key: cord-0001196-r0rfjs05 authors: Wu, Peng; Cowling, Benjamin J.; Wu, Joseph T.; Lau, Eric H. Y.; Ip, Dennis K. M.; Nishiura, Hiroshi title: The epidemiological and public health research response to 2009 pandemic influenza A(H1N1): experiences from Hong Kong date: 2012-08-09 journal: Influenza Other Respir Viruses DOI: 10.1111/j.1750-2659.2012.00420.x sha: bd42860179bf3032b5da35bf4cba948603f8dc10 doc_id: 1196 cord_uid: r0rfjs05 In recent years, Hong Kong has invested in research infrastructure to appropriately respond to novel infectious disease epidemics. Research from Hong Kong made a strong contribution to the international response to the 2009 influenza A (H1N1) pandemic (pH1N1). Summarizing, describing, and reviewing Hong Kong’s response to the 2009 pandemic, this article aimed to identify key elements of a real‐time research response. A systematic search in PubMed and EMBASE for research into the infection dynamics and natural history, impact, or control of pH1N1 in Hong Kong. Eligible articles were analyzed according to their scope. Fifty‐five articles were included in the review. Transmissibility of pH1N1 was similar in Hong Kong to elsewhere, and only a small fraction of infections were associated with severe disease. School closures were effective in reducing pH1N1 transmission, oseltamivir was effective for treatment of severe cases while convalescent plasma therapy has the potential to mitigate future pandemics. There was a rapid and comprehensive research response to pH1N1 in Hong Kong, providing important information on the epidemiology of the novel virus with relevance internationally as well as locally. The scientific knowledge gained through these detailed studies of pH1N1 is now being used to revise and update pandemic plans. The experiences of the research response in Hong Kong could provide a template for the research response to future emerging and reemerging disease epidemics. The emergence of the 2009 influenza A(H1N1) pandemic (pH1N1) and the rapid global spread in 2009 was surprising for a number of reasons. 1 The pandemic virus came from a reassortment event in swine rather than birds, was a strain of H1N1 rather than a subtype that was not concurrently circulating in humans, and appeared to have a mild severity profile similar to seasonal influenza. Furthermore, the pandemic emerged in North America, whereas most attention had been focused on the risk of a novel virus emerging in south-east Asia. 2, 3 Hong Kong, a subtropical city on the south coast of China, has been identified with influenza research for decades; indeed, the 1968 pandemic influenza A(H3N2) virus was named after the city after being first identified there in July 1968. 4 Hong Kong has found itself on the front lines of recent emerging infectious disease outbreaks, including the first human outbreak of highly pathogenic avian influenza A(H5N1) in 1997, 5 and the severe acute respiratory syn-drome (SARS) outbreak from 2002-2003, which spread from southern China through Hong Kong to the rest of the world. Following SARS, the Centre for Health Protection was established to take a leading role in the prevention and control of diseases in Hong Kong. In 2004, the Hong Kong Government created the Research Fund for the Control of Infectious Diseases with an endowment of US$57 million, aiming to encourage, facilitate, and support research on the prevention, treatment, and control of infectious diseases. The population of Hong Kong have on one hand been sensitized to the risk of emerging infectious diseases through these experiences in the last 15 years, while Hong Kong's close connectivity to China and south-east Asia has led to fears that it may be one of the first developed cities affected by a novel pathogen such as a new pandemic influenza strain that emerges in the region. 3 As a result, Hong Kong has invested heavily in infrastructure in preparation for future epidemics and pandemics. There has also been substantial investment in research infrastructure, essential to guide evidence-based policy locally as well as internationally. Following the World Health Organization (WHO) global alert in April 2009, Hong Kong health authorities initially operated under containment efforts, including entry screening at airports, ports and border crossings, hospital isolation of cases, tracing and quarantine of contacts, and routine antiviral prophylaxis. Once the first local case was identified on June 11, Hong Kong transitioned to mitigation efforts, with greater attention to public health promotion of preventive measures. All kindergartens and primary schools were closed from June 12 until summer vacation in early July, while 43 secondary schools were closed after 1 or more confirmed case was identified. Incidence peaked in September, and the first wave petered out by early November. Confirmed pH1N1 infection was a notifiable disease throughout the first wave. Figure 1 summarizes a timeline of the first wave of pH1N1 in Hong Kong. Here, we review the epidemiological and public health research response to pH1N1 in Hong Kong. Summarizing, describing, and reviewing the Hong Kong's response to the 2009 pandemic, this article aimed to identify key elements of the successful real-time research response. In particular, we consider some of the factors that facilitated a rapid and comprehensive research response to pH1N1 that could be a potential template for the research response in other countries. Studies were retrieved from the electronic databases PubMed and EMBASE on April 19, 2012 . We used the following free text search terms ( OR OR OR OR in 'Title ⁄ Abstract') AND ( in 'Title ⁄ Abstract' or 'Affiliation') to identify studies on pH1N1 in Hong Kong. We also limited the search to articles published after the WHO issued the first alert on the novel H1N1 virus (April 24, 2009). Therefore, we included papers that were published within 3 years of the identification of pH1N1. Other relevant studies identified by the authors were manually retrieved. All titles of the papers identified by the search strategy were independently screened by two authors (P. W. and B.J.C.). Abstracts (plus full text) of manuscripts with potentially relevant titles (abstracts) were reviewed for eligibility. Articles were considered as eligible when falling under one or more of three following categories of interest: (i) studies on the epidemiological dynamics and clinical course of infection with pH1N1, including transmission, severity, risk Details of the included studies were examined to identify the focal interests of research, the study design and the data used in the study, and the key findings of the study were extracted. The studies were analyzed according to the categories listed above. Articles could be included in more than one category. Based on the data, we enumerated essential components of findings that were independently covered in Hong Kong through its own epidemiological studies. Three hundred and seventy-six titles were identified through the database search. Of the 85 articles assessed for inclusion after examining the abstracts, we excluded 30 articles, which belong to case reports, commentaries, views, reviews, studies on genetics, or duplicate studies. Fifty-five full-length articles were finally included in this review ( Figure 2 ). Articles relevant to infection dynamics and natural history, impact, or control are listed in Tables 1-3 , respectively. All of the studies were conducted by first authors whose primary affiliation was an institute in Hong Kong. All studies were supported by local funding, including 32 (58%) that were supported by the Research Fund for the Control of Infectious Diseases. In addition, 13 (24%) studies acknowledged funding from international sources. Of the 22 studies investigating pH1N1 infection dynamics and natural history, 14 described the epidemic dynamics of pH1N1 transmission, [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] three examined the risk of infection and ⁄ or severity of the disease, [20] [21] [22] and five studies assessed clinical features of pH1N1 infection [23] [24] [25] [26] [27] ( Table 1) . The initial effective reproduction number was estimated to decrease from around 1AE4-1AE5 at the start of the epidemic to around one during the school closures and summer vacations based on patterns in the incidence of confirmed cases and hospitalizations. 9,10 Geographical clustering of confirmed cases was observed. [14] [15] [16] The risk of confirmed secondary pH1N1 infection among household contacts of 65 confirmed index cases was estimated at around 6% in a contact investigation of a school outbreak of pH1N1. 13 Another household transmission study found that the risk of confirmed secondary pH1N1 infection was similar for pH1N1 and seasonal influenza in 99 households. 18 Children appeared to be more susceptible to infection 13 and more infectious than adults. 18 Similarity in household transmissibility of pH1N1 and seasonal influenza was also observed in a prospective household cohort study during the pandemic. 12 Seasonal influenza and pH1N1 had similar patterns of viral shedding, 18 clinical presentation, 25 and risk of admission to an intensive care unit (ICU) and death, 24 while hospitalized patients with pH1N1 infection tended to be younger and have higher mortality rates and higher frequency of complications, 21 with different patterns of preexisting risk factors of severe disease. 24 One small case-control study could not confirm whether serum immunoglobulin G2 deficiency was a risk factor for severe infection. 20 A series of serologic studies were conducted in Hong Kong to estimate the cumulative incidence of infection through the course of the first wave. 7, 8, 11, 19, 26 These studies indicated that about half of all children and 10-15% of the population had been infected with pH1N1 during the first wave of the pandemic. In combination with data on the number of hospitalizations, ICU admissions, and deaths associated with confirmed pH1N1, these serologic studies were also used to infer the severity profile of pH1N1 infection. While only around 10 and 1 per 100 000 infections were associated with admission to ICU or death in children, respectively, the risk of severe disease increased substantially with age to 220 per 100 000 in those aged 60 years or older. 7, 19 Serologic surveillance has the potential to provide timely estimates of transmissibility and severity in the next pandemic. 8 A serologic study found similar seroprevalence among healthcare workers compared with the general community, 22 while another study estimated similar risk of confirmed pH1N1 infection among clinical Among the 27 studies describing the impact of pH1N1, six reported the clinical impact, [6] [7] [8] 10, 11, 19 20 investigated psychological and ⁄ or behavioral responses to pH1N1 infection, [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] and one study reported changes in the dynamics of circulating respiratory viruses potentially caused by the emergence of pH1N1 48 ( Table 2) . No studies were identified that investigated the economic impact of pH1N1. During the first wave in Hong Kong between April and December 2009, there were 7508 hospitalizations, 148 ICU admissions, and 63 deaths associated with pH1N1. 7, 8, 10, 11, 19 One study estimated that there were 127 excess deaths associated with pH1N1, approximately double the number of deaths of confirmed cases. 6 In the early stage of the pandemic, the local population generally did not perceive pH1N1 infection to be a threat nor estimate a high possibility of having a local outbreak. 31 In another serial cross-sectional study, the perceived susceptibility to and severity of pH1N1 infection were fairly stable. 30 Avoidance behaviors, such as hand washing, mask wearing, or social distance, had been taken by many respondents since the beginning of the pandemic, 30, [32] [33] [34] while social distancing measures declined in its frequency through the course of the first wave. 30 Preventive measures taken by the population against the pandemic were dependent on a variety of factors, such as knowledge about the virus 30 and the efficacy and adverse effects of protective measures, 44, 46 perceived risk of infection, 45 trust in formal ⁄ informal information about pH1N1, 37 and previous experiences with avian influenza and SARS. 29 A study conducted in July 2009 reported reasonable acceptability of the pH1N1 vaccine, with around 50% of survey respondents reporting intention to receive pH1N1 vaccine for free, declining to 15% if the cost of the vaccine was higher than US$25. 41, 42 The government subsequently ordered 3 million doses of pH1N1 vaccine for the local population of 7 million, and began distribution in December 2009. However, pH1N1 vaccine uptake was low, with <250 000 doses administered mainly to the elderly and healthcare workers. A subsequent longitudinal study found that intention to receive vaccine was an unreliable predictor of subsequent vaccine uptake. 44 Among healthcare workers, a study conducted in May 2009 found around 50% of survey respondents willing to receive pH1N1 vaccine. 45 Another study of community nurses in June 2009 found only 27% reporting willingness to receive pH1N1 vaccine. 40 Uptake of the monovalent pH1N1 vaccine was associated with previous seasonal Case-control study In the clinical setting, treating severe pH1N1 infections with convalescent plasma could reduce respiratory tract viral load, serum cytokine response, and mortality of the patients influenza vaccination history, and fear of side effects. 46, 49 Given the essential role of healthcare workers in fighting against the pandemic, their responses to the pandemic were also investigated. Around one-quarter of community nurses reported being unwilling to take care of patients during the pandemic. 39 However, during the pandemic period, healthcare workers who worked in isolation wards showed a general willingness and strong sense of duty to work. 38 Information on the effectiveness and impact of control measures on pH1N1 was reported in 14 studies 9,13,49-60 ( Table 3 ). In terms of public health measures, one study estimated that the entry screening measures adopted by Hong Kong and other countries could not have delayed local transmission substantially. 59 Closure of kindergartens and primary schools from mid-June to July 2009 was estimated to reduce transmission within children by 75%. 9 Treatment of pH1N1 patients with oseltamivir was demonstrated to be effective in suppressing viral load and shortening duration of viral shedding when administered within 48 hours of illness onset, 50,51 and empirical treatment was found to be a cost-effective strategy for managing patients hospitalized with severe respiratory infection suspected of influenza. 52 Treatment of severe pH1N1 infections with hyperimmune intravenous globulin produced from convalescent plasma collected from recovered patients was able to the risk of death by 80% and to improve the profile of viral shedding and cytokines in a small number of patients with severe illness. 56 The logistical feasibility of passive immunotherapy was demonstrated in scenarios with relatively lower donor percentage (5-15%) and limited capacity of blood screening and processing. 57 No studies reported efficacy or effectiveness of the monovalent pH1N1 vaccine in Hong Kong. One study investigated the efficacy of seasonal trivalent inactivated vaccine and found some evidence that vaccinated children might face a higher risk of pH1N1, although the biological mechanism was unclear. 53 In a cohort of institutionalized elderly followed through 2010, dual vaccination with the monovalent pH1N1 and trivalent seasonal vaccines was estimated to reduce all-cause mortality by 54% and 74% compared with seasonal vaccine alone and no vaccine, 54 although surveillance data indicated that pH1N1 was not prevalent during this period. In a hospital setting, not wearing a mask was a possible risk factor for nosocomial transmission. 58 The epidemiological and public health research response to pH1N1 in Hong Kong covered many essential areas of research into pH1N1 epidemiology (Table 4 ). In particular, integration of different expertize from various angles of 64 The general public, perhaps sensitized by previous experiences with infectious disease epidemics including SARS, showed little concern or behavioral changes once the mild severity profile of pH1N1 became clear. 28, 30, 32, 37 School closures were effective in suppressing transmission, although incidence rose rapidly once schools reopened in September and half of the school-age children were infected by the end of the first wave. 8 The use of convalescent plasma to treat severe infections was shown to be feasible in a pandemic 57 and evidence of its effectiveness albeit from a small study should justify further studies. 56 While we focused on research into the epidemiology, impact, and control of pH1N1, much important research on pH1N1 has been carried out in other areas outside the scope of our review. To give two specific examples, local researchers confirmed the origins of the 2009 pandemic strain by comparison with a detailed local swine influenza surveillance program, 65 and performed important basic studies on pathogenesis. 66 Two sets of studies made particularly important contributions to international knowledge on pH1N1 epidemiology. First, household transmission studies allowed detailed inferences on the transmissibility of pH1N1 as well as the (mild) clinical profile of cases in the community. 12, 13, 18 Household studies have the unique advantage of a natural setting that allows comparisons of transmission characteristics and the effects of host, viral, and environmental factors on transmission. While the highest pH1N1 infection attack rates occurred among school-age children, investigations of school outbreaks can tend to overestimate transmissibility because of selection bias where larger outbreaks are more likely to be identified and studied. Second, serologic studies allowed robust inference on the cumulative incidence of infection through the first wave of pH1N1, 7, 8, 11, 19, 26 and when combined with surveillance data on severe cases allowed accurate Seroepidemiological studies permitted straightforward estimation of the age-specific cumulative incidence of infection (7, 8) Descriptive epidemiology with respect to time, space, and person The effective reproduction number was around 1AE4-1AE5 at the start of the epidemic (10) The probability of confirmed infection among household contacts was around 9% and similar to seasonal influenza, while children had a higher risk of being infected compared with adults (12, 18) Geographic clustering of confirmed cases was identified (15) Psychological responses among the general population were assessed (28-46) The age-specific risk of severe illness and death was estimated on a per-infection basis (7, 8) Identification of risk factors Healthcare workers were not at particularly high risk of infection (17, 22) Underlying comorbidities of severe cases with pH1N1 were different from those for seasonal influenza (24, 70) Pharmaceutical interventions Timely antiviral therapy (<48 hours of symptom onset) with oseltamivir could reduce viral load, duration of viral shedding among patients, and protect contacts against infection (13, 50, 51) Intention to receive the pandemic vaccine was low in the general population and healthcare workers (40) (41) (42) (44) (45) (46) Passive immunotherapy might reduce the risk of mortality by around 80% in severe pH1N1 infections (56) Non-pharmaceutical interventions School closures can reduce intra-age-group transmission among children by 70% and overall transmission by 25% (9) Entry screening did not yield substantial delay in the spread of pH1N1 (59) Mask wearing might prevent nosocomial infection among healthcare workers (58) estimates of the severity profile of pH1N1 on a per-infection basis. 7, 8, 11, 19 It can be challenging to estimate the cumulative incidence of infection based on data on numbers of confirmed cases, or from routine surveillance of illnesses presenting to healthcare settings, because of the unknown proportion of infections that are subclinical and potential changes in healthcare-seeking behavior in a pandemic. 67 The rapid and comprehensive research response to pH1N1 in Hong Kong can be attributed to a number of factors, such as improvements in public health infrastructure, creation of a supportive environment for academic research, and sustained development of multidisciplinary academic expertize (Table 5) . There were some limitations of the research response. While the unique setting in Hong Kong facilitated some of the studies discussed here, the uniqueness was also a limitation when considering the generalization of research findings. Given the importance of children in the spread of influenza, greater attention could have been given to outbreak dynamics in schools and in particular the many outbreaks in September 2009 once schools reopened after summer vacation. Oseltamivir was widely prescribed to confirmed cases including those with mild disease, yet there has been no systematic evaluation of the effectiveness or cost-effectiveness of this policy. Finally, there has not yet been a thorough investigation of the dynamics of the second wave of pH1N1 in January-February 2011, which unexpectedly had a similar clinical impact to the first wave. Considering future infectious disease epidemics, Hong Kong may be one of the few settings where we have the opportunity to conduct a more concerted and consolidated investigation of the epidemic at an individual level. For instance, we believe that Hong Kong is equipped with the infrastructure to plan a multidisci-plinary (i.e., clinical, epidemiological, and virological) program of investigation of early cases such as the first few hundred (FF100) study in the United Kingdom in 2009. 68 There are some limitations of our review. First, our review only included studies published within around 3 years of the start of the pandemic, and some studies may not have been published yet or may even be ongoing. While the pH1N1 virus was not prevalent through 2010, a second wave of infection occurred in January and February 2011 with a similar clinical impact to the first wave, although detailed epidemiologic examinations of the second wave have not yet been reported. Second, Hong Kong is a densely populated city with a developed economy, and some epidemiologic findings may not generalize to other settings. For example, transmission dynamics may vary owing to the high population density or the subtropical environment, mortality among hospitalized patients may be lower than in other settings with less investment in healthcare facilities, while the population impact may differ owing to the unique historical experiences of the local population with infectious diseases. Nevertheless, many aspects of pH1N1 epidemiology appear to have been similar in Hong Kong to other developed settings. In conclusion, there was a rapid and comprehensive research response to pH1N1 in Hong Kong, providing important information on the epidemiology, impact, and control of the novel virus with relevance internationally as well as locally. The scientific knowledge gained through detailed studies of pH1N1 is now being used to revise and update pandemic plans and preparedness. The experiences of the research response in Hong Kong may also provide a template for the research response to future emerging and reemerging disease epidemics. Improvement of public health infrastructure Establishment of the Centre for Health Protection in 2004 to improve preparedness and response to disease outbreaks Establishment of scientific committees in the government early in the pandemic to provide guidance to policy makers Creation of a supportive environment for academic research Identification of the essential role of scientific evidence in guiding health policy and consequently building capacity in infectious disease research Encouragement and development of a multidisciplinary research approach through collaborative studies and regular joint meetings Establishment of a system for rapid review and funding for projects in public health emergencies Expedited IRB review and approval procedures to ensure rapid initiation of research projects during public health emergencies Sustained development of multidisciplinary academic expertize Maintenance of routine active research into influenza across disciplines Initiation of a rapid 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This work received financial support from the Harvard Center for Communicable Disease Dynamics from the National Institute of General Medical Sciences (grant no. U54 GM088558), and the Area of Excellence Scheme of the Hong Kong University Grants Committee (grant no. AoE ⁄ M-12 ⁄ 06). HN is supported by the JST PRESTO program. The funding bodies were not involved in the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. BJC has received study funding from MedImmune Inc and consults for Crucell MV. DKMI has received study funding from F. Hoffmann-La Roche. The authors report no other potential conflicts of interest. We declare that we have each participated in the conception, design, analysis, and writing of the report and that we have read and approved the final version.