學校停課在世界各國的流感大流行應對方案中常被列為一項社區緩疫措施，而這項措施亦在2009年H1N1流感大流行中被廣泛地使用。然而，這項緩疫措施經常被質疑是否恰當，原因是因為停課會對教育構成重大的影響，而且過往的流行病學硏究亦表示這項緩疫措施不一定有效。本論文硏究學校停課對2009年H1N1流感大流行在香港首5個月疫情中降低大流行流感傳播的效能。 / 在香港，在該大流行流感病毒於2009年4月在美國被發現後，香港政府實施了控疫措施(containment phase measures)，並開始對該流感大流行進行監測。為了判定大流行是否已在香港內蔓延，衛生防護中心設定了一個報告準則來讓本地醫生報告疑似大流行流感感染個案，並為每個懷疑個案作確診測試及為每個確診個案追溯感染源頭。當大流行流感在6月開始在香港內蔓延時，香港政府實施了緩疫措施(mitigation phase measures)。在緩疫措施底下，帶有流感病症的病人求診於指定流感診所和公共醫院急症室會被測試是否感染大流行流感，而停課措施亦在此時開始實行去減低大流行流感的傳播。停課措施一直維持至7月直至暑假開始，並經修改後於9月開學時繼續實行。在9月，鑑於已不再需要對流感大流行進行監測，對懷疑感染個案進行確診測試的政策止於該月下旬。確診個案中記錄了的病人資料，與及由學校停課和暑假所引起的學期變化，為這課題提供了一個理想硏究的機會。 / 在2009年的5月至9月，一共確診了27,687宗大流行流感個案。在確診個案中，所有個案都記錄了確診者的年歲和確診日期，而88%確診者提供了一個可定位的住宅地址。為了觀察學校停課的緩疫效果，本硏究定義了5個社會經濟年齡級別(socio-economic age classes) (當中包括有小學生和中學生)，並繪製了年齡級別與地域特定的疫情曲線(age-class-and-district-specific epidemic curves)。所有的疫情曲線在大流行流感在6月開始在香港蔓延後均穩步上升，而在屬於小學生和中學生的疫情曲線中能看到一個不尋常的上升出現在9月新學年開始時，意味著中小學生在學校的活動提升了大流行流感在他們之間的傳播。 / 先前，學校停課對減低2009年H1N1流感大流行在香港的傳播已被Wu et. al (2010a)進行了調查。透過使用一個具年齡結構的SIR模型(age-structured SIR model)來分析收集至8月27日的監測數據，該硏究表示流感大流行的傳播在暑假開始時減低了25%。在這研究中，我應用了Wu et. al (2010a)的方法來分析整個監測期間所收集的數據。在發現到該數學模型不能準確地擬合附加的監測數據後，我在該模型添加了兩個傳播特徵(當中包含兒童和成人之間的傳染在學校停課期間增加)去更準確地代表現實中的疫情。我的硏究顯示，學校停課雖然降低了兒童的感染率，但卻增加了成年人的感染率，令整體傳播在暑假開始時只減低了7.6%。這硏究結果表示，在將來的流感大流行中，封閉學校不大可能延遲流感大流行疫情至一個可令疫苗產生作用的程度，而且封閉學校可能會增加成人的感染率，從而有可能導致社會運作出現更混亂的情況。 / School closure is often included in national pandemic influenza response plans as a community mitigation measure and it was widely applied in Pandemic (H1N1) 2009. However, the appropriateness of this intervention is often questioned, as school closure causes major disruption to the education system and past epidemiological studies reveal this intervention is not necessarily effective. The present thesis evaluates the effect of school closure in mitigating transmission of Pandemic (H1N1) 2009 in Hong Kong in the initial 5 months of the pandemic. / In Hong Kong, following identification of the pandemic virus in US in April 2009, the government implemented containment phase measures and began surveillance on the pandemic. The Centre for Health Protection established a reporting criteria for doctors to report suspected cases of pandemic infection for laboratory confirmation, and the source of infection of confirmed cases was traced to determine if the pandemic was spreading locally. When local transmission of the pandemic began in June, the government began mitigation phase measures, in which patients with influenza-like- illness seeking treatment at designated flu clinics and public hospital emergency departments were tested for pandemic infection, and school closure was implemented for pandemic mitigation. The school closure policy lasted until summer holiday commenced in July, and was revised and continued in September when the new school season started. At the end of September, in view of pandemic surveillance was no longer useful, laboratory testing for suspected pandemic cases was halted. Patient demographic data collected from confirmed pandemic cases, together with temporal changes in school session induced by school closure and summer holiday, provided an ideal opportunity for investigation. / From May through September 2009, a total of 27,687 pandemic cases were confirmed, in which the age and confirmation date were recorded in all cases, and 88% provided a locatable residential address. To visualise the mitigative effect of school closure, 5 socio-economic age classes (which include primary and secondary school-aged children) were defined, and age-class-and-district-specific epidemic curves were constructed. All epidemic curves rose steadily after local transmission began in June, and an unusual upsurge in the epidemic curve of primary and secondary school-aged children is observed when schools resumed session in September, suggesting school session facilitated transmission amongst them. / Previously, the effect of school closure in mitigating Pandemic (H1N1) 2009 transmission in Hong Kong was investigated in Wu et al. (2010a). By analysing surveillance data collected as of 27 August with an age-structured susceptible- infectious-recovered (SIR) model, the study reported transmission was reduced by 25% when summer holiday commenced. In this study, I adapted the methodology in Wu et al. (2010a) to analyse data collected in the entire surveillance period. Upon observing the model fitted poorly to the additional data, I added 2 transmission features to the model (which include increased transmission between children and adults during school closure) to better represent the epidemic in reality. My analysis revealed that while school closure reduced incidence in children, it increased incidence in adults, leading to a reduction in overall transmission by only 7.6% when summer holiday started. The findings of this study suggest that school closure in a future influenza pandemic is unlikely to be able to delay the pandemic for vaccine to arrive in time, and that implementing this intervention may increase incidence in adults, which may lead to causing more disruption on the functioning of society. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chau, Kwan Long. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 148-154). / Abstracts also in Chinese. / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Influenza --- p.2 / Chapter 1.2 --- Public health response to pandemic influenza & School closure --- p.8 / Chapter 1.3 --- Pandemic (H1N1) 2009 --- p.13 / Chapter 1.4 --- Hong Kongs response to Pandemic (H1N1) 2009 --- p.17 / Chapter 1.5 --- Data and Research Objective --- p.24 / Chapter Chapter 2 --- Descriptive and Exploratory Analysis of Surveillance Data --- p.31 / Chapter 2.1 --- Introduction --- p.31 / Chapter 2.2 --- Methodology --- p.36 / Chapter 2.3 --- Results --- p.40 / Chapter 2.4 --- Discussion --- p.57 / Chapter Chapter 3 --- Evaluating the effect of School Closure by Modelling --- p.62 / Chapter 3.1 --- Introduction --- p.62 / Chapter 3.2 --- Methodology --- p.90 / Chapter 3.3 --- Results --- p.98 / Chapter 3.4 --- Discussion --- p.105 / Chapter Chapter 4 --- Discussion --- p.108 / Chapter 4.1 --- Study Findings --- p.108 / Chapter 4.2 --- Study Limitations --- p.109 / Chapter 4.3 --- Comments on using school closure in future influenza pandemics --- p.111 / Appendices --- p.116 / Bibliography --- p.148

Resumo Introdução: A Vigilância Sanitária se constitui como campo de intervenção da Saúde Pública tendo como uma de suas responsabilidades, garantir o controle sanitário de aeroportos e a proteção da saúde dos viajantes. Objetivo: Neste sentido, o presente estudo teve como objetivo conhecer, descrever e analisar a prática sanitária adotada frente à Pandemia de Influenza A (H1N1) 2009, pela Vigilância Sanitária no Terminal de Passageiros do Aeroporto de Guarulhos. Metodologia: A pesquisa qualitativa foi adotada, tendo como referencial teórico as representações sociais. Utilizou-se o referencial metodológico da hermenêutica dialética, fazendo uso de uma abordagem interpretativa reconstrutiva das falas dos entrevistados. A construção das três categorias empíricas Trabalho, Comunicação, Intersetorialidade - permitiu resgatar junto às falas dos profissionais pesquisados a prática vivenciada pela Vigilância Sanitária durante a pandemia. Resultados: Pôde-se apreender que as dificuldades evidenciadas durante a Pandemia de H1N1 estiveram relacionadas aos recursos humanos, à estrutura física e de material, ao fluxo de procedimentos e de informações. Conclusões: Os resultados evidenciaram a prática da VISA associada diretamente a sua estrutura organizacional; a uma atuação coadunada com o desenvolvimento atual do país; e uma experiência que serviu como o mais importante e único teste de enfrentamento para uma pandemia de influenza / Abstract Introduction: The Health Surveillance is a field of Public Health with the one of its responsibilities to ensure the sanitary control of airports and heath protection of travelers. Objective: In this sense, the present study aimed to understand, describe and analyze the sanitary practice adopted on the face of Influenza A (H1N1) Pandemic in 2009, by the Health Surveillance Agency in the passengers arrival gates of Guarulhos Airport. Methodology: The qualitative research was adopted in this study, using as a theoretical reference the social representations. In this document it was used the referral method of Hermeneutic Dialectic, using the interpretation of the interviews. It was built three empirics categories, which allowed retrieving in the interviews the practical experience of the employees of the Health Surveillance during the Pandemic period. Outcomes: It could be learnt that the difficulties during the A H1N1 Pandemic was related to the human resources, physical and material infrastructure and the process and information flows. Conclusion: The outcomes emphasized the way the Health Surveillance works directly linked to its organizational structure; its behavior, aligned with the current Brazil situation; and the experience which was a unique test of how they face the Influenza pandemic

Introdução: Desde 1999, o serviço público de saúde tem promovido a vacinação anual de idosos contra a gripe no país. Poucos estudos avaliaram a efetividade da intervenção focalizando especificamente sua contribuição para a redução da mortalidade atribuível aos surtos de gripe. Objetivos: O presente estudo teve como propósito comparar a mortalidade por gripe e pneumonia de idosos (65 anos ou mais) antes e depois do início da vacinação nas regiões Nordeste e Sul do Brasil, e comparar os resultados obtidos para cada região, procurando referenciar hipóteses relativas às diferentes condições climáticas e condições socioeconômicas. Métodos: Dados oficiais de população e de mortalidade por gripe e pneumonia foram levantados junto às agências governamentais (Fundação IBGE e DATASUS) responsáveis pelo gerenciamento dessas informações. Foram estimados coeficientes semanais de mortalidade com ajuste por diferenças na distribuição por sexo e por idade. Para a identificação de surtos de gripe e a estimação da mortalidade especificamente atribuível a esses surtos, foi utilizado o modelo de Serfling. As taxas foram estudadas para os períodos 1999-2009 (em que a vacinação foi realizada) e 1996-1998 (em que a vacinação não foi realizada). Foram descritas e analisadas a magnitude das taxas em cada período, sua possível redução associada à vacinação e a ocorrência de variação sazonal. Os indicadores resultantes da comparação entre os dois períodos foram objeto de análise comparativa entre as regiões Nordeste e Sul. Resultados: Durante o período de vacinação, a média anual do número de períodos com excesso de mortalidade foi reduzida em 32,8 por cento na região Sul; em 4,5 por cento na região Nordeste. Na região Sul, a duração média de tais períodos foi reduzida em 66,2 por cento e a mortalidade por semana foi reduzida em 43,9 por cento . Na região Nordeste; a duração média de tais períodos aumentou 22,2 por cento e a mortalidade atribuível à influenza por semanaaumentou 140,2 por cento . Conclusão: O presente estudo reforça a hipótese de quea vacinação contra gripe em idosos foi efetiva para a região Sul, mas nãopara a região Nordeste do Brasil. A inadequação entre o período do ano em que a vacinação é realizada e a variação sazonal da mortalidade por gripe epneumonia na região Nordeste são apontadas como possíveis fatores que teriam contribuído para esse achado / Introdução: Desde 1999, o serviço público de saúde tem promovido a vacinação anual de idosos contra a gripe no país. Poucos estudos avaliaram a efetividade da intervenção focalizando especificamente sua contribuição para a redução da mortalidade atribuível aos surtos de gripe. Objetivos: O presente estudo teve como propósito comparar a mortalidade por gripe e pneumonia de idosos (65 anos ou mais) antes e depois do início da vacinação nas regiões Nordeste e Sul do Brasil, e comparar os resultados obtidos para cada região, procurando referenciar hipóteses relativas às diferentes condições climáticas e condições socioeconômicas. Métodos: Dados oficiais de população e de mortalidade por gripe e pneumonia foram levantados junto às agências governamentais (Fundação IBGE e DATASUS) responsáveis pelo gerenciamento dessas informações. Foram estimados coeficientes semanais de mortalidade com ajuste por diferenças na distribuição por sexo e por idade. Para a identificação de surtos de gripe e a estimação da mortalidade especificamente atribuível a esses surtos, foi utilizado o modelo de Serfling. As taxas foram estudadas para os períodos 1999-2009 (em que a vacinação foi realizada) e 1996-1998 (em que a vacinação não foi realizada). Foram descritas e analisadas a magnitude das taxas em cada período, sua possível redução associada à vacinação e a ocorrência de variação sazonal. Os indicadores resultantes da comparação entre os dois períodos foram objeto de análise comparativa entre as regiões Nordeste e Sul. Resultados: Durante o período de vacinação, a média anual do número de períodos com excesso de mortalidade foi reduzida em 32,8 por cento na região Sul; em 4,5 por cento na região Nordeste. Na região Sul, a duração média de tais períodos foi reduzida em 66,2 por cento e a mortalidade por semana foi reduzida em 43,9 por cento . Na região Nordeste; a duração média de tais períodos aumentou 22,2 por cento e a mortalidade atribuível à influenza por semanaaumentou 140,2 por cento . Conclusão: O presente estudo reforça a hipótese de quea vacinação contra gripe em idosos foi efetiva para a região Sul, mas nãopara a região Nordeste do Brasil. A inadequação entre o período do ano em que a vacinação é realizada e a variação sazonal da mortalidade por gripe epneumonia na região Nordeste são apontadas como possíveis fatores que teriam contribuído para esse achado

Influenza, também conhecida como gripe, é uma doença infecciosa viral que acomete um grande número de indivíduos anualmente, sendo responsável por um elevado número de internações e óbitos. O agente etiológico é o Myxovirus influenzae, vírus envelopado, de RNA de fita simples e polaridade negativa. A vacinação é a forma mais eficaz de se prevenir a infecção pelo vírus, no entanto, a capacidade produtiva dessa vacina não é suficiente para a vacinação da totalidade da população mundial, principalmente em casos de pandemia. Esse projeto teve por objetivo desenvolver uma vacina influenza (fragmentada e inativada) adjuvada, visando aumentar a capacidade produtiva dessa vacina no Instituto Butantan, que hoje é estimada em aproximadamente 40 milhões de doses por campanha. A utilização de adjuvantes na formulação da vacina influenza é capaz de produzir a mesma resposta imunológica protetora contra esse vírus, utilizando uma quantidade menor dos antígenos vacinais, aumentando a capacidade de produção da vacina em até quatro vezes. Foram estudadas 23 formulações adjuvantes utilizando o esqualeno como referência (formulação similar ao MF59®, adjuvante desenvolvido pela Novartis), vitaminas lipossolúveis (vitaminas A, D e E), vitamina B2 (vitamina hidrossolúvel), MPLA (monofosforil lipídio A, produzido pelo Instituto Butantan como subproduto da vacina pertussis low) e gel de hidróxido de alumínio. Para tanto, foram avaliadas a resposta imune conferida a camundongos BALB/c após imunização com diferentes formulações de vacina influenza (fragmentada e inativada) adjuvada e a existência, ou não, de toxicidade induzida pelas formulações vacinais estudadas. As formulações vacinais mais promissoras farão parte das formulações candidatas para realizações de ensaios clínicos. Os animais foram imunizados por via intraperitoneal com as formulações vacinais e foram colhidas amostras de sangue para ensaios sorológicos (inibição de hemaglutinação e ELISA) e células esplênicas para avaliação celular (dosagem de citocinas por citometria de fluxo: IL-2, IL-4, IL-6, IL-10, IL-17 TNF-α e INF-γ). Além disso, em um dos experimentos avaliou-se a formação de memória imunológica contra influenza, parâmetro importante em se pensando em uma vacina. Os três primeiros experimentos foram uma triagem a partir da qual selecionaram-se as melhores formulações que foram testadas no último experimento. Nele foram avaliados além da indução de resposta imune a toxicidade e a memória imunológica. Todas as 23 formulações estudadas induziram resposta minimamente protetora nos animais, com exceção da formulação contendo apenas MPLA como adjuvante. As formulações que se mostraram mais promissoras continham além do gel de AI(OH)3 MPLA de B. pertussis ou vitamina B2. Isso sem considerar o tocoferol (vitamina E), que embora tenha apresentado bons resultados acabou preterido em decorrência de sua potencial relação com casos de narcolepsia descritos na literatura. O teste de memória foi capaz de demonstrar que essas formulações produzem resposta de memória imunológica duradoura. Assim, tem-se resultados promissores para novos estudos pré-clínicos e clínicos com a vacina influenza (fragmentada e inativada) sazonal (trivalente). / Influenza, also known as flu, is a viral infectious disease that infects a large number of people annually, being responsible by large morbidity and mortality rates. The etiologic agent is the Myxovirus influenzae, an enveloped virus with single-stranded RNA and negative polarity. Vaccination is the best way to prevent the virus infection; however, the production capacity of this vaccine is not sufficient to vaccinate the entire world population, especially in cases of pandemics. This project aimed to develop an adjuvanted influenza vaccine (split and inactivated), increasing the productive capacity of this vaccine in Instituto Butantan, which is estimated in approximately 40 million of doses by campaign. Influenza vaccines formulated with adjuvants can produce the same protective immunological response against the virus using less amount of antigen increasing the production capacity of this vaccine up to four times. Twenty-three adjuvants containing fat-soluble vitamins (vitamins A, D and E), vitamin B2 (water-soluble vitamin), MPLA (monophosphoryl lipid A, produced by Instituto Butantan as a byproduct of pertussis low vaccine production) and aluminum hydroxide gel were studied. An adjuvant similar to MF59® (Novartis adjuvant) containing squalene was used as control. The immune response elicited in BALB/c mice after immunization with the different formulations of the influenza vaccine and the existence or not of toxicity induced by the vaccines formulations were studied. The most promising formulation will be part of the candidate formulations of clinicai trials. The animais received the vaccine formulations intraperitoneally and at specific days blood samples were taken to serological tests (hemagglutination inhibition and ELISA). At the end, they were euthanized to collect the spleens and splenic cells were cultivated to evaluate cytokines by flow cytometry: IL-2, IL-4, IL-6, IL-10, IL-17 TNF-α and INF-γ. Furthermore, in one experiment the immunological memory against influenza was evaluated, an important parameter to vaccines. The most promising formulations contained besides to alum either B. pertussis MPLA or B2 vitamin. Tocopherol (vitamin E) presented good results too, however it has a potential relationship with reported cases of narcolepsy. The memory test was able to demonstrate that these formulations induced long lasting immune memory response. Thus, these are promising results for new pre-clinical and clinical trials with seasonal trivalent influenza vaccine (split and inactivated).

published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Influenza A virus infections in pigs is a disease of concern to the swine industry and to the ecology and epidemiology of influenza viruses in humans. Pigs have been proposed as a “mixing vessel” for generation of pandemics via reassortment between avian and mammalian viruses. The H1N1pdm 2009 virus probably emerged from swine into humans though reassortment between the recent North American triple reassortant H1N2 swine viruses and Eurasian avian-like swine viruses. Swine influenza viruses of H1N1, H1N2 and H3N2 subtypes have been regularly detected in pigs in most parts of the world. Nevertheless, ecological and virological data on swine influenza is not available in Sri Lanka, and indeed, little documented data is available in the South Asian continent. The swine population in Sri Lanka is about 80,000, and live pigs are not regularly imported to the country. Swine husbandry is largely confined to four neighboring administrative districts in the country. Systematic virological and serological surveillance carried in swine abattoirs in Sri Lanka during 2009-2013 detected H1N1pdm 2009 like virus in local herds. Infection in pigs followed each of the H1N1pdm 2009 outbreaks in humans; October 2009 – January 2010, October 2010 – February 2011 and November 2012 – March 2013, respectively. Genetic, phylogenetic, and epidemiologic analysis of the human, and swine influenza viruses indicated spillover events of H1N1pdm 2009 from humans into pigs, with self-limited transmission and extinction within pig herds. The data also indicated that although H1N1pdm 2009 was able to spill over from humans to swine, it is not ideally adapted to establish sustained transmission among swine in the absence of further reassortment with other swine influenza virus lineages. Theses finding might reflect characteristics of swine husbandry in Sri Lanka, which has a low density pig population and remains isolated from global swine influenza viruses because of the absence of regular cross-border and cross-continental movements of swine. In contrast to some other parts of the world, we failed to isolate established lineages of swine influenza viruses, viz. Classical, North American triple reassortant and European Avian lineages. Sero prevalence to these endemic swine viruses was largely absent in local swine herds. In vitro replicative kinetic study indicated that H1N1pdm 2009 viruses isolated from swine have undergone some adaptation to swine led to decreased fitness for replication in human cells. / published_or_final_version / Public Health / Doctoral / Doctor of Philosophy

Mannose-binding lectin (MBL) functions as pattern recognition molecule to mediate first-line host defense against invading pathogens. Although MBL is well-known for its anti-bacterial action, its role towards virus infection is less comprehensively understood. In 2009, the pandemic H1N1 2009 (pdmH1N1) influenza A virus caused more than 18,000 deaths worldwide and is still circulating in human community as a seasonal strain. In this study, the role of MBL in pdmH1N1 infection was investigated. Using in vitro microtiter capture assay, MBL was found to bind to pdmH1N1 virus via its carbohydrate recognition domain. Under transmission electron microscope (TEM), MBL was clearly visible on the surface of pdmH1N1 virus. By infecting C57B6/J wild-type (WT) and MBL knockout (KO) mice with a sub-lethal dose of pdmH1N1 virus, WT mice displayed greater weight loss and more severe lung damage than MBL KO mice. Using flow cytometry-based profiling analysis of the lung homogenates isolated from infected mice, a variety of proinflammatory cytokines and chemokines were found to be significantly up-regulated. These results indicate that the presence of MBL can cause excess proinflammatory cytokine production and result in a more severe pdmH1N1 infection. To provide physiologically relevant insight into the immunomodulating role of MBL, the investigation was further extended to the use of human cell line model. Infection of A549 cells, which is a human lung epithelial cell line, with MBL-bound pdmH1N1 virus elevated the production of MCP1, RANTES and IL-8 significantly more than unbound pdmH1N1 infection. The increased production of chemokines also enhanced recruitment of monocytes as demonstrated by transwell migration assay. Interestingly, MBL did not affect viral entry or replication kinetics. TEM and confocal imaging revealed the presence of MBL-bound pdmH1N1 inside infected A549 cells, suggesting that the endocytosed MBL may interact with intracellular components to promote the release of cytokines and chemokines. To this end, expressions of Toll-like receptors were examined (TLR3, TLR7, TLR8 and TLR9) and found that TLR3 expression was dramatically enhanced upon pdmH1N1 infection. Interestingly, in MBL-bound pdmH1N1 infection, TLR3 mRNA and protein expression was significantly higher than unbound pdmH1N1 infection in A549 cells. In addition, the NF-κB signaling was further activated in the presence of MBL-bound pdmH1N1. A novel physical interaction between MBL and TLR3 was also delineated as evidenced by MBL’s capability to bind to TLR3 in vitro; and their colocalization in the endosomes of the infected A549 cells. In summary, MBL can bind to pdmH1N1 virus but fails to inhibit its infection in human lung epithelial cell line. Upon pdmH1N1 infection, MBL is internalized with the virus into the cell, where it may associate with TLR3 to further amplify the NF-κB signaling and augment the cytokine production in the human lung epithelial cells. The present findings advocate the adverse immunomodulating role of MBL during pdmH1N1 infection. / published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

With the threat of avian influenza, influenza laboratory testing and surveillance capacity has increased globally. Data from global surveillance activities have been used to identify circulating influenza strains for vaccine policy decisions, and have provided evidence of influenza disease among various populations. A recent meta-analysis, which includes findings from these surveillance efforts, has shown that influenza contributes to 10% of pediatric respiratory hospitalizations. Although statistical models indicate a high burden of influenza-associated morbidity among older adults and pandemic studies reveal an increase in hospitalizations among young adults, the global burden of seasonal influenza among adults remains unknown. In order to estimate the global burden of seasonal influenza among adult respiratory hospitalizations, we conducted a systematic review of the published literature, and identified 48 eligible articles published between January 1996 and June 2012 that met our inclusion criteria. We combined these published datasets with 29 eligible, unique datasets from year-round, influenza hospital-based surveillance. These combined data covered 50 countries with varying income and vaccine policies. Extracting numbers tested and positive for influenza, we calculated crude median positive proportions and evaluated potential differences in crude proportions among variables using Kruskal-Wallis non-parametric tests. We observed differences by data source and country development status when we included the 2009 pandemic year. With the exclusion of the 2009 pandemic year, we then generated adjusted pooled estimates using the log binomial model. We found 11% of cases from adult respiratory hospitalizations worldwide were laboratory-confirmed for influenza. This pooled estimate was independent of age but increased as country development or income level decreased. Our findings suggest that influenza is an important contributor to severe acute respiratory illness among both young and older adult populations. For countries without reliable influenza data, we provide an estimate that they may use in planning and allocating resources for the control and prevention of influenza.