconomic disruption and a high risk of spread to other countries. on august , , who declares the evd outbreak in west africa a "public health emergency of international concern". preparedness and response plan were made available in most of the health authorities all over the world. the aim is to detect the first imported case for early isolation in order to prevent local transmission in the community and healthcare setting. risk assessment in the port health, emergency room, and outpatient clinics for any patient fulfilling both clinical and epidemiological criteria for evd is important. for the clinical definition, patient suffering from a sudden onset of fever with over c, or having at least one of the following signs including inexplicable bleeding, bloody diarrhea, bleeding from gums, bleeding into skin or eye, or hematuria should be alerted, while the epidemiological definition includes close contact with a confirmed or probable case of evd or resided in or history of travel to an affected area or countries within days before onset of symptoms. for healthcare workers working in volunteer medical services or non-government organizations, who have direct contact with patients in the affected areas or countries, should also perform medical surveillance for at least days after leaving the affected areas or countries. they are required to seek medical advice promptly if there are any symptoms of fever, diarrhea, vomiting, rash or bleeding during medical surveillance. one of the major problems with the current outbreak is the panic associated with the disease. many patients with symptom did not seek medical care because of the fear of contracting the disease from the hospital [ ] . therefore, the local governments and health authorities should focus on the health education and give a clear instruction to the person for seeking early medical attention in the unaffected areas of africa. however, when the community transmission of ebolavirus is uncontrolled, implementation of home quarantine for up to days (one incubation period) can be considered. home quarantine measure had been used to control the community spread of sars in beijing, taiwan, singapore, and toronto [ ] . however, the public health staff is expected to face unprecedented challenges in implementing an extensive quarantine policy, as they have a dual role of monitoring compliance and providing support of daily necessities to people in quarantine. the countries next to the affected areas require implementing border control measures to screen for any suspected case of ebolavirus. although these measures may adversely affect the international travel and economy, it may be worthwhile to implement such a strict measure to control this re-emerging infectious disease with high mortality and psychological fear in a timely manner. humans are constantly under the threat of infectious diseases. some emerging infectious diseases have been especially important in human history with significant loss of population, economic disruption and political instability. yersinia pestis caused the black death in europe, killing up to one-third of the population [ ] . the e cholera outbreak after the major earthquake in haiti reminded us that a seemingly easyto-treat and control infection can cause large outbreaks when the infrastructure is damaged [ ] . sars coronavirus, mers coronavirus, and the avian influenza viruses have caused epidemics with major health and economic effects [ e ]. the current west africa evd outbreak is unprecedented in that this is the largest evd outbreak with local transmission outside africa. one of the major differences from previous outbreaks is that it has affected crowded major cities in west africa where the infrastructure has been heavily damaged due to civil wars. the rapid spread is facilitated by the efficient person-to-person transmission due to high viral loads in blood, bodily secretions and the contaminated environment. the large amount of virus particles shed in body fluid makes this virus very contagious, even among healthcare workers who are already equipped with ppe. whole genome study showed that the current west africa ebolavirus strain is phylogenetically distinct from previous outbreak strains, and this current ebolavirus strain has higher mutation rate than previous strains. however, it is currently not known whether this strain is particularly virulent or transmissible. currently, there are major gaps in our understanding of the disease due to the lack of systematic epidemiological, pathological, clinical and virological studies that are taken for granted in developed countries. for example in the pandemics and epidemics caused by coronaviruses and influenza viruses, many studies were conducted quickly within few months of the outbreak, and the results allowed early control of the outbreak and the implementation of scientifically sound clinical management of the patients [ , , ] . a coordinated effort involving virologists, clinicians, epidemiologists, governments and international organizations is necessary to prevent this evd outbreak to become a pandemic. all authors declare no conflict of interest. world health organization. ebola virus disease emergence of zaire ebola virus disease in guinea first imported case of ebola diagnosed in the united states ebola outbreak in west africa who ebola response team. ebola virus disease in west africa -the first months of the epidemic and forward projections clinical illness and outcomes in patients with ebola in sierra leone assessment of the potential for international dissemination of ebola virus via commercial air travel during the west african 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transmembrane ebola virus glycoproteins evidence against ebola virus sgp binding to human neutrophils by a specific receptor effects of ebola virus glycoproteins on endothelial cell activation and barrier function sgp serves as a structural protein in ebola virus infection molecular basis for ebola virus vp suppression of human dendritic cell maturation ebola virus vp targets a unique nls binding site on karyopherin alpha to selectively compete with nuclear import of phosphorylated stat how ebola and marburg viruses battle the immune system human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis ebola haemorrhagic fever analysis of human peripheral blood samples from fatal and nonfatal cases of ebola (sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels pathogenesis of the viral hemorrhagic fevers mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of 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luciferase-based reverse genetics systems for identifying inhibitors of marburg and ebola viruses broadspectrum antivirals for the emerging middle east respiratory syndrome coronavirus medwatch fda saf information and adverse event report program. fareston (toremifene citrate) tablets avigan® tablet mg administered to a french woman infected with ebola virus identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and ebola, hendra, and nipah viruses by using a novel high-throughput screening assay managing potential laboratory exposure to ebola virus by using a patient biocontainment care unit a replication defective recombinant ad vaccine expressing ebola virus gp is safe and immunogenic in healthy adults a dna vaccine for ebola virus is safe and immunogenic in a phase i clinical trial safety and immunogenicity of dna vaccines encoding ebolavirus and marburgvirus wild-type glycoproteins in a phase i clinical trial infectious diseases. ebola vaccine trials raise ethical issues ebola virus vaccines: an overview of current approaches world health organization. frequently asked questions on ebola virus disease ebola enew challenges, new global response and responsibility efficiency of quarantine during an epidemic of severe acute respiratory syndromeebeijing, china cholera surveillance during the haiti epidemicethe first years the emergence of influenza a h n in human beings years after influenza a h n : a tale of two cities from sars coronavirus to novel animal and human coronaviruses is the discovery of the novel human betacoronavirus c emc/ (hcov-emc) the beginning of another sars-like pandemic severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection world health organization. global alert and response. ebola virus disease. disease outbreak news centers for disease c, prevention. ebola viral disease outbreakewest africa single-dose pharmacokinetic study of clomiphene citrate isomers in anovular patients with polycystic ovary disease pharmacokinetic analysis of high-dose toremifene in combination with doxorubicin t- (favipiravir) post-exposure efficacy of oral t- (favipiravir) against inhalational ebola virus infection in a mouse model drugdex system (micromedex . ). truven helath anal bioequivalence study of two imatinib formulations after single-dose administration in healthy korean male volunteers this work was partly supported by the commissioned research grant from the research fund for the control of infectious diseases of the food and health bureau of the hong kong sar and the consultancy service for enhancing laboratory surveillance of emerging infectious disease for the hksar department of health. key: cord- - ey dv authors: seymour, i.j.; appleton, h. title: foodborne viruses and fresh produce date: - - journal: j appl microbiol doi: . /j. - . . .x sha: doc_id: cord_uid: ey dv nan raw and minimally processed fruits and vegetables are typically sold to the consumer in a ready-to-use or readyto-eat form. these products do not generally contain preservatives or antimicrobial agents and rarely undergo any heat processing prior to consumption. for many years raw fruits and vegetables have been implicated as vehicles for transmission of infectious micro-organisms. although fresh produce can support the growth and/or survival of many pathogenic bacteria there is little published information on the stability of human pathogenic viruses on these food products. viruses cannot grow in or on foods but may sometimes be present on fresh produce as a result of faecal contamination. this contamination can arise at source in the growth and harvesting area from contact with polluted water and inadequately or untreated sewage sludge used for irrigation and fertilization. alternatively, fruits or vegetables handled by an infected person might become contaminated with virus and transmit infection. the most frequently reported foodborne viral infections are viral gastroenteritis and hepatitis a: both have been associated with the consumption of fresh fruit or vegetables. in recent years it has been recognized that viruses are an important cause of foodborne disease. unlike bacteria, viruses do not grow or multiply in or on foods, but foods may become contaminated with human viruses and transmit infection. there are many groups of viruses which could contaminate food items, but the major foodborne viral pathogens are those that infect via the gastrointestinal tract, such as the gastroenteritis viruses and hepatitis a virus. it is these viruses that are the main subject of this review. viruses that infect via the gastrointestinal tract are excreted in faeces and may also be present in vomit. foods become contaminated either directly by infected people or through sewage pollution. those enteric viruses, which are commonly associated with foodborne outbreaks, either cannot be cultured in the laboratory or can only be cultured with dif®culty. hence information and experimental studies on survival and recovery of viruses from foods often relates to other virus types that are readily cultured. some of these viruses may be good models for important foodborne viral pathogens, but others may have widely differing characteristics. enteroviruses, such as coxsackieviruses and vaccine strains of poliovirus, have been used particularly. they infect via the gastrointestinal tract, occur in the environment as a result of sewage contamination and are relatively stable. however, there are very few published reports of foodborne outbreaks of illness caused by enteroviruses. there is the potential for contamination with other virus groups, such as respiratory viruses, although transmission to humans through foods has not been recognized. infrequently endogenous contamination of meat and milk can occur with viruses such as tick-borne encephalitis. such zoonotic infections have been reviewed by and need not be considered in this review. viruses are usually transmitted directly from person to person, but epidemiological and laboratory investigations indicate that viral diseases can on occasions be transmitted via foods, particularly those that are minimally processed. these include seafood, especially the bivalve molluscan shell®sh, and fresh fruits, vegetables and salad items. it might be expected that any virus that infects via the gastrointestinal tract could be foodborne. in practice, however, the most commonly reported foodborne viral infections are viral gastroenteritis and less frequently hepatitis a. it is believed that the incidence of both is greatly under reported, but for different reasons. viral gastroenteritis is a relatively mild disease and most people do not consult a medical practitioner; hence, the majority of cases are not investigated and are not reported. a recent national study funded by the department of health of infectious intestinal disease (iid) in the community indicated that for every case of iid detected by national laboratory surveillance, there are cases in the community. the study also concluded that a smaller proportion of cases due to common viral pathogens are reported than cases due to common bacterial pathogens (wheeler et al. ; food standards agency, ) . viral gastroenteritis has a short incubation period of ± days depending on the type of virus. this means that when cases are investigated, the possibility of foodborne transmission is likely to be considered. in contrast, hepatitis a is often a more severe disease and is more likely to be reported. however, the incubation period is ± weeks and hence an association with a food source is unlikely to be made, unless there is a very clearly de®ned outbreak. several different viruses cause gastroenteritis: the most important include rotavirus, the small round-structured viruses (srsv) otherwise known as norwalk-like viruses (nlv), astrovirus and adenovirus types and . however, in almost all foodborne outbreaks where a virus is identi®ed, it is an nlv. rotavirus and astrovirus are only rarely implicated. adenovirus has not been associated with food or waterborne transmission. viral gastroenteritis is usually regarded as a mild selflimiting disease lasting ± h. however, people can feel debilitated for or weeks, which has considerable economic implications in terms of working days lost and impaired performance. symptoms include malaise, abdominal pain, pyrexia, diarrhoea and/or vomiting. a range of symptoms occurring in an outbreak should alert investigators to the possibility of a viral cause. the viruses are usually transmitted by the faecal±oral route, but they are also present in vomitus. onset of viral gastroenteritis may be sudden and can commence with projectile vomiting. virus will be disseminated over a wide area in aerosol droplets, which is a particular hazard where food is being prepared * where the organism identi®ed in an outbreak was the main aetiological agent. outbreaks in which there was foodborne transmission followed by person-to-person transmission, but the proportion of each mode was unknown. data from phls communicable disease surveillance centre. and laid out. although most transmission is directly from person to person, contaminated food and water can give rise to common source outbreaks. the infective doses are not known, but the evidence from volunteer studies and the typically high attack rates observed in outbreaks suggest that they are very low (westwood and sattar ; caul et al. ) . for instance, it has been estimated that nlvs have an infective dose of between and virus particles (caul ; stolle and sperner ) . viruses account for % of foodborne and % of waterborne outbreaks occurring in england and wales reported to the phls communicable disease surveillance centre (cdsc) (appleton, ; o'brien et al. ) (table ) . a recent paper prepared by the public health laboratory service (phls) reported on the microbiological status of ready-to-eat fruit and vegetables between and in england and wales (o'brien et al. ) . fruit and vegetables accounted for á % ( / ) of the total foodborne outbreaks reported during that period. the most commonly identi®ed aetiological agent was the nlvs, which were linked to % of the outbreaks. the causative organism of a further % of outbreaks was reported as unknown, although the clinical and epidemiological features of these outbreaks suggested that the majority ( %) were also viral. . . norwalk-like viruses. this group of viruses infects all age groups. there is a variable incubation period of ± h, which is thought to be dose-dependent. it occurs all year round, although in temperate climates most infections occur over the winter months. these viruses are responsible for both sporadic cases of gastroenteritis in the community and for outbreaks in schools, hospitals, old people's homes, hotels and cruise ships. the national iid study indicated that viruses are the most common cause of iid in the community, with nlv the most frequently reported organism (wheeler et al. ; food standards agency, ) . from to , nlvs accounted for one-third of all gastroenteritis outbreaks reported to the phls communicable disease surveillance centre (cdsc) and the number of outbreaks of nlv gastroenteritis exceeded the number of outbreaks of salmonellosis. unlike the salmonellosis outbreaks, however, only % of the nlv outbreaks were known to be food or waterborne (appleton, ) . the virus is extremely infectious and secondary cases are a characteristic feature of foodborne outbreaks. therefore, it is not always possible to determine whether illness is acquired from a foodborne source or by person-to-person transmission (see table ). this accounts partly for underrecognition of the extent of foodborne transmission of these viruses. in a review of nlv (srsv) infection in england and wales between and by the phls, direct foodborne transmission could be ascertained in only % of outbreaks (dedman et al. ). there have been reports of outbreaks where nlvs have been epidemiologically associated with various items of fresh produce, such as washed salads (lieb ; lo et al. ) , imported frozen raspberries (ponka et al. ) , coleslaw (currier ) , green salads (grif®n et al. ) , fresh cut fruits (herwaldt et al. ) and potato salad (patterson et al. ) . the virus was discovered in by electron microscopy (kapikian et al. ) (fig. ). the ®rst virus originated from the town of norwalk in the united states, and became the prototype of the group. the name small roundstructured virus (srsv), which describes the morphology of the virus particle (caul and appleton , appleton, ) , was used in the united kingdom and elsewhere until recently. it has now been agreed informally by virologists working with this group to adopt the name norwalk-like virus, for the present, so as to bring some conformity to the nomenclature of these viruses. however, formal names have not yet been agreed by the international committee on virus nomenclature. the nlvs form a complex group of viruses. they have formally been classi®ed with the caliciviridae and are often referred to as human caliciviruses. they are split into two broad genogroups. most viruses in these two groups have the typical morphology of a ± nm diameter particle with an amorphous surface and ragged outline, as originally described for the srsv group (caul and appleton ) . within the caliciviridae there is a second genus of human gastroenteritis viruses, provisionally named sapporo-like viruses (slvs). the slvs have the morphology of classical caliciviruses and are genomically distinct from the nlvs . on sequencing, some strains with there are suggestions that the epidemiology of slvs differs from nlvs, in that slvs mainly cause infections of young children. it is not clear whether slvs are of signi®cance in foodborne infections and more studies are needed to clarify their role. genotypic analysis is being used increasingly to investigate the epidemiology of these two groups of viruses (fankhauser et al. ; maguire et al. ; hale et al. ; hedlund et al. ; koopmans et al. ) . there are several serotypes of human caliciviruses, which correspond broadly with the genotypic groups. most studies have been carried out with nlvs, and indicate that immunity is complex and short-lived (matsui and greenberg, ) . volunteer studies have shown that people can be infected repeatedly with the same virus strain (parrino et al. ; johnson et al. ). . . rotavirus. rotaviruses mainly infect young children . it is estimated that they cause one million deaths a year in children under years of age, mostly in developing countries. in developed countries deaths are relatively rare, but rotavirus gastroenteritis is the most frequent reason for admission of young children to hospital. rotaviruses consistently account for around % of all gastroenteritis viruses reported to cdsc, although this ®gure is probably biased by reports of hospitalized children, rather than the occurrence in the community, where nlvs are of greater signi®cance. foodborne and particularly waterborne spread are probably a signi®cant route of transmission in developing countries, but in developed countries reports are rare (table ) . . . astrovirus. the astroviruses form a morphologically distinct group of viruses, and are named from the ®ve-or six-point star seen by electron microscopy on the surface of some particles. astroviruses have mainly been associated with illness in young children, often under year of age. reports of astrovirus infection in older children and adults are infrequent, although outbreaks have been reported in the elderly. this may re¯ect testing policy: detection normally relies on electron microscopy, which is insensitive and often not performed on sporadic samples from adults. the use of more sensitive molecular detection methods is required to assess the incidence and epidemiology of these viruses. astroviruses have been seen in some adults following the consumption of shell®sh or contaminated water, but these incidents appear to be comparatively rare (kurtz and lee ; kurtz ) (table ) . there are two forms of enterically transmitted hepatitis ± hepatitis a and hepatitis e (cromeans et al. ). the most characteristic symptom of hepatitis a is jaundice, but milder symptoms of nausea and general malaise without jaundice are common. patients may feel unwell for several weeks, but recovery is complete. deaths are rare. some infections, particularly in children, may be asymptomatic. like viral gastroenteritis, transmission is by the faecal±oral route, but the primary site of viral replication is the liver. virus excretion may commence up to a week before symptoms are apparent, making control dif®cult. the epidemiology of foodborne hepatitis a is essentially similar to that of viral gastroenteritis. food-and waterborne outbreaks have been recognized for over years, but are infrequently reported. epidemiological evidence to link hepatitis infection to food and water sources is sparse, because of the long incubation period. between and , outbreaks occurring in england and wales were reported to cdsc, but only one of these was known to be foodborne. that outbreak was associated with shell®sh. from to , cdsc received laboratory-con®rmed reports of cases of hepatitis a. the source of most of these infections was unknown and just were recorded as foodborne. in the united states, the centers for disease control and prevention (cdc) placed hepatitis a as the sixth leading cause of foodborne disease from to (centers for disease control and prevention ) . outbreaks associated with fresh produce, particularly soft fruits and salads, have been reported from several countries. iceberg lettuce (rosenblum et al. ), strawberries (niu et al. ) , diced tomatoes (williams et al. ) and salad items (pebody et al. ) have all been implicated. a recent outbreak of hepatitis a in the united states was associated with consumption of food items containing frozen strawberries imported from mexico (anon ; cliver ) . in the united kingdom, outbreaks have been traced to frozen raspberries. there was evidence that the raspberries in these outbreaks were contaminated by infected fruit-pickers (noah ; reid and robinson ; ramsay and upton ) . there is only one serotype of hepatitis a. following infection immunity is lifelong. an effective vaccine is available. currently it is used for persons at high risk, such as travellers (department of health et al. ) . food packagers and food handlers in the united kingdom have not been associated with hav transmission suf®ciently often to justify routine immunization, except in outbreaks. the incidence of hepatitis a in developed countries has fallen in recent years and hence a susceptible population has built up. as endemic infection declines, it is possible that an increase in foodborne outbreaks will be seen. the yearround global distribution of fruit and vegetable products poses a risk of infection, particularly when these products are imported from countries with a high incidence of hepatitis a. hepatitis e has been associated with large waterborne outbreaks in some developing countries, notably in asia, africa and central america. foodborne transmission has been suggested, but not proved conclusively. illness appears more severe than hepatitis a, particularly in pregnant women where a death rate of ± % has been observed (cromeans et al. ) . the primary source of infection appears to be contaminated water rather than person-to-person spread. secondary person-to-person transmission is estimated at only á ± % (cromeans et al. ) . cases in the united kingdom are reported infrequently and are mainly imported from endemic areas. with the worldwide distribution of foods, vigilance should be maintained. viruses are very small micro-organisms, and basically comprise a nucleic acid core of either dna or rna, surrounded by a protein coat. they require living cells in order to replicate and generally have a very restricted host range. viruses do not multiply in foods or water, or in or on any other environmental sample. however, viruses can survive outside living cells and remain infectious. enteric viruses are hardy and survive well in the environment. these viruses survive on inanimate surfaces, on hands and in dried faecal suspensions (green et al. a; barry-murphy et al. ; bidawid et al. ; sattar et al. ) . lingering outbreaks have occurred in hospitals, in residential homes and on cruise ships, probably as a result of environmental contamination. nlvs have been detected by pcr in environmental swabs from hospital lockers and hotel carpets supposedly cleaned after incidents of vomiting (green et al. a) . the viruses survive just as well on kitchen surfaces and food preparation areas. in one reported outbreak, a kitchen worker vomited into a sink. the following day the sink, which had been cleaned with a chlorine-based disinfectant, was used for washing salad and an outbreak of gastroenteritis associated with nlvs ensued (patterson et al. ) . enteric viruses are acid stable and so are able to survive in the gastrointestinal tract. it is likely that they will survive food processes designed to produce the low ph that inhibits bacterial spoilage organisms (e.g. pickling in vinegar and fermentation processes that produce foods such as yoghurt). both nlvs and hepatitis a virus retain activity after exposure to acidity levels below ph scholtz et al. ) . most viruses remain infectious after refrigeration and freezing. frozen foods, that have not received further cooking, have been implicated in a number of incidents of viral gastroenteritis and hepatitis a (noah ; reid and robinson ; ramsay and upton ; niu et al. ) . gastroenteritis viruses and hepatitis a virus are inactivated by conventional cooking processes, but retain their infectivity after heating to °c for min parry and mortimer ; fleming et al. ; millard et al. ; slomka and appleton ) . it is uncertain whether they would be inactivated completely in some pasteurization processes. nlvs cannot be cultured in the laboratory and until recently detection relied on the use of electron microscopy. this technique is fairly insensitive and requires a minimum of virus particles per ml of sample. it has been used widely for detection of virus in faecal samples from patients, but cannot be used for looking for the lower concentration of virus particles present in contaminated food, water and environmental samples. sequencing of the genome of the norwalk virus has led to the development of pcr assays, with greatly enhanced sensitivity for virus detection . however, there is great genomic diversity among the nlvs and one set pcr primers will not detect all strains (norcott et al. ) . pcr assays are being used for the examination of food samples, particularly shell®sh, but far more complex nucleic acid extraction techniques are required than when working with clinical specimens from patients (atmar et al. ; green et al. b ). there are also greater problems with naturally occurring inhibitors to the pcr reaction in these types of samples. nlvs have been detected in samples of raspberries associated with an outbreak of gastroenteritis in quebec. sequence analysis demonstrated that the strain of nlv identi®ed in the raspberries was identical to that found in the patients (gaulin et al. ) . expression of recombinant virus capsids in yeast and insect cells is allowing the development of elisa-based diagnostic assays, but reagents are not widely available and so far the tests only detect a very limited number of nlv strains (jiang et al. ) . further development and more widespread use of elisa tests will greatly facilitate the detection of nlvs in clinical samples, although such tests may not be suf®ciently sensitive to detect virus in food samples. at the present time, pcr and elisa assays for nlvs are only available in specialist laboratories and are not used for the routine testing of food samples. commercial test kits are not yet available. rotavirus and astrovirus can both be grown in cell cultures in the laboratory. however, it is unreliable and time-consuming for isolation from primary specimens and is not normally used. rotavirus is frequently detected using commercial elisa or latex agglutination tests and pcr assays are available. rotavirus has been detected in lettuce (hernandez et al. ) and shell®sh samples, but it is not clear if these were of human origin. electron microscopy is still the most usual method for the detection of astroviruses, although pcr assays are used in a few laboratories. diagnosis of hepatitis a infection in patients is by detection of speci®c igm antibody, since virus excretion has largely ceased by the time illness becomes apparent. the virus can be cultured in the laboratory, but this is a long and unreliable procedure. in one outbreak at a summer camp in the united states, virus was isolated from the drinking water supply, but this took weeks. pcr assays have been developed and have been used for detecting virus in water, shell®sh and other food and environmental samples. due to the long incubation period of hepatitis a, food items are not usually available for testing, even if suspected as the source of illness. in particular, minimally processed fruits and vegetables have a short shelf life. there have been a few experimental studies to investigate seeding and recovery of viruses from fresh produce. transfer of hepatitis a virus to lettuce leaves has been investigated sattar et al. ) . rotavirus and poliovirus were recovered from the surface of vegetables in a method described by badawy et al. ( b) . average recovery rates of and %, respectively, were obtained from lettuce; however, recovery of rotavirus from non-leafy vegetables was lower, averaging %. ward et al. ( ) also recovered poliovirus and adenovirus from vegetable surfaces, obtaining mean ef®ciencies of approximately ± %. there is a need to develop more effective quantitative methods in order to assess the survival of viruses on fresh produce and to determine the decontamination ef®ciencies of current commercial washing systems for fruit and vegetables. fruits and vegetables may become contaminated with viruses in two ways. first, they may be contaminated in their growing area before harvest by coming into contact with inadequately treated sewage or sewage polluted water. secondly, contamination can arise during processing, storage, distribution or ®nal preparation either directly from infected people or by contact with a contaminated environment. in most outbreaks of foodborne viral disease involving fresh produce, it is not known whether contamination took place before, during or after harvest. guidelines issued by the world health organization state that fruits and vegetables to be eaten raw should not be fertilized with sewage or irrigated with contaminated water (beuchat ) . sewage sludge is sometimes applied to agricultural land, with the bene®t that useful plant nutrients and organic matter are recycled to the soil. however, the uk government is proposing more stringent controls for harvesting vegetables from land where conventionally processed sewage sludge is applied (adas, ) . the transmission of viruses is thought to be mainly by surface contamination. there are relatively few reported studies on the possible uptake of viruses within damaged plant tissues during primary growth. studies with poliovirus report that virus can in®ltrate into the roots and body of plants from the soil (oron et al. ) , but there is no evidence of illness from this source. viruses from sewage do not bind readily with soil particles and can enter groundwaters leading to contamination of water sources. the viruses causing gastroenteritis and hepatitis a appear to be extremely infectious in very low doses. large numbers of virus particles can be excreted in the faeces from an infected person. levels of the order of ± infective units per gram have been estimated (feachem et al. ) . poor personal hygiene is therefore a major route through which viruses can directly reach foods. virus can be transferred from faecally contaminated ®ngers to foods or to work surfaces and door handles. there is a signi®cant risk of contamination from ®eld workers who do not have adequate on-site toilet and hand-washing facilities. even when these facilities are put in place, the workers need to be supervised in such a way as to ensure that the facilities are used (cliver ) . in an outbreak of hepatitis a, associated with frozen raspberries, infection was con®rmed in a fruit picker on the farm where the raspberries were cultivated (ramsay and upton ). a number of outbreaks have also been linked to contamination of fresh produce from the vomitus of infected food handlers ). it has been suggested that between and million virus particles are liberated during vomiting (reid et al. ; caul ) . as well as direct transmission, aerosols produced by vomiting can contaminate exposed food, or surfaces with subsequent transfer to foods. human enteric viruses will potentially be present in any type of water contaminated by human faecal material and by sewage. the department of environment, transport and regions (detr) jointly with uk water industry research limited and the environment agency, recently commissioned four reviews on enteroviruses. these covered the source (sellwood et al. ) and survival (irving and morris ) in the environment and their fate through sewage treatment processes (merrett and weatherley ) . mounting evidence suggests that viruses can survive long enough and in high enough numbers to cause human diseases through direct contact with polluted water or contaminated foods (nasser ; bosch ) . irving and morris ( ) concluded that a thorough and valid assessment of the occurrence and signi®cance of viruses in natural waters is hampered by lack of reliable information. they suggested that this is due to inef®cient analytical techniques, and because different analytical methods have been used so that comparisons on survival data between different studies cannot be made. however, it does appear that different types of viruses are inactivated at different rates under identical conditions, and therefore no single microorganism can be expected to be an indicator for all viruses. temperature is an important factor, with low temperatures favouring viral survival in natural waters. raphael et al. ( ) found no signi®cant drop in rotavirus titre after days at °c in raw water, treated tap water or ®ltered water. however, a % drop in titre was observed after days at °c. astrovirus survival has been demonstrated in drinking water after days at °c (abad et al. b ). nasser et al. ( ) concluded that hepatitis a virus and poliovirus could survive in wastewater and groundwater for days or more at °c . hepatitis a virus and poliovirus were shown to survive in excess of one year in mineral water stored at °c (biziagos et al. ). hepatitis a virus can survive in fresh or salt water for up to a year (sobsey et al. ) . evidence suggests that adsorption of viruses to particulate matter and sediments confers substantial protection against inactivating in¯uences. salinity and ph do not appear to have a signi®cant direct effect on virus survival under conditions normally found in natural waters, but may have indirect effects by modifying interaction of viruses with particulates. there is some evidence that solar radiation promotes inactivation of viruses, but the effects have not been extensively studied. development of pcr-based assays has allowed the detection of nlvs in both river water and seawater wyn-jones et al. ) . in , an outbreak of nlv gastroenteritis occurred among canoeists and was associated with river water at a water sports centre (gray et al. ) . when hepatitis a virus was detected in lettuce from costa rica, it was suggested that the possible source of contamination was the discharge of untreated sewage into river water used to irrigate crops, which is common practice in some less well-developed countries (hernandez et al. ) . in another outbreak of hepatitis a, traced to commercially distributed lettuce or tomatoes, it was hypothesized that contamination may have occurred in the ®elds from dirty water used for growing or irrigation, or possibly from the use of night soil, although this was dif®cult to prove (rosenblum et al. ) . enteric viruses may contaminate soil through the land disposal of sewage sludge and dirty irrigation water. a number of research studies have investigated the survival of human pathogenic viruses in soils with con¯icting results. survival appears to depend on a number of different variables, particularly the growing season, soil temperature, rainfall, soil type and composition. for example, viable poliovirus was recovered from spray-irrigated soil after days during the winter season tierney et al. ) . this compared to a maximum survival period of only days during the summer, which suggested the higher temperature and solar radiation levels in the warmer seasons accelerated viral inactivation. the possibility also exists that viruses may be mechanically transmitted to fruits and vegetables during harvest. sadovski et al. ( ) noted the persistence of inoculated poliovirus in drip irrigation pipes and soil. moderate environmental conditions and alluvial-type soil, which restricts water in®ltration, enhanced viral recoveries in the upper soil layers. oron et al. ( ) found that relatively high soil temperature ( °c) and a low moisture content hindered poliovirus survival. wet soil conditions are frequently associated with low soil temperature. gerba ( ) reported that a large proportion of outbreaks of waterborne disease in the unite states resulted from contaminated groundwater. climate, the nature of the soil and the nature of the resident micro¯ora determine virus survival and retention within soil particles. both electrostatic and hydrophobic interactions are thought to contribute towards virus adsorption and are controlled by the characteristics of the soil. some investigations have focused on the survival of viruses on inanimate environmental surfaces such as stainless steel, glass and plastics. abad et al. ( ) observed that a range of enteric viruses, including hepatitis a virus and rotavirus, persisted for extended periods (greater than days) on several types of porous and nonporous surfaces. greater virus survival was noted at °c than at °c. the effect of relative humidity on survival of hepatitis a virus on nonporous surfaces has been investigated sattar et al. ) . at °c, relative humidity had little effect on survival time, but at °c survival was longest when relative humidity was low. it is apparent from the lingering outbreaks that have occurred on cruise ships that nlvs survive well on environmental surfaces. nlvs have been detected in swabs of lockers in hospital outbreaks and from hotel carpets (green et al. a; barry-murphy et al. ) . a disinfectant formulation is considered to be effective if it is capable of inducing a -fold ( á %) or greater reduction in the virus titre springthorpe et al. ) . experimental studies have shown that a free chlorine level of ppm reduced the infectivity titre by more than á % on stainless-steel disks v i r u s e s a n d f r e s h p r o d u c e contaminated with the enteric viruses coxsackievirus b and hepatitis a virus, and the respiratory viruses adenovirus type , parain¯uenza virus type and coronavirus e (sattar et al. ; mbithi et al. ). the virucidal action of sodium hypochlorite ( ppm at ph á ) was also tested against hepatitis a virus, human rotavirus and a bacteroides fragilis bacteriophage dried on polystyrene (abad et al. a ). overall, a less than -fold titre reduction was achieved for all the viruses examined. chlorine is a common disinfectant used by many fresh produce processors to wash fruits and vegetables (beuchat ; seymour ) . however, chlorine levels greater than ppm are thought to cause adverse discoloration (bleaching) and off avours in the ®nished product (hurst and schuler ) . survival times for some enteric viruses have been determined on a range of different fruit and vegetable commodities. it is dif®cult to draw conclusions from the different studies, since experimental conditions and methods varied. however, most of these studies report viability in excess of the product shelf life. konowalchuk and speirs ( ) established no signi®cant loss in coxsackievirus b titre when contaminated lettuce was stored for d under moist conditions at °c, but some inactivation took place during storage under dry conditions. they hypothesized that under conditions of low or no moisture the aqueous part of the virus inoculum evaporated leaving the virus exposed to air and/or salts. celery, lettuce and carrots stored at °c supported the survival of a range of enteric viruses for up to days (konowalchuk and speirs a) . badawy et al. ( a) indicated that rotavirus sa- (a simian rotavirus that can be cultured) survived on lettuce, radishes and carrots for up to days at °c. viral inactivation at room temperature ( °c) was signi®cantly greater than at °c; however, viable rotavirus sa- was still detected on lettuce after days. they concluded that the rough or irregular surfaces present on lettuce might offer some additional protection for virus particles. indeed, protected segments of plants such as the roots, closed leaves and internal fruit parts, may offer favourable conditions that increase survival time up to days (smith ) . viable poliovirus was recovered from ef¯uent spray-irrigated lettuce and radishes days after inoculation tierney et al. ) . sadovski et al. ( ) isolated polioviruses from cucumbers grown in ef¯uentirrigated soil for a full days after inoculation. oron et al. ( ) investigated the transmission of poliovirus from subsurface drip-irrigated soil to tomato plant leaves and tomato fruits. virus was not detected in the tomato fruits. however, a number of leaf samples were positive for poliovirus even though the virus was injected cm below the surface of the soil. this result suggests that poliovirus can penetrate into plant tissue through the root system. the lack of viable poliovirus in the tomato fruits may be due to the presence of antiviral substances as witnessed by other authors. chilled storage temperatures ( ± °c) typically retard respiration, senescence, product browning, moisture loss, and microbial growth in minimally processed fruits and vegetables, but may contribute to the survival and transmission of viruses to the human host. speirs ( b, ) described the potent antiviral properties of different fruit extracts at neutral ph, particularly strawberry. they found signi®cant differences in viral recovery on strawberries, cherries and peaches held in a humid atmosphere at °c. recoveries of coxsackievirus and echovirus were also greater than those of poliovirus and reovirus, although the authors did not offer an explanation for this result. most of the aqueous fruit extracts and infusions demonstrated notable antiviral properties. although the active compounds were not isolated, these agents could be phenolic in nature. in grapes, these chemicals are thought to be located primarily in the skin (konowalchuk and speirs ) . fruits and vegetables are known to contain a vast array of antimicrobial substances, particularly organic acids, phenolic and sulphur compounds and small polypeptide proteins. despite this, outbreaks of viral gastroenteritis and hepatitis a have been associated with fruits and fruit juices. in the absence of formal studies it could be inferred that the gastroenteritis and hepatitis a viruses are relatively resistant to these virucidal chemicals. in view of the increasing use of ready-to-eat vegetables sold in modi®ed atmosphere packaging (map), the survival of hepatitis a virus on lettuce in map, stored at room temperature and °c, has been investigated . survival at °c was the same in map as under normal conditions of packaging. at room temperature viral survival was slightly better in map containing higher carbon dioxide levels. it was suggested that enhanced virus survival might be due to inhibition of ethylene by carbon dioxide, resulting in reduced physiological spoilage of vegetables such as lettuce and possibly less toxic effects on the virus. studies have indicated that indigenous micro¯ora in the water environment are deleterious to survival of enteric viruses (raphael et al. ) . these ®ndings highlight the importance of avoiding contamination of food items before packaging in map . bardell ( ) studied the survival of herpes simplex virus type , suspended in saliva, on the skin of tomatoes and the upper surface of lettuce. although storage times of only h were studied, temperature was shown to have a signi®cant effect on virus titre. there was no loss of virus infectivity titre at °c compared to a -log reduction at room temperature ( ± °c). although not an enteric virus and not a virus that comes to mind as a possible foodborne infection, herpes viruses could invade through the mucous membranes of the mouth. most fruit and vegetable washing systems are designed to remove gross contamination such as dirt, insects, and foreign matter. however, they are reported to be less successful at removing microbial contaminants (beuchat ; seymour ) . vigorous washing of fruits and vegetables with clean potable water typically reduces the number of micro-organisms by ± -fold (beuchat ) and is often as effective as treatment with mg l ) chlorine, the current industry standard (elphick ; seymour ) . raw materials are typically immersed in cooled sanitized water and then dewatered to remove surface moisture and fruit and vegetable juices from the product (simons and sanguansri ) . product agitation is optimized by using water or air jets which enhance surface contact, carriage of product, and suspension of solids and vegetable debris (simons and sanguansri ) . there has been recent concern over the possible migration of bacterial pathogens into the core tissue of fruits and vegetables during washing. zhang and farber ( ) found that uptake of bacterial cells was associated with a negative temperature differential between the water and the product. however, the uptake of human viruses by fruits and vegetables under similar conditions has not been studied. lodging or attachment of microorganisms in tissue crevices may protect cells from direct contact with disinfectants and consequently aid in their survival (beuchat ) . recent studies by seo and frank ( ) found that escherichia coli o :h could survive in the stomata and on cut edges of lettuce following chlorine treatment. although there are no available data for viruses, cell surface structures are likely to offer some additional protection. numerous authors have reported on the ef®cacy of disinfectants for the inactivation of readily culturable human viruses using standard suspension tests, but data for gastroenteritis viruses and hepatitis a virus are lacking. the authors of this review were unable to ®nd any data on the effectiveness of disinfectants and processing aids for the decontamination of enteric viruses on fruits and vegetables. the most commonly used sanitizers and processing aids for cleaning fruits and vegetables are chlorine, chlorine dioxide, organic acids and surfactants, while ozone is receiving renewed interest. the mechanism of action of these disinfectants on viruses and their interaction with plant materials is poorly understood and there are con¯icting reports on their ef®cacy. there are no positive lists of permitted processing aids in the united kingdom or european community, although an inventory has been produced by the codex alimentarius commission (codex alimentarius general requirements, volume a, nd edition . fao/who isbn ± - ± ). directive / /ec of the european parliament contains a list of biocidal products, which have been approved and authorized for use. council regulation (eec) no. / highlights the food additives, processing aids and other substances permitted for the organic production of agricultural products. the use of chlorine, for the treatment of organically grown fruits and vegetables, has recently been banned in the united kingdom and the fresh produce industry is currently trying to ®nd viable and effective alternatives. chlorine is the most widely used disinfectant for washing fresh produce because it is relatively cheap, easy to use and exhibits rapid microbiological action in aqueous solution (elphick ) . the food and drug administration (fda) in the united states permits the use of chlorine as a disinfectant in wash, spray and¯ume waters in the raw fruit and vegetable industry (garret ) . however, in certain ec countries, chlorine is not permitted as a wash water additive. disinfectants such as chlorine and ozone have a strong af®nity for organic matter and are`used up' rapidly in wash tanks containing dirty produce. therefore, for any washing system, it is important to monitor and control the level of disinfectant at all times, to ensure that it is optimal. it is also imperative to maintain chlorine disinfectants within a suitable ph range (boyette et al. ) . chlorine-based disinfectants are usually considered to be the most effective against enteric viruses. however, nlvs and hepatitis a virus appear to be relatively resistant to chlorine (grabow et al. ; peterson et al. ; keswick et al. ) . nlvs are inactivated by mg chlorine l ) , which is the concentration used to treat a water supply after a contamination incident. in the united states a level of mg chlorine l ) with a contact time of min is recommended for inactivation of hepatitis a virus. in recent studies (doultree et al. ) feline calicivirus was shown to be surprisingly resistant to chlorine, requiring mg l ) freshly reconstituted granular hypochlorite for complete inactivation. clearly there is a need for further studies on disinfection of these persistent organisms. chlorine dioxide is not as susceptible to ph changes or the presence of organic matter as chlorine (simons and sanguansri ) . chlorine dioxide is unstable, must be generated on-site and can be explosive when concentrated. the oxidizing power of chlorine dioxide is reported to be about á times that of chlorine (beuchat ) . however, zhang and farber ( ) found no signi®cant difference in decontamination ef®ciency between chlorine and chlorine dioxide. several authors have reported the sensitivity of a range of animal viruses to chlorine dioxide (harakeh ; chen and vaughn ) although there is no information for nlvs and hepatitis a virus. organic acids can occur naturally in many fruits and vegetables and may retard the growth of some microorganisms and prevent the growth of others (beuchat ) . most of these acids behave primarily as fungistatic agents, while others are more effective at inhibiting bacterial growth. these include acetic, citric, succinic, malic, tartaric, benzoic, propanoic and sorbic acids. due to recent changes in legislation, washes and sprays containing organic acids are becoming more popular for the processing of organically grown fruits and vegetables. a number of products are now commercially available. however, scholtz et al. ( ) found that hepatitis a virus remained infectious for min at ph . nlvs and hepatitis a virus survive exposure to acidity levels below ph , while rotavirus is inactivated below ph and above ph palmer et al. ; weiss and clark ; scholtz et al. ) . viruses that infect via the gastrointestinal tract are acid stable since they have to survive the harsh low ph environment of the stomach. organic acids are therefore unlikely to have a signi®cant effect on the viability of hepatitis a virus and nlvs during the typically short contact times used for washing fruits and vegetables (seymour ) . several authors have reported the action of surfactants (wetting agents) in combination with disinfectants (adams et al. ; zhang and farber ) . however, these agents may reduce the antimicrobial effect of chlorine disinfectants and adversely affect product quality (adams et al. ). ozone is lethal to a wide variety of microorganisms, including enteric viruses (finch and fairbairn ) . it is a potent oxidizing agent, is very reactive and unstable, leaves no residues in water and naturally decomposes into ordinary oxygen. this absence of toxicity is one of its major advantages over chlorine disinfectants. ozone has recently been approved as a disinfectant for food applications in the united states (graham ) and industry suppliers are working to develop appropriate systems for fresh produce washing. ozone is unstable, cannot be stored and must therefore be generated on-site. however, due to perceived safety problems and a lack of information on the ef®cacy of ozone, this technology has not yet been readily taken up in europe. although ozone can be used safely, it can cause irritation of the eyes, headache, dryness of the throat, and coughing at exposure levels in the range of á ± á ppm (boisrobert et al. ). the occupational safety and health administration (osha) has set the permissible exposure limit of workers to ozone at á ppm if ozone is to be used in aqueous or gaseous form it is essential that the air is monitored for ozone and that suitable control measures are in place to remove it. the control of foodborne viral infection was considered in the report of the advisory committee on the microbiological safety of food ( ). sewage pollution is a major factor in the contamination of food and water. this is particularly pertinent to fruits and vegetables that will not be cooked before consumption. untreated or inadequately treated sewage discharged into natural waters can cause contamination of crops. sewage sludge is applied to agricultural land, with the bene®t that useful plant nutrients are recycled to the soil. in april , the agricultural development and advisory service (adas, uk) published the safe sludge matrix (adas, ) . this document gives clear guidance on the minimum acceptable level of treatment for any sewage sludge applied to agricultural land and provides a framework to ensure microbiological safety. as from december application of all untreated sludge on agricultural land used to grow food crops has been prohibited in the united kingdom. use on all agricultural land will be prohibited from the end of . untreated sludge is produced by either the primary settlement or secondary biological stages of sewage treatment. further processing may be undertaken to produce treated sludge, resulting in improved stability and a reduction in health hazards and odour problems. (maff ) . currently, treated sludge may be applied to land used for salad crops, but harvesting is not permitted for months. vegetables cannot be harvested for months. a -month harvest interval is required if enhanced treated sludge is used. all applications must comply with the sludge (use in agriculture) regulations and detr code of practice . these controls may help to reduce the risks of microbiological contamination of fruits and vegetables in the uk, but still do not address the potential problem of imported produce from countries with different standards for organic fertilisers or irrigation water. the other major source of contamination is from infected people handling food. people with symptoms should be excluded from food handling. however, food-handlers with only very minimal symptoms have been implicated in transmission of viral gastroenteritis. current recommendations state that food-handlers should be allowed to return to work h after symptoms have ceased. (phls ) . these recommendations appear to work satisfactorily, but were based on the rapid decrease in virus excretion observed by electron microscopy. using more sensitive pcr assays, nlvs can be detected for longer periods than electron microscopy and, in some instances, for up to a week after onset of symptoms. it is not clear if people shedding virus detectable by pcr are infectious, but recommendations on how long to exclude people from food-handling need to be kept under review. the main period of excretion for hepatitis a virus is before symptoms become apparent and therefore control is dif®cult. the wearing of disposable gloves is recommended if foods are to be manipulated by hand, but this does not prevent transfer of viruses to gloves by touching contaminated surfaces. if vomiting occurs, virus may be spread over a wide area in aerosol droplets. uncovered food that is not to receive cooking should be discarded. the environment should be thoroughly cleaned, including work surfaces, sinks and door handles. recent studies by the phls demonstrated the presence of virus on surfaces and materials that had been cleaned by recommended decontamination methods. this suggests that the current recommendations for the removal of nlvs from contaminated surfaces are inadequate (barry-murphy et al. ) . cliver ( ) advised thorough cooking of virus-contaminated foods. however, ready-to-eat fruits and vegetables are unlikely to withstand such harsh treatment and may show deleterious changes in sensory quality. larkin ( ) suggested a wash at °c for min to ensure the microbiological safety of fresh produce. he concluded that this heat treatment does not affect the appearance and taste of most fruits and vegetables provided the food is eaten within h. however, the majority of minimally processed fruits and vegetables require a shelf life in excess of day and therefore this heating step is not applicable. meticulous attention to good food handling practices and education is essential. there should be provision of adequate toilet and hand-washing facilities, not only in the catering and retail industry, but also for farm workers. there is an effective vaccine for hepatitis a and it has been suggested that food handlers should be vaccinated (cliver ) . epidemiological data currently suggest that food-handlers in the united kingdom do not pose a signi®cantly greater risk of transmitting hepatitis a infec-tion than other people, and use of vaccine in this group may not be cost-effective. no vaccines have been developed for nlvs but research studies with nlv recombinant capsid antigens offer the potential for future development of vaccines. there are challenges, however, in designing effective vaccines in that ®rst, there are multiple types of nlvs and secondly, the mechanisms for inducing immunity to these agents is poorly understood (estes et al. ) . fresh produce contributes to the transmission of viral infections. there is a lack of information on the survival of viruses on fresh produce related to shelf life and types of packaging. information is also lacking on the ef®ciency of current washing and decontamination processes for the removal of viruses. studies are therefore required to provide this information for nlvs and hepatitis a virus in particular. there is a need for information on rotaviruses and astroviruses. both these viruses have been implicated in foodborne and waterborne outbreaks in the united kingdom, although only very infrequently. the role and extent of food or waterborne transmission needs to be more clearly de®ned for both these viruses. the infectivity of nlvs and hepatitis a virus is dif®cult to study in the laboratory. nlvs cannot be cultured in vitro and culture techniques for hepatitis a virus are timeconsuming. other viruses that can be cultured readily have been used as models for these pathogens in a number of studies. although only the use of speci®c human pathogenic viruses will give clear and unequivocal data on survival, inactivation and removal, this is not always safe and practical. model systems using similar non-pathogenic human or mammalian viruses may be the most satisfactory alternative. for example, feline calicivirus has been used as a model system for nlvs in assessing the ef®cacy of commercially available disinfectants (doultree et al. ) . feline calicivirus was also used as a model for nlvs in another study on the heat treatment of shell®sh (slomka and appleton ) . this organism would appear to be a good candidate for virus studies on fresh produce. in order to undertake studies on the survival and removal of viruses, there is a need to develop better methods for inoculation and recovery of virus from a range of fresh produce items. there have been recent suggestions that faecal coliforms on fresh produce may be an indicator of the probable presence of enteric viruses. however, several authors have found no signi®cant correlation (keswick et al. ; le guyader et al. ) . despite the shortcomings of indicator organisms such as bacteriophages, there is a need for a safe and convenient model that can be used to help the food industry to assess and optimize new treatment processes. this is not intended as an indicator to monitor food samples directly. other studies have shown that the behaviour and survival of bacteriophages mimic human viruses more closely than bacteria and would be suitable for such purposes. the optimization of washing and decontamination processes to remove viruses from fruits and vegetables will ultimately contribute to the overall safety of these food products. survival of enteric viruses on environmental fomites disinfection of human enteric viruses on fomites factors affecting the ef®cacy of washing procedures used in the production of prepared salads the safe sludge matrix. ref: ampu /b/ anonymous (reported by: united states of america, calhoun department of public health) ( ) hepatitis a associated with consumption of 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of the food standards agency for the production of this paper (project: bo ). key: cord- -bcxkycjh authors: karimata, yosuke; kinjo, takeshi; parrott, gretchen; uehara, ayako; nabeya, daijiro; haranaga, shusaku; higa, futoshi; tateyama, masao; miyagawa, keiko; kishaba, tomoo; otani, kanako; okamoto, michiko; nishimura, hidekazu; fujita, jiro title: clinical features of human metapneumovirus pneumonia in non-immunocompromised patients: an investigation of three long-term care facility outbreaks date: - - journal: j infect dis doi: . /infdis/jiy sha: doc_id: cord_uid: bcxkycjh background: several studies have reported outbreaks due to human metapneumovirus (hmpv) in long-term care facilities (ltcf) for the elderly. however, most of these reports are epidemiological studies and do not investigate the clinical features of hmpv pneumonia. methods: three independent outbreaks of hmpv occurred at separate ltcf for intellectually challenged and elderly residents. a retrospective evaluation of hmpv pneumonia and its clinical and radiological features was conducted using available medical records and data. results: in hmpv infections, % of patients developed pneumonia. the median age of pneumonia cases was significantly higher than non-pneumonia cases (p < . ). clinical manifestations of hmpv pneumonia included high fever, wheezing in %, and respiratory failure in % of patients. an elevated number of white blood cells as well as increased levels of c-reactive protein, creatine phosphokinase, and both aspartate and alanine transaminases was also observed among pneumonia cases. evaluation of chest imaging revealed proximal bronchial wall thickenings radiating outward from the hilum in most patients. conclusions: the aforementioned characteristics should be considered as representative of hmpv pneumonia. patients presenting with these features should have laboratory testing performed for prompt diagnosis. human metapneumovirus (hmpv) was discovered in ; however, seroprevalence studies indicate this virus has circulated among humans for at least years [ ] . although it is considered a community-acquired respiratory virus, children < years of age experience hmpv infection at least once, and reinfection is common [ ] . seasonal patterns of infection have been observed in several regions, with the majority of cases occurring from late winter to early spring in european countries, the united states, and canada, and between spring and summer in asian countries, including japan [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . even though it is usually a mild and self-limiting disease, hmpv can potentially cause severe lower respiratory infections, especially in young children, the elderly, and immunocompromised patients [ ] [ ] [ ] [ ] [ ] [ ] . several studies have reported outbreaks due to hmpv in long-term care facilities (ltcf) for the elderly and described the high incidence of pneumonia [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, most reports are epidemiological studies, and they often do not include the clinical and radiological features of hmpv pneumonia. three independent outbreaks of hmpv occurred in ltcf for intellectually challenged and elderly residents in okinawa, japan. as a result, approximately % of the symptomatic patients developed pneumonia during the outbreaks. the objective of the present study was to retrospectively evaluate the clinical features, laboratory, and radiological findings of hmpv pneumonia. patients with hmpv infection were identified during independent ltcf outbreaks in okinawa, a subtropical region of japan. the outbreaks were designated as outbreak a, b, and c, and the facilities where those outbreaks occurred are also identified as facility a, b, and c, respectively. outbreak a occurred in an ltcf for intellectually challenged patients from march to april , . outbreak b occurred in a complex containing a nursing home and a hospital for the elderly from march to may , . outbreak c occurred in a different ltcf for intellectually challenged patients from may to june , . within their grounds, facilities a and b have the capacity and staff to provide primary care and routine check-ups; however, facility c does not. during the outbreaks, confirmed cases of hmpv were defined as having clinical respiratory samples positive for virus via an hmpv-specific polymerase chain reaction (pcr) and/or rapid antigen test (rat). probable cases had recently acquired clinical manifestations compatible with a respiratory infection (eg, respiratory symptoms and fever ≥ . °c), within the appropriate time frame. cases of febrile disease without respiratory symptoms, or diagnosed with alternative causation, were excluded from the sample population. the medical records for both confirmed and probable cases were retrospectively evaluated. the institutional review board of the university of the ryukyus approved this study. informed consent from each patient was waived because the study was retrospective in approach and caused no additional adverse events for any subjects. during outbreak a, nasal swabs were collected from patients and tested with a rat for influenza virus. after all patients returned negative results, the residual liquid underwent nucleic acid extraction using a commercially available extraction kit (ribospin vrd; geneall, seoul, korea). purified eluent from the sample was tested using a multiplex reverse-transcription pcr kit (seeplex rv onestep ace detection; seegene, seoul, korea), which can detect respiratory viruses, including hmpv, influenza virus a/b, human adenovirus, coronavirus, parainfluenza virus / / , rhinovirus a/b/c, respiratory syncytial virus a/b, bocavirus / / / , and enterovirus, simultaneously. the seeplex rv onestep ace detection kit targets the hmpv n and l genes. during outbreak b, nasal swabs from patients were tested with an hmpv rat (check hmpv; sa scientific, san antonio, tx) targeting the hmpv n and f proteins. residual liquid from the hmpv rat was also tested using the multiplex pcr method described above. during outbreak c, hmpv rat and multiplex pcr were used for patients each. overall, multiplex pcr and rat was performed in and patients and returned and positive results, respectively. serum antibodies against hmpv were also examined in a subset of patients (n = ) from outbreak a. acute phase serum samples were collected within week after the onset of symptoms, and convalescent phase samples were collected month later. the hmpv antibody titers were determined by enzyme-linked immunosorbent assay (elisa) using purified virion as the antigen, a method described by okamoto et al [ ] . in brief, microwell plates (thermo fisher scientific, waltham, ma) were coated with a sendai- -d (hmpv-a) and sendai- - (hmpv-b) antigen mixture and refrigerated at °c for hours. plates were then blocked for hour at room temperature and washed. starting at a : dilution, -μl serial -fold dilutions of samples were added to the prepared plates and incubated at °c for hour. plates were labeled with horseradish peroxidase-labeled goat anti-human igg (millipore, billerica, ma) and detected using a peroxidase substrate kit (bio-rad laboratories, hercules, ca) at nm. patients with a ≥ -fold increase of antibody titers between the acute and convalescent phase were regarded as having an acute hmpv infection [ ] . chest x-rays and computed tomography (ct) images were analyzed by pulmonologists. attention was focused on distribution, location, and pattern of the abnormal shadows. bronchial wall thickenings and pleural effusions were also assessed. final decisions were reached by consensus. for chest ct images, dense consolidation was considered to be present when vascular margins were obscured. ground-glass opacity (ggo) was defined as a hazy increase in attenuation without obscuring vascular markings. centrilobular nodule was defined as either a nodule recognized near the peripheral pulmonary artery branches or to mm away from the pleura, interlobular septa, or pulmonary veins. continuous variables, such as age, body temperature, and laboratory findings, between pneumonia and non-pneumonia cases were compared using the wilcoxon/kruskal-wallis test. categorical variables were evaluated using the pearson's χ test or fisher's exact test, when appropriate. a two-sided p value of <. was considered to be statistically significant. all data were analyzed with jmp version (sas institute inc., cary, nc). during the outbreaks, patients with hmpv infections ( confirmed cases and probable cases) were identified. each facility experienced ( confirmed cases), ( confirmed cases), and ( confirmed cases) hmpv infections. the attack rates were % ( of residents) in outbreak a, % ( of residents) in outbreak b, and % ( of residents) in outbreak c. patient characteristics and clinical manifestations are shown in table . the most frequently encountered disorders were intellectual disabilities, cerebral palsy, and schizophrenia. among hmpv infections, cases ( %) developed pneumonia as evident on chest x-rays and/or ct. for of ( %) cases, pneumonia was diagnosed within days after the onset of symptoms. pneumonia patients were significantly older than non-pneumonia cases (median age, vs ; p < . ). it is interesting to note that almost all patients with dementia or in a bedridden state acquired pneumonia. however, these patients were frequently septuagenarians or older (age range, - and - , respectively; data not shown). pneumonia patients also developed higher fever (p = . ), wheezing (p < . ), and needed oxygen therapy administered (p = . ) more frequently. sputum culture for bacterial identification was performed for pneumonia patients; were positive for pathogenic bacteria and were negative. streptococcus pneumoniae was the most commonly isolated (n = ) followed by pseudomonas aeruginosa (n = ) (supplementary table ). moraxella catarrhalis and haemophilus influenzae were coinfected in patient. all pneumonia patients were treated with empirical antibiotics regardless of the bacterial test results. seven pneumonia patients from facility c, where acute medical care could not be provided, required admittance to a local hospital for care. most patients improved within week and none of the patients died. blood tests were performed in patients including pneumonia and non-pneumonia patients. median white blood cell (wbc) count, c-reactive protein (crp), aspartate aminotransferase (ast), alanine aminotransferase (alt), and creatine phosphokinase (cpk) concentrations were significantly higher for pneumonia cases than non-pneumonia cases ( figure ). more than a -fold increase in antibody titers was observed between the acute and convalescent phase of patients. these patients were regarded as having acute hmpv infection. among other patients, had titers more than at either the acute or convalescent phase. because % of healthy japanese adults do not have titers over [ ] , these symptomatic patients were assumed to have an acute hmpv infection during an hmpv outbreak, regardless of pcr results. one final patient had no significant elevation in antibody titers but was also regarded as having acute hmpv infection due to a positive pcr result (supplementary table ). the chest x-ray findings of pneumonia patients are summarized in table . for these patients, abnormal shadows were primarily found in the proximal area of the lung ( %) and bilateral distribution was common ( %). bronchial wall thickenings were observed in all pneumonia patients. of note, proximal bronchial wall thickenings radiating outward from the hilum were observed in most patients, and representative images are depicted in figure . abnormal opacities were observed in a patchy pattern ( %) more frequently than confluent ( %). table summarizes the chest ct findings of pneumonia patients. multilobar distribution was observed in all cases and lower lobes were frequently involved. again, abnormal shadows were primarily found in the proximal rather than peripheral areas of the lung. lobular opacity was the most common shadow pattern ( %), in contrast to ggo ( %) and dense consolidation ( %). bronchial wall thickenings were also frequently seen on ct images ( %). representative ct images of selected pneumonia patients are shown in figures and . a follow-up chest x-ray or ct was performed in of pneumonia patients ( . %), and abnormal shadows seen during the outbreaks were diminished, as demonstrated in figures and . to date, many outbreaks due to hmpv have been reported; however, few studies focus on the clinical features of hmpv pneumonia. our data shows older ltcf residents, especially those with dementia or in a bedridden state, frequently developed pneumonia due to hmpv when compared with other residents. moreover, high fever, respiratory failure, wheezing, and elevated wbc, crp, ast, alt, and cpk levels were frequently observed among hmpv pneumonia cases. typical hmpv pneumonia chest images exhibit proximal bronchial wall thickenings radiating outward from the hilum. although it is frequently the cause of a mild, self-limiting respiratory infection in healthy children and adults, hmpv infection can also induce a severe infection in the elderly. falsey et al [ ] reported that older adults more frequently experience dyspnea and wheezing, during the course of the disease, compared with younger patients. although no fatal cases were recorded in this cohort, the mortality rate of elderly patients in ltcf during an hmpv outbreak has been reported to be approximately % . the box and whisker plots describe the th, th, th, th, and th percentiles. *, p < . ; **, p < . . [ , ] , demonstrating again that elderly patients are susceptible to more severe hmpv infections. darniot et al [ ] also demonstrated that older mice develop a more severe hmpv infection compared with young mice. nevertheless, outbreaks of hmpv also occurred in ltcf for intellectually disabled patients (facilities a and c), where residents were not elderly. in general, the immune system of intellectually disabled patients is not weak; however, we speculate they may have been susceptible to hmpv due to isolation and lack of exposure to natural infection of hmpv for an extended time. therefore, it is possible their antibodies against hmpv might be unusually diminished. the present study demonstrated that wbc and crp, ast, alt, and cpk concentrations were higher in patients with pneumonia than non-pneumonia infections. although scheuerman et al [ ] reported that ast and alt were slightly human immunodeficiency virus, and coxsackie virus are the most commonly documented [ ] , whereas legionella species, francisella tularensis, and s. pneumoniae [ , ] are common among bacterial pathogens. respiratory pathogens, such as chlamydophila psittaci and mycoplasma pneumoniae, have also been implicated [ ] . however, neither rhabdomyolysis nor elevated levels of cpk have been reported in patients with hmpv pneumonia before. more importantly, these data indicate that hmpv infection should be included in the differential diagnosis when we treat pneumonia patients with elevated cpk. chest imaging revealed bronchial wall thickenings radiating out from the hilum were common for hmpv pneumonia. proximal tramlines arising out from the hilum seem like "spider legs" on the chest x-ray. although some studies report the radiological findings of hmpv pneumonia in immunocompromised patients, studies conducted within immunocompetent a Á bb adults or the elderly are limited. previous studies have shown interstitial infiltrates, ggo, as well as centrilobular nodules suggestive of bronchitis and bronchiolitis are common radiological features for hmpv pneumonia in immunocompromised patients [ ] [ ] [ ] [ ] . however, only report describes chest images among elderly, immunocompetant inpatients during an hmpv outbreak. four of the affected patients had abnormal shadows in the chest x-ray, and of the had linear shadows and were diagnosed with hmpv-induced bronchitis or bronchiolitis [ ] . because ciliated airway epithelial cells are the primary targets for hmpv infection [ ] , it is easily justifiable for bronchial wall thickenings, evidence of bronchitis or bronchiolitis, to be common radiological features in hmpv pneumonia. centrilobular nodules, interstitial infiltrates, and ggo were not frequently observed in the present study. it is possible that an immunocompromised host's weaker immune response to hmpv may allow the virus to spread into the peripheral bronchiole and lung parenchyma. however, this cohort did not contain immunocompromised individuals, and radiological findings may reflect a more reasonable host response to hmpv infections. unfortunately, complete and detailed information regarding symptoms and physical examinations were not possible due to study design. in addition, this study may contain other limitations beyond those expected of a retrospective study. first, hmpv rat and/or pcr were not performed in all symptomatic patients during the outbreaks. due to the restrictions of the national health insurance system in japan, rat and pcr testing for hmpv is not approved for diagnostic decisions in adult patients. as such, attending physicians in each ltcf consulted the university of the ryukyus' department of infectious diseases, respiratory, and digestive medicine as each outbreak waned. as a result, only a subset of affected patients could be tested. other laboratory testing, bacterial cultures, and imaging tests (eg, chest x-ray and ct) were also only performed on subsets of patients. moreover, by including fever in the case definition, it is possible that the mildest forms of hmpv infection were overlooked. elderly patients do not always exhibit fever during infection. however, using respiratory symptoms alone may have broadened the case definition beyond usefulness. our cohort contained multiple, and in many cases severe, underlying disorders. therefore, patients were frequently unable to self-report andphysicians had to rely solely on observation. thus, bias should be considered when interpreting these data. in conclusion, we report the clinical and radiological features of hmpv pneumonia in non-immunocompromised patients collected from outbreaks in ltcf in okinawa, japan. as a common virus, hmpv is capable of causing outbreaks in ltcf and causing pneumonia, especially in the elderly. when treating adult pneumonia patients that present with the features described, physicians should consider hmpv infection and perform laboratory testing for prompt diagnosis and adequate infection control, especially in isolated and at-risk populations. supplementary materials are available at the journal of infectious diseases online. consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. a newly discovered human pneumovirus isolated from young children with respiratory tract disease epidemiology of human metapneumovirus outbreaks of human metapneumovirus in two skilled nursing facilities -west virginia and idaho an outbreak of severe respiratory tract infection caused by human metapneumovirus in a residential care facility for elderly in an outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility outbreak of human metapneumovirus infection in norwegian children performance of a rapid human metapneumovirus antigen test during an outbreak in a long-term care facility outbreak of human 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adults-initial ct findings, disease course and comparison to respiratory-syncytial-virus (rsv) induced pulmonary infections experimental human metapneumovirus infection of cynomolgus macaques (macaca fascicularis) results in virus replication in ciliated epithelial cells and pneumocytes with associated lesions throughout the respiratory tract we thank haley cash for help in laboratory testing. we also thank the physicians and other healthcare workers of the national hospital organization ryukyu hospital, hokuzan hospital, and okinawa ryouikuen.financial support. this work was funded by a research grant from okinawa prefectural government.potential conflicts of interest. all authors are without any conflict of interest. all authors have submitted the icmje form for disclosure of potential conflicts of interest. key: cord- -c qnwfm authors: le guyader, françoise s; atmar, robert l; le pendu, jacques title: transmission of viruses through shellfish: when specific ligands come into play date: - - journal: curr opin virol doi: . /j.coviro. . . sha: doc_id: cord_uid: c qnwfm shellfish are known as vectors for human pathogens and despite regulation based on enteric bacteria they are still implicated in viral outbreaks. among shellfish, oysters are the most common vector of contamination, and the pathogens most frequently involved in these outbreaks are noroviruses, responsible for acute gastroenteritis in humans. analysis of shellfish-related outbreak data worldwide show an unexpected high proportion of nov gi strains. recent studies performed in vitro, in vivo and in the environment indicate that oysters are not just passive filters, but can selectively accumulate norovirus strains based on viral carbohydrate ligands shared with humans. these observations contribute to explain the gi bias observed in shellfish-related outbreaks compared to other outbreaks. françoise s le guyader , robert l atmar and jacques le pendu shellfish are known as vectors for human pathogens and despite regulation based on enteric bacteria they are still implicated in viral outbreaks. among shellfish, oysters are the most common vector of contamination, and the pathogens most frequently involved in these outbreaks are noroviruses, responsible for acute gastroenteritis in humans. analysis of shellfish-related outbreak data worldwide show an unexpected high proportion of nov gi strains. recent studies performed in vitro, in vivo and in the environment indicate that oysters are not just passive filters, but can selectively accumulate norovirus strains based on viral carbohydrate ligands shared with humans. these observations contribute to explain the gi bias observed in shellfish-related outbreaks compared to other outbreaks. although first described years ago [ ] , it has only recently become very clear that food plays an important role in virus transmission. in , the cdc identified viruses as the causative agent of % of illnesses due to food consumption in outbreaks with an identifiable etiologic agent. noroviruses (novs) were the most common cause, being responsible for outbreaks, while salmonella, the second leading cause, was responsible for outbreaks [ ] . recent estimates from the cdc are that there are . million episodes of foodborne illness caused annually by major pathogens in the united states, and novs are responsible for % of these illnesses. besides novs, foodborne transmission has been documented for at least viral families, but only a few families have been implicated repeatedly (table ) [ ] . if viral zoonotic transmission (e.g. hepatitis e) is not considered, the two primary routes for food contamination are infected food-handlers and the production process (such as contact of the food with sewage-contaminated waters) [ , ] . several factors influence the transmission process, including the manner of contamination, binding or attachment of the virus to the food, survival and persistence of the virus on the food, the manner of food preparation (raw, cooked, peeled), and the susceptibility of the person eating the food to the contaminating virus [ ] . the food itself also has an important role. for example, lettuce maintains a higher quantity of viable hepatitis a virus and for a longer period of time compared to fennel and carrots [ ] . recognition of foodborne illness also is influenced by public sensitivity and awareness of such illness, which can bias the tendency to report an illness. all but of the outbreak notifications involving viruses reported during an -year period ( - ) in the european food alert system for food and feed (rasff) were due to novs. the other three were recent reports of hav linked to dried tomatoes. among the nov foodborne outbreaks, were associated with berries and with oysters [ ] . although reporting bias may play a role in the predominance of outbreaks associated with berries and oysters, as they are known to be high-risk foods, these data also highlight the association between shellfish and viral gastroenteritis. novs belong to the caliciviridae family, a group of nonenveloped, icosahedral viruses with a single-stranded, positive sense rna genome [ ] . these viruses are highly diverse and are currently divided into genogroups [ ] . genogroups i, ii and iv contain human strains. each genogroup is further subdivided into genotypes based upon analyses of the amino acid sequence of the major capsid protein, vp . other genotyping systems based upon shorter sequences [ ] or analysis of the polymerase gene [ ] have also been described. new strains and genogroups infecting animals also have been described [ ] . nov infection causes gastroenteritis that is characterized by vomiting and diarrhea [ ] . the prevalence of vomiting along with the short incubation period ( - days) and short clinical illness ( - days) has been used epidemiologically to identify probable outbreaks of novassociated gastroenteritis [ , ] . the infectious dose % has been estimated to be as low as fewer than virions [ ] . novs bind to histo-blood group antigens (hbgas), phylogenetically highly conserved complex glycans present on many different cell types and proposed as an attachment factor necessary to initiate infection in people [ , , ] . novs are the major cause of epidemic nonbacterial gastroenteritis worldwide and have been identified as the cause of % to more than % of outbreaks [ ] . these outbreaks involve all age groups in a wide variety of settings, with a large dominance of gii strains that can constitute up to % of clinical strains [ , ] . over the past years, nov sequence analyses of outbreak strains collected from around the world show that gii. viruses have accounted for % of all human cases [ ] . shellfish are known to be a high-risk food for viral outbreaks but clear strain identification in shellfish is still often difficult. one of the first reports providing the sequence of a nov strain described an outbreak in the us. a gi. strain was found in oyster samples, but the sequence was not identical to those detected in patients' stools [ ] . at the same time in japan, a mixture of gi and gii novs was detected both in stool and the related oyster samples but no sequencing was performed [ ] . since then, improvements in detection methods and the development and harmonization of molecular typing strategies have simplified data comparisons, allowing a compilation of outbreak reports that used comparable methods (table ) . one characteristic of shellfish-related outbreaks is their frequent association with multiple virus strains observed both in infected patients and in the involved shellfish. when a number of different virus strains are detected in patients, association of the infection with shellfish consumption can be difficult if only a few stools from an outbreak are collected. thus, it is essential to collect as many stool samples as possible from affected individuals so that all strains that may be present can be identified. it is also important to rapidly identify the outbreak in order to trace the oyster production and to quickly collect the samples related to the outbreak. these data can be used with collected epidemiological data to fully understand the role played by shellfish in the outbreak. primers and probe sets specific for each nov genogroup have been developed for detection by real time rt-pcr [ , ] . however, genotyping remains a challenge, especially in shellfish where low viral concentrations are observed and in stools containing several different strains. in addition, a cocktail of primers is often required to detect the various nov strains because of the diversity of these viruses [ , , ] . most outbreaks of shellfish-associated nov disease are linked to oyster consumption, presumably because oysters are the most commonly consumed shellfish and they are usually consumed raw (although some outbreaks have been linked to cooked oysters) [ ] . overall, contamination by multiple nov strains has been reported in % of reported outbreaks, with gi and gii novs detected, respectively, in % and % of stool samples and in % and % of shellfish samples. the frequency of each genogroup detected in shellfish-related outbreaks is clearly distinct from that of other nov outbreaks. gi strains are more frequently encountered in shellfish-related outbreaks, and the gii. genotype is not as dominant (figure ). among gi novs, the most frequently reported genotype is gi. , followed by gi. and gi. ( figure ). among gii novs, the gii. genotype is the most frequently reported from both stool and shellfish samples. the gii.b variant was reported four times in patient's stool from oyster-related outbreaks, but confirmed in shellfish only once. its frequent involvement in human to human outbreaks raises the possibility of another source of infection for these individuals involved in the alleged shellfish-related outbreaks [ , ] . transmission of viruses through shellfish le guyader, atmar and le pendu oysters -no sample [ ] nd: not detected, two manuscripts report data from (a) and (b) individual outbreaks. some reports provide only stool analyses without shellfish data, such as the description of gi. and gii. strains implicated in an oyster-related outbreak reported from the uk [ ] . in japan gi novs alone were detected in four out of outbreaks related to oyster consumption, with the remaining outbreaks being associated with a mixture of gi and gii novs. in that study, gi. strain was detected in of the outbreaks [ ] . a previous study, also from japan, reported the presence of a mixture of gi and gii novs in stools from out of oyster-outbreaks. in contrast, of outbreaks not linked to shellfish consumption, all but were due to gii novs, with both gi and gii strains being found in the remaining three [ ] . screening of shellfish not involved in outbreaks for the presence of novs has also been performed in several countries. highly variable frequencies of contamination have been reported. these studies have also observed a relatively higher frequency of gi nov contamination than seen in community outbreaks (table ) . both studies that reported sequencing results identified gi. strains in the contaminated shellfish. on numerous occasions viral contamination in shellfish has persisted following measures, such as depuration or relaying, that have been used successfully to remove bacterial pathogens [ ] . for example, in a laboratorybased study there was only a % decrease in the levels of bioaccumulated norwalk virus compared to a % reduction in bacterial levels following hours of depuration [ ] . in another study, a gii. nov persisted for at least days under depuration conditions while a feline calicivirus was promptly eliminated [ ] . a third study reported that, after a contaminating event in a french production area, the percentage of samples positive for gi and gii novs, respectively, were % and %. the prevalence decreased to % and %, respectively, after weeks, suggesting a greater persistence in oyster tissues of gi novs compared to gii strains [ ] . these observations led to the hypothesis that novs may bind specifically to oyster tissues through carbohydrates, as observed in humans, and that this binding may facilitate bioaccumulation and increase persistence in shellfish. using immunohistochemistry, we demonstrated that nov vlps specifically bind to glycans of crassostrea gigas oyster tissues, and that strain-specific variation in binding occurs. gi. novs bind to the midgut and digestive diverticula but not to gills or mantle, whereas gii. and gii. novs bind to all of these tissues. human saliva from type a and o secretors, but not of type b secretors, inhibited binding of the gi. norwalk vlps, in accordance with the strain hbga binding specificity. in addition, introduction of a mutation in the virus-like particles (vlps) glycan-binding site that abrogates glycan binding was sufficient to eliminate binding to oyster tissues, demonstrating specificity of the binding [ ] . binding was also inhibited by a lectin and anti-blood group a antibodies, indicating that the gi. nov binds to c. gigas as well as crassostrea virginica oyster tissues though an a-like antigen [ ] . the a-like antigen is also implicated in the binding of gii. and gii. strains to oyster digestive tissues. binding of these gii strains to the oyster's gills and mantle occurs through a sialic acid residue [ ] . the influence of ligand expression on nov binding to oyster tissues was first demonstrated using vlps. gi. vlps were very efficiently bioaccumulated by c. gigas oysters and were detected by immunohistochemistry even at a low level of exposure, whereas a mutant vlp that was unable to recognize the a-like antigen was only detected in oyster tissues at a thousand fold higher concentration [ ] . these results were confirmed using a gi. -positive stool that bioaccumulated very efficiently table frequency of nov gi and gii in shellfish contamination in non-outbreak samples from different countries. a individual samples consisted of pools of - individual shellfish except for the study [ ] in which individual mussels were assayed. b mollusks (clams, oysters or cockles) were imported from morocco, peru, vietnam and south korea. in a dose-dependant manner. when these experiments were performed at different times of the year, there was a clear seasonal impact on bioaccumulation efficiency that paralleled expression of the hbga ligand in oyster digestive tissue [ ] . the quantitative approach also showed that the gi. nov directly accumulates in digestive tissues with negligible concentration in other tissues. performing bioaccumulation using two gii nov positive stools (one stool positive with a gii. and one with a gii. strain) led to very different results. these two strains bound to digestive tissues, gills and mantle with a similar pattern [ ] . the gii. strain, as well as gii. vlps, was bioaccumulated at very low levels, although they were found in a number of tissues as also reported by others [ , ] . in contrast, the gii. strain was efficiently bioaccumulated, although less well than the gi. strain, with a transient retention in the gills likely due to binding to sialic acid [ ] . in contrast to the findings with the gi. strain, no seasonal impact was observed in the bioaccumulation of the two gii novs or of the sialic acid containing ligand present in all tissues. our interpretation of these data is that the gi. strain is efficiently accumulated and retained through an hbga a-like ligand present in the gut. gii strains are less well accumulated because of a sialic acid containing ligand expressed in all tissues that contributes to their retention in the gills and leads to their destruction (or elimination) by an unknown mechanism. the latter process would be more efficient in the case of a gii. than of a gii. strain. shellfish species may also impact bioaccumulation as demonstrated comparing two oysters species (crassostrea ariakensis and c. virginica). the gi. strain was more efficiently concentrated by c. ariakensis and persisted for a longer time compared to c. virginica [ ] . it will be interesting to compare the glycan ligand expression between these species. since many environmental conditions may interfere with oyster's filter capacity and consequently with contamination, a field study was conducted to determine if the above observations performed in laboratory conditions are valid in the environment. thus, concentrations of gi and gii novs in waters collected during a year were compared to concentrations in oyster digestive tissues. as expected, much higher concentrations of gii novs than of gi were detected in waters. gi novs were concentrated to a greater degree than gii strains, with gi viruses requiring viral rna copies/l water to bioaccumulate viral rna copy/g oyster tissue compared to gii viruses that required viral copies/l of water to observe viral copy per gram of oyster tissue. these data provide additional evidence for the specific selection and persistence of gi novs in oysters. this field study was conducted in an area with a large amount of cattle breeding. bovine novs (giii) were detected in % of water samples at high levels, but only one shellfish sample contained a giii nov strain [ ] . the agal hbga epitope, identified as the virus-specific glycan ligand in bovine tissues [ ] , was absent from oyster tissues, potentially explaining the poor bioaccumulation efficiency observed for giii nov strains. these data suggest a selective transmission of nov strains via oysters through specific binding to carbohydrate ligands. ligands that facilitate bioaccumulation (the a-like antigen) or that contribute to the elimination of the virus (the sialic acid-containing ligand) may both influence nov accumulation and survival in oysters (figure ). for a long time, oysters were believed to act as filters or ionic traps, passively concentrating particles. however, this is clearly not the case for novs, especially for nov gi. that is more actively and efficiently concentrated than gii strains. the differential accumulation efficiency provides a possible explanation for the unexpectedly high proportion of gi strains associated with shellfish-related outbreaks. this new concept demonstrating a special relationship between oysters and nov should be explored for other transmission of viruses through shellfish le guyader, atmar and le pendu influence of oyster in the selection of nov transmission. : shedding in the environment of large amounts of gii novs (blue) and much lower amounts of gi strains (red) due to the overwhelming predominance of nov gii in human outbreaks. shedding of nov giii (green) in cattle is also shown. : viruses present in seawater are ingested by oysters. gi novs particles are very rapidly directed to the gut, whereas gii particles are retained in mantle or gills possibly via a sialic acid containing ligand. giii novs are probably randomly distributed. : nov gi and gii are accumulated in the gut via an hbga a-like ligand, most gii and giii particles outside the gut are presumably destroyed. : upon consumption of a nov-contaminated oyster, infection caused by gi and gii strains occur with similar frequency because of the selective accumulation and retention of gi viral particles. giii nov transmission is unlikely to happen as few particles persist in oysters and humans do not express the glycan ligand. enteric viruses, including aichi virus and oysters, sapovirus and clams, and other foods such as nov and berries or hepatitis a virus and tomatoes. food trade may contribute to dispersal of a virus strain, as virus-contaminated imported shellfish have been responsible for outbreaks (table ) [ ] . a better understanding of virus-food interactions may provide strategies to prevent contamination, to increase viral elimination, and thus to increase consumer safety. third outbreak of epidemic poliomyelitis at west kirby surveillance of foodborne disease outbreaks -united states emerging foodborne viral diseases efsa panel on biological hazards: scientific opinion on an update on the present knowledge on the occurrence and control of foodborne viruses progress in understanding norovirus epidemiology. curr opin inf dis binding and inactivation of viruses on and in food, with a focus on the role of the matrix the survival of hepatitis a virus in fresh produce noroviruses: state of the 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approach to estimate norwalk-like virus contamination of oysters implicated in an outbreak detection of noroviruses in shellfish in the netherlands norovirus gastroenteritis general outbreak associated with raw shellfish consumption in south italy detection of multiple noroviruses associated with an international gastroenteritis outbreak linked to oyster consumption internationally distributed frozen oyster meat causing multiple outbreaks of norovirus infection in australia an outbreak of norovirus caused by consumption of oysters from geographically disperse harvest sites multiple viral infections and genomic divergence among noroviruses during an outbreak of acute gastroenteritis a new zealand outbreak of norovirus gastroenteritis linked to the consumption of imported raw korean oyters molecular analysis of an oyster-related norovirus outbreak comprehensive analysis of a norovirusassociated gastroenteritis outbreak, from the environment to the consumer detection of sapoviruses and noroviruses in an outbreak of gastroenteritis linked genetically to shellfish genotyping and quantitation of norovirus in oysters from two distinct sea areas in japan this study describes nov quantification in oysters and molecular typing based on partial sequences of the capsid gene. these data are valuable as sequencing from shellfish samples is difficult and thus such reports are still uncommon determination of norovirus contamination in oysters from two commercial harvesting areas over an extended period, using semiquantitative real-time reverse trancription pcr comparison between quantitative real-time reverse transcription pcr results for norovirus in oysters and selfreported gastroenteritis illness in restaurant customers norovirus distribution within a estuarine environment detection and quantification of noroviruses in shellfish occurence of norovirus and hepatitis a virus in us oysters assessment of human enteric viruses in cultured and wild bivalve molluscs tracing of norovirus outbreaks strains in mussels collected near sewage effluents norovirus detection in shellfish using two real-time rt-pcr methods imported mollusks and dissemination of human enteric viruses this letter illustrates the risk of introduction of specific strains following the importation of shellfish this work was supported in part by a grant (cimath) from the region des pays de la loire, by dgal (direction gé nérale de l'alimentation) and by a grant from the nih (po ai ). this study demonstrated that persons involved in oyster-related outbreaks were infected with multiple enteric viruses, including novs and sapoviruses. key: cord- -zupocnuf authors: li, junxiong; hallsworth, alan g.; coca‐stefaniak, j. andres title: changing grocery shopping behaviours among chinese consumers at the outset of the covid‐ outbreak date: - - journal: tijdschr econ soc geogr doi: . /tesg. sha: doc_id: cord_uid: zupocnuf this study focuses on the embryonic stages of the covid‐ pandemic in china, where most people affected opted to abide by the chinese government’s national self‐quarantine campaign. this resulted in major disruptions to one of the most common market processes in retail: food retailing. the research adopts the theory of planned behaviour to provide early empirical insights into changes in consumer behaviour related to food purchases during the initial stages of the covid‐ outbreak in china. data from the online survey carried out suggest that the outbreak triggered considerable levels of switching behaviours among customers, with farmers’ markets losing most of their customers, while local small independent retailers experienced the highest levels of resilience in terms of customer retention. this study suggests avenues for further scholarly research and policy making related to the impact this behaviour may be having around the world on society’s more vulnerable groups, particularly the elderly. since its outbreak in wuhan (china) in early january , the covid- strain of the novel coronavirus spread rapidly across china and beyond to affect countries with tragic consequences -over million cases (over . million in europe alone) of reported infections with in excess of , people dead by the end of april of (who ) . this has had a major impact on consumers and the retail sector across europe and further afield (feng and fay ; evans ) . as a response to the initial outbreak, china was the first country in the world to impose a mandatory nation-wide self-quarantine between january and february (bloomberg news ). since then, many other countries in europe and further afield have followed suit by issuing restrictions to their citizens' movements in order to stem the spread of the virus (chinazzi et al. ; hedgecoe et al. ) . although the full impact of this crisis on the retail sector will only emerge once it has been brought under control, early indications show that retail outlet closures ordered by governments around the world as well as changes in consumer behaviours associated with this pandemic are having a detrimental impact on the sector already, to the point that up to , high street retail outlets have been forecast to close in the uk alone as a result of this pandemic (munbodth ) . indeed, earlier research has shown that major pandemics, such as the severe acute respiratory syndrome (sars) outbreak in or the middle eastern respiratory syndrome (mers) outbreak in , can have major impacts on supply chains (cavinato ; oke & gopalakrishnan ) and consumer behaviour in retail with a specific focus on online food shopping even if most of this research has been carried out primarily from a hospitality (alan et al. ; chien and law ; jayawardena et al. ) or tourism perspective (wen et al. ; kuo et al. ; jamal & budke ) with the majority of studies focusing on asia (mckercher & chon ; kuo et al. ) due to the prevailing geography of earlier pandemics. this study seeks to contribute to current knowledge of customer behaviour in retail within the context of a major public health crisis, which has been somewhat dominated by research related to supermarkets and online purchases (e.g. forster & tang ) and largely ignored other retail formats, including small independent retailers and traditional markets. for this purpose, the theory of planned behaviour first posited by ajzen ( ) is adopted to explore planned changes to consumer food shopping behaviours at the early stages of the covid- outbreak in china. due to the geographical origin of the covid- pandemic, the data was collected in china with a focus on eliciting early insights from food and grocery shopping behaviours during the embryonic stages of the pandemic when it was still classified as a mere outbreak. during this difficult time, the supply and demand of food was unbalanced due to the shortage of supply and potentially by panic buying behaviours (cachero ) , which have since been replicated in much of the rest of the world. as such, this study presents a customer-centred enquiry of supply versus demand to grocery retailing at the outset of the covid- pandemic. as part of this study, insights were sought on prior shopping patterns -familiar sources of food shoppingas well as evidence of how switching took place. the implications of the findings are discussed later against the backdrop of similar issues emerging in leading western economies currently facing the fallout of this growing pandemic. initially, a number of possible theoretical frameworks were considered for this study, including the technology acceptance model (tam) and ajzen's ( ) theory of planned behaviour, when seeking to characterise how consumers tried to purchase food and groceries before and during the covid- outbreak. building on earlier retail studies with a similar theoretical framework (e.g. spence & townsend ; lobb et al. ; hansen ) , the theory of planned behaviour (tpb) was adopted for this study to analyse planned changes in consumers' food shopping behaviour during the early stages of the covid- outbreak in china, in line with research published recently on the impacts of this pandemic on food supply chains, where authors speculated with major potential changes to consumer behaviour in grocery retailing in canada and elsewhere (richards & rickard ) . first, food availability was investigated among different retailers, including online retailers, local independent small shops, supermarket chains and farmers markets. food was categorised broadly as fresh, packed and canned, cooked and ready to eat, and frozen. data for this study was collected using a selfadministrated online questionnaire launched during the chinese government's mandatory national 'self-quarantine' campaign adopting a non-probability snowball sampling strategy. the survey was distributed using china's most popular social media platform -wechat. in order to avoid repeat responses, wechat account login was required in each case. response rates were boosted by means of a survey panel provided by tencent group. the survey was closed on february -the last day of the mandatory national self-quarantine campaign. a total of respondents participated in the survey, with an average survey completion time of minutes. an outline of the survey respondents' profile is shown in table . respondents were asked to what extent they could buy food from those channels ( = very difficult, = very easy). overall, customers found it difficult to buy all categories of food across all shopping channels (mean = . ). supermarkets had the greatest availability of food across all categories (mean = . ), while farmers markets (mean = . ) were the most difficult place to find food during the outbreak (table ) . although there were a number of food categories the ministry of commerce of china had to take control over to ensure supply chain safety (china news service ), this study investigated the food categories most in demand by chinese consumers during the early stages of the covid- outbreak. for this purpose, each respondent was asked to indicate his/ her most wanted food categories at this early stage in the covid- outbreak. the result ( figure ) shows that vegetables, rice (with rice-related products) and meat were the most wanted food categories during the early stages of this fast-evolving pandemic. a preliminary, first-cut, principal component analysis (pca) indicated the presence of four distinct factors: perceived usefulness, perceived ease of use, trust in retailer (q: retailer will ensure food hygiene and safety), trust in government (q: local government will ensure food hygiene and safety) (kmo = . , cronbach's alpha = . ). we quickly concluded that the overriding factor in a time of great change and crisis was, understandably, perceived usefulness (see below). this construct characterised online shopping as a means of reducing the risk of getting infected, as well as the helpfulness of online shopping in one's daily life during the outbreak. it explained per cent of variances of online shopping intention (p = . vif < . ), while other variables were insignificant. there was a mild level of anxiety on food supply (q: "i am worried that there is a food shortage in my local area" = strongly disagree, = strongly agree; mean = . std. dev. = . ). anova and subsequent post hoc tests were applied to various demographic variables (including age, gender, household size, income, etc.). the results suggested that respondents with a masters degree or a higher level of educational attainment (p < . ), were less worried about food shortages, while the fear of running out of food showed no difference within other demographic categories. clearly these patterns require further research, particularly in the context of western economies. before the outbreak, as many as per cent of the survey's respondents bought their food and groceries from supermarkets. however, while supermarkets remained a popular choice during the outbreak, the proportion of consumers choosing supermarkets dropped to per cent. there was also a sharp decline in purchases from farmers markets, with the proportion of people shopping from this channel dropping from per cent to per cent. in contrast, there was a surge in online shopping, with the percentage of consumers buying food and groceries online increasing from per cent before the outbreak to per cent, with online food shopping becoming the most popular channel during the outbreak. local independent small shops also saw an increase during the outbreak from per cent to per cent, as shown in figure . in line with this, consumers' switching behaviour (table ) unveils that per cent of online shoppers remained online, the rest moved to local independently owned small shops ( %) and supermarkets ( %). we do not have the detail to know if any switching from the internet was due to inability to arrange a delivery in time. however, small independent shops demonstrated a high level of customer retention. among consumers who used to do their food shopping primarily in small independent shops, per cent remained buying from their local independent small shops during the outbreak, with per cent moving to online shopping. on the other hand, among supermarket shoppers, per cent moved to shop online while per cent continued using the supermarket for their food and grocery shopping during the pandemic. farmers markets experienced the highest levels of customer churn, which may be attributable to the outbreak being identified initially in a wet market in wuhan -only per cent of consumers continued buying from this channel, per cent of consumers moved online, per cent moved to local privately-owned small independent shops, while per cent switched their food shopping to supermarkets. however, the nation-wide governmentimposed lockdown, which coincided with the chinese new year national holiday, resulted in a general shortage in food supply (cachero ; rosner ) . largely as a result of this nation-wide lockdown, per cent of respondents reported that the retail outlets where they previously bought their food had closed. while respondents based in larger cities (e.g. beijing, shanghai, shenzhen and guangzhou) only reported a food retail outlet closure rate of per cent, respondents from smaller cities and towns (kim ; kim & hallsworth ) and particularly in china (goldman ; tacconelli & wrigley ) has undoubtedly brought new formats into the system and left local communities with an enhanced range of possible purchase opportunities. this study has focused on how such changes played out in a short but turbulent time, namely a major pandemic. a particular characteristic of supermarkets and yet larger outlets is their capacity to process large numbers of shoppers in a short space of time. that focus on high volume and rapid turnover was in dramatic opposition in this particular instance to the need for isolation and quarantine. figure and table both provide similar evidence of a move away from close contact, mass formats to smaller retail formats or online purchases, though further research is required to explore the longer-term implications of this behavioural change and whether it will remain in place once the covid- crisis is over. as in south korea with its world-leading fast broadband, china facilitated online shopping well before the present covid- crisis. it is, therefore, likely that online retail will go from strength to strength globally as a result with early movers most likely to benefit. this could offer a tentative explanation for the lower expressions of stress displayed by survey respondents with a higher level of educational attainment, though further research is required on this front to establish whether job security and expendable income may not be key here instead of the respondents' level of educational attainment. what, then, does this tell us about the relevance of competing theoretical approaches towards understanding (rapid) retail change? building on the work of ajzen ( ) , the theory of planned behaviour attempted to understand the interface between the individual and the choices presented by a rapidly retail environment in the context of a major public health crisis. in common with similar approaches, the underlying initial proposition was that people would make broadly rational decisions given the known choices available. in the context of switching behaviours to online shopping, earlier studies have investigated this (e.g. elms et al. ) . underpinning this, by implication, is an ongoing assessment of the available options that themselves slowly and steadily evolve through time. if we look at the evolution of the work of leading retail researchers, timmermans ( ) , for instance, rapidly moved from rational choice models to cognitive/ behavioural approaches. in recent decades, building on the work of kahneman and tversky ( ) and their successors (see thaler & sunstein ), there has been a growing acceptance of behavioural economics including the importance of routine, habit, heuristics and so on. at the consumer/structure interface, clarke et al. ( ) argued that local shopping behaviour was fitted into complex lifestyles rather than consumers exerting free choices, unhindered by their time-juggling complex lifestyles. perfect information, time availability, utility maximisation functions, human (ir)rationality, consumer preferences, willingness and ability to know and compare, are everyday underpinnings to routinised food shopping behaviour. all such approaches, it would seem, inherently struggle with rapid, sudden and dramatic change. for instance, behavioural approaches founded in game theory (gt) place special emphasis (again see kahnemann & tversky) on how individuals respond when they do not, or cannot, know how others will act, namely, decision making under uncertainty. however, government-imposed restrictions in china and elsewhere have effectively contributed a fundamental element of certainty even if only by removing certain shopping options. if events surrounding the early days of the covid- outbreak in china are to be understood through a retail prism, the fundamental challenge for local residents was to find an available format (or formats) that (still) worked in a rapidly changed environment. in line with this, it could be posited that what emerged was in effect a variant on the technology acceptance model (tam). although with tam it is possible to add variables such as trust (in government or retailer/supplier), the perceived usefulness dimension of tam over-rides other considerations. online shopping is a tam-based 'fix' that pretty much explained all the variances of intention to use in this study. ease of use, conversely -always popular in times of stability -was surely not a factor because it was often difficult for customers to rely on online channels due to unusually high traffic volumes. in china, retailers often had to close down their sites and this seems to have recurred in the uk and elsewhere less than two months since the survey was carried out. at root, online (like downsizing to use smaller, quieter outlets) was effectively a functional choice and one that appears to have worked for many hard-pressed consumers in china consulted in this study. transparently, there will be specific local factors in other countries. italy, for instance, has a notably low penetration rate for internet grocery shopping (some times lower than that of the uk). in contrast as noted above, internet grocery shopping has grown rapidly in china -and especially so in south korea, also affected by this pandemic, with its fast internet and high population densities as key structural facilitators. overall, this study has attempted to offer a retail-focused insight to the early development stages of the covid- outbreak in china. many people -most of whom would not go on to be affected by the pathogenwere advised to self-quarantine but without any clear behavioural precedents on which to work. as in venice, milan, madrid, paris, new york and other major cities affected by the coronavirus, this involved a sudden, immediate and major disruption to one of the most common market processes: food retailing. this research note, albeit not in a conclusive manner, attempts to nevertheless shed some light on how such a large number of people initially sought to find food supplies under unusual, difficult and rapidly changing circumstances. what has emerged since our data gathering is that countries, and their citizens, have varied in their preparedness and responsiveness. it is alleged that in the british government felt able to ignore warnings of a potential future shortage of ventilators and protective equipment: the very shortage it now faces. surely similar errors cannot be repeated in the future. nevertheless, our focus is on consumer responses to covid- . our data relate to the first time-period when residents faced the rapid removal of options to buy food. they had no precedents on which to rely on aside from the sars pandemic of - , which was far less virulent due to the specific characteristics of the pathogen's strain involved. in the case of the covid- outbreak and subsequent global pandemic, a large proportion of governments around the world, including the chinese government, acted to close down retail outlets on which many relied for food -including restaurants, cafes, bars and, in the uk, the traditional 'pub' -with a dramatic impact on the service sector and, more specifically, catering, hospitality, food retail and their wider supply chains. similarly, in china and elsewhere social distancing and self-quarantine measures were introduced by governments, which varied considerably from one country to another in terms of their severity. the still-functioning food system, however, is and remained a free market operation, even when it has long been known that home delivery is not cost-effective for retailers. on occasions of food stockpiling or instances of buying excessive amounts of food, as experienced in much of europe, australia and other western economies, it was the decision of retailers -not national governments -that this should be curbed. one of the key findings of this study is that a significant response from consumers was to switch their food shopping to online channels; a trend copied in several other countries where internet shopping and home deliveries were available options. in the case of the united kingdom, as kirby-hawkins et al. ( ) revealed, consumer take-up of internet shopping was exhibiting clear trends well before the covid- crisis. none of those trends particularly favoured the older, less mobile, less wealthy, less tech-savvy shoppers who have been the ones most affected by government 'lock-down' policies related to the covid- crisis only to compound the fact that many of these groups, certainly more elderly consumers, remain particularly vulnerable to this pandemic physically and mentally. given that the heaviest internet users tend to be younger, wealthier, but time-pressed, home deliveries of food purchases made online have become difficult due the lack of availability of delivery slots. this is often affecting particularly the more vulnerable groups discussed here. however, further research is required to analyse how these dynamics are affecting consumers, including whether more elderly consumers have had little option but to come out of self-isolation to buy their food in supermarkets, markets or local shops and, in doing so, increasing their risk of contracting the virus. the same issue applies to ethnic minorities and socio-economically disadvantaged groups, as there is a growing body of evidence showing that they have been disproportionately affected by this pandemic in the united states, the united kingdom and other european countries. future policy research must surely address how those most affected can reliably obtain basic food under future pandemic conditions. overall, this study has attempted to offer a retail-focused insight to the implications of the early development stages of the covid- outbreak in china. as we have stressed, many people -most of whom would not go on to be affected by the pathogen -were advised to self-quarantine but without any clear behavioural precedents on which to work. as in venice, milan, madrid, paris, new york and other major cities affected by the coronavirus, this involved a sudden, immediate and major disruption to one of the most common market processes: food retailing. this research note, albeit not in a conclusive manner, attempts to nevertheless shed some light on how such a large number of people initially sought to find food supplies under unusual, difficult and rapidly changing circumstances. the theory of planned behavior crisis management and recovery: how restaurants in hong kong responded to sars european food cultures: an exploratory analysis of food related preferences and behaviour in european regions the internationalisation of grocery retailing wuhan residents on coronavirus lockdown are facing food shortages. business insider supply chain logistics risks: from the back room to the board room the impact of the severe acute respiratory syndrome on hotels: a case study of hong kong ministry of commerce: increase the supply of rice, oil, meat, eggs, vegetables, etc". 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in china on living and cooking under coronavirus lockdown the grocers: the rise and rise of the supermarket chains examining consumer behavior toward genetically modified (gm) food in britain organizational challenges and strategic responses of retail tncs in post-wto-entry china nudge: improving decisions about health, wealth, and happiness unidimensional conjoint measurement models and consumer decisionmaking retail structure of beijing the impacts of sars on the consumer behaviour of chinese domestic tourists food scares: a comprehensive categorisation available at <https://covid .who.int/>. accessed on aldi and the german model: structural change in german grocery retailing and the success of grocery discounters the deadly coronaviruses: the sars pandemic and the novel coronavirus epidemic in china key: cord- - pw y authors: koch, lionel; lopes, anne-aurelie; maiguy, avelina; guillier, sophie; guillier, laurent; tournier, jean-nicolas; biot, fabrice title: natural outbreaks and bioterrorism: how to deal with the two sides of the same coin? date: - - journal: journal of global health doi: . /jogh. . sha: doc_id: cord_uid: pw y nan f or the last three decades, the outbreak events have constantly increased and became more complex to prevent, predict and contain. nowadays, health authorities concern is to identify which ones are bioterrorist outbreaks. however, natural outbreaks and biological attacks have a too intertwined nature to be considered separately and hence, in the absence of any attack evidence, differentiate them is a delicate task requiring complex, long and rigorous scientific investigations. furthermore, and as demonstrated by the covid- outbreak, the effectiveness of the response to an outbreak is closely dependent on the timeliness of the response: the effort should thus rather focus on the development of early detection and preparation measures such as the development of global contingency plans organising the action of all entities (civilians, militaries, governmental and non-governmental) in a common effort. innovative artificial intelligence is becoming unavoidable to detect the crisis and to manage it, especially in the phases of preparedness and response effectiveness. this technology largest impact will be to complement and enhance human capabilities but cannot substitute them. the human experts monitoring new threats and able to work with these systems will stay at the centre of the stage. in the last thirty years, the pace of emerging infectious disease outbreaks has significantly increased [ ] . the globalisation of international exchanges contributes to the inefficiency of common quarantine measures to contain the disease [ ] . the last ebola outbreak in in west africa was regarded as a paradigm of the issues caused by emerging infectious diseases nowadays: this extremely deadly pathogen has naturally emerged in a large new area, and its overwhelming spread has subsequently impacted europe and the united states [ ] . this observation was confirmed and emphasised by the coronavirus disease pandemic caused by the new human coronavirus sars-cov- . the effectiveness of the ongoing lockdown of billions of people during the covid- will have to be evaluated and compared to other strategies. thus, outbreaks can no longer be considered as a local and distant issue but should be regarded as a global concern [ ] . natural outbreaks and bioterrorism: how to deal with the two sides of the same coin? of course, in history, some outbreaks have been the starting point of biological attacks, even long before the discovery of microbiology. in , mongols exploited the second plague pandemic by catapulting the bodies of soldiers died from plague over the city walls of caffa [ ] . in the same lines, in the th century, the distribution of infected blankets from a smallpox hospital of english settlers probably caused the deadly smallpox outbreaks in the native americans population [ ] . in the th century, after the discovery of microbiology, a period of extensive industrial biological weapon programs started with scenarios of massive biological attacks against military troops. since , the threat is considered more focused on actions against the population or vital interest points of the nations. these biological attacks could be perpetrated by state or non-state groups in the context of low intensity or hybrid wars and bioterrorist attacks [ ] . nowadays, when an outbreak occurs, one of the first concern of the authorities is to separate a natural outbreak [ ] from an intentional act involving a biothreat agent [ ] in order to adapt their management. even the sars-cov- did not escape the suspicion to have been laboratory-engineered [ , ] . thus, this review will show that there are no easy ways to distinguish one from each other but that they share the same consequences and hence should have a shared management. accordingly, group together preparation measures and response tools against both the emergence of an unknown pathogen and an unpredictable attack will optimise the effectiveness of the response. the biological weapons convention signed in outlaws the use of biological weapons [ ] . since then, the identification of a biological attack is a major international political and judiciary issue [ ] . however, multiple nested events such as global warming [ ] , natural catastrophes [ ] , human actions [ ] and conflicts [ ] affect natural outbreaks in an unpredictable way [ ] . several authors proposed algorithms to determine, during crisis or shortly after, if the biological event had natural or induced causes [ ] [ ] [ ] . except for some criteria, like evidence of a release explicitly referring to attacks, the great part of the arguments should be carefully analysed before being attributed to a biological attack. the use of some spontaneously rare agents could denote a criminal origin, as it has been the case with the use of bacillus anthracis during the amerithrax crisis in [ ] , and, to a lesser extent, with the aum shinrikyo sect in japan in [ ] . however, the agent is not a sufficient criterion to identify natural or induced biohazard. for example, the rajneesh sect used a quite common salmonella enteric [ ] to perpetrate attacks, and some bacterial toxins are considered as a potential warfare agent precisely because of their high prevalence [ ] . in sharp contrast, recent natural outbreaks involved top select agents like ebola virus in west africa in - [ ] or yersinia pestis causing pulmonary plague in madagascar in [ ] . even the emergence of a peculiar new strain cannot be a stand-alone criterion to differentiate both events. indeed, even if there is no evidence of using such agents through history, natural agents can be modified by humans to increase their transmission, lethality or drug resistance capabilities [ ] . at the same time, some natural outbreaks were caused by naturally altered pathogens like the escherichia coli o :h in europe in , a strain that acquired and combined unusual virulence factor and drug resistance genes [ ] or in the new human coronavirus (sars-cov) identified with surprise in front of severe acute respiratory syndrome cases [ ] . if a pathogen is detected in a location where it has never been detected before, it can constitute a hint for a biological attack suspicion. it was the case with the amerithrax crisis in when a texan b. anthracis strain was found on the east coast of the usa [ ] . however, the biggest outbreak of the ebola virus occurred in a part of the continent recognised as free of the disease until then [ ] . one other clue for biological attacks could be the seasonality, arguing that if an outbreak appears during a season not compatible with the pathogen time-life, human activity could be the cause [ ] . here too, some natural outbreaks disrupted both experts and ai will have to learn how to work together and assist each other by developing collaborative intelligence. all rules like the influenza virus h n pandemic in , which appeared in april in north america with two epidemiological spikes [ ] . it unusually emerged from infected pig populations and was followed by a unique global spread [ ] . multiple starting points are commonly considered a sign of a biological attack like the five letters containing b. anthracis spores [ ] as well as the several restaurants targeted by the rajneesh cult [ ] . an attack can also occur in a single place, like the "shigella dysenteriae poisoning" in a laboratory in in the us, where one unique set of pastries has been deliberately contaminated by a laboratory strain [ ] . in contrast, the natural tularaemia outbreak in kosovo in - reached several districts simultaneously in a tensed geopolitical context [ ] and, in , the plague outbreak in madagascar had multiple index cases [ ] . even the assumption that an unusual swift spread or a large share of the population rapidly affected could be evidence for a biological attack is disputable: recent terrorist actions used non-contagious pathogen and hence reliable epidemiological data for the intentional use of a contagious disease do not exist [ ] . by contrast, the influenza virus [ ] , the sars-cov [ ] and the sars-cov- [ ] propagated very fast all around the world with more than countries affected in one year for the first one and countries in months for the second. for the current covid- pandemic, the centre for systems science and engineering (csse) of johns hopkins university (baltimore, md, usa) created a website to visualise and track the reported cases in real-time [ ] . in april , less than five months after the first alert, countries declared at least one case of infection (https://coronavirus.jhu.edu/map. html). in the same vein, the last zika virus natural outbreak showed an unusual spread, as it emerged in africa, travelled across the pacific ocean to finally trigger a pandemic in south america [ ] . is there any interest to identify one from the other? thus, to characterise an infectious phenomenon, we should merge the most advanced technics with thorough epidemiological investigations. results have to be interpreted very carefully by taking into account contextual elements and technical biases to avoid any misunderstanding [ ] . the list of common-sense items is beneficial to process data and improve awareness but should not be solely used to distinguish the origin of an ongoing event because of a lack of reliability (). it should be noted that all criteria and weightings have been determined retrospectively based on past outbreaks and bioterrorist attacks. one of these algorithms has been reviewed in the light of new infectious events but have not yet proven its effectiveness on a prospective basis [ ] . the confusion surrounding these criteria confirms that both phenomena have intertwined nature. moreover, during a natural outbreak, depending on the knowledge about its hazardousness and transmission, the infectious agent can be secondarily regarded as a biothreat agent, like it is now the case with the us department of justice currently considering people who intentionally spread the sars-cov- as terrorists [ ] . however, these political considerations are far away from health workers and do not consider the public health issues of quick detection and response. indeed, even if the substantial remaining risk in the case of an attack is the possibility of secondary actions aiming to maximise damages to the emergency infrastructure [ ] , the real challenge for global safety remains the early detection, the accurate characterisation and the establishment of specific measures, whatever the outbreak origin [ , ] . during the covid- crisis, it had been estimated that the early detection and isolation of cases would have been more efficient to prevent infections than travel restrictions and contact reductions [ ] . the challenge of an early detection some diseases like influenza are internationally monitored [ ] while some others are subject to active surveillance in an outbreak context, like the ebola virus during the last outbreak in west africa [ ] . for such well-known diseases, the case definition is clear and an outbreak is declared when the number of cases exceeds what has been expected [ ] . this classic and passive way of detection is efficient but has numerous drawbacks as it requires an expensive and complex public health network and is often activated with a certain delay. however, when it comes to a new disease or pathologies with polymorphic or nonspecific symptoms, the case definition and the outbreak declaration threshold are subject to debate [ ] . the source of the infection can be as unpredictable as the local outbreak of anthrax in reindeers triggered by a permafrost melting [ ] or the detection of the variola virus in ancient mummies [ ] . most of the time, the high volatility lying in the infectious process complicates the record of the cases. for the same exposition, symptoms can differ according to individual variables like health status or genetic factors [ ] or to collective variables involved, for example, in the chain of transmission [ ] but also cultural or socio-economic factors: the most-disadvantaged individuals will develop more severe and hence more specific forms of the disease but will have a belated use of health care [ ] . on the other hand, systematic environment monitoring for all diseases is, for now, impossible due to technological barriers and cost challenges. experts in biodefense suggested that more targeted measurements in delimited spaces or during a large gathering of people should be the priority to improve the sensitivity and specificity of the early detection of a biological attack but, also for a natural outbreak, while reducing the cost [ ] . for example, the analysis of wastewater could be a good way to monitor the spread of sars-cov- in the community [ ] . however, these measurements should always be paired with epidemiological investigations to avoid any misinterpretation of the results [ ] . thus, for the moment, health workers would first notice an unusual event (disease or an unusual number of cases) and should be able to alert public health officials [ ] as protecting themselves from contagiousness. given the importance of early detection, training has to be a building block in infectious diseases programs in order to promote unusual event awareness [ ] . the implementation of information technologies leaves room for improvement in the outbreak detection process [ ] as more and more stakeholders of the health care system use informatics tools in their daily practice. yet, considerable efforts have been made on information technologies and electronic query of a data set to improve the efficiency of surveillance [ ] . it's an imperative prerequisite for the implementation of an electronically assisted surveillance. currently, data management tools can aggregate several inputs and are already used for epidemiological studies or trigger an alert [ ] . internet-based surveillance systems offer a logistically and economically appealing extension to this traditional surveillance approach. the results are immediate and allow access to a paucisymptomatic population or people who are not using the health care system [ ] . this methodology has been used in in china to reconstruct the progression of the sars-cov- outbreak [ ] . despite ethical concerns and regulatory barriers, social networks appear to be a powerful data collection tool and can also be used as a medium to communicate sanitary messages or alerts [ ] . however, here again, these data are subject to many biases and should be carefully interpreted. indeed, the simple act of online documentation is just an indi-rect marker of disease, and such detection system could trigger an alert just because a worldwide released blockbuster movie increases the anxiety of population or a massive hacking produces millions of requests. taken to its logical extreme, the next step of this epidemiologic watch would probably allow the contribution of the internet of things (iot) already used to follow chronic illness [ ] and for biomedical research [ ] . a smartphone or a smartwatch is now able to detect modifications of vital parameters like temperature or heart rate. the capability of crossing these types of information with, for example, geotracking solutions, could alert competent authorities on an ongoing infection and help them to implement more rapidly appropriate measures and focus on a possible source of contamination. this seems to be only the beginning of iot possibilities as the future could be even more connected with the development of projects like smart cities. nowadays, china is already using video surveillance systems to follow its citizens and detect incivilities [ ] . likewise, criminality hot spots prediction by artificial intelligence (ai) is no more fictional in los angeles [ ] . these new technologies already have some applications in epidemiology as the detection in real-time of restaurants with a higher risk to be sources of foodborne diseases [ ] . in the medical field, computers start to help clinicians in the diagnostic of mental illness through the facial expressions and head gesture in a video [ ] but could also be used to detect an infectious disease at the prodromal phase with potential highest efficiency than thermic portals. the crossing data obtained from surveillance systems combined with machine learning capabilities in prediction and diagnostic could be used to help early detection of an infectious phenomenon in a population. this early detection could guide further specific actions of screening to identify potential patients and even the source of the infection. in korea, during the covid- crisis, gps from cellular phone, credit card transaction log and video footage had been used to monitor the patient's contact and avoid further transmissions [ ] . however, the implementation of such surveillance systems is not without legal and ethical issues and should be carefully considered. the privacy policy has to be carefully examined as well as the securing of the transmission and storage of sensitive medical data, not to mention the possible human rights abuses in non-democratic countries [ ] . these concerns have already been raised during the current covid- pandemic [ ] but there is still no international consensus on the use of personal data. pending the advent of ai tools, many initiatives have been recently proposed to facilitate the investigation of epidemics in the genomic era. the whole-genome sequencing already can help to determine the origin of an outbreak and also to explain the dispersion of the pathogen through its local evolution [ ] . new tools may include online data processing [ ] up to the development of original algorithms to aggregate spatial, temporal, epidemiological and genomic data [ ] . the interactions of this technological surveillance system with the previously described classic one are also possible at the condition to continue to improve the data-sharing practices [ ] . the use of the nextstrain tool [ ] in the context of sars-cov- (https://nextstrain.org/ncov) perfectly illustrates the potential of such approaches in the context of spreading epidemics [ ] . in the years to come, the epidemiological monitoring system of our societies will probably rely on economic capacities, technical development capabilities and societal choices, with the common objective to early detect outbreaks, regardless of their causes (). even if the epidemiological monitoring is the crucial step to respond to an outbreak, detection is useless if the resources to deal with the crisis are unavailable. being pre- pared includes but is not limited to health workers being trained to detect, react and alert the health authorities: quick and reliable equipment has to be available and health workers have to be used to work with them. dedicated infrastructures have to be prepared and ready for activation and personal protective equipment (ppe), intensive care devices and treatments have to be stockpiled. the covid- crisis revealed that the lack of simple ppe put the all health system at high risk [ ] . several authorities (civilians or militaries, governmental or non-governmental entities) already have some contingency plans but the compartmentalisation between different governmental branches and the nebulous labelling of the means between natural outbreak or bioterrorist attack dedicated sometimes prevent an accurate global appreciation [ ] . as it is, and as unfortunately still demonstrated during the covid- pandemic, if an outbreak would occur, there is a risk, even for the highly trained first aid service in the most developed countries, to get in each other's way. by learning how to work together, synergies could be developed to improve health response [ ] . after the failure in the control of the last ebola virus outbreak by the who, international agencies called for better international preparation to respond to future outbreaks [ ] . thus, international and european research networks managed to improve the speed and effectiveness of the present deployment on a validated diagnostic workflow for sars-cov- [ ] . this demonstrating the response capacity that can be released through the coordinated action of academic and public laboratories like pre-pare [ ] . in , in china, coordination by the central authority allowed to deploy medical staff and built new hospitals in wuhan in a tight schedule. in europe, crisis management strategies were different among countries, but cooperation helped relieve overloaded intensive care units in some regions and saved lots of patients. in the meantime, other consortiums like grace may also help us to prepare the possible future sanitary crisis [ ] . developments of ai do not only help for early detection, but make available a full set of possibilities in crisis management to the authorities. by using classic risk analysis documentation with ai tools, it is now possible to generate predictions to improve the resilience of a system and to mitigate the risk [ ] . the preparation phase of the crisis can also benefit from ai tools by ordering the reuse of information from previous crises [ ] , improving the stockholders' training with a serious game approach [ ] , helping to design realistic plans [ ] or even boosting the discovery of new drugs [ ] . resources management can also be improved by the use of ai in terms of network structuration [ ] as well as for the mean's allocation [ ] . during the crisis, ai can also sort information from many sensors, merge it and make it relevant for the user responsible of the situation assessment [ ] , which will be helped by a decision-support system [ ] to design the best crisis response. for example, during the covid- crisis, social contact matrices had been used to project the benefit to maintain social distancing measures [ ] . over the past ten years, epidemiological and mathematical modelling data were essential for risk characterisation and management during infectious disease outbreaks [ ] but ironically, the rising power of ai systems will not erase the role of human experts [ ] . indeed, intuition and emotions are known for a long time to be part of the decision-making process [ ] . during crisis management, expert intuition developed through years of practice is described as more realistic than pure analytical thinking [ ] . moreover, both intuition and creativity are part of the problem-solving process [ ] . both experts and ai will have to learn how to work together and assist each other by developing collaborative intelligence, which will be the best way to solve complex problems (). this was experienced during the covid- crisis in which experts, assisted by simulations, had to make decisions to control the spread of a virus still little known. inevitably, to develop an anticipation-centred view required investment. the economic justification of such an investment was underlined for a long time (even before the amerithrax crisis) [ ] , and recently, a panel of usa experts recommended reinforcing the biological threat characterisation research at a federal level with clear safety, ethical and practical guidelines [ ] . splitting outbreaks into two causes is not cost-efficient and seems absurd as dangerous pathogens to human can be used for biological attacks but are first and foremost causing natural outbreaks [ ] . however, studies about the burden-adjusted research intensity showed that diseases with a greater impact are still underfunded [ ] in an economical context where citizens are more and more concerned by public expenses. indeed, if the vaccine policy implemented were economically profitable in the usa during the influenza pandemic [ ] , a sim-ilar strategy caused substantial wastage in australia [ ] . thus, authorities have to be very careful to dimension their actions appropriately, even though a delayed response is severely judged by public opinion as during the ebola outbreak [ ] . hence, authorities and experts should improve the global contingency plans, especially on catastrophic biological risks, which represent a small portion of the biological threats but with substantial potential consequence for humanity [ ] . for a health care system, the preparation for a biological attack [ , ] or a natural outbreak [ , ] is globally the same challenge. moreover, preparedness for biological attacks has a significant added value that helps to strengthen preparedness for natural outbreaks, and vice versa [ ] . it is therefore economically interesting to consider the natural biological risk and the possibility of an attack as a single threat in the preparation of the response to an infectious event with epidemic potential. the crisis generated by the numerous deaths of covid- and the lockdown of billions of people will probably trigger a new evaluation of public policies to control outbreaks with the opportunity that the public opinion will look at it through fresh eyes. indeed, the uncertainty associated with scientific knowledge often challenges decision making and opens the way to the contestation of expertise [ ] . sometimes, the best intentions can result in a health disaster, such as the deployment of a peacekeeping force and the cholera outbreak in haiti in [ ] or the project of spreading some modified mosquitoes to fight against malaria [ ] . technology allows us to modify organisms specifically leading to the reconstitution of the spanish influenza virus [ ] or to unexpected results as a test for a new poxvirus vaccine resulted with an ultra-virulent strain able to neutralise the immune system [ ] or, during research experiments mimicking natural phenomenon, the generation of highly-resistant b. anthracis spores [ ] and viruses acquiring airborne transmission [ ] . nowadays, these widely used technics appear to be almost obsolete in comparison with the new capacities of gene synthesis: a horsepox virus has been reconstructed using only internet-bought sequences [ ] , and a new bacterium has been created de novo in a laboratory [ ] . currently, the possibilities of genome editing technologies like crispr-cas seems to be limitless [ ] . some malicious scenarios have already been imagined with a genetically modified virus infecting mosquitoes able to perform gene modification of crops in a field [ ] . the south african « coast » project [ ] that aimed at developing a bacterial agent able to selectively kill a part of the population could now be a terrifying technical possibility. thus, even if applications of some of these modified organisms may be highly beneficial, as the recycling complex wastes [ ] , they are swamped in the middle of the wanderings reported by the media [ ] . due to all these miscalculations and misguidances, society lost confidence in the authorities and national programs. it leads to society-born threats with notably the growing emergence of highly antibiotic-resistant bacteria due to the improper antibiotic use [ ] or the re-emergence of nearly forgotten pathogens linked to the mistrust in public health programs like vaccination programs [ ] . this lack of confidence extends to crisis management programs and can compromise outbreak management measures the same way it happened with the ebola outbreak in [ ] or currently, with the beginning of the management of the covid- pandemic and the lockdown decision [ ] . however, during the co-vid- pandemic, the transparency about its progress reported in real-time, for the first time in the outbreaks' history, lead to better comprehension and cooperation of people [ ] . thus, every decision can have a dual nature and should be considered carefully before being implemented (). that is why, while encouraging research, technologies and their application must be controlled to avoid any misuse and major communication actions are needed to overcome the public reluctance. ethics in research and data publication must also be placed at the centre of researchers' concerns. the intricate nature of natural outbreaks and biological attacks is too important to consider them separately. to create an efficient way to detect and contain them, the first step is to anticipate them by performing continuous scientific and epidemiological monitoring. still, the most serious and unpredictable events are referred as "black swan events" and despite our inability to foresee their occurrence, knowledge keeps being the key concept to anticipate them [ ] . thus, we need to continue and intensify networking at local, regional and global levels. stakeholders from a broader range of backgrounds must be involved to monitor the evolution of threats and update existing procedures by developing concrete and immediately applicable solutions in crisis. the biological crisis is becoming a field of expertise by itself, and it is no longer enough to be a specialist in crisis management, infectious disease or epidemiology to be able to understand the implications of their own decisions fully. new technologies and ai will have more impact on crisis management, and experts will have to better work with these tools to improve their preparedness. the evolution of threats as well as technologies developments will require permanent adjustments in the strategies to optimise the public health response. communication will also be a key point of the future strategies to promote the acceptance of financial and societal investment by both the public authorities and the population and to avoid false information spreading. current covid- crisis is the first pandemic to benefit from so much advanced research and several major articles are published every day. however, sars-cov- is probably not the deadliest virus we will ever have to fight. we must learn from this crisis while 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virus disease in sierra leone initial impacts of global risk mitigation measures taken during the combatting of the covid- pandemic covid- : fighting panic with information emerging risk -conceptual definition and a relation to black swan type of events -sciencedirect phd institut de recherche biomedicale des armees departement de microbiologie et maladies infectieuses unite de bacteriologie bretigny sur orge france lionel the authors ensure the quality and integrity of their research and declare that their research the authors completed the icmje unified competing interest form (available upon request from the corresponding author), and declare no conflicts of interest. key: cord- -odzrco q authors: drake, john m.; chew, suok kai; ma, stefan title: societal learning in epidemics: intervention effectiveness during the sars outbreak in singapore date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: odzrco q background: rapid response to outbreaks of emerging infectious diseases is impeded by uncertain diagnoses and delayed communication. understanding the effect of inefficient response is a potentially important contribution of epidemic theory. to develop this understanding we studied societal learning during emerging outbreaks wherein patient removal accelerates as information is gathered and disseminated. methods and findings: we developed an extension of a standard outbreak model, the simple stochastic epidemic, which accounts for societal learning. we obtained expressions for the expected outbreak size and the distribution of epidemic duration. we found that rapid learning noticeably affects the final outbreak size even when learning exhibits diminishing returns (relaxation). as an example, we estimated the learning rate for the outbreak of severe acute respiratory syndrome (sars) in singapore. evidence for relaxation during the first eight weeks of the outbreak was inconclusive. we estimated that if societal learning had occurred at half the actual rate, the expected final size of the outbreak would have reached nearly cases, more than three times the observed number of infections. by contrast, the expected outbreak size for societal learning twice as effective was cases. conclusion: these results show that the rate of societal learning can greatly affect the final size of disease outbreaks, justifying investment in early warning systems and attentiveness to disease outbreak by both government authorities and the public. we submit that the burden of emerging infections, including the risk of a global pandemic, could be efficiently reduced by improving procedures for rapid detection of outbreaks, alerting public health officials, and aggressively educating the public at the start of an outbreak. rapidly spreading outbreaks of infectious diseases are an increasing concern for global public health [ , ] and security [ ] . emerging infections, which are typically defined as infectious diseases that have newly appeared in a population or are rapidly increasing in incidence or geographic range [ ] , are a particular concern because at the time of emergence little is known about their epidemiology, particularly pathology, symptomatology, and transmissibility. thus, the crucial tasks of assessing epidemic risk and determining what public health interventions should be taken are complicated by uncertainty that borders on complete ignorance. of course, this uncertainty is rapidly reduced as the outbreak progresses and information concerning symptoms of infection, the biology of the infectious agent, the epidemiology of transmission, and the effectiveness of health precautions and intervention is collected and disseminated. this learning process has not been considered in theories of outbreak control [ , ] or in near real-time models of emerging infections [ , ] (compare correspondence in refs [ , ] ). here, we study the collective effects of various processes (including possibly unidentified phenomena) on the change in the rate at which infectious persons are isolated. we refer to this set of processes collectively as ''societal learning''. a partial list of the processes contributing to societal learning includes isolation and identification of the infectious agent, development of tests for clinical diagnosis, disseminating information to public health and medical personnel, disseminating information to the public, and implementing public health policies including restrictions on individual movement or quarantine. disease control theory focuses on an quantity called the reproductive ratio, designated here as r at the start of the outbreak and, if changing over time, r t at time t. outbreaks are considered to be under control when r t , , implying that outbreak conditions are such that on average disease prevalence will decline. most research in theoretical epidemiology has focused on how r t is related to disease and population parameters in order to understand how to induce the change from r . , during emergence, to r t , . recent developments include techniques for estimating r from the initial stages of an outbreak [ , ] and a model to ascertain the effect of a delay between the onset of an outbreak and the implementation of public health policies aimed at controlling disease spread [ ] . here, we contribute to this developing toolbox for disease forecasting a model to understand how societal learning affects the expected final size and duration of disease outbreak. though some computational disease-specific models have recognized the importance of time-varying rates in disease spread, particularly with respect to the outbreak of sars in [ , ] (compare [ ] ), we believe this is the first analytical treatment of the concept. we also retrospectively explore the effect of societal learning during the outbreak of sars in singapore, using weekly data on the time between onset of symptoms and removal of infectious individuals. we speculate that societal learning will generally exhibit diminishing returns because increasing the removal rate becomes more difficult as individual isolation approaches a theoretical maximum rate. in such a case, the rate of societal learning is said to relax. we introduce statistical models to distinguish between relaxing and non-relaxing learning and test for relaxation during this outbreak. finally, we discuss societal and epidemiological factors that might affect societal learning, we observe that a difficult task during the early stages of an outbreak is to estimate the learning rate and suggest that the rate estimated here might be used as prior information in future outbreaks, and we conclude by recommending rapid investment in research at the time of initial detection when actions taken to reduce disease spread can be most efficient and cost effective. public health officials routinely make judgments whether or not to raise alarms about developing outbreaks. this decision is complicated by severe uncertainty during the early phases of an outbreak. further, bureaucratic inertia and the ignorance that necessarily accompanies emerging infections discourage rapid response. by contrast, false alarms resulting from hasty and premature assessment of outbreak risk can be very costly, and must be avoided if possible. understanding the role of societal learning in disease outbreaks is important for properly balancing these competing objectives. our concept of societal learning is characteristically reflected in outbreak dynamics as an increase over time in the rate at which infectious individuals are removed from circulating in the population. that is, we expect that as information about clinical symptoms, modes of transmission, the duration of incubation, etc., is collected and disseminated, the average time between the onset of symptoms and individual self-removal from the population (for instance by admission to hospital) or forced isolation (e.g., quarantine) will decline. from a dynamical perspective, we represent the average removal rate of individual cases as a function of time since the outbreak began, marked by the time at which the index case became infectious. for emerging diseases we assume that direct transmission between infected persons is the primary source of infection and that development of immunity and removing infectious individuals have negligible impact on the susceptible population. these assumptions are reasonable for outbreaks that ultimately do not infect more than a small fraction of the total population, i.e., emerging infections with relatively low prevalence. finally, we assume that transmission is a markov process, an approximation that amounts to assuming that individual infectious contacts are independent (compare [ ] ). thus, representing the individual rate of infection by the constant parameter b and the rate of removal as a function of time c(t), these assumptions imply that the growth of the epidemic is a timeinhomogeneous stochastic birth-death chain [ ] [ ] [ ] . accordingly, the change over time in the probability distribution of the number of infected individuals x is given by this model has been previously studied and applied to problems ranging from population dynamics to astronomy [ , , ] . in particular, the expected final epidemic size for this model is [ ] : where and i is the initial number of infected individuals. further, the distribution function for the duration of the outbreak with i = is: this is a very general model, as we have only specified that the transmission rate b is constant and that the rate of removal c(t) changes over time, consistent with the concept of societal learning. conceptually, we decompose the removal rate, c(t), into two components. the first component represents removal in the absence of societal learning (i.e., through unexceptional health procedures or natural recovery) and is referred to as the base removal rate. the second component is an effect of societal learning and is assumed to be additive to the base removal rate. consequently, we represent the total removal rate as function of time c(t) = a(t)+b where b is the base removal rate and a(t) is a function for the additional effect of societal learning. (refer to table for biological interpretations of parameters discussed in this section.) next, we consider two different learning scenarios. first, we suppose that societal learning is constant, i.e., that over any interval a doubling in time since the outbreak began corresponds to a doubling in the learned component of the removal rate. then, the effect due to learning can be represented as a line a(t) = a t, where a is called the 'basic learning rate', and the removal rate is linear: c (t) = a t+b. special cases of this model have a = , where there is no effect of societal learning (resulting in the simple stochastic epidemic), and b = where there is no natural recovery. the model with linear removal rate implies that the average time between infection and removal over time follows a hyperbola, g(t) = (c (t)) = (a t+b) , and that there is no upper bound to the rate at which infected individuals can be isolated; effectively, we suppose that the average time between infection and removal can be brought arbitrarily close to . for most (perhaps all) diseases this is an unreasonable assumption in the long run (though it may be a reasonable approximation at the start of an outbreak). in particular, the effect of societal learning probably decreases as the removal rate gets high and the interval between the onset of symptoms and isolation approaches a minimum biologically plausible quantity. this is a scenario in which cumulative number of removed patients is a decelerating function of time marked by diminishing returns. to incorporate such relaxation in our model we should generalize a(t) for instance a(t) = a t a , with a # . where a = this model is equivalent to the linear model discussed above. of course, there is no principled theoretical reason why a cannot be greater than . such a case is unlikely, however, and would imply acceleration not only in removals, but in the removal rate. in either case we have the general model for the removal rate c (t) = a t a +b and the associated model of the duration of the interval between onset of symptoms and removal g (t) = c (t) = (a t a +b) . in this case g(t) is approximately a power law with respect to time. we remark that learning relaxation could also result from diminishing returns on methods for disseminating information. for instance, if diagnostic information is transmitted by word-of-mouth, models for the spread of a rumor suggest that the fraction of the population which remains uninformed declines roughly logistically: first approximately proportional to the number of people who are in possession of the rumor but declining constantly over time as uninformed individuals become increasingly rare [ , ] . examples of c and c and the associated g and g are shown in figure . substituting the above model for societal learning in eqns ( ) and ( ) obtains two quantities of special interest: the expected outbreak size, and the distribution of extinction times, from which the probability density of the duration of outbreaks is obtained as the derivative with respect to time, finally, in this representation of the epidemic process, the concept of the reproductive ratio (designated by r at the beginning of the outbreak, r t thereafter) is deterministic and is given by setting this equation to one and solving for t obtains the time until the outbreak is brought under control. for the case c(t) = c (t), the time to control is given by t c = (b b)/ a .still more models could be considered. however, we report below that the final epidemic size is affected mostly by the parameter a , the rate of societal learning at the beginning of the outbreak, so that the precise shape of the removal function does not greatly matter. to test for societal learning in the outbreak of sars in singapore, we used the mean number of days between the onset of clinical symptoms and removal, by week, to fit different models for the removal process c. these data are slightly different than those that appeared previously as figure in [ ] and include some reclassified cases based on serological tests (s. ma, unpublished data). societal learning models were fit to the reciprocal of the mean of observed lags between onset of symptoms and removal c i = /g i for each week i, using nonlinear least squares regression. model fit was assessed using akaike's information criterion (aic) assuming the observations are drawn from a normal distribution with mean c i and homogeneous variance. we tested three hypotheses: (i) the null hypothesis of no base removal rate corresponding to b = ; (ii) the null hypothesis of no saturation in learning corresponding to a = ; finally, (iii) the null hypothesis of no societal learning at all is given by a = for a = . to represent the full epidemic process for sars the societal learning theory developed above must be modified to account for a significant latent period [ ] . accordingly, we adopt the familiar s-e-i-r modeling framework (figure a in [ ] ), modified to represent stochastic (markov) dynamics with time-inhomogeneous parameters. as before, we adopt the reasonable assumption that the population is large compared to the eventual size of the outbreak so that s remains constant throughout. thus, by substituting b = as and ignoring the dynamics of removed individuals, we obtain the two-compartment model in figure b , where x and y designate the classes that were formerly e and i. finally, consistent with our earlier definition of societal learning, we allow the removal rate c to be a function of time, designated c(t). we assume that each state variable x and y can take only integer values (demographic stochasticity) and that individual transitions between classes are markovian. this model is a pair of coupled birth-death chains and is a generalization of the model studied in the earlier part of this paper. we obtained parameter values for these simulations as follows. using a bayesian approach, lipsitch et al. [ ] determined that the basic reproductive ratio (r ) for this outbreak was in the range [ . , . ] . these values accord well with the likelihood-based estimate of wallinga and teunis [ ] , who report a point estimate ofr ~ : and % confidence interval [ . , . ]. interpreting the estimates of lipsitch et al. [ ] as the rate of secondary infection in a wholly susceptible population, r is related to our parameters through the relation b = r c . recognizing that uncertainty in both r and c will affect the accuracy of model projections we obtain an upper limit on b (not a confidence interval because the parameters are not independent) from b + = r + c + and a lower limit from b = r c , where (+) and ( ) indicate the upper and lower limits on the estimate intervals for the respective parameters. to obtain a central (''best'') estimate of b we take the midpoint of the range [ . , . ] = . and multiply by the point estimate of our regressionĉ ~ : to obtainb~ : . throughout, we used the point estimate from the regression analysis above ( . , see also results) for the basic learning rate after dividing by seven to convert from weeks to days: a = . . as the learning rate never declined over the course of this outbreak, no relaxation was included in the model. finally, the transition rate between latent and infectious individuals (g) is approximately equal to the reciprocal of the duration of the incubation period. we used a transition rate of . d , corresponding to an average incubation period of approximately . . days. this is roughly consistent with, e.g., the ranges of estimates compiled by the world health organization (table in [ ] ) and the estimate ( . d) and % confidence interval [ . , . ] reported by donnelly et al. [ ] , but slightly larger than the estimate of . d ( % confidence interval: [ . , . ] ) obtained by kuk and ma [ ] under the assumption that incubation times are drawn from a weibull distribution. retrospectively comparing model-based estimates of the expected outbreak size with the observed cases (a partially circular comparison to begin with) is complicated by the fact that the number of initially infected individuals (the initial condition) is not defined by the model but must be asserted. one possibility is to assume that the outbreak begins with the index patient (i = ), but then the outbreak size of the theoretical model is biased by a significant portion of outbreaks that fail due to stochastic fadeout [ ] . an alternative is to compare the observed outbreak size with the theoretical distribution of outbreak sizes for outbreaks initialized at i = conditioned on a 'major' or 'observable' outbreak occurring. however, this simply pushes back the problem of specifying the initial condition as some number of cases must be in four compartments corresponding to susceptible, exposed, infectious, and removed (or recovered) individuals. the rate at which individuals move from susceptible to exposed is according to massaction dynamics with proportionality constant a. individuals move from exposed to infectious at rate g and from infectious to removed at rate c. (b) by assuming that the number of susceptible individuals is approximately constant (an appropriate approximation for outbreaks in which prevalence is never a large fraction of the total population) we introduce the new variable b = as and reduce the four-compartment s-e-i-r model to a two-compartment model, designated here by the state variables x and y. doi: . /journal.pone. .g specified to correspond with 'major' or 'observable'. we adopted a third alternative. we reasoned that the first time medical personnel are alerted to the fact that there might be an emerging outbreak is the time that the index patient is observed to be infectious, corresponding to the removal of the patient from the population. at this time, the patient has infected an expected additional r individuals (by the definition of r ) and these infectious, or soon-to-be-infectious individuals are circulating in the susceptible population. we refer to this as the 'second generation initialization'. alternatively, the hospitalization of one individual with an anomalous infection is unlikely to attract significant attention. consideration of a possible outbreak more likely corresponds to the admittance in quick succession of several patients with anomalous infections, that is when the second generation of infected individuals is isolated and a third generation of individuals is infected. this is the 'third generation initialization'. accordingly, we simulated two distributions of final outbreak sizes. first we initialized at i = , which is the midpoint of the estimated interval for r identified by lipsitch et al. [ ] , i ~r ~ : , rounded to the nearest integer, corresponding to second generation initialization. second, we initialized at i = , which is the rounded value of the expected number of infected individuals in the third generation, i ~r & : . to understand the importance of societal learning during the actual outbreak in singapore, we simulated , iterations of the stochastic s-e-i-r model described above using gillespie's direct method [ ] with double and half the estimated basic learning rate while all other parameters were set to their best estimates and with initial condition i = . empirical quantiles and the coefficient of variation (a measure of dispersion, the ratio of the standard deviation to the mean) were used to summarize the distributional properties of simulations. to look at the effects of societal learning and relaxation on outbreak control, we studied the average outbreak size over a range of scenarios (figure ). for simplicity, we assumed b = throughout and compared different versions of the removal and learning process by tuning the parameters for the basic learning rate (a ) and the relaxation rate (a ). the temporal resolution of this model is therefore not explicit. thus, for concreteness assume that all rates are in units of days and that the baseline infectious period (g = c ) is d. then, the basic reproductive ratio is r ~b =c~ and we obtained the average epidemic size from eqn these ranges illustrate the range of cases between extremes in which societal learning is slow and relaxation is rapid (practically no effect of societal learning) and where societal learning is fast and no relaxation occurs at all (similar to the outbreak of sars). figure shows that a , the basic rate of societal learning, can be important for controlling outbreaks. the effect of relaxation can be examined by comparing the average outbreak size at various values of a , with the value at a = , where there is no relaxation. evidently, relaxation must be extremely rapid (around a = . ) for the effect to be noticeable. of course, this phenomenon is accentuated by its interaction with the basic societal learning rate so that if learning is extremely slow the effect of relaxation becomes more important. the observed removal rate increased consistently over the course of the sars outbreak in singapore (figure ) . we found no effect of relaxation in the rate of societal learning, although there was strong evidence for both a baseline removal rate and an effect of learning (table ) . we first fit the full model, but failed to reject the null hypothesis of no relaxation. consequently, we fit the reduced model with a constant learning rate, which is equivalent to the full model with exponential parameter a = . in this model, both the base removal and learning parameters were highly significantly different than zero (base: p = . ; learning rate: p, . ). we remark that the reciprocal of the estimated base removal rate (b) can be interpreted as the duration of the infectious period in the absence of special intervention. accordingly, we obtained an estimate of . d ( % confidence interval: [ . , . ] , obtained by inverting the confidence limits reported in table ). inspection of the plots in figure suggests that the observation in week may be of exceptional importance to the final model. in terms of regression diagnostics, it may have high leverage (greatly affecting the uncertainty in parameter estimates) and high influence (greatly affecting the estimates themselves). a plot of standardized residuals versus leverage for the reduced model shows that this point is indeed matched by only one other point (week ) for leverage ( figure ). overlaying contour intervals for cook's distance, a measure of influence, shows that this point also has high influence. accordingly, so that the reader may compare we re-fit both the full and reduced models after dropping this point ( table ). in this case the aic difference is less than two, so that neither model is better supported by the data. further while the maximum likelihood estimate for a is quite low (a = . ; to be interpreted as considerable relaxation), the confidence interval barely fails to include , so the evidence is not conclusive. to study the effect of the duration of the latent period on average outbreak size, we simulated iterations of the model at each of different durations for the average latent period. the average outbreak size decreased with the duration of the latent period as shown in figure . the average size of simulated outbreaks initiated with the second generation initialization condition (i = ) was cases. the . % and . % quantiles were and cases, respectively. the coefficient of variation in the final outbreak size was . . the average size of simulated outbreaks initiated with the third generation initialization condition (i = ) was cases. the . % and . % quantiles were and cases, respectively, with coefficient of variation . . thus, the observed total outbreak size ( cases; [ ] ) is consistent with either the second or the third generation initialization conditions. outbreak simulations in which learning occurred at half the observed rate had average final outbreak size of cases while outbreak simulations in which learning occurred at twice the observed rate had average final outbreak size of cases. we found little evidence for relaxation in the learning rate for sars in singapore. first, restricting our discussion to the analysis with all data, we find that the maximum likelihood estimate of the relaxation parameter is extraordinarily close to one (differing by . %), perfect non-relaxation. admittedly, the confidence interval on this parameter is large. one interprets this to mean that the vigilance of the public health community as a whole continued throughout the outbreak and that improvement in intervention effectiveness continued unabated. however, we also found that one relatively uncertain data point was important to this analysis (week ). whether this point should be excluded from interpretation is unclear. on one hand, it is a real observation and (because of its high influence) is known to contain a great deal of information. therefore, one is inclined to allow this observation considerable weight. on the other hand, its importance, especially at the end of the data series is suspicious. if we exclude this point from analysis post hoc, we find that we are unable to make any strong conclusions at all. what most likely occurred is that the distribution of average infectious period at the point where the outbreak was rapidly brought under control was highly dispersed (high variance) and highly skewed. accordingly, the mean removal rate probably does relax, but the data that were available to this study are too aggregated to make this inference conclusively. it is unknown if the rate of learning estimated in this study is unique to this outbreak or if it might be more representative. we remark that both parameters in the learning rate model are readily interpreted, and that theoretical effects of improvement in surveillance, mechanisms for informing public health personnel and the public, and rapid research response could be studied by extending this simple model to represent more realistically the effects of alternative policies as covariates. the final size of an outbreak is greatly affected by transmission events early during the outbreak process. outbreaks can be curtailed when public health interventions are rapid and efficient. but the severity of an outbreak is often unclear during these initial stages of transmission when intervention can be most effective [ , ] . further, there are limits to how quickly diagnostic information about an emerging infection can be obtained and disseminated to health care providers. this is not the first model to consider the effect of changes in the removal rate (e.g., [ , ] ). however, in contrast to earlier studies, we first explicitly considered societal learning parametrically in a theoretical model. our model also more realistically represents the ramping up of intervention in contrast to models that simply have ''before control'' and ''after control'' regimes (e.g., [ ] ). we showed that the final outbreak size decreases rapidly with a modest investment in learning. we also found strong evidence of learning in data from the outbreak of sars in singapore. public health interventions for sars include encouragement to report to hospital rapidly after the onset of clinical symptoms, contact tracing for confirmed and suspected cases, and quarantine, monitoring, and restricting the travel of contacts [ , ] . we believe these interventions were highly effective at reducing the final size of the sars outbreak. a limitation of this analysis is that we only consider temporal changes in removal, though information dissemination and public concern almost certainly led to a decline in transmission (b ) too [ ] . unfortunately, this effect is much more difficult to independently estimate and must instead be inferred from the information provided by the epidemic curve together with observations of the onset-of-symptoms to removal interval. in general, however, the model studied here (eqn ) and its solution (eqn ) will also apply to this situation and can be used wherever such data are available. the effects of biological and social factors that might bring about changes in transmissibility is an important area for further theoretical research. our estimate of the duration of the infectious period ( . d, % ci: [ . , . ] ) is consistent with measures of viral shedding, obtained by peiris et al. [ ] using quantitative reverse transcriptase on sequential nasopharyngeal aspirates/throat and nose swabs (npa/tns), in which maximum virus excretion occurs around the tenth day of illness (compare also [ ] ). indeed, only about % of npa/tns continued to test positive by the third week since the onset of symptoms [ ] . figure . relationship between the average latent period (x-axis) and average total outbreak size in simulations (y-axis). latent period is log transformed (to illustrate a wide range of possible values) and ranges from d to d (, y). the approximate location of sars is indicated by the arrow. doi: . /journal.pone. .g these results underscore the value of immediate action at the start of an outbreak (high a ). the processes considered to contribute to societal learning include such publicly visible actions as declaring a state of emergency, global health alert, or (minimally) disseminating information to the public. the societal and economic costs of mistakenly declaring a state of emergency can be tremendous, but are probably small in comparison to the costs of failing to intervene in a major preventable outbreak. thus, we echo anderson et al. [ ] in concluding that the major lessons of the outbreak of sars are to improve surveillance and detection, including real-time data collection; develop capability for rapid response by the research community; and devise mechanisms for immediate implementation of effective interventions. important topics for research include estimating the effect of learning on transmission (the parameter b in the model), and identifying the different activities that contribute to learning (a ) and relaxation (a ) and their costs. then, a cost sensitive model should be developed to balance the competing goals of raising unnecessary alarm and preventing a major outbreak. such a model would be most useful if it had reference points that would trigger alerts at different levels (i.e., to function as an early warning system) and could guide intervention efforts. such a model would not need to be purely economical, but could incorporate loss of human life and well-being as constraints on the decision set. of course, learning rates (and possibly relaxation) will vary geographically reflecting different societal conditions, research institutions, levels of emergency preparedness, etc. further, these phenomena may also differ among emerging diseases, for instance depending on their similarity to diseases that are well understood or their resistance to laboratory isolation and characterization. despite these limitations, we suggest that our estimate of the basic learning rate ( . d ; % confidence interval [ . , . ]) could be used as prior information during future outbreaks. the difficulty of forecasting the total epidemic curve at an early stage is well appreciated [ ] . by eliminating the need to simultaneously estimate highly correlated parameters, a good understanding of the dynamical consequences of public health response would enable real-time modeling to focus on estimating disease parameters like transmission rates [ ] . then, estimated disease components and known or conjectured models for response, including models of societal learning, could be integrated in a single modeling framework for projections. a systematic analytic approach to pandemic influenza preparedness planning heading off an influenza pandemic factors in the emergence of infectious diseases infectious diseases of humans: dynamics and control epidemic modelling: an introduction sars, lay epidemiology, and fear severe acute respiratory syndrome epidemic in asia sars epidemiology modeling (reply) estimation and inference of r of an infectious pathogen by a removal method appropriate models for the management of infectious diseases limits to forecasting precision for outbreaks of directly transmitted diseased transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions transmission dynamics and control of acute severe respiratory syndrome a branching mode for the spread of infectious animal diseases in varying environments realistic distributions of infectious periods in epidemic models: changing patterns of persistence and dynamics on the generalized birth-and-death process the elements of stochastic processes with applications to the natural sciences uncertainty in sars epidemiology stochastic processes and population growth all-or-none elements and mathematical models for sociologists different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures consensus document on the epidemiology of severe acute respiratory syndrome (sars) epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong the estimation of sars incubation distribution from serial interval data using a convolution likelihood superspreading and the effect of individual variation on disease emergence a general method for numerically simulating the stochastic time evolution of coupled chemical reactions summary of probable sars cases with onset of illness from public health measures implemented during the sars outbreak in singapore clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study epidemiology, transmission dynamics and control of sars: the - epidemic we thank members of the penn state center for infectious disease dynamics for helpful discussion of this study. a referee suggested fitting the model to the data without the observation at week . key: cord- -b z zb t authors: cruickshank, marilyn; shaban, ramon z. title: covid‐ : lessons to be learnt from a once‐in‐a‐century global pandemic date: - - journal: j clin nurs doi: . /jocn. sha: doc_id: cord_uid: b z zb t the year will mark a once‐in‐a‐century global event: the outbreak and pandemic of covid‐ . on the december the world health organization (who) reported a cluster of pneumonia‐like cases of a novel coronavirus zoonosis in wuhan city, hubei province, china. the outbreak was due to a new or novel coronavirus, which would later be called severe acute respiratory syndrome coronavirus (sars‐cov‐ ). economists and the general public-in a way that few world-wide health events have done, and has dominated -hour news cycles for months. the headlines and bulletins for all news and media channels have led with updates on the spread of covid- , moving from the initial epicentre in china to northern italy, iran, spain, the united kingdom, and more recently, the usa. the global and regional tally of the number of confirmed cases and the horrific death toll seem incomprehensible, and are expressed in numbers so huge that we need to use a log scale to record them. terms such as 'self-isolation', 'containment', 'quarantine', 'flattening the curve', 'social distancing', 'lock down', 'elimination' and 'home schooling' are now part of our everyday lexicon. in a few short weeks, we have witnessed extraordinary social and economic disruption in global efforts to stop the spread of covid- . those who can, work from home. those that can't, often work in situations where social distancing can be difficult, and thus potential exposure to infected persons can be high. millions of highly skilled full-time employees have joined with the casually employed and contractors for state and philanthropic emergency relief for sustenance. governments around the world have introduced economic stimulus programs to avoid recession or depression of their economies (cavanough & tai, ) . other strategies, once unimaginable, have been implemented to delay the spread of the disease such as ensconcing the homeless in hotels, closing of state borders, and the abrupt suspension of air travel. occupations often ignored or taken for granted such as cleaners and supermarket stockists have been relegated to an essential services status. while the speed and consequences of the covid- pandemic may seem to have come out of nowhere, for those who work in infection prevention and control (ipc), it comes as no surprise or shock. sars-cov- is not the first coronavirus infection in humans. it was not that long ago that we had the outbreak and elimination of severe acute respiratory syndrome coronavirus (sars-cov- ) in / , and the outbreak middle east respiratory syndrome coronavirus (mers-cov) in which has occurred sporadically ever since (de wit, van doremalen, falzarano, & munster, ; yin & wunderink, ) . the global pandemic of covid- has resulted in more than . million cases and , deaths (center for systems science and engineering, ), eclipsing the previous two coronavirus outbreaks. in comparison, there were cases and deaths with the sars-cov- accepted article outbreak and the mers-cov outbreak has reported , cases and deaths (mahase, ) . a pandemic such as covid- has always been on the radar; as in not if, but when. many countries have been preparing for an influenza-type pandemic for some years, although some countries have been better prepared than others. the outbreaks of sars-cov- , mers-cov, ebola and h n , and the lessons learned from each have been noteworthy: importance of good hygiene (hands and surroundings), testing when possible, isolation of those infected, personal protection equipment for health care workers and others involved in the care of the infected, expurgated search for treatments, and vaccines. the global health security (ghs) index published a report on the global health security capabilities of countries, including assessment of pandemic preparedness (cameron et al., ) . in this report, australia ranked th on the ghs index score behind the usa, the uk and the netherlands. these rankings will undoubtedly be subject to scrutiny and review given the success, or otherwise, of national responses to covid- . one of the complexities of mounting national responses to such a pandemic is that the lead is taken by political leaders on advice from health experts, and assisted by health policy makers. it can be challenging for political leaders to understand the need to be adaptable, agile and quick to change tack, should information or circumstances demand it in order to respond adequately. even more challenging is that what we 'know' today may and will change tomorrow as new evidence emerges. balancing strategies to achieve good health outcomes with the opposing economic consequences of those strategies is also problematic in dealing with outbreaks of infectious diseases. the economic consequences of managing outbreaks in a single region or jurisdiction are can be quote problematic. doing so on a global scale is, however, quite something else, with grave predictions for the future of the global economy. in may of the international monetary fund reported that it has secured more than $ trillion dollars in lending capacity to service unprecedented emergency financing requests from over countries (georgieva, ) . covid- is a new pathogen, and the race and thirst for knowledge about covid- is like nothing we have ever seen. while there is much that we don't know about covid- , there is much we do know about coronaviruses and respiratory infections more broadly. this can help us prevent the spread, plan for a pandemic and manage infected patients while we this article is protected by copyright. all rights reserved seek a treatment or even a cure and, importantly, a vaccine. in ipc we know what works to prevent and control the spread of contagion based on key principles and concepts. most of these principles have not changed for centuries, are taught to children in formative years, and form the backbone of contemporary care. we use them together with the emerging and available evidence and considering our experiences with other outbreaks. arguably the most notable of these is the 'chain of infection' and that our effort to arrest and contain an outbreak is based on breaking the chain. fundamental principles such as hand hygiene, respiratory etiquette, and staying home if unwell are core to the response to covid- . healthcare workers are well versed in the use of isolation to prevent spread of infection. education and training of healthcare workers in the use of personal protection equipment such as masks, gloves, face shields and gowns is mandatory in many settings, even before the outbreak of covid- . it appears that much of the anxiety and stress associated with the outbreak among healthcare workers has been not only the ready supply of the equipment but also relative unfamiliarity and lack of confidence in using it correctly. we continue to rely on the available and relevant evidence, guided by basic infection control principles that we know work. however, as new information emerges it can be confusing as our experience changes, especially if the new information is conflicting. it can be challenging for political leaders to understand the need to be adaptable, agile and quick to change tack, should information or circumstances demand it. even more challenging is that what we 'know' today may and will change tomorrow as new evidence emerges. some of this includes the extent to which humans develop a protective immune response to covid- via antibodies (the world health organization, ), the extent to which asymptomatic people can spread the infection (bai et al., ; kimball et al., ) , whether the use of face masks by asymptomatic members of the community can affect transmission (feng et al., ) , the significance of the loss of smell as an early predictive or differential symptom of disease, the role of herd immunity and whether infection confers immunity, and if so, for how long. modelling by epidemiologists can help with devising strategies for containment, mitigation and elimination. such modelling draws on the limited available but emerging data and promulgates scenarios based on a range of varying assumptions. while useful, modelling accepted article will never give all us the answers. rather, it gives us insight into the future might look like given particular circumstances. models include projected outcomes with no containment measures in place; others with changing elements of containment in place over time. modelling for the worst-case scenario is important in the early days of a pandemic to understand what resources and capabilities might be required. . not all countries, or even geographic areas within a country, will have the same transmission course due to demographics, health system, and prevention responses, although many are following similar trajectories. containment, mitigation and elimination are different phases in outbreak management and disease control. the central aim for all is to arrest community transmission and to break the chain of infection. arresting community transmission is an essential strategy required to give health services the ability to develop capacity such as freeing up hospital beds or increasing resources and staffing for intensive care services. once the number of new cases have stabilised, there can be a move to mitigation strategies which might not necessarily stop the spread, but can help to protect those most at risk of severe disease by isolating suspected cases and their households, while continuing to implement social distancing measures for older people and others at high risk. mitigation strategies also require planning during the suppression stages. these include increased surveillance through testing in the wider community, better and more efficient contact tracing, and concerted responses to outbreaks when they emerge. the aim of all these strategies is to keep each infected accepted article person from infecting fewer than one other person. until this can be achieved, the infection will continue to spread. there has been much made of the concept that 'we are all in this together' as though everyone has equal risk of acquiring and surviving the virus. in reality, some people are more likely than others to be infected and typically older people and those with chronic illness such as diabetes, hypertension and respiratory disease will be associated with higher morbidity and mortality. other populations at high risk of infection include those living and working in confined spaces such as nursing homes and prisons, cruise liners, refugee camps, people travelling on crowded public transport, and even politicians meeting and greeting. of great concern are the socioeconomically disadvantaged communities around the world where individuals with poor health status, poor access to health services, and are subject to conscious and unconscious discrimination receive poorer quality or delayed treatment (ahmed, ahmed, pissarides, & stiglitz, ) . the lack of access to healthcare will mean more morbidity and more mortality. individuals and families in low-income communities may be unable to practice social distancing and self-quarantine, and are often forced to choose between their health and income (alston, ; noppert, ) . non-health related consequences of covid- , such as financial economic recession and depression, will ricochet around the world with lasting socioeconomic effects for decades to come. as such, the containment and elimination of covid- is vital for local, regional and global prosperity, with infection control professionals and other healthcare workers at the forefront of these efforts. to do so we implement interventions to break the chain of infection, and draw on our collective to provide the best possible preventative care for communities and populations. while covid- is new, the way in which we response to it in many ways is not. large-scale infectious diseases outbreaks are with us to stay. while this time, so far, some countries have escaped the severity and spread seen in europe and north america (probably because of rapid action in closing boarders, initiating strict restrictions to movement and initiating test and trace protocols), no country can be complacent. some measures have stood some countries in good stead: healthcare systems providing universal access to medical and hospital services; high-level national committees composed of senior this article is protected by copyright. all rights reserved public health officials that provide advice to state, territory and national health policy makers; and a responsive citizenship. over the coming months and years, there will be lessons learned which will require thoughtful analysis of how we can further improve the care we provide to patients and communities whilst also stopping community spread. better understanding of why our infection control experts were called to implement and oversee what should have long been standard practice-most notably familiarity with person protective equipment based its systematic use, and hospital cleaning-is required. a better understanding of, and resolution to, the barriers to recognition of nurse leaders in events like these, in particular those in infection prevention and control, is also required given that outbreaks of infectious diseases are here to stay and the fundamental role that nurses play in outbreak responses now and into the future. the authors declare no conflicts of interest. why inequality could spread covid- responses to covid- are failing people in poverty worldwide" -un human rights expert [press release presumed asymptomatic carrier transmission of covid- global health security index / / ). a timeline of global economic responses to covid- global cases a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster sars and mers: recent insights into emerging coronaviruses rational use of face masks in the covid- pandemic confronting the crisis: priorities for the global economy first known person-to-person transmission of severe acute respiratory syndrome coronavirus (sars-cov- ) in the usa initial investigation of transmission of covid- among crew members during quarantine of a cruise ship -yokohama this article is protected by copyright. all rights reserved key: cord- - ofgekoj authors: donthu, naveen; gustafsson, anders title: effects of covid- on business and research date: - - journal: j bus res doi: . /j.jbusres. . . sha: doc_id: cord_uid: ofgekoj abstract the covid- outbreak is a sharp reminder that pandemics, like other rarely occurring catastrophes, have happened in the past and will continue to happen in the future. even if we cannot prevent dangerous viruses from emerging, we should prepare to dampen their effects on society. the current outbreak has had severe economic consequences across the globe, and it does not look like any country will be unaffected. this not only has consequences for the economy; all of society is affected, which has led to dramatic changes in how businesses act and consumers behave. this special issue is a global effort to address some of the pandemic-related issues affecting society. in total, there are papers that cover different industry sectors (e.g., tourism, retail, higher education), changes in consumer behavior and businesses, ethical issues, and aspects related to employees and leadership. there has been a long history of fear of pandemic outbreaks. the discussion has not focused on whether there will be an outbreak, but when new outbreaks will happen (stöhr & esvald, ) . the events leading to influenza pandemics are recurring biological phenomena and cannot realistically be prevented. pandemics seem to occur at - -year intervals as a result of the emergence of new virus subtypes from virus re-assortment (potter, ) . as the global population increases and we need to live closer to animals, it is likely that the transfer of new viruses to the human population will occur even more frequently. all our society can do is take preventive measures so that we are able to act quickly once we suspect an outbreak. we should also make an effort to learn from the consequences of pandemic outbreaks to prepare our societies for if-and, more likely, when-this happens again. as we are in the middle of a pandemic outbreak, it is very difficult to estimate its longterm effects. although society has been hit by several pandemics in the past, it is difficult to estimate the long-term economic, behavioral, or societal consequences as these aspects have not been studied to a great extent in the past. the limited studies that do exist indicate that the major historical pandemics of the last millennium have typically been associated with subsequent low returns on assets (jorda, singh, & taylor, ) . for a period after a pandemic, we tend to become less interested in investing and more interested in saving our capital, resulting in reduced economic growth. given the current situation, in which saving capital means negative returns, it is not at all certain that we will be as conservative as we have been in the past. behavioral changes related to pandemic outbreaks seem to be connected with personal protection (funk, gilad, watkins, & jansen, ), such as the use of face masks, rather than general behavior changes. our lives, as humans in a modern society, seem to be more centered around convenience than around worrying about what might happen in the future. on a societal level, we seem to be completely unprepared for large-scale of outbreaks. our societies are more open than ever; we rely on the importing of important products, such as food, energy, and medical equipment, rather than sourcing them from close to where they are needed; and there are limited efforts to prepare for pandemic outbreaks. the guiding principle of our society seems to be efficiency and economic gain rather than safety. this may change after the current outbreak. it is also important to point out that the principles (eg. openness and global trade) on which society is based have lifted a large number of countries around the globe out of poverty and produced well-developed economies. it is not unlikely that our societies will backoff some of them leading to more poverty in the world. the covid- pandemic outbreak has forced many businesses to close, leading to an unprecedented disruption of commerce in most industry sectors. retailers and brands face many short-term challenges, such as those related to health and safety, the supply chain, the workforce, cash flow, consumer demand, sales, and marketing. however, successfully navigating these challenges will not guarantee a promising future, or any future at all. this is because once we get through this pandemic, we will emerge in a very different world compared to the one before the outbreak. many markets, especially in the fields of tourism and hospitality, no longer exist. all organizational functions are intended to prioritize and optimize spending or postpone tasks that will not bring value in the current environment. companies, especially start-ups, have implemented an indefinite hiring freeze. at the same time, online communication, online entertainment, and online shopping are seeing unprecedented growth. as research indicates that pandemics are reoccurring events, it is very likely that we will see another outbreak in our lifetime. it is apparent to anyone that the current pandemic has had enormous-but hopefully short-term-effects on all our lives. countries have closed their borders, limited the movement of their citizens, and even confined citizens in quarantine within their homes for weeks. this is a rather unique occurrence, as we are used to freedom of movement, but in the midst of the pandemic outbreak, people have been fined just for being outside. although our societies seem to be very accepting of these limitations and condemn people that do not follow the rules, but we need to ask ourselves how this will affect the views of our society (e.g., views regarding freedom, healthcare, government intervention). we should also be aware that infrastructure and routines to monitor citizens in order to limit the spread of the virus have been rolled out, and so we should ask ourselves how accepting we will be of monitoring in the future. we must realize that once these systems are in place, it is highly unlikely that they will be rolled back. furthermore, in some countries, the ruling politicians have taken advantage of this situation and increased their control over the state, suppressing opposing opinions and thus jeopardizing democratic systems. some of the worst examples are turkmenistan, which has banned the use of the word "corona," and hungary, which is letting viktor orbán rule by decree indefinitely. as previously mentioned, people have been confined to their homes. there has also been a constant stream of news on this invisible external threat from which we cannot protect ourselves. we have been occupied trying to figure out how best to protect ourselves and our loved ones. on top of that, many feel pressure due to losing their jobs or due to working in close proximity to potentially infected people, as society depends on them fulfilling their duty. the consequences of the pandemic outbreak have hit various sectors of society in different ways. people that are working in sectors connected to healthcare must endure endless tasks and very long working days. additionally, people are losing their jobs at rates we have not seen since the great depression of the s. the sectors that have seen the largest increases in unemployment are those that are hedonic in nature and require the physical presence of the customer (e.g., hospitality, tourism, and entertainment), as demand for these services has ceased to exist. the employees in these sectors tend to be younger and female. past experience also indicates that once someone is outside the job market, it is very difficult to get back in as they will face more competition that may be more competent. all countries that can are trying to stimulate their economies to keep as much as possible of their necessary infrastructure intact and to keep citizens productive or ready to become productive once the pandemic has been overcome. in order to keep society from deteriorating, people not only need jobs or a way to support themselves but also need access to what they view as necessary products and services. if this infrastructure does not exist, people start to behave in what is considered uncivil behavior (e.g., hording or looting). countries around the globe have adopted very different approaches to handle the current stress on the job markets and infrastructure. some countries have chosen to support businesses in order to help them keep the workforce intact, but others with less financial strength cannot do the same. countries also have directly supported their citizens in various ways. there is an enormous body of rich information that researchers can collect to determine the best approaches for when when and if a major disaster happens in the future. around the globe, societies are in lockdown, and citizens are asked to respect social distance and stay at home. as we are social beings, isolation may be harmful for us (cacioppo & hawkley, ). feelings of loneliness have, among other things, been connected to poorer cognitive performance, negativity, depression, and sensitivity to social threats. there are indications that this is happening during the current pandemic, as there has been an increase in domestic violence, quarrels among neighbors, and an increase in the sales of firearms (campbell, ) . however, we have also seen an increase in other, more positive types of behavior caused by social distancing that have not been researched. people have started to nest, develop new skills, and take better care of where they live. for instance, they may learn how to bake, try to get fit, do a puzzle, or read more. there has also been an increase in purchases of cleaning products, and more trash is being recycled. at the same time, we are eating more junk food and cleaning ourselves less. people are also stockpiling essentials, panic buying, and escaping to rural areas. this is an indication that what is happening to us and our behaviors is complex, and it would be interesting to study this phenomenon further. another consequence of the lockdowns is the extreme increase in the usage of internet and social media. previous research has indicated that humans who feel lonely tend to use social media more and, in some cases, even prefer social media over physical interaction (nowland, necka, & cacioppo, ) . social media also may bring out the worst in us through trolling or sharing of fake news. this is, to some degree, not as damaging as the "real life" is lived in the physical world and the internet is an "add on" with, in most cases, limited impact on the physical world. by this, we are able to compartmentalize and distinguish what matters and what does not matter. however, the current situation has made social media the main mode of contacting or socializing with others. in many cases, the internet is at present also the main way to get essential supplies and receive essential services, like seeing a doctor. the question, then, is what happens to us when the "real life" is lived online and becomes a way to escape the physical world? as humans, we rely to a large degree on our senses; we are built to use them in all situations of life. thus, we rely on them heavily when making decisions. however, the current isolation is depriving us of our senses, as we are not exposed to as many stimuli as normal situation. thus, we are, in a sense, being deprived of stimulation. we are also being told by authorities not to use our senses; we should not touch anything, wear a mask, or get close to other humans. thus, what happens once our societies open up? how long will this fear of using our senses linger, and will we be over-cautious for a while or may we try to compensate as we have to some degree been deprived of using them? these are just some aspects of consumer behavior; many more are covered by this special issue. the covid- outbreak is likely to cause bankruptcy for many well-known brands in many industries as consumers stay at home and economies are shut down (tucker, ) . in the us, famous companies such as sears, jcpenney, neiman marcus, hertz, and j. crew are under enormous financial pressure. the travel industry is deeply affected; % of hotel rooms are empty (asmelash & cooper, ) , airlines cut their workforce by %, and tourism destinations are likely to see no profits in . furthermore, expos, conferences, sporting events, and other large gatherings as well as cultural establishments such as galleries and museums have been abruptly called off. consulting in general and personal services, like hairdressers, gyms, and taxis, have also come to a standstill due to lockdowns. finally, important industries like the car, truck, and electronics industries have abruptly closed (although they started to open up two months after their closure). there are an endless number of questions we could ask ourselves in connection to this rather abrupt close-down. for instance, how do we take care of employees in such situations? why are companies not better prepared to handle such situations (e.g., putting aside earnings or thinking of alternative sources of income)? how are the companies and even countries using the current situation to enhance their competitive situation? one of the countries that seem to be using the situation is china that is buying european based infrastructure and technology (rapoza, ) . while some businesses are struggling, some businesses are thriving. this is true for a number of internet-based businesses, such as those related to online entertainment, food delivery, online shopping, online education, and solutions for remote work. people have also changed their consumption patterns, increasing the demand for takeout, snacks, and alcohol as well as cleaning products as we spend more time in our homes. other industries that are doing well are those related to healthcare and medication as well as herbs and vitamins. typically, when studying markets, it is assumed that they are static, a natural conclusion since they tend to change slowly. however, if there is one thing the covid- outbreak has shown us, it is that markets are dynamic (jaworski, kohli, & sahay, ) and can move rapidly. furthermore, a market is not just a firm; it is a network of actors (i.e., firms, customers, public organizations) acting in accordance with a set of norms. these systems are sometimes referred to as dynamic ecosystems that exist to generate value (vargo & lusch, ) . the covid- outbreak poses a unique opportunity to study how markets are created and how they disappear within a very limited time span. it would also be interesting to explore whether the disappearance of one solution for a market may be replaced by another (e.g., combustion engines for electric or physical teaching for online teaching). based on past experiences, we have become more conservative and protective after a pandemic outbreak. we save resources in order to be prepared if the unthinkable happens again. countries are starting to stockpile things like food, equipment, and medicine or prepare to produce them locally. it is also essential for larger global firms to have reliable supply chains that do not break. consequently, it is very likely that this pandemic will make these firms rethink their supply chains and, probably, move supply chains closer to where they are needed in order to avoid stopping production in the future. furthermore, authorities have implied that other humans from other countries are dangerous as they may carry the virus. a closed border implies that the threat is from the outside. in addition, international flights are not likely to be an option for many in the coming years. together, these circumstances mean that countries may become more nationalistic and less globalized. this may be a dangerous development, as long-term protection from the consequences of a pandemic outbreak is likely to require global effort and sharing of resources. such cooperation is also key to tackle other global challenges that we may face in the future. in this special issue, we have invited scholars from different areas of business and management to write brief papers on various aspects of the effects of the covid- pandemic. in total, there are articles in the special issue, which are summarized below. the first contribution, by jagdish sheth, is titled "impact of covid- on consumer behavior: will the old habits return or die?" it explores how the current pandemic has affected several aspects of consumers' lives, ranging from personal mobility to retail shopping, attendance at major life events like marriage ceremonies, having children, and relocation. the author investigates four contexts of construed consumer behavior, namely social context, technology, coworking spaces, and natural disasters. additionally, the author foresees eight immediate effects of the pandemic on consumer behavior and consumption. hoarding-the mad scramble observed at the start of the covid- outbreak-applies not only to consumers but also to unauthorized middlemen who buy products in excess to sell at increased prices. consumers learn to adapt quickly and take an improvised approach to overcome constraints that have been imposed by governments. pent-up demand may lead to a significant rebound in sales of durable products, like automobiles, houses, and large appliances, and some of the realities of covid- will put consumers in a buying mood soon. embracement of digital technology, either through online services or information-sharing platforms like zoom, has kept people connected around the world. digital savviness will become a necessity, rather than an alternative, for schools, businesses, and healthcare providers. with the onset of lockdowns in many countries, online shopping, including grocery shopping, has become more prevalent. the desire to do everything in-home has impacted consumers' impulse buying habits. slowly but surely, work-life boundaries will be blurred when both tasks are carried out from home. there should be efforts to compartmentalize the two tasks to make this a more efficient way of life. reunions with friends and family are now restricted to digital interactions, especially for people who work and live away from their families. we can expect a dramatic change in consumers' behavior because of sophisticated technology. in addition, consumers may discover new talents as they spend less time on the road and more at home. they may experiment with cooking, learn new skills, and, soon, become producers with commercial possibilities. in the end, most consumer's habits will return to normal, while some habits may die due to adaptation to the new norm. forecasting and overcoming pandemics, global warming, corruption, civil rights violations, misogyny, income inequality, and guns," written by arch g. woodside, discusses whether there is an association between public health interventions, national and state/provincial governments interventions, and improved control of the covid- outbreak in certain countries. the paper suggests "ultimate broadening of the concept of marketing" in order to design and implement interventions in public laws and policy, national and local regulations, and the everyday lives of individuals. it also lays out effective mitigating strategies by examining designs, implementations, and outcomes of covid- interventions by examining deaths as a natural experiment. while covid- eradication intervention tests are being run for promising vaccines, these are considered true experiments, and analyzing the data from these interventions may involve examination of the success of each vaccine for different demographic subgroups in treatment and placebo groups in randomized control trials. comparing the designs and impact of the current covid- mitigation interventions across nations and states within the u.s. provides useful information for improving these interventions, even though they are not "true experiments." the third contribution, "employee adjustment and well-being in the era of covid- : hatak. they claim that covid- is becoming the accelerator for one of the most drastic workplace transformations in recent years. how we work, socialize, shop, learn, communicate, and, of course, where we work will be changed forever. person-environment (p-e) fit theories highlight that employee-environment value congruence is important because values influence outcomes through motivation. however, given the current environment, in which the fulfillment of needs and desires like greater satisfaction, higher engagement, and overall well-being is drastically altered, there is an increased likelihood of misfits working in organizations. in response to this, organizations need to use virtual forms of recruitment, training, and socialization in lieu of face-to-face interactions. increasing job autonomy will alleviate the family-related challenges that may arise within remote work environments by providing employees with the right resources to manage conflicting work and family demands. human resource leaders within the organization must enhance relationship-oriented human resources systems in order to combat the risk of unforeseen and prolonged isolation among single, independent employees and to better prepare them for situations like the current crisis. the field of entrepreneurship can offer insights that can be adapted by organizations coping with the pandemic. entrepreneurs' struggles are largely caused by the lack of work-related social support in comparison to salaried employees. nevertheless, some entrepreneurs are known to overcome these limitations by leveraging alternative, domain-specific sources of social support, such as positive feedback from customers, which ultimately enhances their well-being. recycling such approaches to identify overlooked or untapped sources of social support is likely to be beneficial for employees given the current work environment dynamic. the fourth contribution, written by hongwei he and lloyd c. harris, is titled "the impact of covid- pandemic on corporate social responsibility and marketing philosophy." the worldwide demand for hand sanitizers, gloves, and other hygiene products has risen because of the covid- pandemic. and, in some countries, there has been a surge in complaints about profiteering and opportunism. as doctors combat the virus, prosecutors are pursuing the opportunistic profiteers who prey on the fearful. many large corporations have a social purpose and set of values that indicate how much they appreciate their customers, employees, and stakeholders. this is the time for these corporations to make good on that commitment. some organizations strive to set great examples. for example, jack ma, the co-founder of alibaba, donated coronavirus test kits and other medical supplies to many countries around the world through the jack ma foundation and alibaba foundation. large corporations have often written off the costs of product failures, restructuring, or acquisitions. when writing off losses due to the coronavirus pandemic, it is understandable to pursue the bond established between the brand and consumer. this gesture can turn out to be more meaningful and lasting than when implemented during "normal" times. on the bright side, the covid- pandemic offers great opportunities for companies to supermarket will reassure them that they are being cared for. fourth, messages that retailers spread online during emergencies need to include information about products' availability on the shelves and at digital outlets; control panic buying by restricting the quantity that customers can purchase; devise and implement protection plans for consumers and employees; contribute to overall public health; and use surveillance measures to limit the spread of the virus. to these ends, retailers need to improve their customer relationship management systems and promote safe interactions with customers (e.g., through online chats with employees) to provide real-time customer assistance. smes in times of crisis," he identifies small-to medium-sized businesses with low or unstable cashflow as particularly vulnerable during crises, as they are currently struggling for profitability. studies reveal the interconnectedness between finance and strategy, particularly entrepreneurial orientation and market orientation in strategies. the paper highlights that a combination of entrepreneurial orientation and market orientation can lead to lean and flexible marketing efforts, which are particularly valuable in times of crisis. in addition, entrepreneurial orientation and market orientation can be combined into an entrepreneurial marketing postdisaster business recovery framework that highlights that seeking opportunities, organizing resources, creating customer value, and accepting risk are markedly different in a post-disaster context. sandeep krishnamurthy contributed with "the future of business education: a commentary in the shadow of the covid- pandemic." the paper highlights that social distancing is prompting educational institutions to rethink how they are connecting with their student bodies. spatial interaction is becoming the new norm, and the blurring of physical and virtual communication is likely to continue until the pandemic is overcome. globally, the higher education system will undergo a decade of radical technology-led transformation, according to the author. the author identified five trends that will revolutionize how we educate after covid- : . the algorithm as professor -rather than taking a traditional route and learning from a human professor in classrooms, students will learn remotely from an algorithm. the aienabled algorithm will provide customized personal learning experiences. students will be able to quickly master rudimentary and routinized tasks. then, the algorithm will prepare them for an in-person experience, where a "warm body" will engage them in socratic dialogue. . the university as a service -traditionally, we have followed a linear formulation of society. students go through k- education, some get an undergraduate degree, and some go on to further studies. however, the current and future environment is too volatile to sustain this educational structure. students will need to learn what they need when they need it. personalized, continuing education will become the norm. . the university as assessment powerhouse -in a world characterized by ai and automation, learning can come from many sources. students will learn from each other, algorithmic systems, and public information. however, universities will continue to have a powerful place as assessors of learning. students will come to universities to gain objective credentials based on powerful assessments of learning. . learning personalization to support diversity -students of the future will have access to multiple pathways to learn the same content. for example, a course may be available through algorithmic engagement, animation/video/augmented reality, face-to-face instruction, or any mixture thereof. using assessment data, the university of the future will be able to pinpoint the learning needs of each student and provide a personalized experience. . problem solving through ethical inquiry -as the influence of artificial intelligence and automation grow exponentially in our lives, there will be a great need for students to become problem solvers through ethical inquiry. clearly, the future will not simply be about what the answers are; it will be about which problems we wish to solve, given what we know. students will need to become more comfortable with the need to evaluate ai algorithms based on their efficacy and their ethical foundation. contribution number ten, "consumer reacting, coping and adapting behaviors in the covid- pandemic," is written by colleen p. kirk and laura s. rifkin. in it, the authors explore numerous consumer insights during a major pandemic outbreak. mainly, they examine consumer behaviors across three phases: reacting (e.g., hoarding and rejecting), coping (e.g., maintaining social connectedness, do-it-yourself behaviors, and changing views of brands), and longer-term adapting (e.g., potentially transformative changes in consumption and individual and social identity). the authors also identify a number of negative aspects of the pandemic that will likely impact consumer behavior. as they state, given the mandatory close quarters people must keep due to stay-at-home requirements, domestic abuse may be on the rise. in addition, throughout history, pandemics provide an excuse for increased racial and anti-immigrant biases. in "how firms in china innovate in covid- crisis? an exploratory study of marketing innovation strategies," written by yonggui wang, aoran hong, xia li, and jia gao, the authors explore how firms in china worked to make their marketing strategies a success. they do so by identifying the typology of firms' marketing innovations based on two dimensions: the motivation for innovations and the level of collaboration in innovations. the authors outline four innovative strategies to combat crises for businesses. the responsive strategy works predominantly for firms that involve physical contact, but it can easily be transferred from offline marketing channels to online channels. a collective strategy can be implemented by firms that are highly affected by the crisis, which need to develop new business by collaborating with other firms during the crisis. a proactive strategy is for firms that are less affected by the covid- crisis (mostly online businesses) to develop new businesses to meet the special demands of existing customers during the covid- crisis. firms that are less affected during the covid- crisis can take an alternative approach: a partnership strategy. firms should usually develop new offerings through collaboration with other firms. professors amalesh sharma, anirban adhikary, and sourav bikash borah contributed with "covid- impact on supply chain decisions: strategic insights for nasdaq firms using twitter data." during black swan events like the covid- pandemic, which may have severe long-term consequences, a deep understanding of business risks can help organizations establish the right plan. in this article, the authors identified supply chain challenges faced by companies using their twitter data. to develop insights from the findings, the authors constructed unigrams, bigrams, and trigrams that revealed the supply-chain-related aspects that gain attention on twitter. a topic analysis was performed to identify keywords used in discussions about covid- . the obtained insights show that the greatest challenge for the organizations was accessing realistic customer demands. a pandemic may increase or decrease demand for specific products, making estimation of realistic final customer demand more difficult and more urgent to address. some user accounts suggested that organizations are still lacking in terms of technological readiness and that companies are looking to gain visibility across value chains. there are growing discussions about building supply chain resilience by identifying risks. many organizations are not only focusing on social sustainability but also turning their attention toward environmental sustainability. to deal with the challenges brought on by unprecedented times, the leaders of organizations must reimagine and redesign the supply chain; rely on technology such as artificial intelligence, the internet of things, and blockchain in their supply chain designs; and focus on sustainable supply chain. finally, marianna sigala wrote "tourism and covid- : impacts and implications for advancing and resetting industry and research." tourism is experiencing a rapid and steep drop in demand during the covid- pandemic. despite the tourism industry's proven resilience in other unprecedented times, the impact of the current pandemic will likely last longer for international tourism than for other affected industries. however, the tourism industry should not only recover but also reimagine and reform the next normal economic order. currently, there is a lack of research on how crises can alter the industry, how the industry adapts to changes with innovative techniques, and how research that can establish the next norms can be conducted. to study the needs and gaps in research work, the author reviews past and emerging literature to capture its impacts and impart some ideas from different research fields that will allow tourism to grow and evolve. nearly % of hotel rooms in the us are empty, according to new data perceived social isolation and cognition an increasing risk of family violence during the covid- pandemic: strengthening community collaborations to save lives the spread of awareness and its impact on epidemic outbreaks market-driven versus driving markets longer-run economic consequences of pandemics (report no. w ) loneliness and social internet use: pathways to reconnection in a digital world a history of influenza watch out for china buying spree, nato warns will vaccines be available for the next influenza pandemic coronavirus bankruptcy tracker: these major companies are failing amid the shutdown it's all b b… and beyond: toward a systems perspective of the market key: cord- -s wjg ar authors: cobrado, l.; silva-dias, a.; azevedo, m. m.; rodrigues, a. g. title: high-touch surfaces: microbial neighbours at hand date: - - journal: eur j clin microbiol infect dis doi: . /s - - - sha: doc_id: cord_uid: s wjg ar despite considerable efforts, healthcare-associated infections (hais) continue to be globally responsible for serious morbidity, increased costs and prolonged length of stay. among potentially preventable sources of microbial pathogens causing hais, patient care items and environmental surfaces frequently touched play an important role in the chain of transmission. microorganisms contaminating such high-touch surfaces include gram-positive and gram-negative bacteria, viruses, yeasts and parasites, with improved cleaning and disinfection effectively decreasing the rate of hais. manual and automated surface cleaning strategies used in the control of infectious outbreaks are discussed and current trends concerning the prevention of contamination by the use of antimicrobial surfaces are taken into consideration in this manuscript. in spite of the growing global commitment towards an effective reduction of healthcare-associated infections (hais), it is unfortunately certain that such infections will continue to be responsible for very high morbidity, increased costs and length of stay (los) for the coming decades [ , ] . among potential sources of pathogens causing hais, the most frequent are the patient's microbiota and the hands of healthcare personnel [ ] . additionally, evidence that hightouch surfaces (hts) will work as an extra source of microbial pathogens accumulated over the years, e.g., several microorganisms can survive on medical equipment for hours to months, improved cleaning and disinfection of surfaces decrease the rate of hai, and hospital environmental screening results and the study of clonal outbreaks, all have given support to the role of contaminated hts in the transmission of pathogens between patients and healthcare personnel [ ] . from surfaces, microbial transmission may occur either through direct patient contact or, indirectly, through healthcare personnel hands or gloves [ ] . therefore, upon potentially preventable sources of microorganisms, contaminated hts deserve strong consideration. microbial pathogens most frequently involved in the contamination of hospital environmental surfaces are (methicillinresistant) staphylococcus aureus (mrsa), vancomycinresistant enterococci (vre), clostridium difficile, multidrug resistant gramme-negative bacilli (such as pseudomonas, acinetobacter and enterobacteriaceae), norovirus, coronavirus and candida species [ ] [ ] [ ] [ ] [ ] . strategies for cleaning contaminated hts may include manual and automated techniques. wipes and cloths with application of detergents or disinfectants are examples of manual techniques, while automated methods may involve uv light, hydrogen peroxide, steam vapour, ozone and hins (high-intensity narrow-spectrum light). on the other side, in order to prevent contamination of hts, antimicrobial surfaces are being developed. the inhibition of microbial adhesion with repellent films is a possible strategy, as it is the surface treatment with antimicrobial coatings of silver, copper, polycations, triclosan, bacteriophages or, even, light-activated biotoxic radicals. the aim of this manuscript is to review the role of hightouch surfaces in healthcare-associated infections, from the aetiology to strategies for surface cleaning and addressing preventive trends. as early as , spaulding proposed a classification of inanimate surfaces into three general categories based on the risk of infection if the surfaces were contaminated at the time of use [ ] . these categories can be applied to devices or instruments as follows: critical (exposed to normally sterile areas of the body; require sterilization), semi-critical (touch mucous membranes; may be sterilized or disinfected), and noncritical (touch skin or come into contact with people only indirectly; can be either cleaned and then disinfected with an intermediate-level disinfectant, sanitized with a low-level disinfectant or, simply, cleaned with water and soap). in , the cdc proposed environmental surfaces (floors, walls and other bhousekeeping surfaces^that do not make direct contact with a person's skin) as an additional category [ ] . more recently, the cdc's and healthcare infection control practices advisory committee's guidelines for environmental infection control in healthcare facilities [ ] divided surfaces into patient care items and environmental surfaces. environmental surfaces were further divided into medical equipment and patient room surfaces (table ) . over the years, research has been done in order to better target room disinfection practices. following recommendations made by the cdc to clean and disinfect hts more frequently than minimal-touch surfaces, data published in by huslage et al., based on the real frequency of contact, defined the top five most touched surfaces in hospitals: bed rails, bed surface, supply cart, over-bed table and intravenous pump [ ] . hts may be classified as non-critical items (the contact occurs with intact skin that effectively acts as a barrier to most pathogens, but not with mucous membranes) and must be subject to cleaning and disinfection procedures as recommended, but with no absolute need for sterilization [ ] . many pathogens may thrive on healthcare-associated equipment and environmental surfaces. among such organisms, mrsa, vre, c. difficile, p. aeruginosa, a. baumannii, enterobacteriaceae, stenotrophomonas maltophilia, burkholderia cepacia, norovirus, coronavirus and candida spp. may persist and contribute to the infection risk to which patients are systematically exposed. several studies have demonstrated that basic cleaning leads to mrsa elimination from environmental surfaces and enhanced cleaning may terminate outbreaks in intensive care units, with cost savings of $ , up to $ , per year [ ] [ ] [ ] [ ] . recently, two studies reported positively about pulsed xenon uv and hydrogen peroxide methods to boost the decontamination of patient rooms, contributing towards a reduction of mrsa bioburden [ , ] . its inherent ability to resist certain antimicrobial agents (such as cephalosporins and aminoglycosides) allied to a great capacity to acquire determinants of antibiotic resistance (like gene clusters of vancomycin resistance) turn enterococci into a versatile nosocomial multidrug-resistant pathogen. the number of vre infections has been increasing worldwide, most frequently afflicting patients with serious comorbidities or undergoing prolonged hospitalization [ ] . vre are known to survive for a long time in the hospital environment. viability on surfaces may range from days to months [ ] . moreover, enterococci are tolerant to heat, chlorine and some alcohol preparations, making them very resilient to conventional cleaning practices, thus becoming easily disseminated among healthcare facilities [ ] . therefore, besides thorough environmental cleaning several times a day with disinfectants, vre management protocols should include strict adoption of contact precautions and implementation of comprehensive educational programs for staff [ , ] . spores of c. difficile can hold on to a healthcare environment for more than months [ , ] . fortunately, the use of chlorine-releasing disinfectants reduces the amount of spores in the environment, with some evidence suggesting that it may reduce the risk of recurrence and transmission of c. difficileassociated infections [ ] . transmission of p. aeruginosa may easily occur from contaminated sinks to hands of healthcare personnel during washing, since this organism may thrive in biofilms that are adherent to sink traps, pipes, water lines and hospital drains [ ] , turning these fashion-organized bacteria more prone to resist to disinfectants [ ] . additionally, p. aeruginosa can resist hours to months on dry inanimate surfaces [ ] . programs to control transmission should include, therefore, repeated cleaning with chlorine-based disinfectants, physical removal of persistent biofilm, replacement of components whenever feasible and regular inspection [ , ] . the increase in the number of hais caused by a. baumannii might be explained not only by its ability to persist from days to more than months in undisturbed surfaces of healthcare equipment [ ] , but also by its high resilience to cleaning with conventional detergent and alcohol disinfectants [ ] . hence, outbreaks in hospital or other healthcare settings are difficult to contain because of the easy environmental contamination by this pathogen [ ] [ ] [ ] . targeted infection control measures may be needed, including intensive cleaning with sodium hypochlorite and subsequent measurement of cleanliness, hand hygiene training, adoption of barrier precautions and contact isolation, as well as patient surveillance [ , ] . there has been a growing concern about klebsiella pneumoniae infections, mainly because of its extensive β-lactamase resistance. k. pneumoniae are usual colonizers of the human gastrointestinal tract, pharynx and skin that may cause wound infections, pneumonia and sepsis, particularly in immunocompromised patients [ ] . more recently, given its wide dissemination and selective advantage to resist to carbapenem antibiotics, k. pneumoniae have been showing a propensity to cause outbreaks in healthcare institutions [ ] . it is known that k. pneumoniae may survive for more than months in the healthcare environment [ ] and that the origin of some outbreaks has been related to sinks and related pipes [ , ] . another member of the enterobacteriaceae family, serratia marcescens, are known to cause pneumonia, meningitis, urinary tract and bloodstream infections. mdr isolates, including colistin resistant [ ] , have been responsible for serious outbreaks among intensive care units and critically ill neonates [ ] [ ] [ ] . s. marcescens are known to survive up to months on dry inanimate surfaces [ ] and have frequently been recovered from water pipes and hospital disinfectants [ ] . because of the easy transmission and environmental persistence of enterobacteriaceae in healthcare facilities, adequate solutions aiming its eradication should ensure comprehensive educational interventions, hand hygiene training, chlorine-based cleaning and even the replacement of sinks and pipes [ , , ] . similarly to other bacteria, it can persist in biofilms that may turn cleaning products and disinfectants more ineffective [ ] . long-term control of s. maltophilia will be dependent upon the integration of an efficient cleaning strategy into a targeted healthcare facilities maintenance program [ ] . it is widely distributed in soil and water habitats and recent healthcare-associated outbreaks have been linked to b. cepacia persistence in disinfectants, drugs, medical devices (e.g., respiratory nebulizers), sinks and contiguous aerator filters [ ] [ ] [ ] . strict and repeated cleaning and replacement of aerators with flow straighteners may be required to stop outbreaks [ , ] . the origin of norovirus outbreaks in healthcare facilities has been traced not only to sites near bathroom showers and toilets but also to sites near patients, including clinical equipment (e.g., blood pressure and pulse oximeter monitors), thermometers, trolleys and soap and alcohol gel containers [ ] . after suspected or confirmed case contact, use of soap and running water is recommended [ ] , probably with a superior efficacy than ethanol-based sanitizers [ ] . however, detergent-based cleaning may be insufficient to eliminate norovirus from the environment and, therefore, hypochlorite solutions of at least ppm for an appropriate contact time represent a better strategy for cleaning [ , ] . human coronavirus, usually responsible for acute respiratory syndromes, have been causing increased concern due to contact transmission during healthcare-associated outbreaks. viral persistence on doorknobs and surgical boom shelves has already been identified, with a presumed viability of h; scrupulous environmental cleaning is certainly highly advisable in reducing the spread [ , ] . moreover, biocidal surfaces based on copper alloys are very effective in inactivating coronavirus and could be employed in high touch surfaces in order to prevent the transmission of this respiratory virus [ ] . although candida spp. are more resistant to germicidal chemicals than most vegetative bacteria, there are no specific recommendations other than general healthcare surface decontamination with disinfectants. nevertheless, in order to control a recent outbreak by a mdr c. auris, measures implemented included isolation of cases and contacts, protective clothing, screening of all other ward patients, skin decontamination with chlorhexidine, environmental cleaning with chlorine-based disinfectants and hydrogen peroxide vapour [ ] . a clinical alert issued in june by the cdc on the global emergence of invasive infections caused by the mdr c. auris recommended thorough daily and terminal cleaning and disinfection of patient rooms using an epa-registered hospital grade disinfectant with a fungal claim. preventing the environmental surface transmission of healthcare-associated pathogens general strategies based on patterns of microbial resistance to physical and chemical germicidal agents and on the instrument/surface classification, spaulding has proposed three levels of disinfection [ ] : high-level disinfection, that inactivates all vegetative bacteria, mycobacteria, viruses, fungi and some bacterial spores by the action of chemicals such as glutaraldehyde, peracetic acid and hydrogen peroxide; intermediate-level disinfection, which is effective against vegetative bacteria, some spores, mycobacteria, fungi, lipid and medium size viruses, but not against all nonlipid and small size viruses (e.g., sodium hypochlorite, alcohols, some phenolics and some iodophors); and low-level disinfection, that inactivates vegetative bacteria, fungi, enveloped viruses and some non-enveloped viruses (e.g., adenoviruses) by the action of quaternary ammonium compounds, some phenolics and some iodophors [ ] . in order to prevent the persistence of microbial pathogens on medical equipment and environmental surfaces, education of healthcare staff, checklists and assessment of the adequacy of cleaning (by direct observation, use of fluorescent markers, of atp bioluminescence systems, swab cultures or agar slide cultures) with feedback to the staff are general interventions that need to be implemented to improve the frequency of adequate cleaning [ ] [ ] [ ] . as general principles, all patient care items should be cleaned and/or decontaminated before and after use, for all patients [ , ] ; whenever these items come into contact with blood or other body fluids, stringent cleaning and disinfection is warranted before and after use [ ] . manufacturers of medical equipment usually provide care and maintenance instructions regarding servicing decontamination, compatibility with germicidal agents and water-resistance. in the absence of such instructions, the cdc and the healthcare infection control practices advisory committee (hicpac) recommend non-critical medical equipment (e.g., stethoscopes, blood pressure cuffs, equipment knobs and controls) to be subject to low or intermediate-level disinfection after cleansing, depending on the nature and degree of contamination. for instance, ethyl or isopropyl alcohol ( - % v/v) may be used to disinfect small surfaces (e.g., rubber stoppers of multiple-dose medication vials and thermometers) and surfaces of healthcare equipment (e.g., stethoscopes and ventilators) [ ] , while for large surfaces it may be impractical due to the rapid evaporation of alcohol and absence of the adequate contact time [ ] . as a whole, frequently touched environmental surfaces benefit from enhanced cleaning. routine decontamination and disinfection are practices normally included within institutional cleaning policies. nevertheless, evidence has been built in order to favour the use of less toxic detergents over disinfectants in non-outbreak situations, without losing cleaning efficacy or adding costs [ ] . detergents are less likely to contribute to the accumulation or dispersal of tolerance or resistance genes among healthcare-associated microbial isolates [ , ] . according to the cdc, for medical equipment (particularly in the case of monitor touch screens, controls and cables), a disposable plastic barrier protection can be useful whenever these surfaces, touched frequently by gloved hands, may become contaminated with body fluids or present difficulties to cleaning. manual cleaning the physical removal of soil is a very important step in the cleaning process since its presence will impede the microbicidal activity of disinfectants, if needed. in order to control the bioburden on regular wards, daily cleaning with neutral detergent wipes is usually sufficient. however, more attention is essential on high-risk intensive care units because of the easiness of microbial recontamination [ ] . moreover, patients colonized or infected with specific pathogens may demand cleaning regimens with disinfectants with registered label claims [ ] . after patient discharge, terminal or deep cleaning is usually performed by removal of all detachable objects from the room and systematically wiping all surfaces downward to the floor level, with detergent cloths or disinfectant wipes. new liquid disinfectants are under development and include: improved hydrogen peroxide disinfectants, effective in reducing bacterial levels on surfaces [ , ] , related to fewer hais [ ] and able to reduce contamination by mdr pathogens on soft surfaces such as bedside curtains [ ] ; peracetic acid and hydrogen peroxide disinfectants, a sporicidal combination that was shown to lower bacterial levels on surfaces and to reduce the contamination by mrsa, vre and c. difficile as effectively as sodium hypochlorite [ ] ; electrolyzed water (hypochlorous acid) disinfectant, which may reduce bacterial levels on surfaces near patients in a higher degree than quaternary ammonium disinfectants [ ] ; further promising, electrolyzed water has been sprayed onto medical equipment (with a short contact time and without the need for wiping because no toxic residue remains on surfaces) with a reduction of aerobic bacteria and c. difficile spores [ ] ; coldair atmospheric pressure plasma systems, which generate reactive oxygen species (ros) with bactericidal activity and have potential use as surface disinfectants [ , ] ; nebulized polymeric guanidine, under investigation for its antimicrobial activity against several healthcare-associated pathogens [ ] . together with disinfectants, novel materials for liquid application such as microfiber cloths or mops and ultramicrofiber cloths are under development. when used according to manufacturers' instructions, an increased cleaning efficacy is to be expected as compared to standard cotton cloths or mops [ ] . automated cleaning on the pathway to improve quality and ease of cleaning environmental surfaces, considerable efforts have been dedicated towards the development of automated devices. however, because of yet unsolved safety risks, mainly for patients, automated solutions are invariably targeting terminal cleaning. in most instances, these solutions do not preclude preliminary manual cleaning of surfaces to remove residual debris and reduce the bioburden. the microbicidal effect of uv light has been in use for disinfection of environmental surfaces, instruments and air. by damaging the molecular bonds in dna, a reduction in contamination by mrsa, vre and c. difficile on high-touch surfaces has been achieved [ ] . automated mobile uv light devices are easy to use, with minimal need for special staff training. nonetheless, several issues have been raised that may hinder its efficacy, namely, the time and intensity of light exposure and potential barriers that may exist between the lamp and its target surface. as such, uv light is regarded as an effective adjunct, but not a stand-alone strategy for disinfection [ ] . by producing free radicals that lead to oxidation of dna, proteins and membrane lipids [ ] , vapour and aerosol hydrogen peroxide systems have already been shown to be effective against mrsa, vre, mdr gramme-negative bacilli, c. difficile, viruses and fungi [ ] [ ] [ ] [ ] [ ] [ ] . this excellent wide spectrum antimicrobial activity is not without drawbacks, such as toxicity after accidental exposure, minor erosion of environmental polymers and damage of electronic equipment. in addition, there is the need for trained operators, long cycle times for disinfection and the cost is high [ ] . experiments suggest that vapour-phase hydrogen peroxide is a more potent oxidizer of protein than liquid-phase hydrogen peroxide [ ] and, when supplementing other strategies, microcondensation hydrogen peroxide vapour systems may have contributed to control outbreaks by mrsa, mdr grammenegative bacteria and c. difficile in intensive care units, surgical wards and long-term care facilities [ , [ ] [ ] [ ] [ ] [ ] . a novel silver-stabilized hydrogen peroxide is under investigation for its enhanced biocidal activity towards gramme positive and negative bacteria capable of producing catalase, both in planktonic and biofilm cultures. silver probably helps to stabilize and target hydrogen peroxide to the bacterial cell surface acting, therefore, synergistically [ ] . in fact, a previous report on the effect of a dry-mist system using a mixture of hydrogen peroxide ( %) and silver cations (< ppm) was effective in decontaminating burn patient rooms, as well as a fungal research laboratory: a reduction in growth of at least two log was observed for tested bacteria, mycobacteria and fungi [ ] . steam cleaning is a non-toxic and rapid method that may reduce the total bioburden from environmental surfaces by more than % [ ] , with effectiveness against mrsa, vre and gramme-negative bacilli [ ] . concerns about security when steam is applied to electrical items such as switches and buttons and risk of burns and scalds when cleaning a crowded ward are the reasons precluding its widespread use in healthcare facilities [ ] . the oxidizing capacity of ozone justifies its previous evaluation as a gaseous decontaminant for controlling c. difficile on environmental surfaces and e.coli in hospital laundries [ , ] . while it seems highly effective against vegetative bacterial cells, a smaller impact has been found in case of bacterial spores and fungi [ ] . moreover, corrosiveness and toxicity issues may restrain further the use of ozone in healthcare settings [ ] . by targeting intracellular porphyrins that absorb the light and produce ros with bactericidal activity [ ] , highintensity narrow-spectrum (hins) light stands as another light-based method with possible application for decontamination of high-touch surfaces, although its efficacy is lower than uv light. as clear advantages, hins light is safe for patients, allowing continuous decontamination of the clinical environment [ ] and it exhibits a wide-range microbicidal activity that includes mrsa, p. aeruginosa and a. baumannii [ , ] . however, hins light has yet to prove its effectiveness in clinical settings and benefits upon hai rates, given the small range of published studies [ , , ] . antimicrobial surfaces instead of focusing on the reduction of the bioburden on surfaces solely by cleaning, there are solutions designed to prevent surfaces from working as a microbial reservoir and that may be used as an adjunct to other strategies in reducing hais. antiadhesive surfaces target microbial adhesion usually by the interaction of antagonist physicochemical properties. easy-clean surfaces that are hydrophobic repel bacteria better than glass-coated controls [ ] , while hydrophilic surfaces favour water sheeting and subsequent cleaning. similarly, polyethylene glycol coated surfaces promote a hydrophilic interaction against bacteria, preventing attachment [ ] . the use of diamond-like carbon films has already been tried for medical implanted devices such as joint prostheses and stents in order to repel microbial adhesion [ ] . despite being non-toxic and appealing, the lack of biocidal properties may turn discouraging a more generalized implementation of such easy-clean technologies. currently, there are available antimicrobial coatings that can produce a microbicidal effect and could lead to an effective reduction of high-touch surface bioburden. for instance, inorganic metals have been investigated for a long time and it is known that silver binds with disulphide and sulfhydryl groups present in proteins of microbial cell wall leading to death [ ] , inhibiting not only environmental contamination but also colonization of medical implanted devices [ , ] ; copper and copper alloys may form reactive oxygen radicals that damage nucleic acid and proteins [ ] and have already demonstrated a potent antimicrobial effect when applied to surfaces, reducing the rate of healthcare-associated infections [ , ] . polycationic surfaces, such as those coated with polyethyleneimines, hydrophobically attract and kill bacteria by physically damaging the cell wall [ ] . triclosan has been in use for more than years in detergents, soaps and cosmetics. at lower concentrations, it is bacteriostatic by inhibiting an enzyme involved in fatty acid synthesis and, at higher concentrations, it is bacteric i d a l b y d e s t a b i l i z i n g m i c r o b i a l m e m b r a n e s . compatibilization of triclosan with polymers may extend the duration of its wide-spectrum antimicrobial activity [ ] and could prove effective in reducing environmental surface load of pathogens. bacteriophages applied to surfaces and targeting specific microorganisms have been attempted and mixtures of phages have been further suggested in order to effectively reduce the environmental bioburden. particularly interesting in healthcare settings is the fact that mdr pathogens keep vulnerable to the lytic action of phages [ , ] . light-activated antimicrobial surfaces, such as those coated with titanium dioxide and activated by uv light [ ] , generate reactive oxygen radicals with nonselective toxicity towards both bacteria and yeasts [ ] . similarly, photosensitized surfaces could reduce the healthcare bioburden without promoting microbial drug resistance mechanisms. although antimicrobial coatings may seem very promising, especially as an adjunct measure to more traditional and proven cleaning strategies, some concerns keep hindering its wider use in healthcare settings. robust cost-effectiveness studies are still lacking since reliable information about antimicrobial coatings durability, resistance and possible toxicity is yet somewhat insufficient [ , ] . given the high morbidity and costs associated with hais, improved strategies are urgently needed to reduce effectively the rate of infection. certainly, one good step forward would be the blockade of transmission from environmental hightouch surfaces. at the moment, manual and automated techniques for cleaning surfaces exhibit variable success. concerns over durability, resistance and toxicity may be precluding a much wider application of the novel antimicrobial coatings. admitting an albeit limited performance of the traditional cleaning methods, the supplementation with newer technology should be indicated. hence, more randomized controlled trials and cost-effectiveness studies are needed and further investigation on antimicrobial surfaces is welcomed in order to face the challenge imposed by the global advance of antimicrobial drug resistance and the pressure to reduce bed turnover times with shortages in nursing personnel, housekeeping staff and budgets. funding none to declare. ethical approval this type of study does not involve human participants and/or animals. informed consent for this type of study, informed consent is not required. multistate point-prevalence survey of health care-associated infections point 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