key: cord- -cisrvghj authors: fredricks, david n; relman, david a title: the infectious aetiology of disease: the search for new agents date: - - journal: medicine doi: . /medc. . . . sha: doc_id: cord_uid: cisrvghj abstract there are many diseases for which a microbial aetiology is suspected. the hypothesis that a disease has an infectious cause is supported by: clinical features (similar to those of known infectious diseases, e.g. fever, leucocytosis), epidemiology (case clustering in time or location), histology (inflammation of affected tissues, e.g. granulomata) or characteristic microbial structures, treatment (clinical response to antimicrobial treatment), and prevention of disease by vaccines targeting microbial antigens. proof that a microbe causes a disease requires more rigorous evidence. future attempts to identify novel microbes associated with human disease may use sequence-based approaches. high-throughput sequencing may allow identification of unique microbial nucleic acid sequences in a background of host dna. the complete sequencing of the human genome and multiple microbial genomes make this approach more feasible. dna microarrays are also likely to be used in the search for novel pathogens. just when we think we have a good understanding of the microbes that occupy our planet and cause disease, nature reminds us that our knowledge is incomplete. in the last few decades, a novel retrovirus (hiv) has emerged from the jungles of africa to infect and kill millions of individuals from all continents. less dramatically, newly described microbes have been linked to human diseases since ( figure ). are there other microbial pathogens that are significant causes of human disease and await discovery? there are many diseases for which a microbial aetiology is suspected ( figure ). the hypothesis that a disease has an infectious cause is supported by: • clinical features -similar to those of known infectious diseases (e.g. fever, leucocytosis) • epidemiology -case clustering in time or location • histology -inflammation of affected tissues (e.g. granulomata) or characteristic microbial structures • treatment -a clinical response to antimicrobial treatment • prevention of disease by vaccines targeting microbial antigens. proof that a microbe causes a disease requires more rigorous evidence. if microbes are the cause of some idiopathic diseases, why have we not discovered them yet? • one reason is failure to consider the hypothesis of infection. the association between helicobacter pylori infection and peptic ulcer disease was not made until recently, despite our ability to cultivate this bacterium in the laboratory and to see it under the microscope in gastric biopsies. • another reason is failure of conventional microbial detection technologies. studies of bacterial biodiversity in various envi- ronmental and human niches have shown that cultivation can detect only a fraction of the bacteria identified using nucleic acid sequences. microbes may exist in viable but non-culturable states, or as sessile members of biofilm communities in which individual cells may be difficult to cultivate. accordingly, failure to propagate a microbe in the laboratory does not mean that the sample is free of microbes. • microbes may evade detection through a pathogenic process of 'hit and run'. organisms such as streptococcus pyogenes may initiate an immunological response that continues to cause disease long after the microbe is eradicated (rheumatic fever). • ubiquitous microbes can cause rare diseases as a result of aberrant host responses. when a common virus causes a rare neurological disease in a small subset of susceptible hosts, for example, it is difficult to make an association. infection with the some micro-organisms described since and the diseases they cause many of the recently discovered microbial pathogens were identified by detecting their unique nucleic acid sequences in tissues. an example of this approach is the discovery of bartonella as the a cause of bacillary angiomatosis. although bacterial structures are visible in bacillary angiomatosis tissues, a cultivated bacterium was not initially apparent. oligonucleotide primers complementary to highly conserved sequences in known bacterial s rrna genes were used in a polymerase chain reaction (pcr) to amplify small quantities of bacterial dna present in bacillary angiomatosis tissues. the s rrna gene also contains regions of sequence variability that, when amplified using this consensus pcr approach, can be used to identify the bacteria or to infer evolutionary relationships to other bacteria. a unique s rdna sequence was detected in the tissues of three patients with bacillary angiomatosis but not in control tissues, identifying a bacterium in the bartonella genus as a cause of a the disease. this organism was later named bartonella henselae. b. quintana is another cause of bacillary angiomatosis, and also a causes trench fever and endocarditis, and b. henselae is responsible e for cat-scratch disease in immunocompetent hosts. b. bacilliformis (oroya fever, verruga peruana) and b. elizabethae (endocarditis) e are also human pathogens. a sequence-based approach to novel pathogen discovery has several advantages. all infectious agents should be detectable because they contain nucleic acids (excluding prions), and because each contains a unique complement of nucleic acid, different microbes should be distinguishable. nucleic acid amplification and probe-based signal amplification methods allow detection of microbial nucleic acid sequences down to the single-copy level, yielding impressive assay sensitivities. several sequence-based approaches to pathogen discovery have yielded novel microbes that cause human disease. consensus pcr has been used to identify the bacterial cause of whipple's disease (tropheryma whipplei) and the viral cause of hantavirus pulmonary syndrome (sin nombre virus and others). hepatitis c virus was identified by screening expression libraries of cdna for antigen that reacted with immune serum from patients. human herpesvirus (the cause of kaposi's sarcoma) was identified using representational difference analysis. in this method, a unique microbial dna fragment was enriched in a tissue sample using subtractive hybridization and pcr-based amplification. the novel coronavirus associated with severe acute respiratory syndrome (sars) was detected using a pan-viral dna microarray. an unidentified virus was cultivated from a patient with sars using vero cells, the rna from this culture was reverse transcribed and amplified using pcr, and the labelled cdna was hybridized to a microarray containing oligomers complementary to numerous known viruses. hybridization of the cdna to known coronavirus sequences suggested that the viral isolate was a member of the coronavirus family. the viral genome revealed that it was a newly characterized coronavirus. future attempts to identify novel microbes associated with human disease may use other sequence-based approaches. high-throughput sequencing may allow identification of unique microbial nucleic acid sequences in a background of host dna. the complete sequencing of the human genome and multiple microbial genomes make this approach more feasible. dna microarrays are also likely to be used in the search for novel pathogens. microarrays containing thousands of dna spots, representing a diversity of microbial and viral genes, may be used to detect microbial nucleic acids in tissues by hybridization. microarrays of human dna may also be used to monitor host gene expression in disease, as a means of looking for characteristic host response profiles that help identify infectious agents. identification of novel or previously described infectious agents may improve diagnosis, prevention and treatment of disease. because of the continued evolution of microbes and of humans, the emergence of new pathogens and diseases is a virtual certainty. the agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens identification of the uncultured bacillus of whipple's disease genetic identification of a hantavirus associated with an outbreak of acute respiratory illness isolation of a cdna clone derived from a blood-borne non-a, non-b viral hepatitis genome identification of herpesvirus-like dna sequences in aids-associated kaposi's sarcoma viral discovery and sequence recovery using dna microarrays stereotyped and specific gene expression programs in human innate immune responses to bacteria infectious agents and the etiology of chronic idiopathic diseases bacterial diversity within the human subgingival crevice a molecular view of microbial diversity and the biosphere characterization of a novel coronavirus associated with severe acute respiratory syndrome key: cord- - o kte i authors: beeching, nick title: fever in the returning traveller date: - - journal: medicine doi: . /medc. . . . sha: doc_id: cord_uid: o kte i abstract fever is a common reason for acute hospital admission for tropical illness in uk referral units. a sensible working diagnosis can usually be formulated from a careful history and examination and initial simple investigations. the history should include details of exactly where the patient has been, what conditions he or she was living in, and the exact dates of arrival and departure. the quality of pre-travel advice and vaccinations, adherence to chemoprophylaxis against malaria, avoidance of insect bites and general behaviour abroad (including sexual history) are also important. localizing features of the illness should be sought on examination. maintain a high index of suspicion for underlying hiv. the most important illness to consider and exclude is malaria (about % of cases), and most of the remainder have cosmopolitan viral infections or imported infections such as an arbovirus (dengue), enteric fever or viral hepatitis. rarer causes are usually evident from the history and examination, which presupposes a good knowledge of geographical medicine. initial investigations should include adequate malaria films (supplemented by quick antigen detection tests in many laboratories) and blood count, repeated as necessary, blood, urine and faecal cultures, serum biochemistry, chest radiography and other imaging (e.g. liver ultrasonography) as indicated. in patients in whom malaria is suspected despite negative films, the combination of thrombocytopenia and splenomegaly is supportive but not diagnostic of malaria. febrile illnesses account for about % of hospital admissions for tropical illness in uk referral units. the initial assessment of travellers is aimed primarily at early detection and treatment of malaria (see medicine : , ), which can be rapidly fatal. malaria is the most common diagnosis, followed by nonspecific, self-limiting infections, and respiratory and gastrointestinal infections. [ ] [ ] [ ] [ ] [ ] start with the question: "have you ever been overseas?" every possibly relevant trip should be recorded in detail. where? -the precise area of travel should be identified, not just the continent or country. why? -the reason for travel and the patient's activities there may suggest or exclude specific diseases. when? -precise dates of departure and return are required. viral haemorrhagic fevers can be excluded when more than days have elapsed since the traveller left an endemic area in africa. malaria does not develop until at least days after arrival in an endemic area, and most cases of falciparum malaria present within months of exposure. malaria developing more than months after leaving the indian subcontinent is almost always caused by plasmodium vivax, symptoms of which may develop up to years after exposure. what? -a risk assessment of behaviour and activities while overseas should include a detailed sexual history. swimming in fresh water carries a risk of schistosomiasis (africa) or leptospirosis (particularly asia, and central and south america). a history of tsetse fly bite (usually vividly remembered) in a game park in africa, or of tick bites (often unnoticed) is helpful. who? -details of pre-travel immunization and malaria prophylaxis should be recorded, and adherence to antimalarial regimens and antimosquito measures should be assessed, though full compliance does not exclude malaria. pre-travel health is also important, particularly in patients who are immunocompromised. fever -the presence of fever should be confirmed; it is usually futile to pursue detailed diagnosis of a minor febrile illness that has already resolved. patterns of fever are seldom as useful as textbooks suggest. falciparum malaria usually causes continuous rather than periodic fever, though up to % of patients with malaria may be afebrile at presentation. the general condition of the patient should be assessed, looking for localizing signs and for complications of severe malaria, including confusion or drowsiness, shock and jaundice. insect bites commonly become infected with streptococci or staphylococci. careful examination is needed to find the eschar (scab) of tick bites (figure ), which may be hidden in the hairline or under constricting garments (e.g. bra straps, underwear elastic). diarrhoea may be a presenting feature of falciparum malaria, pneumonia, atypical respiratory infections including severe acute respiratory syndrome, or enteric infection. jaundice suggests malaria, hepatitis or leptospirosis. hepatosplenomegaly is found in many infections. less than % of patients with malaria have a palpable spleen, so this sign has little negative predictive value. lymphadenopathy should always raise suspicion of hiv seroconversion illness, but is also seen in dengue, brucellosis, rickettsial infections and the 'glandular fever' group of infections. blood tests -investigations should include full blood count, differential wbc count, renal function, liver function tests and at least two sets of blood cultures. it is always worth storing an acute serum or plasma sample on admission for paired serological tests or for polymerase chain reaction-based diagnosis later. blood films for malaria are essential. most laboratories are accustomed to interpreting thin blood films, which are most useful for diagnosing the type of malaria and determining the degree of parasitaemia. however, thin films are less sensitive than thick films, which are preferred where local expertise allows. chemoprophylaxis makes blood films more difficult to interpret because the parasitaemia is more scanty. ultrasound scan showing amoebic liver abscess in a merchant seaman with fever, neutrophilia and dullness at the right lung base. liver abscess may mimic pneumonia. dipsticks for plasmodium species-specific lactate dehydrogenase can detect p. falciparum and p. vivax with almost the same sensitivity as a thick film examined by an expert. in a district general hospital setting, out of hours, these tests should supplement thin film examination. if the first film is negative and malaria is possible, films should be repeated after hours, and possibly repeated again hours later. thrombocytopenia is present in more than % of patients with malaria, but is also caused by dengue and other infections. malaria or leptospirosis is more likely in those with both raised serum bilirubin and thrombocytopenia, and the combination of spenomegaly and thrombocytopenia is strongly suggestive of malaria. neutrophilia suggests bacterial sepsis, including meningococcal disease, or amoebic liver abscess (serology is positive in the latter). eosinophilia suggests nematodes or cestodes, typically acute schistosomiasis (serology and parasitology are often negative at this stage) or filariasis. antibiotic sensitivities should be reported. pneumococci from many parts of the tropics are penicillin resistant, and salmonella typhi and s. paratyphi a isolates from asia are usually multi-drug resistant. tropics, bite of anopheline undifferentiated fever, later stupor, thrombocytopenia, hypoglycaemia, mosquito anaemia, shock, renal failure blood films (thick and thin), (plasmodium falciparum); antigen tests regular rigors (p. vivax or p. ovale) tropics, bite of aedes fever for about days, severe leucopenia, polymerase chain reaction (stegomyia) mosquito, headache, retro-orbital pain, myalgia, analysis (early), serology (after first sometimes epidemic, lymphadenopathy, blanching skin week of illness) incubation - days rash on third day, rarely haemorrhages and shock rural west or central africa persistent fever with severe malaise, leucopenia, virus isolation, polymerase or hospital workers exposed pharyngeal exudate, swollen face, chain reaction analysis or serology to rodent urine or blood of stupor and hypotension patients, incubation - days isolation required (maximum) mediterranean, southern and black eschar (scab) at site of tick leucopenia, serology east africa, bite of hard tick bite, generalized maculopapular erythematous rash from fourth day, headache, cough typhoid fever worldwide headache, persistent fever, leucopenia, blood culture abdominal discomfort, splenomegaly, rose spots (rare) worldwide, but mainly tropics persistent fever, right upper neutrophil leucocytosis, abdominal pain and tenderness, ultrasonography of liver, serology signs at right lung base african trypanosomiasis visitors to african game parks, chancre at bite site, tachycardia, hypoglycaemia, thrombocytopenia, tsetse fly lymphadenopathy, splenomegaly, thick blood films, serology, consider transient oedema, variable rashes csf examination only after obtaining expert advice mediterranean, middle east, persistent fever and wasting in leucopenia, bone marrow, microscopy, india, east africa and relatively well individuals, polymerase chain reaction analysis, south america, sandflies progressive splenomegaly, culture (nnn medium); skin biopsy or anaemia and lymphadenopathy, buffy coat examination in hiv-positive infants affected in mediterranean patients countries, pyrexia of unknown origin and skin rash in hiv-positive patients bathing in infected fresh water persistent fever, urticaria, diarrhoea, eosinophilia at presentation, ova in (katayama fever) in africa, asia, middle east, liver and splenic enlargement, stool, urine or semen (later only), south america cough serology (later) imaging -chest radiography is useful in patients with respiratory symptoms, bearing in mind legionella infection, tuberculosis (tb) and atypical chest infections. ultrasonography of the liver is required in patients who may have amoebic liver abscess ( figure ). unless the patient clearly has a minor upper respiratory infection, hospital admission for investigation may be necessary for - hours. falciparum malaria must be excluded, and is the diagnosis in - % of patients hospitalized after visiting sub-saharan africa, compared with - % of those returning from asia, who are more likely to have dengue fever. , a combination of geographical and exposure history, presenting syndrome and simple laboratory tests should lead to a sensible working diagnosis ( figure ). more detailed, evidence-based diagnostic algorithms have recently become available and could be adapted for local use. if malaria cannot be excluded in a patient who is severely ill, empirical treatment for sepsis should include quinine. management of malaria is discussed in medicine : , . further investigations and management should be determined by the most likely diagnosis. early therapy is often appropriate before investigations confirm a clear diagnosis; this usually comprises doxycycline for leptospirosis or tick typhus, or a fluoroquinolone when there is a strong suspicion of enteric fever (with or without a third-generation cephalosporin or azithromycin). when viral haemorrhagic fever or multi-drug-resistant tb is suspected, public health authorities must be involved immediately and the patient should be managed in appropriate isolation facilities. rare exotic infections should be discussed with an expert in tropical diseases at the earliest opportunity.  fever from the tropics fever as the presenting complaint of travellers returning from the tropics fever in returned travelers: review of hospital admissions for a year period clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travelers with fever burden and cost of imported infections admitted to infectious disease units in england and wales in and practice guidelines for evaluation of fever in returning travelers and migrants further reading fever in children returning from abroad comprehensive tables and references for all imported diseases; a good starting point.) www.nathnac.org (national travel health network and centre; risks of travel worldwide and preventive measures to reduce risk.) www.promedmail.org/ (promed; an excellent website key: cord- -bzrh fni authors: zambon, maria title: influenza, respiratory syncytial virus and sars date: - - journal: medicine doi: . /medc. . . . sha: doc_id: cord_uid: bzrh fni abstract acute lower respiratory tract infections (lrtis) are a major worldwide health problem, particularly in childhood, and are ranked first among the conditions contributing to the global burden of disease. about – % of acute lrtis are viral in origin; of these, influenza and respiratory syncytial virus (rsv) are associated with the greatest disease burden in humans. vaccination against circulating human influenza strains and the use of neuraminidase inhibitor drugs have improved the options for control of influenza, but as yet there are no successful vaccines or antiviral drugs for use against rsv infection. the recent emergence of the sars coronavirus in the human population in , with an ensuing global epidemic affecting more than individuals with a case fatality of about %, underlines the fact that respiratory viral infections of humans may originate in animals, and that many different influenza a viruses also occur naturally in animal reservoirs, representing a constant threat of zoonotic infections of humans and ensuing global pandemics. avian influenza viruses have transmitted directly to humans from domestic poultry on several occasions in the last decade, and the current extensive burden of disease from avian influenza in south east asia provides a real possibility for the emergence of a novel influenza virus pathogenic in humans. acute lower respiratory tract infections (lrtis) are a major worldwide health problem, particularly in childhood. about - % of acute lrtis are viral in origin; of these, influenza and respiratory syncytial virus (rsv) are associated with the greatest disease burden in humans. the emergence of the severe acute respiratory syndrome (sars) coronavirus in , and the ensuing worldwide epidemic, highlights the fact that respiratory viral infections in humans may originate in animals. many different influenza a viruses occur naturally in animal reservoirs, and present a constant threat of zoonotic infections and global pandemics. influenza viruses are small ( - nm diameter), contain rna and are enveloped. there are three types -a, b, and c. type a is further classified according to the properties of the surface proteins haemagglutinin and neuraminidase. all a subtypes are found in aquatic birds, which are the natural reservoir ( figure ) ; only a few subtypes circulate in humans and other mammals. type b and c influenza have only one subtype and are restricted to humans. seasonal illness, epidemics and pandemics -influenza viruses circulating in humans (a h n , h n , b and c) cause respiratory tract disease. influenza a is generally considered to be clinically more severe than influenza b; influenza c causes only a mild illness confined to the upper respiratory tract. circulation of influenza a and b viruses in humans ( figure ) causes unpredictable seasonal epidemics of disease in temperate climates, with excess population morbidity and mortality, usually occurring between october and march in the northern hemisphere and lasting about - weeks. in the uk, - , deaths are associated with influenza a and b epidemics every year, and more than , in severe years. widespread pandemics of severe disease occur less frequently, occurring on at least three occasions in the last century ( , , ) , and have been associated with high mortality. clinical features -influenza a and b illness in humans ranges from subclinical or mild upper respiratory tract symptoms to more severe illness including laryngotracheitis and pneumonia or, less commonly, death from respiratory system failure. the most common presenting symptoms are cough, high temperature, joint pain and general malaise ( figure ). the rapid onset and short incubation period (about hours) are characteristic, though incubation can last up to days. individuals at greatest risk of complications are those with pre-existing cardiac and respiratory disease, the elderly, and those with impaired immune systems ( figure ). the severity of the illness reflects pre-existing host immunity and the prevailing virus strain. virus variability -protective immunity to influenza is conferred by antibodies. the ability of influenza to cause re-infections is related to the genetic mutability of the virus. in every replication round, mutant viruses are generated, some of which have a growth advantage because they can partially evade host immune responses. variants capable of causing epidemics in susceptible populations emerge by a process termed 'antigenic drift'. new influenza a drift variants arise every - years; influenza b drift variants arise every - years. influenza as a zoonosis -the segmented nature of the influenza genome allows reassortment of segments when a single host is infected with more than one virus. this occurs regularly in aquatic birds, in which almost all combinations of influenza a virus segments can be detected, but is less common in mammals. it was previously thought that, for a novel subtype of influenza to arise in humans, reassortment of two virus subtypes had to occur in a mammal that could then transmit to humans. the pig was considered a suitable 'intermediate host', because both avian and human viruses, which differ slightly in their surface receptor requirements, can replicate in pigs. however, following transmission of h n directly from birds to humans on occasions figure ), it is evident that cross-species barriers to transmission may be less stringent than was thought. nevertheless, the requirements for adaptation of avian viruses to mammals are poorly understood. cross-species transmission of novel subtypes into susceptible human populations (antigenic shift) are thought to be the source of pandemics of influenza. zoonotic infections involving several different subtypes of influenza have occurred in the last few years, indicating the pandemic potential of influenza viruses circulating in domestic poultry. control -the presence of a large, mobile animal reservoir of influenza a virus suggests that eradication of this agent will be impossible. control strategies focus on limiting the opportunities for cross-species transmission of novel subtypes; for example: • housing domestic poultry in shelters to avoid contact with overflying migratory birds • eliminating/reducing live bird markets • housing aquatic birds and domestic poultry separately • slaughtering domestic flocks infected with highly pathogenic influenza a viruses. these measures may achieve some success in preventing zoonotic transmission of influenza a to humans, but have little impact on its annual cycle. unprecedented levels of h circulating in domestic poultry in south east asia present a particularly high risk for emergence of a novel pandemic influenza a strain. immunization -antibodies against haemagglutinin (and, to a limited extent, neuraminidase) can prevent disease caused by the same strain of virus. this is the basis of vaccination for influenza. currently, most vaccines used worldwide are subunit vaccines. however, the high variability of influenza virus means that antibodies to one strain confer only limited protection against drift variants. thus, influenza vaccines are given annually before the influenza season to boost pre-existing immunity, and the composition of the vaccine is updated regularly. in developed countries, the benefit of immunization has led to expansion of age-related vaccination policies. in the uk in , vaccination was introduced for all individuals over years of age, irrespective of pre-existing illness. vaccination rates vary considerably between countries. there is increasing interest in vaccination of children. they induce broader, long-lasting immunity. child vaccination may also help to prevent transmission in the community in general. antiviral drugs -despite the preventive efficacy of vaccination, the need for treatment of severe influenza remains. amantadine (or the related compound rimantadine) was, until recently, the only anti-influenza drug available. it selectively targets a viral protein (m ) and inhibits viral replication, but its use has been limited in the last years, partly because of side-effects (dizziness, confusion) that particularly affect the elderly, and also because drug-resistant mutants arise frequently and can be readily transmitted. neuraminidase inhibitors are a more recently developed, novel class of anti-influenza compounds ( figure ). they act on viral neuraminidase, prevent release of virus particles from infected cells, and are likely to be most efficacious when given early in illness. since , the uk national institute for clinical excellence has recommended that neuraminidase inhibitors may be used for treatment and prophylaxis, with certain restrictions. mutations conferring resistance to neuraminidase inhibitors do not arise very frequently in vivo, and viruses containing them generally lose reproductive fitness and are at a disadvantage in transmission. this suggests that widespread resistance to antiviral drugs is unlikely to emerge and is most likely in treated children, probably because the viral load is highest and therefore the capacity for viral replication in the presence of drugs is greatest. rsv (figure ) is a negative-sense, non-segmented, enveloped rna virus of - nm diameter. it is best known as a cause of bronchiolitis in infants, but can cause respiratory tract infection in all age groups. upper respiratory tract infections (urtis) and lrtis range in severity from subclinical infection to pneumonia and death. more than % of children have been infected with rsv by their first birthday and more than % by years of age; thereafter, individuals are infected approximately every years. rsv infections in adults are probably under-recognized, and the severity of rsv infection in the elderly may be much underestimated as a cause of pneumonia. about % of elderly individuals are thought to become infected with rsv every year. transmission of rsv is primarily through large aerosol droplet or secretions, causing widespread nosocomial infection. outbreaks in adult and paediatric facilities are difficult to control. rsv infection in immunocompromised individuals is severe and lifethreatening; mortality may be - % in adult bone marrow transplant recipients, in whom viral shedding may be prolonged. pathophysiology -rsv infects the respiratory epithelium, leading to increased goblet cell production of mucus. dying infected ciliated epithelial cells combine with mucus to form plugs that block the airways; the consequences are most severe in very small babies with narrow airways. this leads to the characteristic signs and symptoms of atelectasis and the clinical syndrome of bronchiolitis. in rsv bronchitis and pneumonia, the peribronchiolar and interstitial infiltrate is characteristically lymphocytic. clinical features -the severity of rsv infection is related to age. in young infants, the illness is seldom asymptomatic and lasts for - weeks. early signs of infection may include difficulty in feeding, nasal congestion, cough and otitis media compatible with urti. fever is often but not invariably present in rsv infection. abnormal breath sounds, tachypnoea and hypoxaemia suggest lower respiratory tract involvement. bronchiolitis and pneumonia are the two primary manifestations of progression to lrti; they may be difficult to distinguish and can occur simultaneously. the clinical features of bronchiolitis are wheezing and hyperaeration, and these are characteristic of infants with rsv infection. in the usa, rsv is estimated to cause deaths per year in children under years of age. the risk of hospitalization in otherwise healthy under- s is . - %, and - % of children admitted to hospital require mechanical ventilation. these rates are higher in the first months, and may be higher still in children with underlying acquired or congenital cardiopulmonary disease. older children and adults with rsv infection or re-infection usually have a milder or asymptomatic respiratory infection with a lower likelihood of lrti. adults with rsv-associated respiratory tract infections may experience prolonged symptoms. disease in the elderly may be particularly severe; up to % develop pneumonia. investigations -rsv infection is often diagnosed on the basis of the clinical features. the certainty of the diagnosis is increased when rsv is known to be circulating in a seasonal epidemic. chest radiography findings are nonspecific and commonly include hyperaeration and peribronchial thickening, with areas of consolidation and interstitial infiltrates in patients with rsv pneumonia. there is a range of respiratory findings in immunocompromised adults, including pleural effusions. laboratory diagnosis depends on detection of viral antigen in respiratory secretions by immunofluorescence, rapid antigen tests or culture of the virus. serological tests are of little help in diagnosis of rsv infection, because they rely on the use of paired acute and convalescent sera. complications -premature and very young infants are more likely to suffer acute apnoeic episodes and require assisted ventilation. bronchiolitis and pneumonia are the major complications of rsv disease in young children. children with congenital heart disease or chronic lung disease, and immunocompromised children and adults, are also at risk of severe disease. pneumonia is the major complication in adults and the elderly. estimates of the incidence range from % in nursing homes to % in a hospital in-patient population; estimated mortalities in the elderly are - % in the former and - % in the latter. rsv infection has very high mortality ( - %) in severely immunocompromised individuals. management -supportive care is the mainstay of management of rsv disease in infancy. maintenance of oxygenation, hydration and nutrition is essential in hospitalized patients, and ventilatory support may be necessary in severe cases. a trial of bronchodilators may be beneficial. controlled trials of corticosteroids and vitamin a supplementation have not proved efficacy in infant rsv disease. immunization -there are two subtypes of rsv -a and b. the surface glycoproteins f and g are the major antigens of the virus to which neutralizing antibodies are directed. protective immunity to rsv is complex. antibodies generated during natural infection are not necessarily protective. a high proportion of primary rsv infections occur before months of age, when maternal antibody levels are highest. overall, current (controversial) data suggest that neutralizing antibody to rsv is beneficial. neutralizing antibody titres in human sera correlate inversely with the likelihood of hospitalization as a result of rsv infection, and neutralizing antibody titre correlates with a reduced risk of re-infection. immunoglobulin infusions with high neutralizing titres of antibody to rsv (rsvig, figure ) have been used to treat rsv illness in normal-risk and high-risk infants. in normal infants, there is little evidence to justify rsvig for treatment of rsv infection. however, prophylaxis may be useful in high-risk infants (e.g. those with bronchopulmonary dysplasia). assessment of risk is important, because intravenous rsvig is contraindicated in congenital cyanotic heart disease. recombinant humanized rsv monoclonal antibodies are now available for intramuscular treatment and prophylaxis of rsv. early clinical data suggest that this preparation of passive antibodies may have wider application, with fewer limitations than rsvig; however, it is extremely expensive. few antiviral drugs are available for rsv. ribavirin is a guanosine analogue that has been used widely, though its precise mode of action is uncertain and many clinical studies show conflicting results. several studies have raised further doubts about the clinical effectiveness of ribavirin in infants and children at risk of severe rsv disease, and in ventilated children. in most centres, its use is now restricted to the immunocompromised or severely ill. several rsv vaccines (live attenuated, subunit and recombinant) are undergoing clinical trials. development of safe vaccines has been impeded by poor understanding of the factors governing immune protection in different age groups, and early vaccination attempts in which more severe disease was seen in vaccinees. it is likely that there will be significant progress in future and that the types of vaccines suitable for different age groups may differ. transmission -sars cov spread worldwide within weeks in early . the major route of transmission was respiratory, primarily through droplet, secretions and aerosol formation. about % of cases resulted from infection in health-care settings, emphasizing the importance of close contact and exposure to bodily secretions. (the syndrome was noticed through unusual clusters of severe respiratory illness in hospital settings.) peak virus shedding is - days after the onset of illness (figure ). the virus is found in various body fluids. infectious virus has not been recovered later than days after illness onset. neutralizing antibody is detected from about days post-onset. risk factors for sars cov infection are: • close contact with civet cats/racoon dogs • eating/preparing civet meat • laboratory work with sars cov • contact with a known case of sars. clinical features -presentation is with fever and respiratory illness with cough and shortness of breath, progressing to acute respiratory distress syndrome and death in % of cases. fatalities increase significantly over the age of years; mortality is up to % in the over- s. onset of illness is - days post-infection, with a mean of about - days. about % of patients suffer later gastrointestinal symptoms of diarrhoea and vomiting. management and control -specific control measures have not yet been developed, though work is in progress on antiviral drugs and suitable vaccines. during the epidemic, various nonspecific therapeutic measures were used with variable success: • corticosteroids • antimicrobials to prevent secondary bacterial infection • positive-pressure ventilatory support • anti-inflammatory drugs • infusion of antisera from convalescent patients. the epidemic was controlled mainly through public health measures such as contact-tracing and quarantining. this policy was effective because there is little evidence of transmission before symptom onset, so infected individuals are easily identified.  • consider for prophylaxis in infants < years receiving oxygen therapy for bronchopulmonary dysplasia • infants born < weeks with bronchopulmonary dysplasia are likely to benefit from - months' prophylaxis • infants born > weeks with bronchopulmonary dysplasia may not benefit • should not be used in cyanotic congenital heart disease • not evaluated in paediatric or adult immunocompromised patients • main emphasis in nosocomial outbreaks should be infection control; efficacy is improved in such settings • initiate treatment before onset of respiratory syncytial virus season • defer live virus vaccines (e.g. mmr) until last dose the contribution of influenza to acute respiratory infections, hospital admissions and deaths in winter the japanese experience with vaccinating school children against influenza neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir age related differences in humoral immune response to respiratory syncytial virus infection in adults confirmation of a novel corona virus as the primary cause of severe acute respiratory syndrome key: cord- - njpw zz authors: ferguson, neil m title: mathematical prediction in infection date: - - journal: medicine doi: . /medc. . . . sha: doc_id: cord_uid: njpw zz abstract it is now increasingly common for infectious disease epidemics to be analysed with mathematical models. modelling is possible because epidemics involve relatively simple processes occurring within large populations of individuals. modelling aims to explain and predict trends in disease incidence, prevalence, morbidity or mortality. models give important insight into the development of epidemics. following disease establishment, epidemic growth is approximately exponential. the rate of growth in this phase is primarily determined by the basic reproduction number (r ), the number of secondary cases per primary case when the population is susceptible. r also determines the ease with which control policies can control epidemics. once a significant proportion of the population has been infected, not all contacts of an infected individual will be with susceptible people. infection can now continue only because new births replenish the susceptible population. eventually, an endemic equilibrium is reached whereby every infected person infects one other individual on average. heterogeneity in host susceptibility, infectiousness, human contact patterns and the genetic composition of pathogen populations introduces substantial additional complexity into the models required to model real diseases realistically. the contribution concludes with a brief review of the recent application of mathematical models to emerging human and animal epidemics, notably the spread of hiv in africa, the variant creutzfeldt-jakob disease epidemic in the uk and its relationship to bovine spongiform encephalitis in cattle, the foot and mouth epidemic in uk livestock, bioterrorism threats such as smallpox, and the sars epidemics in . an epidemic is a chain reaction of disease spread within a population. epidemics can be described and sometimes predicted by mathematical models because they involve relatively simple processes occurring within large populations of individuals. 'simple' means that infection and disease progression can be characterized by the transition of an individual from one state to another; for example, from a state of being uninfected and susceptible to infection, or to an infected state following contact with an infectious individual, or from the infected to the recovered state following recovery from infection and the acquisition of immunity. defining a model therefore involves classifying the possible infection states of an individual and the processes causing movement between those states. the aim then is to predict changes through time in the proportions of the population in different infection states, and the incidence of disease-related events. this contribution discusses the modelling of epidemics, but similar techniques can be used to study the pathogenesis of viral or bacterial infections within an infected individual. an understanding of basic concepts is informed by consideration of the spread of a new infectious disease within a large population with no prior exposure. this process can crudely be divided into three phases (figure ) , establishment -the epidemic grows from the first infected t individual to a point at which sufficient individuals are infected that random extinction of the disease is unlikely. many epidemics can die out after infection of only one or two individuals, if the last infected individual recovers (or dies) before infecting anyone else. this randomness means that the establishment phase can be relatively long and is variable in duration -a possible explanation for the several decades that passed between hiv entering the human population before and the recognition of a large-scale epidemic in the early s. exponential growth -growth of epidemics is approximately exponential following disease establishment. how fast an epidemic grows is largely determined by two factors -the number of secondary cases generated by one primary case when the epidemic starts (the basic reproduction number, r ) and the average time taken for secondary cases to be infected by a primary case (generation time, t g t t ). r characterizes the intrinsic transmissibility of infections and depends on both disease biology (determining neil m ferguson is professor of mathematical biology in the department of infectious disease epidemiology at imperial college london, uk. infectiousness) and host population structure (determining contact rates). t g t t is largely determined by the incubation period of the disease and the duration of infectiousness. r > is essential to epidemic growth because, for an infection to be self-sustaining, every infected individual must infect at least one other. the target of vaccination campaigns is to reduce r below , thereby driving the disease extinct. endemicity -once a significant proportion of the population is immune, dead or chronically infected, not all contacts of an infected individual are with susceptible people. hence, the number infected by one individual is now reduced by the proportion of the population that is no longer susceptible. this causes the incidence of new infections to decline, and when the susceptible population is exhausted, the primary epidemic is over. disease extinction is again possible by chance, particularly in small populations. otherwise, infection continues, with new births replenishing the susceptible population, and eventually an endemic equilibrium is reached in which every infected person infects one other individual on average. from the definition of r , this occurs when /r of an individual's contacts are susceptible at any point in time, and thus r not only determines the epidemic growth rate, but also the proportion of the population that are infected by the disease, and the steady-state incidence of infection. in theory, knowledge of r (and the duration of infectiousness) enables simple prediction of many key aspects of epidemic and endemic disease transmission. in reality, estimation of multifactorial quantities such as r is problematic, except in some childhood diseases (e.g. measles) for which serological data can be used. disease epidemiology typically has many additional complexities: establishment exponential growth endemicity epidemics spread through contact (e.g. person to person) the 'chain reaction' nature of the process results in exponential growth (once infected numbers are great enough to make random effects small), until there are no further susceptible contacts medicine : • the nature of the transmission process (e.g. insect-borne, foodborne) • heterogeneities in the pathogen population (e.g. multiple strains with different virulence and antigenic properties) • patterns of host contact (e.g. stronger mixing within age-defined or geographically defined peer groups than without, variability in contact rates because of differences in, for example, sexual behaviour) • long and variable incubation periods (e.g. hiv) • seasonally varying contact rates (e.g. measles). incorporation of this complexity is often essential to generate a model that it is not just qualitatively reasonable (in the sense of reproducing the basic pattern of observed trends), but capable of quantitative predictions. sufficiently realistic models thus tend to incorporate multiple parameters that must be estimated from available epidemiological, clinical and behavioural data. biostatistical techniques for such estimations are developing rapidly, but many problems remain, largely caused by the non-linear nature of transmission models and the extremely complex dynamics that they sometimes produce; this can include chaotic behaviour and stochastically induced intermittency in epidemic timing. dynamic complexity can also place fundamental limits on the predictability of trends in the incidence of infectious disease. in some cases, short-term prediction of the course of an epidemic may be possible. in others, models may be predictive only in a probabilistic sense; for example, it might be possible to predict the number of epidemics of a certain size likely to occur in the next years, but impossible to precisely predict weekly disease incidence over the next few months. distinguishing these situations is a key challenge in epidemic modelling. despite these challenges, most infectious diseases have now been modelled, and modelling has achieved notable successes in recent years ( figure ). • trends in the incidence of hiv in southern africa in the last years have validated predictions made more than years ago (and then often dismissed) that aids would reverse population growth in sub-saharan africa in the st century. • models have given insights into the potential scale and duration of the epidemic of variant creutzfeldt-jakob disease caused by the bovine spongiform encephalitis epidemic in cattle. • in the uk in , mathematical models had a pivotal role in shaping disease-control policy during the foot and mouth epidemic in livestock -the first example of real-time application of such techniques. • during the severe acute respiratory syndrome epidemic in , epidemiological analysis and modelling quantified key and then unknown disease parameters such as incubation period distribution, case mortality rate and transmissibility (as quantified by r ). • greater computer power and improved statistical techniques are enabling construction of increasingly realistic simulation models, which are having a key role in contingency planning for bioterrorism and influenza pandemic planning. the spread of hiv- in africa -sexual contact patterns and the predicted demographic impact of aids the role of mathematical modelling in the control of the fmd epidemic in the uk in , mathematical models were used to predict the course of the foot and mouth disease epidemic in uk livestoc k k, and to evaluate the potential effect of control measures. the predictions above were made by a team at imperial college london and released by the uk government in early april . k they indicated that additional culling or vaccination at farms f f neighbouring infected farms was nec f f essary to control the epidemic; simply accelerating the slaughter of animals at infected farms was insufficient.in , models were used to analyse the sars epidemic. the graph below shows the fit of a model to the epidemic in hong kong. this analysis showed that r for sars was about .