Highly Pathogenic Avian Influenza (H5N1): Pathways of Exposure at the Animal‐Human Interface, a Systematic Review
Identifieur interne : 000B21 ( Pmc/Corpus ); précédent : 000B20; suivant : 000B22Highly Pathogenic Avian Influenza (H5N1): Pathways of Exposure at the Animal‐Human Interface, a Systematic Review
Auteurs : Maria D. Van Kerkhove ; Elizabeth Mumford ; Anthony W. Mounts ; Joseph Bresee ; Sowath Ly ; Carolyn B. Bridges ; Joachim OtteSource :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries) with a high case fatality rate (approximately 60%), the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans.
Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; consuming uncooked poultry products; exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets.
Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species. Collaboration between human and animal health sectors for surveillance, case investigation, virus sharing, and risk assessment is essential to monitor for potential changes in circulating H5N1 viruses and in the epidemiology of H5N1 in order to provide the best possible chance for effective mitigation of the impact of H5N1 in both poultry and humans.
The opinions expressed in this article are those of the authors and do not necessarily reflect those of the institutions or organizations with which they are affiliated.
Url:
DOI: 10.1371/journal.pone.0014582
PubMed: 21283678
PubMed Central: 3025925
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Highly Pathogenic Avian Influenza (H5N1): Pathways of Exposure at the Animal‐Human Interface, a Systematic Review</title><author><name sortKey="Van Kerkhove, Maria D" sort="Van Kerkhove, Maria D" uniqKey="Van Kerkhove M" first="Maria D." last="Van Kerkhove">Maria D. Van Kerkhove</name><affiliation><nlm:aff id="aff1"><addr-line>MRC Centre for Outbreak Analysis and Modelling, Imperial College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mumford, Elizabeth" sort="Mumford, Elizabeth" uniqKey="Mumford E" first="Elizabeth" last="Mumford">Elizabeth Mumford</name><affiliation><nlm:aff id="aff2"><addr-line>World Health Organization, Global Influenza Programme, Geneva, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mounts, Anthony W" sort="Mounts, Anthony W" uniqKey="Mounts A" first="Anthony W." last="Mounts">Anthony W. Mounts</name><affiliation><nlm:aff id="aff2"><addr-line>World Health Organization, Global Influenza Programme, Geneva, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bresee, Joseph" sort="Bresee, Joseph" uniqKey="Bresee J" first="Joseph" last="Bresee">Joseph Bresee</name><affiliation><nlm:aff id="aff3"><addr-line>Influenza Division, National Center for Immunization and Respiratory Diseases (NCIRD), Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ly, Sowath" sort="Ly, Sowath" uniqKey="Ly S" first="Sowath" last="Ly">Sowath Ly</name><affiliation><nlm:aff id="aff4"><addr-line>Institut Pasteur du Cambodge, Phnom Penh, Cambodia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bridges, Carolyn B" sort="Bridges, Carolyn B" uniqKey="Bridges C" first="Carolyn B." last="Bridges">Carolyn B. Bridges</name><affiliation><nlm:aff id="aff3"><addr-line>Influenza Division, National Center for Immunization and Respiratory Diseases (NCIRD), Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Otte, Joachim" sort="Otte, Joachim" uniqKey="Otte J" first="Joachim" last="Otte">Joachim Otte</name><affiliation><nlm:aff id="aff5"><addr-line>Animal Production and Health Division, Food and Agriculture Organization of the United Nations, Rome, Italy</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21283678</idno><idno type="pmc">3025925</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025925</idno><idno type="RBID">PMC:3025925</idno><idno type="doi">10.1371/journal.pone.0014582</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000B21</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B21</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Highly Pathogenic Avian Influenza (H5N1): Pathways of Exposure at the Animal‐Human Interface, a Systematic Review</title><author><name sortKey="Van Kerkhove, Maria D" sort="Van Kerkhove, Maria D" uniqKey="Van Kerkhove M" first="Maria D." last="Van Kerkhove">Maria D. Van Kerkhove</name><affiliation><nlm:aff id="aff1"><addr-line>MRC Centre for Outbreak Analysis and Modelling, Imperial College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mumford, Elizabeth" sort="Mumford, Elizabeth" uniqKey="Mumford E" first="Elizabeth" last="Mumford">Elizabeth Mumford</name><affiliation><nlm:aff id="aff2"><addr-line>World Health Organization, Global Influenza Programme, Geneva, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mounts, Anthony W" sort="Mounts, Anthony W" uniqKey="Mounts A" first="Anthony W." last="Mounts">Anthony W. Mounts</name><affiliation><nlm:aff id="aff2"><addr-line>World Health Organization, Global Influenza Programme, Geneva, Switzerland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bresee, Joseph" sort="Bresee, Joseph" uniqKey="Bresee J" first="Joseph" last="Bresee">Joseph Bresee</name><affiliation><nlm:aff id="aff3"><addr-line>Influenza Division, National Center for Immunization and Respiratory Diseases (NCIRD), Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ly, Sowath" sort="Ly, Sowath" uniqKey="Ly S" first="Sowath" last="Ly">Sowath Ly</name><affiliation><nlm:aff id="aff4"><addr-line>Institut Pasteur du Cambodge, Phnom Penh, Cambodia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bridges, Carolyn B" sort="Bridges, Carolyn B" uniqKey="Bridges C" first="Carolyn B." last="Bridges">Carolyn B. Bridges</name><affiliation><nlm:aff id="aff3"><addr-line>Influenza Division, National Center for Immunization and Respiratory Diseases (NCIRD), Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Otte, Joachim" sort="Otte, Joachim" uniqKey="Otte J" first="Joachim" last="Otte">Joachim Otte</name><affiliation><nlm:aff id="aff5"><addr-line>Animal Production and Health Division, Food and Agriculture Organization of the United Nations, Rome, Italy</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries) with a high case fatality rate (approximately 60%), the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans.</p></sec><sec><title>Methods and Findings</title><p>Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; consuming uncooked poultry products; exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets.</p></sec><sec><title>Conclusions</title><p>Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species. Collaboration between human and animal health sectors for surveillance, case investigation, virus sharing, and risk assessment is essential to monitor for potential changes in circulating H5N1 viruses and in the epidemiology of H5N1 in order to provide the best possible chance for effective mitigation of the impact of H5N1 in both poultry and humans.</p></sec><sec><title>Disclaimer</title><p>The opinions expressed in this article are those of the authors and do not necessarily reflect those of the institutions or organizations with which they are affiliated.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gross, Pa" uniqKey="Gross P">PA Gross</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kilbourne, E" uniqKey="Kilbourne E">E Kilbourne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oxford, J" uniqKey="Oxford J">J Oxford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Horimoto, T" uniqKey="Horimoto T">T Horimoto</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hsieh, Y C" uniqKey="Hsieh Y">Y-C Hsieh</name></author><author><name sortKey="Wu, T Z" uniqKey="Wu T">T-Z Wu</name></author><author><name sortKey="Liu, D P" uniqKey="Liu D">D-P Liu</name></author><author><name sortKey="Shao, P L" uniqKey="Shao P">P-L Shao</name></author><author><name sortKey="Chang, L Y" uniqKey="Chang L">L-Y Chang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Webster, R" uniqKey="Webster R">R Webster</name></author><author><name sortKey="Bean, W" uniqKey="Bean W">W Bean</name></author><author><name sortKey="Gorman, O" uniqKey="Gorman O">O Gorman</name></author><author><name sortKey="Chambers, T" uniqKey="Chambers T">T Chambers</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reid, Ah" uniqKey="Reid A">AH Reid</name></author><author><name sortKey="Fanning, Tg" uniqKey="Fanning T">TG Fanning</name></author><author><name sortKey="Hultin, Jv" uniqKey="Hultin J">JV Hultin</name></author><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trifonov, V" uniqKey="Trifonov V">V Trifonov</name></author><author><name sortKey="Khiabanian, H" uniqKey="Khiabanian H">H Khiabanian</name></author><author><name sortKey="Rabadan, R" uniqKey="Rabadan R">R Rabadan</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Claas, Ecj" uniqKey="Claas E">ECJ Claas</name></author><author><name sortKey="Osterhaus, Adme" uniqKey="Osterhaus A">ADME Osterhaus</name></author><author><name sortKey="Van Beek, R" uniqKey="Van Beek R">R van Beek</name></author><author><name sortKey="De Jong, Jc" uniqKey="De Jong J">JC De Jong</name></author><author><name sortKey="Rimmelzwaan, Gf" uniqKey="Rimmelzwaan G">GF Rimmelzwaan</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Rabinowitz, P" uniqKey="Rabinowitz P">P Rabinowitz</name></author><author><name sortKey="Perdue, M" uniqKey="Perdue M">M Perdue</name></author><author><name sortKey="Mumford, E" uniqKey="Mumford E">E Mumford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mounts, A" uniqKey="Mounts A">A Mounts</name></author><author><name sortKey="Kwong, H" uniqKey="Kwong H">H Kwong</name></author><author><name sortKey="Izurieta, H" uniqKey="Izurieta H">H Izurieta</name></author><author><name sortKey="Ho, Y" uniqKey="Ho Y">Y Ho</name></author><author><name sortKey="Au, T" uniqKey="Au T">T Au</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="Wilina, Lim" uniqKey="Wilina L">Lim Wilina</name></author><author><name sortKey="Bridges, Cb" uniqKey="Bridges C">CB Bridges</name></author><author><name sortKey="Rowe, T" uniqKey="Rowe T">T Rowe</name></author><author><name sortKey="Hu Primmer, J" uniqKey="Hu Primmer J">J Hu-Primmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bridges, C" uniqKey="Bridges C">C Bridges</name></author><author><name sortKey="Katz, J" uniqKey="Katz J">J Katz</name></author><author><name sortKey="Seto, W" uniqKey="Seto W">W Seto</name></author><author><name sortKey="Chan, P" uniqKey="Chan P">P Chan</name></author><author><name sortKey="Tsang, D" uniqKey="Tsang D">D Tsang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bridges, C" uniqKey="Bridges C">C Bridges</name></author><author><name sortKey="Lim, W" uniqKey="Lim W">W Lim</name></author><author><name sortKey="Hu Primmer, J" uniqKey="Hu Primmer J">J Hu-Primmer</name></author><author><name sortKey="Sims, L" uniqKey="Sims L">L Sims</name></author><author><name sortKey="Fukuda, K" uniqKey="Fukuda K">K Fukuda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Apisarnthanarak, A" uniqKey="Apisarnthanarak A">A Apisarnthanarak</name></author><author><name sortKey="Erb, S" uniqKey="Erb S">S Erb</name></author><author><name sortKey="Stephenson, I" uniqKey="Stephenson I">I Stephenson</name></author><author><name sortKey="Katz, Jm" uniqKey="Katz J">JM Katz</name></author><author><name sortKey="Chittaganpitch, M" uniqKey="Chittaganpitch M">M Chittaganpitch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Areechokchai, D" uniqKey="Areechokchai D">D Areechokchai</name></author><author><name sortKey="Jiraphongsa, C" uniqKey="Jiraphongsa C">C Jiraphongsa</name></author><author><name sortKey="Laosiritaworn, Y" uniqKey="Laosiritaworn Y">Y Laosiritaworn</name></author><author><name sortKey="Hanshaoworakul, W" uniqKey="Hanshaoworakul W">W Hanshaoworakul</name></author><author><name sortKey="O Reilly, M" uniqKey="O Reilly M">M O'Reilly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dinh, P" uniqKey="Dinh P">P Dinh</name></author><author><name sortKey="Long, H" uniqKey="Long H">H Long</name></author><author><name sortKey="Tien, N" uniqKey="Tien N">N Tien</name></author><author><name sortKey="Hien, N" uniqKey="Hien N">N Hien</name></author><author><name sortKey="Mai, L" uniqKey="Mai L">L Mai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hinjoy, S" uniqKey="Hinjoy S">S Hinjoy</name></author><author><name sortKey="Puthavathana, P" uniqKey="Puthavathana P">P Puthavathana</name></author><author><name sortKey="Laosiritaworn, Y" uniqKey="Laosiritaworn Y">Y Laosiritaworn</name></author><author><name sortKey="Limpakarnjanarat, K" uniqKey="Limpakarnjanarat K">K Limpakarnjanarat</name></author><author><name sortKey="Pooruk, P" uniqKey="Pooruk P">P Pooruk</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, C" uniqKey="Lu C">C Lu</name></author><author><name sortKey="Lu, J" uniqKey="Lu J">J Lu</name></author><author><name sortKey="Chen, W" uniqKey="Chen W">W Chen</name></author><author><name sortKey="Jiang, L" uniqKey="Jiang L">L Jiang</name></author><author><name sortKey="Tan, B" uniqKey="Tan B">B Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ortiz, J" uniqKey="Ortiz J">J Ortiz</name></author><author><name sortKey="Katz, M" uniqKey="Katz M">M Katz</name></author><author><name sortKey="Mahmoud, M" uniqKey="Mahmoud M">M Mahmoud</name></author><author><name sortKey="Ahmed, S" uniqKey="Ahmed S">S Ahmed</name></author><author><name sortKey="Bawa, S" uniqKey="Bawa S">S Bawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schultsz, C" uniqKey="Schultsz C">C Schultsz</name></author><author><name sortKey="Vo, C" uniqKey="Vo C">C Vo</name></author><author><name sortKey="Nguyen, V" uniqKey="Nguyen V">V Nguyen</name></author><author><name sortKey="Nguyen, T" uniqKey="Nguyen T">T Nguyen</name></author><author><name sortKey="Lim, W" uniqKey="Lim W">W Lim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thanh Liem, N" uniqKey="Thanh Liem N">N Thanh Liem</name></author><author><name sortKey="Lim, W" uniqKey="Lim W">W Lim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vong, S" uniqKey="Vong S">S Vong</name></author><author><name sortKey="Goghlan, B" uniqKey="Goghlan B">B Goghlan</name></author><author><name sortKey="Mardy, S" uniqKey="Mardy S">S Mardy</name></author><author><name sortKey="Holl, D" uniqKey="Holl D">D Holl</name></author><author><name sortKey="Seng, H" uniqKey="Seng H">H Seng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Santhia, K" uniqKey="Santhia K">K Santhia</name></author><author><name sortKey="Ramy, A" uniqKey="Ramy A">A Ramy</name></author><author><name sortKey="Jayaningsih, P" uniqKey="Jayaningsih P">P Jayaningsih</name></author><author><name sortKey="Samaan, G" uniqKey="Samaan G">G Samaan</name></author><author><name sortKey="Putra, A" uniqKey="Putra A">A Putra</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cai, W" uniqKey="Cai W">W Cai</name></author><author><name sortKey="Schweiger, B" uniqKey="Schweiger B">B Schweiger</name></author><author><name sortKey="Buchholz, U" uniqKey="Buchholz U">U Buchholz</name></author><author><name sortKey="Buda, S" uniqKey="Buda S">S Buda</name></author><author><name sortKey="Littmann, M" uniqKey="Littmann M">M Littmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, M" uniqKey="Wang M">M Wang</name></author><author><name sortKey="Fu, C" uniqKey="Fu C">C Fu</name></author><author><name sortKey="Zheng, B" uniqKey="Zheng B">B Zheng</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Dejpichai, R" uniqKey="Dejpichai R">R Dejpichai</name></author><author><name sortKey="Laosiritaworn, Y" uniqKey="Laosiritaworn Y">Y Laosiritaworn</name></author><author><name sortKey="Phuthavathana, P" uniqKey="Phuthavathana P">P Phuthavathana</name></author><author><name sortKey="Uyeki, T" uniqKey="Uyeki T">T Uyeki</name></author><author><name sortKey="O Reilly, M" uniqKey="O Reilly M">M O'Reilly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, M" uniqKey="Wang M">M Wang</name></author><author><name sortKey="Di, B" uniqKey="Di B">B Di</name></author><author><name sortKey="Zhou, D" uniqKey="Zhou D">D Zhou</name></author><author><name sortKey="Zheng, B" uniqKey="Zheng B">B Zheng</name></author><author><name sortKey="Jing, H" uniqKey="Jing H">H Jing</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vong, S" uniqKey="Vong S">S Vong</name></author><author><name sortKey="Ly, S" uniqKey="Ly S">S Ly</name></author><author><name sortKey="Van Kerkhove, Md" uniqKey="Van Kerkhove M">MD Van Kerkhove</name></author><author><name sortKey="Achenbach, J" uniqKey="Achenbach J">J Achenbach</name></author><author><name sortKey="Holl, D" uniqKey="Holl D">D Holl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cavailler, P" uniqKey="Cavailler P">P Cavailler</name></author><author><name sortKey="Chu, S" uniqKey="Chu S">S Chu</name></author><author><name sortKey="Ly, S" uniqKey="Ly S">S Ly</name></author><author><name sortKey="Garcia, J" uniqKey="Garcia J">J Garcia</name></author><author><name sortKey="Ha, D" uniqKey="Ha D">D Ha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gilsdorf, A" uniqKey="Gilsdorf A">A Gilsdorf</name></author><author><name sortKey="Boxall, N" uniqKey="Boxall N">N Boxall</name></author><author><name sortKey="Gasimov, V" uniqKey="Gasimov V">V Gasimov</name></author><author><name sortKey="Agayev, I" uniqKey="Agayev I">I Agayev</name></author><author><name sortKey="Mammadzade, F" uniqKey="Mammadzade F">F Mammadzade</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, L" uniqKey="Zhou L">L Zhou</name></author><author><name sortKey="Liao, Q" uniqKey="Liao Q">Q Liao</name></author><author><name sortKey="Dong, L" uniqKey="Dong L">L Dong</name></author><author><name sortKey="Huai, Y" uniqKey="Huai Y">Y Huai</name></author><author><name sortKey="Bai, T" uniqKey="Bai T">T Bai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Jiang, L" uniqKey="Jiang L">L Jiang</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Yang, Z" uniqKey="Yang Z">Z Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schultsz, C" uniqKey="Schultsz C">C Schultsz</name></author><author><name sortKey="Van Dung, N" uniqKey="Van Dung N">N Van Dung</name></author><author><name sortKey="Hai, Lt" uniqKey="Hai L">LT Hai</name></author><author><name sortKey="Quang Ha, D" uniqKey="Quang Ha D">D Quang Ha</name></author><author><name sortKey="Peiris, Jsm" uniqKey="Peiris J">JSM Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Olsen, S" uniqKey="Olsen S">S Olsen</name></author><author><name sortKey="Ungchusak, K" uniqKey="Ungchusak K">K Ungchusak</name></author><author><name sortKey="Sovann, L" uniqKey="Sovann L">L Sovann</name></author><author><name sortKey="Uyeki, T" uniqKey="Uyeki T">T Uyeki</name></author><author><name sortKey="Dowell, Sf" uniqKey="Dowell S">SF Dowell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oner, Af" uniqKey="Oner A">AF Oner</name></author><author><name sortKey="Bay, A" uniqKey="Bay A">A Bay</name></author><author><name sortKey="Arslan, S" uniqKey="Arslan S">S Arslan</name></author><author><name sortKey="Akdeniz, H" uniqKey="Akdeniz H">H Akdeniz</name></author><author><name sortKey="Sahin, Ha" uniqKey="Sahin H">HA Sahin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ungchusak, K" uniqKey="Ungchusak K">K Ungchusak</name></author><author><name sortKey="Auewarakul, P" uniqKey="Auewarakul P">P Auewarakul</name></author><author><name sortKey="Dowell, Sf" uniqKey="Dowell S">SF Dowell</name></author><author><name sortKey="Kitphati, R" uniqKey="Kitphati R">R Kitphati</name></author><author><name sortKey="Auwanit, W" uniqKey="Auwanit W">W Auwanit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kandun, In" uniqKey="Kandun I">IN Kandun</name></author><author><name sortKey="Wibisono, H" uniqKey="Wibisono H">H Wibisono</name></author><author><name sortKey="Sedyaningsih, Er" uniqKey="Sedyaningsih E">ER Sedyaningsih</name></author><author><name sortKey="Yusharmen" uniqKey="Yusharmen">Yusharmen</name></author><author><name sortKey="Hadisoedarsuno, W" uniqKey="Hadisoedarsuno W">W Hadisoedarsuno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, H" uniqKey="Wang H">H Wang</name></author><author><name sortKey="Feng, Z" uniqKey="Feng Z">Z Feng</name></author><author><name sortKey="Shu, Y" uniqKey="Shu Y">Y Shu</name></author><author><name sortKey="Yu, H" uniqKey="Yu H">H Yu</name></author><author><name sortKey="Zhou, L" uniqKey="Zhou L">L Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kandun, I" uniqKey="Kandun I">I Kandun</name></author><author><name sortKey="Tresnaningsih, E" uniqKey="Tresnaningsih E">E Tresnaningsih</name></author><author><name sortKey="Purba, W" uniqKey="Purba W">W Purba</name></author><author><name sortKey="Lee, V" uniqKey="Lee V">V Lee</name></author><author><name sortKey="Samaan, G" uniqKey="Samaan G">G Samaan</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="De Jong, Md" uniqKey="De Jong M">MD de Jong</name></author><author><name sortKey="Cam, Bv" uniqKey="Cam B">BV Cam</name></author><author><name sortKey="Qui, Pt" uniqKey="Qui P">PT Qui</name></author><author><name sortKey="Hien, Vm" uniqKey="Hien V">VM Hien</name></author><author><name sortKey="Thanh, Tt" uniqKey="Thanh T">TT Thanh</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Vong, S" uniqKey="Vong S">S Vong</name></author><author><name sortKey="Ly, S" uniqKey="Ly S">S Ly</name></author><author><name sortKey="Sek, M" uniqKey="Sek M">M Sek</name></author><author><name sortKey="Holl, D" uniqKey="Holl D">D Holl</name></author><author><name sortKey="Buchy, P" uniqKey="Buchy P">P Buchy</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Kandun, I" uniqKey="Kandun I">I Kandun</name></author><author><name sortKey="Samaan, G" uniqKey="Samaan G">G Samaan</name></author><author><name sortKey="Harun, S" uniqKey="Harun S">S Harun</name></author><author><name sortKey="Purba, W" uniqKey="Purba W">W Purba</name></author><author><name sortKey="Sariwati, E" uniqKey="Sariwati E">E Sariwati</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Greiner, M" uniqKey="Greiner M">M Greiner</name></author><author><name sortKey="Muller Graf, C" uniqKey="Muller Graf C">C Muller-Graf</name></author><author><name sortKey="Hiller, P" uniqKey="Hiller P">P Hiller</name></author><author><name sortKey="Schrader, C" uniqKey="Schrader C">C Schrader</name></author><author><name sortKey="Gervelmeyer, A" uniqKey="Gervelmeyer A">A Gervelmeyer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beigel, J" uniqKey="Beigel J">J Beigel</name></author><author><name sortKey="Farrar, J" uniqKey="Farrar J">J Farrar</name></author><author><name sortKey="Han, A" uniqKey="Han A">A Han</name></author><author><name sortKey="Hayden, F" uniqKey="Hayden F">F Hayden</name></author><author><name sortKey="Hyer, R" uniqKey="Hyer R">R Hyer</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Yu, H" uniqKey="Yu H">H Yu</name></author><author><name sortKey="Feng, Z" uniqKey="Feng Z">Z Feng</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="Xiang, N" uniqKey="Xiang N">N Xiang</name></author><author><name sortKey="Huai, Y" uniqKey="Huai Y">Y Huai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Kerkhove, M" uniqKey="Van Kerkhove M">M Van Kerkhove</name></author><author><name sortKey="Ly, S" uniqKey="Ly S">S Ly</name></author><author><name sortKey="Holl, D" uniqKey="Holl D">D Holl</name></author><author><name sortKey="Guitian, J" uniqKey="Guitian J">J Guitian</name></author><author><name sortKey="Mangtani, P" uniqKey="Mangtani P">P Mangtani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neumann, G" uniqKey="Neumann G">G Neumann</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Gao, Gf" uniqKey="Gao G">GF Gao</name></author><author><name sortKey="Shu, Y" uniqKey="Shu Y">Y Shu</name></author><author><name sortKey="Kawaoka, Y" uniqKey="Kawaoka Y">Y Kawaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Horby, P" uniqKey="Horby P">P Horby</name></author><author><name sortKey="Sudoyo, H" uniqKey="Sudoyo H">H Sudoyo</name></author><author><name sortKey="Viprakasit, V" uniqKey="Viprakasit V">V Viprakasit</name></author><author><name sortKey="Fox, A" uniqKey="Fox A">A Fox</name></author><author><name sortKey="Thai, Pq" uniqKey="Thai P">PQ Thai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Indriani, R" uniqKey="Indriani R">R Indriani</name></author><author><name sortKey="Samaan, G" uniqKey="Samaan G">G Samaan</name></author><author><name sortKey="Gultom, A" uniqKey="Gultom A">A Gultom</name></author><author><name sortKey="Loth, L" uniqKey="Loth L">L Loth</name></author><author><name sortKey="Indryani, S" uniqKey="Indryani S">S Indryani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bird, S" uniqKey="Bird S">S Bird</name></author><author><name sortKey="Farrar, J" uniqKey="Farrar J">J Farrar</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Biswas, P" uniqKey="Biswas P">P Biswas</name></author><author><name sortKey="Christensen, J" uniqKey="Christensen J">J Christensen</name></author><author><name sortKey="Ahmed, S" uniqKey="Ahmed S">S Ahmed</name></author><author><name sortKey="Barua, H" uniqKey="Barua H">H Barua</name></author><author><name sortKey="Das, A" uniqKey="Das A">A Das</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wer" uniqKey="Wer">WER</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fasina, F" uniqKey="Fasina F">F Fasina</name></author><author><name sortKey="Ifende, V" uniqKey="Ifende V">V Ifende</name></author><author><name sortKey="Ajibade, A" uniqKey="Ajibade A">A Ajibade</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Otte, M" uniqKey="Otte M">M Otte</name></author><author><name sortKey="Pfeiffer, D" uniqKey="Pfeiffer D">D Pfeiffer</name></author><author><name sortKey="Roland Holst, D" uniqKey="Roland Holst D">D Roland-Holst</name></author><author><name sortKey="Inui, K" uniqKey="Inui K">K Inui</name></author><author><name sortKey="Tung, N" uniqKey="Tung N">N Tung</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21283678</article-id><article-id pub-id-type="pmc">3025925</article-id><article-id pub-id-type="publisher-id">10-PONE-RA-21626R1</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0014582</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Public Health and Epidemiology</subject><subject>Infectious Diseases/Respiratory Infections</subject><subject>Public Health and Epidemiology/Global Health</subject><subject>Public Health and Epidemiology/Infectious Diseases</subject></subj-group></article-categories><title-group><article-title>Highly Pathogenic Avian Influenza (H5N1): Pathways of Exposure at the Animal‐Human Interface, a Systematic Review</article-title><alt-title alt-title-type="running-head">Human Risk of H5N1</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Van Kerkhove</surname><given-names>Maria D.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mumford</surname><given-names>Elizabeth</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mounts</surname><given-names>Anthony W.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bresee</surname><given-names>Joseph</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ly</surname><given-names>Sowath</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bridges</surname><given-names>Carolyn B.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Otte</surname><given-names>Joachim</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>MRC Centre for Outbreak Analysis and Modelling, Imperial College London, London, United Kingdom</addr-line></aff><aff id="aff2"><label>2</label><addr-line>World Health Organization, Global Influenza Programme, Geneva, Switzerland</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Influenza Division, National Center for Immunization and Respiratory Diseases (NCIRD), Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Institut Pasteur du Cambodge, Phnom Penh, Cambodia</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Animal Production and Health Division, Food and Agriculture Organization of the United Nations, Rome, Italy</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Braga</surname><given-names>Erika Martins</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Universidade Federal de Minas Gerais, Brazil</aff><author-notes><corresp id="cor1">* E-mail: <email>m.vankerkhove@imperial.ac.uk</email></corresp><fn fn-type="con"><p>Analyzed the data: MDVK. Wrote the paper: MDVK. Conceived the paper: MDVK, JO. Reviewed and edited versions of the manuscript: EM AM JB SL CB JO.</p></fn></author-notes><pub-date pub-type="collection"><year>2011</year></pub-date><pub-date pub-type="epub"><day>24</day><month>1</month><year>2011</year></pub-date><volume>6</volume><issue>1</issue><elocation-id>e14582</elocation-id><history><date date-type="received"><day>26</day><month>7</month><year>2010</year></date><date date-type="accepted"><day>21</day><month>10</month><year>2010</year></date></history><permissions><copyright-statement>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p></license></permissions><abstract><sec><title>Background</title><p>The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries) with a high case fatality rate (approximately 60%), the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans.</p></sec><sec><title>Methods and Findings</title><p>Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; consuming uncooked poultry products; exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets.</p></sec><sec><title>Conclusions</title><p>Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species. Collaboration between human and animal health sectors for surveillance, case investigation, virus sharing, and risk assessment is essential to monitor for potential changes in circulating H5N1 viruses and in the epidemiology of H5N1 in order to provide the best possible chance for effective mitigation of the impact of H5N1 in both poultry and humans.</p></sec><sec><title>Disclaimer</title><p>The opinions expressed in this article are those of the authors and do not necessarily reflect those of the institutions or organizations with which they are affiliated.</p></sec></abstract><counts><page-count count="8"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>There have been several human pandemics caused by influenza A viruses over the last 150 years <xref rid="pone.0014582-Gross1" ref-type="bibr">[1]</xref>, <xref rid="pone.0014582-Kilbourne1" ref-type="bibr">[2]</xref>, <xref rid="pone.0014582-Oxford1" ref-type="bibr">[3]</xref>. The first pandemic of the 20<sup>th</sup> century, the “Spanish” influenza (H1N1) pandemic of 1918–1919, was particularly lethal in young, otherwise healthy adults, killing an estimated 40–50 million people worldwide <xref rid="pone.0014582-Kilbourne1" ref-type="bibr">[2]</xref>, <xref rid="pone.0014582-Horimoto1" ref-type="bibr">[4]</xref>, <xref rid="pone.0014582-Hsieh1" ref-type="bibr">[5]</xref>, <xref rid="pone.0014582-Webster1" ref-type="bibr">[6]</xref>. Genetic analyses of specimens collected from victims preserved in the arctic and archived tissues from World War I soldiers suggests that the 1918 H1N1 strain was an avian-origin virus that adapted to humans <xref rid="pone.0014582-Reid1" ref-type="bibr">[7]</xref>. The “Asian” influenza pandemic (H2N2) in 1957 and the “Hong Kong” influenza pandemic (H3N2) in 1968 were less lethal and resulted from avian-human virus reassortment <xref rid="pone.0014582-Horimoto1" ref-type="bibr">[4]</xref>, <xref rid="pone.0014582-Hsieh1" ref-type="bibr">[5]</xref>. The 2009 H1N1 pandemic influenza virus is a reassortant of human, swine and avian-origin influenza virus gene segments, with the HA gene sharing a common ancestry with the 1918 pandemic virus HA that has been circulating in swine populations globally <xref rid="pone.0014582-Trifonov1" ref-type="bibr">[8]</xref>. Since its emergence in the spring of 2009, the pandemic H1N1 virus quickly became the predominant strain globally<xref rid="pone.0014582-WHO1" ref-type="bibr">[9]</xref>.</p><p>The isolation of a highly pathogenic avian influenza A virus, subtype H5N1 (referred to as H5N1 in this manuscript), from a 3-year-old boy in Hong Kong in 1997 was the first detection of this virus strain in humans and raised concerns worldwide of the potential for a pandemic of avian origin with a lethality in the range of the 1918 pandemic <xref rid="pone.0014582-Claas1" ref-type="bibr">[10]</xref>. As with the 1918 virus, all of the genes found in the H5N1 viral strain in Hong Kong originated from avian viruses, <xref rid="pone.0014582-Horimoto1" ref-type="bibr">[4]</xref>, <xref rid="pone.0014582-Claas1" ref-type="bibr">[10]</xref>. While H5N1 has not yet demonstrated the ability to transmit efficiently from person to person, the high case-fatality associated with infection, and because of the immense potential for influenza viruses to mutate and adapt to other hosts, H5N1 remains a continuing public health concern.</p><p>As of 8 June 2010, 15 countries have reported a total of 499 confirmed cases of human H5N1 infection to WHO <xref rid="pone.0014582-WHO2" ref-type="bibr">[11]</xref>. By far, the largest numbers of human cases has been reported from Indonesia, Vietnam and Egypt, each having reported more than 100 cases (these three countries account for 79% of all human cases). No human cases have yet been reported in Western Europe or the Americas, although H5N1 has been detected in poultry in Europe. The number of reported cases and fatalities, case fatality rate (CFR), H5N1 virus clades identified that have infected humans, and the median age and gender (% male) of reported cases <xref rid="pone.0014582-WHO3" ref-type="bibr">[12]</xref>, <xref rid="pone.0014582-Writing1" ref-type="bibr">[13]</xref> vary by country (<xref ref-type="table" rid="pone-0014582-t001">Table 1</xref>). The crude CFR for all cases to date is high (CFR = 59.1%, interquartile range 32.5–77.8), but also varies substantially among the 15 countries.</p><table-wrap id="pone-0014582-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0014582.t001</object-id><label>Table 1</label><caption><title>Characteristics of human cases of highly pathogenic avian influenza H5N1 virus infection reported to WHO from 1997 to 16 March 2010 by country.</title></caption><alternatives><graphic id="pone-0014582-t001-1" xlink:href="pone.0014582.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Country</td><td colspan="2" align="left" rowspan="1">Total</td><td align="left" rowspan="1" colspan="1">Crude CFR (%)</td><td align="left" rowspan="1" colspan="1">Clade(s)<xref ref-type="table-fn" rid="nt101">A</xref></td><td align="left" rowspan="1" colspan="1">Median age of cases (range)<xref ref-type="table-fn" rid="nt102">B</xref></td><td align="left" rowspan="1" colspan="1">% Male n/total (%)<xref ref-type="table-fn" rid="nt102">B</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Cases</td><td align="left" rowspan="1" colspan="1">Deaths</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Azerbaijan</td><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">62.5</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">10 16.5 (5–20) <xref ref-type="table-fn" rid="nt107">‡‡</xref></td><td align="left" rowspan="1" colspan="1">9/16 (56) <xref ref-type="table-fn" rid="nt107">‡‡</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Turkey</td><td align="left" rowspan="1" colspan="1">12</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">33.3</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Bangladesh</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">0.0</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">16 mo (–)</td><td align="left" rowspan="1" colspan="1">1/1 (100)</td></tr><tr><td align="left" rowspan="1" colspan="1">China</td><td align="left" rowspan="1" colspan="1">38</td><td align="left" rowspan="1" colspan="1">25</td><td align="left" rowspan="1" colspan="1">65.8</td><td align="left" rowspan="1" colspan="1">2.2, 2.3.4, 7</td><td align="left" rowspan="1" colspan="1">30 (12–41)<xref ref-type="table-fn" rid="nt105">‡</xref></td><td align="left" rowspan="1" colspan="1">3/8 (38)<xref ref-type="table-fn" rid="nt105">‡</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Hong Kong, SAR (1997)</td><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">33.3</td><td align="left" rowspan="1" colspan="1">0, 1</td><td align="left" rowspan="1" colspan="1">6 (1.5–60)</td><td align="left" rowspan="1" colspan="1">6/15 (40)</td></tr><tr><td align="left" rowspan="1" colspan="1">Djibouti</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">0.0</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">2 (–)</td><td align="left" rowspan="1" colspan="1">0/1 (0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Egypt</td><td align="left" rowspan="1" colspan="1">106</td><td align="left" rowspan="1" colspan="1">32</td><td align="left" rowspan="1" colspan="1">30.2</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">12.5 (1–75)<xref ref-type="table-fn" rid="nt106">α</xref></td><td align="left" rowspan="1" colspan="1">12/38 (32)<xref ref-type="table-fn" rid="nt106">α</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Indonesia</td><td align="left" rowspan="1" colspan="1">163</td><td align="left" rowspan="1" colspan="1">135</td><td align="left" rowspan="1" colspan="1">82.8</td><td align="left" rowspan="1" colspan="1">2.1.2, 2.1.3</td><td align="left" rowspan="1" colspan="1">18.5 (1.5–45)<xref ref-type="table-fn" rid="nt105">‡</xref></td><td align="left" rowspan="1" colspan="1">33/54 (61)<xref ref-type="table-fn" rid="nt105">‡</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Iraq</td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">66.7</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">15 (3–39)</td><td align="left" rowspan="1" colspan="1">2/3 (66.7)</td></tr><tr><td align="left" rowspan="1" colspan="1">Lao People's Democratic Republic</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">100.0</td><td align="left" rowspan="1" colspan="1">2.3.4</td><td align="left" rowspan="1" colspan="1">28.5 (15–42)</td><td align="left" rowspan="1" colspan="1">0/2 (0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Myanmar</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">0.0</td><td align="left" rowspan="1" colspan="1">2.3.4</td><td align="left" rowspan="1" colspan="1">7 (–)</td><td align="left" rowspan="1" colspan="1">0/1 (0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Nigeria</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">100.0</td><td align="left" rowspan="1" colspan="1">2.2</td><td align="left" rowspan="1" colspan="1">22 (–)</td><td align="left" rowspan="1" colspan="1">0/1 (0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Pakistan</td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">33.3</td><td align="left" rowspan="1" colspan="1">NR</td><td align="left" rowspan="1" colspan="1">25 (22–27)</td><td align="left" rowspan="1" colspan="1">3/3 (100)</td></tr><tr><td align="left" rowspan="1" colspan="1">Cambodia</td><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">77.8</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">14–22 (2–58)<xref ref-type="table-fn" rid="nt104">†</xref></td><td align="left" rowspan="1" colspan="1">19/41 (46)<xref ref-type="table-fn" rid="nt104">†</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Thailand</td><td align="left" rowspan="1" colspan="1">25</td><td align="left" rowspan="1" colspan="1">17</td><td align="left" rowspan="1" colspan="1">68.0</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Vietnam</td><td align="left" rowspan="1" colspan="1">116</td><td align="left" rowspan="1" colspan="1">58</td><td align="left" rowspan="1" colspan="1">50.0</td><td align="left" rowspan="1" colspan="1">1, 2.3.4</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Total</td><td align="left" rowspan="1" colspan="1">489</td><td align="left" rowspan="1" colspan="1">289</td><td align="left" rowspan="1" colspan="1">59.1</td><td align="left" rowspan="1" colspan="1">–</td><td align="left" rowspan="1" colspan="1">–</td><td align="left" rowspan="1" colspan="1">–</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label>A</label><p>Clade(s) isolated from humans.</p></fn><fn id="nt102"><label>B</label><p>Data from cases up to 1 Jan 2009.</p></fn><fn id="nt103"><label></label><p>Adapted from sources <xref rid="pone.0014582-Writing1" ref-type="bibr">[13]</xref>, <xref rid="pone.0014582-Mounts1" ref-type="bibr">[17]</xref>, <xref rid="pone.0014582-WHO9" ref-type="bibr">[63]</xref>, <xref rid="pone.0014582-Biswas1" ref-type="bibr">[64]</xref>, <xref rid="pone.0014582-WER1" ref-type="bibr">[65]</xref>, <xref rid="pone.0014582-Fasina1" ref-type="bibr">[66]</xref>, <xref rid="pone.0014582-Otte1" ref-type="bibr">[67]</xref>.</p></fn><fn id="nt104"><label>†</label><p>Includes data from 2004–2005 cases only;</p></fn><fn id="nt105"><label>‡</label><p>Includes data from 2005–2006 cases only;</p></fn><fn id="nt106"><label>α</label><p>Includes data from 2006–2007 cases only;</p></fn><fn id="nt107"><label>‡‡</label><p>Includes data from 2006 cases only;</p></fn><fn id="nt108"><label></label><p>NR = Not released.</p></fn></table-wrap-foot></table-wrap><p>To date H5N1 remains an avian epidemic with sporadic spill-over into the human population and other species. The predominant modes of transmission from poultry to humans remain incompletely understood and limited exposure information from infected persons has restricted our ability to evaluate risk factors for human infection and implement more refined risk reduction measures. Field investigations of cases of H5N1 in humans—usually in locations of low or middle income countries—are generally difficult to conduct, especially in a timely manner, and may result in collection of incomplete exposure information. Conversely, in some countries, good exposure data has been collected during outbreak investigations, but may not be analyzed or published. Thus, information on potential exposures, when given, is typically limited to <italic>recent contact with sick or dead poultry</italic><xref rid="pone.0014582-WHO4" ref-type="bibr">[14]</xref> or the <italic>preparation of sick birds for consumption</italic><xref rid="pone.0014582-WHO5" ref-type="bibr">[15]</xref>. More detailed knowledge of the types of behaviors and interactions with poultry that result in virus transmission would facilitate more effective and targeted risk reduction measures at the human-animal interface.</p><p>Several epidemiologic studies have been published to evaluate risk factors, including contact with poultry and poultry products and non-poultry-related contact such as from H5N1-contaminated water, for H5N1 infection in humans. Most of these have adopted a case-control (or nested case-control) design where researchers have evaluated the risk of exposure to poultry from visiting live bird markets (LBM), food preparation, caring or feeding poultry or exposure risk via contact with a confirmed human case. In 2009, Rabinowitz et al. published a systematic review of published analytical studies and case reports through 2007 on exposure variables for human cases of H5N1 infection. Since this publication, a number of published large-scale seroprevalence studies in areas where H5N1 has occurred or is recurrent have been published. Here we evaluate what is known about pathways of exposure at the animal-human interface using all available publications, including seroprevalence studies and case-control studies not included in previous reviews, which could result in human infection with H5N1 virus.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><p>A systematic search for all available published literature evaluating prevalence of symptomatic or asymptomatic infection with H5N1 and/or risk factors for human infection with the H5N1 virus was performed in MEDLINE using the following keywords together and in various combinations: “H5N1, risk factor, poultry, seroprevalence, antibodies, human, animal-human interface”. All papers published between 1 January 1997 and 1 April 2010 are included in the review regardless of the language of publication. The original search yielded 444 articles. All titles were reviewed to identify epidemiologic studies that evaluated risk factors among human populations. The abstracts were reviewed for papers from which a decision could not be made from the title alone. Case reports, vaccine efficacy studies, laboratory studies and studies in animal populations were excluded from this review. This review updates a previous review by Rabinowitz et al <xref rid="pone.0014582-Rabinowitz1" ref-type="bibr">[16]</xref>, using studies published between 2008–2010.</p><p>Twenty-four published studies evaluating risk and/or risk factors for human infection conducted in 8 countries (Thailand, Vietnam, Indonesia, Cambodia, Nigeria, China, Azerbaijan, and Germany) and Hong Kong were included in the review. Four studies focused on the initial 1997 outbreaks in Hong Kong, while the remaining 20 studies were conducted in Asian, African and European countries in areas with confirmed outbreaks in human and/or domestic poultry populations from 2003–2009. Based on the population under study and principal objective, the 24 studies fall into two categories: case-control studies to evaluate risk factors for human infection among laboratory-confirmed H5N1 cases (n = 5; 2 related to the 1997 outbreak and 3 related to outbreaks occurring 2003 to 2009); or seroepidemiology studies (n = 19; 3 relating to the 1997 outbreak and 16 related to outbreaks occurring 2003 to 2009) to evaluate the predictors of having H5-specific antibody among health care workers (HCW; n = 4), poultry workers (PW; n = 8) or household/social contacts (n = 8) of laboratory-confirmed infected H5N1 cases (one study evaluated both occupational and domestic exposure to poultry and is therefore counted as both a study among PW and social contacts).</p></sec><sec id="s3"><title>Results</title><sec id="s3a"><title>Investigations into the 1997 H5N1 outbreak in Hong Kong (18 cases, 6 deaths)</title><p>The H5N1 virus was first known to cross the animal-human species barrier in 1997 when 18 hospitalized, symptomatic cases, six of whom died, were identified in Hong Kong <xref rid="pone.0014582-Claas1" ref-type="bibr">[10]</xref>. A case-control study of 15 of these confirmed H5N1 cases and 41 controls matched on age, sex and neighborhood found that exposure to live poultry at LBM in the week before illness was associated with a 4-fold increased risk in infection (OR = 4.5 95%CI 1.2–21.7) (<xref ref-type="table" rid="pone-0014582-t002">Table 2</xref>). No association was found with consumption of cooked or undercooked poultry at home or at a restaurant <xref rid="pone.0014582-Mounts1" ref-type="bibr">[17]</xref>.</p><table-wrap id="pone-0014582-t002" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0014582.t002</object-id><label>Table 2</label><caption><title>Risk factors for H5N1 infection: Summary of published case-control studies.</title></caption><alternatives><graphic id="pone-0014582-t002-2" xlink:href="pone.0014582.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Study, year</td><td align="left" rowspan="1" colspan="1">Study Population</td><td align="left" rowspan="1" colspan="1">Risk FactorsRR, OR, 95%CI</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Mounts et al., 1999 <xref rid="pone.0014582-Mounts1" ref-type="bibr">[17]</xref></td><td align="left" rowspan="1" colspan="1">Hong Kong15 cases 41 matched controls</td><td align="left" rowspan="1" colspan="1">Exposure to poultry at live/wet markets was associated with a 4-fold increased risk (OR = 4.5, 1.2–21.7)</td></tr><tr><td align="left" rowspan="1" colspan="1">Dinh et al., 2006 <xref rid="pone.0014582-Dinh1" ref-type="bibr">[23]</xref></td><td align="left" rowspan="1" colspan="1">Viet Nam28 cases 106 matched controls</td><td align="left" rowspan="1" colspan="1">Univariate Analysis: preparing/cooking unhealthy poultry (OR = 31, 2.4–1150), having sick or dead poultry in the household (OR = 7.41, 2.7–59), presence of sick/dead poultry in the neighborhood (OR = 3.9, 1.0–55.7), no indoor water source in the household (OR = 5.0, 1.3–77.0)Multivariate Analysis: No water in the household (OR = 6.5, 1.2–34.8), sick or dead poultry in the household (OR = 4.9, 1.2–20.2), prepare and cook sick or dead poultry (OR = 9.0, 0.98–82.0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Areechokchai et al., 2006 <xref rid="pone.0014582-Areechokchai1" ref-type="bibr">[22]</xref></td><td align="left" rowspan="1" colspan="1">Thailandmatched case control study of 16 cases and 64 controls</td><td align="left" rowspan="1" colspan="1">Direct touching of unexpectedly dead poultry OR 29.0 (2.7–308.2)</td></tr><tr><td align="left" rowspan="1" colspan="1">Zhou et al., 2009 <xref rid="pone.0014582-Zhou1" ref-type="bibr">[39]</xref></td><td align="left" rowspan="1" colspan="1">China10 urban and 18 rural cases; 134 matched controls</td><td align="left" rowspan="1" colspan="1">Infection included direct (OR = 506.6, 95%CI15.7–16319.6) or indirect (OR = 56.9, 95%CI 4.3–745.6) contact with sick or dead poultry, visiting a LBM (OR = 15.4, 95%CI 3.0–80.2)Urban cases were significantly more likely to have visited a LBM, compared with rural cases (p = 0.002)</td></tr><tr><td align="left" rowspan="1" colspan="1">WER, 2006 <xref rid="pone.0014582-World1" ref-type="bibr">[33]</xref></td><td align="left" rowspan="1" colspan="1">Azerbaijan, residents in settlements of confirmed cases</td><td align="left" rowspan="1" colspan="1">9/52 residents tested positive for H5N1 virus.No case-control was initiated, but contact with infected wild birds (defeathering) reported as likely cause of infection</td></tr></tbody></table></alternatives></table-wrap><p>The extent of anti-H5 seroprevalence was evaluated among household/social contacts <xref rid="pone.0014582-Katz1" ref-type="bibr">[18]</xref>, HCW caring for confirmed human H5N1 cases <xref rid="pone.0014582-Bridges1" ref-type="bibr">[19]</xref>, and PW involved in the culling of all poultry in Hong Kong (<xref ref-type="supplementary-material" rid="pone.0014582.s001">Table S1</xref>; in supplemental information) <xref rid="pone.0014582-Bridges2" ref-type="bibr">[20]</xref>. Six of 51 (12%) household contacts and none of 26 social contacts tested positive for anti-H5 antibodies using microneutralization (MN) and Western Blot (WB) techniques<xref rid="pone.0014582-Katz1" ref-type="bibr">[18]</xref>. Although not statistically significant, the authors of this study suggest that common-source exposure of the household contacts to poultry in their homes was a likely risk factor for infection. Among HCW, risk factor data were collected including exposure to the case patient (e.g. provided direct care to case, physical contact, face-to-face talking, worked within two meters of patients, recalled patient coughing/sneezing, suctioned respiratory secretions from or administered breathing treatments to patients, changed bed linens or bathed the patient), age, sex, occupation and exposure to poultry (shopped at live poultry market, had live or freshly cut poultry in their home in the weeks before interview). Because the initial diagnosis was delayed, infection control procedures were not immediately initiated for most cases. Among the exposed and unexposed HCW enrolled, 4% (8/217) and 0.7% (2/309), respectively, tested positive for H5 antibodies, suggesting a risk of patient to HCW transmission. Exposure to poultry did not differ among exposed and unexposed HCW. Risk factors for H5 antibody among exposed HCW included bathing the patient and changing bed linens, tasks that involve close and more prolonged exposure to the patient. Interestingly, no HCWs exposed to mildly ill children had anti-H5 antibodies, only HCW exposed to critically ill patients with pneumonia, both of whom died, had H5 antibody.</p><p>Among 1,525 PW and among 293 government workers (GW) who were involved in the culling of poultry during this outbreak in Hong Kong, 10% of PW were estimated to be seropositive to H5, while 9 (3.1%) GW tested positive <xref rid="pone.0014582-Bridges2" ref-type="bibr">[20]</xref>. A nested case-control study of PW found an elevated risk for those that worked in retail compared to those who worked in wholesale, hatchery, farm, or other poultry industries (OR = 2.7 95% CI 1.5–4.9); worked on a farm with >10% mortality among poultry within the previous two months (OR = 2.2 95% CI 1.3–3.7); butchered poultry (OR = 3.1 95% CI 1.6–5.9); fed poultry (OR = 2.4 95% CI 1.4–4.1); and prepared poultry for restaurants (OR = 1.7 95% CI 1.1–2.7). The risk of having anti-H5 antibody appeared to increase with the amount and intensity of contact with poultry, with stratified analysis suggesting that butchering poultry and exposure to poultry flocks with >10% mortality were exposures most highly associated with having anti-H5 antibody. Feeding poultry was not associated with an increased risk in stratified analyses.</p></sec><sec id="s3b"><title>Sero-epidemiological investigations since 2003 (499 cases, 295 deaths)</title><p>Since 2003, sero-epidemiologic investigations into risk factors for human infection have been conducted primarily in Asian countries and to a lesser extent in African, European and the Middle Eastern countries (<xref ref-type="supplementary-material" rid="pone.0014582.s001">Table S1</xref>) but human seroprevalence studies have not been conducted in all locations with relatively high numbers of human cases (e.g., Egypt, Vietnam and Indonesia). Rather, several small scale studies evaluating the prevalence of anti-H5 antibodies have been conducted in Vietnam, Thailand, Cambodia, China, Indonesia, Germany, and Nigeria in areas (within 1–3 km) surrounding locations of reported human and/or poultry outbreaks <xref rid="pone.0014582-Apisarnthanarak1" ref-type="bibr">[21]</xref>, <xref rid="pone.0014582-Areechokchai1" ref-type="bibr">[22]</xref>, <xref rid="pone.0014582-Dinh1" ref-type="bibr">[23]</xref>, <xref rid="pone.0014582-Hinjoy1" ref-type="bibr">[24]</xref>, <xref rid="pone.0014582-Lu1" ref-type="bibr">[25]</xref>, <xref rid="pone.0014582-Ortiz1" ref-type="bibr">[26]</xref>, <xref rid="pone.0014582-Schultsz1" ref-type="bibr">[27]</xref>, <xref rid="pone.0014582-ThanhLiem1" ref-type="bibr">[28]</xref>, <xref rid="pone.0014582-Vong1" ref-type="bibr">[29]</xref>, <xref rid="pone.0014582-Santhia1" ref-type="bibr">[30]</xref>, <xref rid="pone.0014582-Cai1" ref-type="bibr">[31]</xref>, <xref rid="pone.0014582-Wang1" ref-type="bibr">[32]</xref>, <xref rid="pone.0014582-World1" ref-type="bibr">[33]</xref>, <xref rid="pone.0014582-Dejpichai1" ref-type="bibr">[34]</xref>, <xref rid="pone.0014582-Wang2" ref-type="bibr">[35]</xref>. These sero-studies can be categorized by the study populations evaluated in each study: non-occupational settings (subjects living in close proximity to a confirmed H5N1 case) and occupationally exposed individuals (PW or HCW) (<xref ref-type="supplementary-material" rid="pone.0014582.s001">Table S1</xref>).</p><sec id="s3b1"><title>Non-occupational settings</title><p>Non-occupational exposure largely consists of caring for household poultry, preparing or cooking poultry, visiting a LBM or living in close proximity to poultry. Three studies from Thailand, Cambodia and Indonesia of the seven studies evaluating seroprevalence in rural areas found no evidence of anti-H5 antibodies in their study populations despite frequent contact in households with poultry with probable H5N1 infection <xref rid="pone.0014582-Hinjoy1" ref-type="bibr">[24]</xref>, <xref rid="pone.0014582-Vong1" ref-type="bibr">[29]</xref>, <xref rid="pone.0014582-Santhia1" ref-type="bibr">[30]</xref>. However, evidence of exposure to poultry resulting in asymptomatic human infection was found in 1 study in China, and 2 studies in Cambodia. In the studies from Guangdong China and Cambodia, approximately 1–3% (14/1214<xref rid="pone.0014582-Lu1" ref-type="bibr">[25]</xref>, 7/674 <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>, 18/700 <xref rid="pone.0014582-Cavailler1" ref-type="bibr">[37]</xref>) of the individuals living within a 3 km or 1 km radius, respectively, of H5N1 outbreaks in domestic poultry had antibodies against H5 indicating prior infection with H5N1. In Cambodia, risk factors associated with seropositivity included swimming or bathing in ponds (OR = 11.3, 95% CI 1.25–102.18 <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>; OR = 2.52, 95%CI 0.98–6.51<xref rid="pone.0014582-Cavailler1" ref-type="bibr">[37]</xref>) and gathering poultry and placing them in cages or designated areas (OR = 5.8, 95% CI 0.98–34.12<xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>).</p><p>Two case-control studies were conducted in Vietnam (28 cases; 106 age-, sex-, and neighborhood- matched controls <xref rid="pone.0014582-Dinh1" ref-type="bibr">[23]</xref>) and Thailand (16 cases, 64 age- and neighborhood-matched controls <xref rid="pone.0014582-Areechokchai1" ref-type="bibr">[22]</xref>; <xref ref-type="table" rid="pone-0014582-t002">Table 2</xref>). Using multivariate analysis, the Vietnam study found that risk factors for human infection included preparing or cooking unhealthy poultry (OR = 31, 95%CI 3.4–1150), having sick or dead poultry in the household (OR = 7.41, 95%CI 2.7–59.0), presence of sick/dead poultry in the neighborhood (OR = 3.9, 95%CI 1.0–55.7), and no indoor water source in the household (OR = 5.0, 95%CI 1.3–77.0) <xref rid="pone.0014582-Dinh1" ref-type="bibr">[23]</xref>. In Thailand, cases were more likely to have: touched a dead bird that died unexpectedly (OR = 29, 95%CI 2.7–308.2); dressed poultry (no definition provided, OR = 17, 95%CI 1.6–177.0); had poultry that died unexpectedly around their home (OR = 5.6, 95%CI 1.5–20.7); plucked feathers from poultry (OR = 14, 95%CI 1.3–152.5); stored products of sick or dead poultry in their home (OR = 9.3, 95%CI 2.1–41.3); or directly touched sick poultry (OR = 5.6, 95%CI 1.5–20.7). Risk factors for infection also included living in close proximity to sick (OR = 3.8, 95%CI 1.2–11.7) or dead (OR = 13, 95%CI 1.5–96.3) poultry <xref rid="pone.0014582-Areechokchai1" ref-type="bibr">[22]</xref>. Following an outbreak of H5N1 in wild birds in Azerbaijan in 2006, the clinical specimens (throat, nasal and rectal swabs, plus sera) of 9/52 residents (all symptomatic) tested positive for the presence of H5N1 virus using RT-PCR and virus isolation. These 9 cases, all of whom were from related or neighboring families, were thought to most likely have become infected while defeathering dead wild swans <xref rid="pone.0014582-Gilsdorf1" ref-type="bibr">[38]</xref>.</p><p>In China, a case-control analysis of 10 urban and 18 rural laboratory confirmed human H5N1 cases compared to 134 controls found that risk factors for infection included touching sick or dead poultry (OR = 506.6, 95%CI15.7–16319.6) or living in close proximity to sick or dead poultry (OR = 56.9, 95%CI 4.3–745.6), and visiting a LBM (OR = 15.4, 95%CI 3.0–80.2) <xref rid="pone.0014582-Zhou1" ref-type="bibr">[39]</xref> (<xref ref-type="table" rid="pone-0014582-t002">Table 2</xref>). Urban cases were significantly more likely to have visited a LBM, compared with rural cases (p = 0.002).</p></sec><sec id="s3b2"><title>Occupational exposure</title><p>Risk factors for infection among PW at LBMs or workers involved in culling operations have been evaluated in Nigeria, China (Guangdong), Indonesia (Bali), Vietnam and Germany. Despite presumably frequent and extensive contact with infected poultry, no evidence of H5N1 infection was found among 295 market vendors in Nigeria <xref rid="pone.0014582-Ortiz1" ref-type="bibr">[26]</xref>, 87 market vendors in Bali <xref rid="pone.0014582-Santhia1" ref-type="bibr">[30]</xref>, 68 market vendors in Guandong, China <xref rid="pone.0014582-Wang3" ref-type="bibr">[40]</xref>, or 97 GW involved in culling operations in Germany <xref rid="pone.0014582-Cai1" ref-type="bibr">[31]</xref>. Three studies from Guangdong, China (1 seropositive/110 tested using HI with turkey red blood cells<xref rid="pone.0014582-Wang2" ref-type="bibr">[35]</xref>; 2/231 using HI>1∶80<xref rid="pone.0014582-Lu1" ref-type="bibr">[25]</xref>; 2/2191 using HI [no cutoff mentioned]) and one study from Vietnam (3 seropositive/500 tested using HI>1∶80, 0/500 using MN) found limited evidence of previous H5N1 infection; however, no specific risk factors for infection were reported (<xref ref-type="supplementary-material" rid="pone.0014582.s001">Table S1</xref>) <xref rid="pone.0014582-Lu1" ref-type="bibr">[25]</xref>, <xref rid="pone.0014582-Wang1" ref-type="bibr">[32]</xref>, <xref rid="pone.0014582-Wang2" ref-type="bibr">[35]</xref>, <xref rid="pone.0014582-Schultsz2" ref-type="bibr">[41]</xref>.</p><p>Since 2003, one study from Thailand, and two studies from Vietnam evaluated the frequency of asymptomatic or subclinical infection and evaluated human-to-human transmission risk factors for H5N1 virus among HCW <xref rid="pone.0014582-Apisarnthanarak1" ref-type="bibr">[21]</xref>, <xref rid="pone.0014582-Schultsz1" ref-type="bibr">[27]</xref>, <xref rid="pone.0014582-ThanhLiem1" ref-type="bibr">[28]</xref>. In contrast to the results found in the serosurvey of HCW conducted in Hong Kong in 1997<xref rid="pone.0014582-Bridges1" ref-type="bibr">[19]</xref>, no serologic evidence was found of infection with H5N1 among HCW with direct contact with human H5N1 patients. The use of personal protective equipment (PPE) in Vietnam was well documented <xref rid="pone.0014582-Schultsz1" ref-type="bibr">[27]</xref>, <xref rid="pone.0014582-ThanhLiem1" ref-type="bibr">[28]</xref>. In Thailand, however, the use of PPE (surgical mask, gown and gloves) was not initiated until 48 hours after the patient was admitted to the hospital <xref rid="pone.0014582-Apisarnthanarak1" ref-type="bibr">[21]</xref>.</p><p>Person to Person transmissionClusters of epidemiologically linked H5N1 cases have occurred among relatives in several countries, including Indonesia, China, Turkey, Azerbaijan, Vietnam and Thailand, suggesting that human-to-human transmission between family members in close contact may have occurred <xref rid="pone.0014582-Gilsdorf1" ref-type="bibr">[38]</xref>, <xref rid="pone.0014582-Olsen1" ref-type="bibr">[42]</xref>, <xref rid="pone.0014582-Oner1" ref-type="bibr">[43]</xref>, <xref rid="pone.0014582-Ungchusak1" ref-type="bibr">[44]</xref>, <xref rid="pone.0014582-Kandun1" ref-type="bibr">[45]</xref>, <xref rid="pone.0014582-Wang4" ref-type="bibr">[46]</xref>, <xref rid="pone.0014582-Kandun2" ref-type="bibr">[47]</xref>, <xref rid="pone.0014582-WHO6" ref-type="bibr">[48]</xref>. An early investigation in Vietnam, suggested that between January 2004 and July 2005, 15 suspected family clusters occurred among the first 109 cases, of which nine clusters had ≥2 laboratory confirmed H5N1 cases <xref rid="pone.0014582-Olsen1" ref-type="bibr">[42]</xref>.</p><p>A family cluster in mainland China consisted of a father and son, the former likely infected through close, unprotected contact via care of his son at a hospital during his illness <xref rid="pone.0014582-Wang4" ref-type="bibr">[46]</xref>. Similarly in Thailand, two relatives of an infected patient likely became infected through unprotected hospital care <xref rid="pone.0014582-Ungchusak1" ref-type="bibr">[44]</xref>. In Turkey, several members of the same family became infected with H5N1, however transmission was likely common-source poultry-to-human rather than human-to-human because they all shared the same living space with poultry <xref rid="pone.0014582-Oner1" ref-type="bibr">[43]</xref>.</p><p>In Indonesia, there have been reports of 21 clusters of H5N1 among blood relatives with each cluster involving 2–7 blood relatives <xref rid="pone.0014582-Kandun1" ref-type="bibr">[45]</xref>, <xref rid="pone.0014582-Kandun2" ref-type="bibr">[47]</xref>, <xref rid="pone.0014582-WHO6" ref-type="bibr">[48]</xref>. Limited human-to-human transmission may have occurred in two of the first three clusters in 2005. However, common-source exposure to the virus via a contaminated environment, through contact with contaminated poultry manure or with infected poultry could not be ruled out <xref rid="pone.0014582-Kandun1" ref-type="bibr">[45]</xref>. In a further detailed analysis of all human H5N1 cases in Indonesia, the authors examined exposures to poultry and could not rule out a common source of infection in the clusters as family members usually have similar opportunities for exposure to the virus.</p></sec></sec><sec id="s3c"><title>Environmental exposures leading to transmission of H5N1 virus to humans</title><p>Non-poultry exposures-related H5N1 exposures, defined here as any contact not involving touching poultry or poultry products, e.g. exposure to H5N1 contaminated environments may also lead to H5N1 infection <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>, <xref rid="pone.0014582-deJong1" ref-type="bibr">[49]</xref>, <xref rid="pone.0014582-FAO1" ref-type="bibr">[50]</xref>, <xref rid="pone.0014582-Vong3" ref-type="bibr">[51]</xref>, <xref rid="pone.0014582-WHO7" ref-type="bibr">[52]</xref>. Exposure to H5N1 virus in contaminated feces in garden fertilizer has been reported as a source of human infection <xref rid="pone.0014582-Kandun3" ref-type="bibr">[53]</xref>. Because birds are known to shed high concentrations of virus into water sources, transmission from poultry to humans through contaminated water is also possible <xref rid="pone.0014582-WHO7" ref-type="bibr">[52]</xref>. The epidemiologic investigation of two H5N1 cases in a single family in Vietnam suggested that exposure to possibly contaminated canal water via swimming or washing may have resulted in infection. However, the role of water in transmission could not be confirmed <xref rid="pone.0014582-deJong1" ref-type="bibr">[49]</xref>. More recently, results from environmental sampling within a Cambodian village with confirmed H5N1 in domestic poultry flocks and one human case as well as results from a human seroprevalence study from the same village identified contaminated water as a potential risk factor for H5N1 infection <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>, <xref rid="pone.0014582-Vong3" ref-type="bibr">[51]</xref>.</p></sec></sec><sec id="s4"><title>Discussion</title><p>Several epidemiologic studies have been published to evaluate risk factors, including contact with poultry and poultry products and non-poultry-related contact such as from H5N1-contaminated water, for H5N1 infection in humans. Our review shows that most H5N1 cases are attributed to exposure to sick poultry, while a few were likely due to human-to-human transmission.</p><p>An illustration of possible pathways of poultry-to-human transmission of H5N1 virus is provided in <xref ref-type="fig" rid="pone-0014582-g001">Figure 1</xref>. Potential modes of influenza transmission vary depending on the nature of the contact, and have been suggested to include inhalation; ingestion; conjunctival, oral contact or intranasal inoculation; or aerosol routes <xref rid="pone.0014582-Rabinowitz1" ref-type="bibr">[16]</xref>. Evidence from the published literature has illustrated that exposure to the H5N1 virus has occurred through contact with infected poultry blood or bodily fluids via food preparation practices <xref rid="pone.0014582-Greiner1" ref-type="bibr">[54]</xref> (e.g., slaughtering, boiling, defeathering, cutting meat, cleaning meat, removing and/or cleaning internal organs of poultry); consuming uncooked poultry products (e.g., raw duck blood) <xref rid="pone.0014582-Apisarnthanarak1" ref-type="bibr">[21]</xref>, <xref rid="pone.0014582-deJong1" ref-type="bibr">[49]</xref>, <xref rid="pone.0014582-Beigel1" ref-type="bibr">[55]</xref> or through the care of poultry (either commercially or domestically) <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>. The extent and frequency of risk behaviors and the relative risk of different behaviors is currently unknown across all countries where H5N1 is recurrent or endemic and there may be reluctance to disclose information on possible individual exposures due to legal, social or economic implications, or other reasons. For example, in Azerbaijan the nine human cases were likely exposed during the illegal de-feathering of dead wild swans <xref rid="pone.0014582-Gilsdorf1" ref-type="bibr">[38]</xref>.</p><fig id="pone-0014582-g001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0014582.g001</object-id><label>Figure 1</label><caption><title>Known and suggested pathways of H5N1 exposure to infection from poultry to humans.</title><p>*via swimming/bathing in water frequently used by domestic and/or wild poultry.</p></caption><graphic xlink:href="pone.0014582.g001"></graphic></fig><p>There are also a significant number of human H5N1 cases reported to WHO without known or reported poultry exposure <xref rid="pone.0014582-WHO8" ref-type="bibr">[56]</xref>. Little is understood about non-direct contact exposures to H5N1-infected poultry that may increase the risk of human infection, though recent studies have suggested an association between exposure to a contaminated environment (e.g., water; cleaning poultry cages or their designated areas; using poultry feces for fertilizer) and infection either through ingestion, conjunctival or intranasal inoculation of contaminated water, soil <xref rid="pone.0014582-deJong1" ref-type="bibr">[49]</xref>, <xref rid="pone.0014582-Vong3" ref-type="bibr">[51]</xref>, <xref rid="pone.0014582-Kandun3" ref-type="bibr">[53]</xref> or via fomites e.g. equipment or vehicles <xref rid="pone.0014582-FAO1" ref-type="bibr">[50]</xref>. It is also possible that infection via inhalation of H5N1 aerosolized at LBMs in China may have occurred <xref rid="pone.0014582-Mounts1" ref-type="bibr">[17]</xref>, <xref rid="pone.0014582-Zhou1" ref-type="bibr">[39]</xref>. Other pathways may exist, but are currently unknown.</p><p>The collective results of publically available studies have shown that transmission of H5N1 virus from poultry to humans is infrequent, given that often only a single case may be detected in an area with widespread illness and death among household poultry, for example. Furthermore, the nature of the contact between some H5N1 patients and poultry was extensive, i.e., via preparing infected poultry, while some cases have reported less intense exposure to virus such as during swimming or bathing in potentially virus laden ponds or visiting LBMs without direct contract with poultry, and some have had no known exposure to poultry prior to infection <xref rid="pone.0014582-Kandun3" ref-type="bibr">[53]</xref>, <xref rid="pone.0014582-Yu1" ref-type="bibr">[57]</xref>. A better understanding of the risk of transmission via direct or indirect contact, through ingestion or inhalation or other exposure routes is needed to refine strategies to reduce risk of H5N1 infections in people.</p><p>It is highly likely that types of human-poultry contact differ between and even within countries. For example, there is substantial variation in the frequency of different poultry contact practices (e.g., slaughtering, caring for poultry) by age and gender amongst populations in rural Cambodia living in close proximity to poultry <xref rid="pone.0014582-VanKerkhove1" ref-type="bibr">[58]</xref>. Research has demonstrated that, based on reported poultry contact patterns, males in rural Cambodia have a higher exposure risk potential to H5N1 than females across all age groups and exposure risk is highest among males between the ages of 26–40, followed by 16–25 years old. Males in these age groups reported practices of contact with poultry (e.g., slaughter poultry, remove internal organs, blow in the beak of fighting cocks, clean the trachea of fighting cocks, lick wounds of fighting cocks) that give rise to the highest H5N1 transmission risk potential <xref rid="pone.0014582-VanKerkhove1" ref-type="bibr">[58]</xref>. Such differences demonstrate that the potential risk for transmission of H5N1 from poultry to humans is not uniform across age and gender and therefore may not be uniform within or across countries. The demographic differences in human cases of H5N1 infection to date among countries (<xref ref-type="table" rid="pone-0014582-t001">Table 1</xref>) are likely because such contact patterns with poultry—in addition to animal husbandry practices, biosecurity systems for the production of food animals and systems for detection of clinical disease—also differ among countries. However, data could also suggest that the variation in H5N1 incidence by age may not be due to exposure alone and that there may be differences by age in susceptibility to infection, pre-existing immunity against human influenza viruses that may confer some cross-reactive immunity, clinical presentation of disease, and/or presentation to health care facilities. In some countries, inclusion of contact with sick poultry in the definition of a suspect case could lower the case detection rate as well as falsely increase the proportion of cases with exposure to sick poultry as a risk factor. Additionally, ascertainment and recall biases could have been introduced in exposure assessment due to media coverage and/or lengthy delays between reported human and/or poultry H5N1 cases and follow-up epidemiologic investigations.</p><p>Our results also demonstrate a difference in seropositivity rates among serosurveys conducted following the 1997 H5N1 outbreaks in Hong Kong when compared to serosurveys conducted following outbreaks from 2003 to 2010. The higher rates of seropositivity in the studies following the 1997 outbreak may reflect the genetic differences in the viruses circulating now compared to the 1997 virus, which may have been more adaptable to human infection <xref rid="pone.0014582-Neumann1" ref-type="bibr">[59]</xref>. Sustained vigilance is required to monitor the ever changing nature of these viruses.</p><p>Several important data gaps currently limit our understanding of the transmission of H5N1 from poultry or H5N1 contaminated environments to humans. First, there is likely some unknown level of underreporting of human cases and poultry outbreaks such that the range and types of exposures may differ from reported cases. There may also be data and analyses conducted on H5N1 cases that have not been made publically available. Second, the serologic studies were conducted by different laboratories using a variety of assays and cutoffs for seropositivity, making direct comparisons of results across studies difficult. Seroprevalence studies have identified few asymptomatic individuals with anti-H5N1 antibodies, indicating previous infection with H5N1. However, the duration of immunity after H5N1 infection is not known and the timing of sampling in these studies may have resulted in an underestimation of those having experienced prior infection. In addition, it is possible that some infected individuals may not seroconvert and that some antibody positive individuals have non-specific antibody against H5 and do not represent true prior infections.</p><p>Third, the influence of genetic and/or immunological factors on susceptibility to infection and disease is poorly understood. Although there have been several suspected clusters of H5N1 infection largely among blood relatives <xref rid="pone.0014582-Olsen1" ref-type="bibr">[42]</xref>, <xref rid="pone.0014582-Oner1" ref-type="bibr">[43]</xref>, <xref rid="pone.0014582-Ungchusak1" ref-type="bibr">[44]</xref>, <xref rid="pone.0014582-Kandun1" ref-type="bibr">[45]</xref>, <xref rid="pone.0014582-Wang4" ref-type="bibr">[46]</xref>, the clusters are difficult to interpret because not all potentially exposed family members may have been tested for H5N1 and in most clusters, a common exposure could not be ruled out. While there may have been limited human-to-human transmission among close contacts in some clusters, genetic variation between families could result in the occurrence of clusters because of a predisposition to infection <xref rid="pone.0014582-Kandun2" ref-type="bibr">[47]</xref>, <xref rid="pone.0014582-Horby1" ref-type="bibr">[60]</xref>.</p><p>Finally, improved knowledge is needed on potential routes of transmission of H5N1 virus from poultry or H5N1-contaminated environments to humans and on the prevalence of risky practices in human populations. Studies to date have evaluated exposures through which people might become infected with H5N1, but we currently lack sufficient data from the confirmed H5N1 cases around the world and published epidemiologic studies to fully evaluate other potential risk factors for infection such as the role of water and other environmental factors, or unknown risk factors that have yet to be investigated. Transmission routes could also include oral ingestion, conjunctival or intranasal inoculation from contaminated water while drinking, swimming or bathing or inhalation of the virus in feces while caring for poultry <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>. Furthermore, more asymptomatic cases may occur because of low concentrations of viruses in the environment than have been detected in studies done to date. More studies of environmental contamination, including viral contamination in LBMs <xref rid="pone.0014582-Indriani1" ref-type="bibr">[61]</xref>, would further contribute to this understanding.</p><p>In order to fully evaluate the risk of poultry-to-human transmission, a detailed exposure history needs to be collected from all suspected cases and their contacts. In addition, data variables related to exposures to poultry by species and potentially infected environments ideally should also be standardized across epidemiologic studies to facilitate pooled or meta-analyses. Data collection forms have been developed <xref rid="pone.0014582-Bird1" ref-type="bibr">[62]</xref>; however, these forms must include not only information on contact with poultry by species, but include questions regarding the timing and intensity of such contact. These forms should also not only evaluate general exposure (e.g., handling sick or dead poultry, handling feces or fertilizer from sick or dead poultry, slaughtering poultry), but should include potential exposure via the environment (e.g., contaminated water). In order to build a database from which more robust analysis can be conducted, detailed exposure information should be systematically collected from all confirmed and suspect cases.</p><p>Although infection in humans with H5N1 virus remains rare, human cases continue to be reported. As well, H5N1 is now considered endemic among poultry in parts of Asia, providing opportunities for further dissemination of this virus and opportunities to mutate and adapt to humans and other mammalian species. Collaboration between human and animal health sectors for surveillance, case investigation, virus sharing and risk assessment is essential to understand and reduce the risk of virus transmission at the interface between domestic poultry and humans and to quickly recognize changes that may occur in the virus or in the epidemiology of its spread to humans that signal adaptation to humans. Current exposure data remain too general to explain the current pattern or to predict future cases of H5N1 infection in human populations; however the results of the available studies, including those reporting cases having no contact with poultry, suggest that exposure through the environment may account for many human cases <xref rid="pone.0014582-Vong2" ref-type="bibr">[36]</xref>, <xref rid="pone.0014582-Zhou1" ref-type="bibr">[39]</xref>. Rapid, systematic and standardized collection of detailed information on poultry contact and human case contacts for all suspected and confirmed human cases of H5N1, as well as more systematic epidemiological and seroepidemiologic studies with appropriate controls, would improve our understanding of risks of H5N1 and help inform development and implementation of appropriate public health risk reduction measures.</p></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0014582.s001"><label>Table S1</label><caption><p>Results of seroprevalence studies to determine the frequency of asymptomatic or subclinical infection and evaluate risk factors for H5N1 virus infection.</p><p>(0.50 MB PDF)</p></caption><media xlink:href="pone.0014582.s001.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>The author would like to thank Azra C Ghani, Imperial College London, for her critical and thoughtful review of the original FAO report.</p></ack><fn-group><fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="financial-disclosure"><p><bold>Funding: </bold>The work was supported by the United Kingdom Department for International Development (DFID), funders of the HPAI research project (GCP/INT/804/UK); the Medical Research Council (MVK); and the Bill and Melinda Gates Foundation (MVK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</p></fn></fn-group><ref-list><title>References</title><ref id="pone.0014582-Gross1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gross</surname><given-names>PA</given-names></name></person-group><year>1996</year><article-title>Preparing for the Next Influenza Pandemic: A Reemerging Infection.</article-title><source>Ann Intern Med</source><volume>124</volume><fpage>682</fpage><lpage>685</lpage><pub-id pub-id-type="pmid">8607598</pub-id></element-citation></ref><ref id="pone.0014582-Kilbourne1"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kilbourne</surname><given-names>E</given-names></name></person-group><year>2006</year><article-title>Influenza pandemics of the 20th century.</article-title><source>Emerg Infect Dis</source><volume>12</volume><fpage>9</fpage><lpage>14</lpage><pub-id pub-id-type="pmid">16494710</pub-id></element-citation></ref><ref id="pone.0014582-Oxford1"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oxford</surname><given-names>J</given-names></name></person-group><year>2000</year><article-title>Infuenza A pandemics of the 20th century with special reference to 1918: virology, pathology and epidemiology.</article-title><source>Rev Med Virol</source><volume>10</volume><fpage>119</fpage><lpage>133</lpage><pub-id pub-id-type="pmid">10713598</pub-id></element-citation></ref><ref id="pone.0014582-Horimoto1"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Horimoto</surname><given-names>T</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><year>2001</year><article-title>Pandemic Threat Posed by Avian Influenza A Viruses.</article-title><source>Clin Microbiol Rev</source><volume>14</volume><fpage>129</fpage><lpage>149</lpage><pub-id pub-id-type="pmid">11148006</pub-id></element-citation></ref><ref id="pone.0014582-Hsieh1"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hsieh</surname><given-names>Y-C</given-names></name><name><surname>Wu</surname><given-names>T-Z</given-names></name><name><surname>Liu</surname><given-names>D-P</given-names></name><name><surname>Shao</surname><given-names>P-L</given-names></name><name><surname>Chang</surname><given-names>L-Y</given-names></name><etal></etal></person-group><year>2006</year><article-title>Influenza Pandemics: Past, Present and Future.</article-title><source>Journal of the Formosan Medical Association</source><volume>105</volume><fpage>1</fpage><lpage>6</lpage><pub-id pub-id-type="pmid">16440064</pub-id></element-citation></ref><ref id="pone.0014582-Webster1"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Webster</surname><given-names>R</given-names></name><name><surname>Bean</surname><given-names>W</given-names></name><name><surname>Gorman</surname><given-names>O</given-names></name><name><surname>Chambers</surname><given-names>T</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><year>1992</year><article-title>Evolution and ecology of influenza A viruses.</article-title><source>Microbiol Rev</source><volume>56</volume><fpage>152</fpage><lpage>179</lpage><pub-id pub-id-type="pmid">1579108</pub-id></element-citation></ref><ref id="pone.0014582-Reid1"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reid</surname><given-names>AH</given-names></name><name><surname>Fanning</surname><given-names>TG</given-names></name><name><surname>Hultin</surname><given-names>JV</given-names></name><name><surname>Taubenberger</surname><given-names>JK</given-names></name></person-group><year>1999</year><article-title>Origin and evolution of the 1918 Spanish influenza virus hemagglutinin gene.</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>96</volume><fpage>1651</fpage><lpage>1656</lpage><pub-id pub-id-type="pmid">9990079</pub-id></element-citation></ref><ref id="pone.0014582-Trifonov1"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Trifonov</surname><given-names>V</given-names></name><name><surname>Khiabanian</surname><given-names>H</given-names></name><name><surname>Rabadan</surname><given-names>R</given-names></name></person-group><year>2009</year><article-title>Geographic Dependence, Surveillance, and Origins of the 2009 Influenza A (H1N1) Virus.</article-title><source>N Engl J Med</source><volume>361</volume><fpage>115</fpage><lpage>119</lpage><pub-id pub-id-type="pmid">19474418</pub-id></element-citation></ref><ref id="pone.0014582-WHO1"><label>9</label><element-citation publication-type="other"><collab>WHO</collab><year>2009</year><article-title>Preparing for the second wave: lessons from current outbreaks. August 28, 2009.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html">http://www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html</ext-link>. Accessed January 21, 2010</comment></element-citation></ref><ref id="pone.0014582-Claas1"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Claas</surname><given-names>ECJ</given-names></name><name><surname>Osterhaus</surname><given-names>ADME</given-names></name><name><surname>van Beek</surname><given-names>R</given-names></name><name><surname>De Jong</surname><given-names>JC</given-names></name><name><surname>Rimmelzwaan</surname><given-names>GF</given-names></name><etal></etal></person-group><year>1998</year><article-title>Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus.</article-title><source>The Lancet</source><volume>351</volume><fpage>472</fpage><lpage>477</lpage></element-citation></ref><ref id="pone.0014582-WHO2"><label>11</label><element-citation publication-type="other"><collab>WHO</collab><year>2010</year><article-title>World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO as of 12 March 2010. World Health Organization.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/avian_influenza/country/cases_table_2010_03_12/en/index.html">http://www.who.int/csr/disease/avian_influenza/country/cases_table_2010_03_12/en/index.html</ext-link></comment></element-citation></ref><ref id="pone.0014582-WHO3"><label>12</label><element-citation publication-type="other"><collab>WHO</collab><year>2009</year><article-title>World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO as of 16 December 2008.</article-title><comment>World Health Organization; Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_12_16/en/index.html">http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_12_16/en/index.html</ext-link></comment></element-citation></ref><ref id="pone.0014582-Writing1"><label>13</label><element-citation publication-type="journal"><collab>Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza AV</collab><year>2008</year><article-title>Update on Avian Influenza A (H5N1) Virus Infection in Humans.</article-title><source>N Engl J Med</source><volume>358</volume><fpage>261</fpage><lpage>273</lpage><pub-id pub-id-type="pmid">18199865</pub-id></element-citation></ref><ref id="pone.0014582-WHO4"><label>14</label><element-citation publication-type="other"><collab>WHO</collab><year>2004</year><article-title>World Health Organization. Avian influenza: situation in Viet Nam, update 30 December 2004.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/don/2004_12_30/en/">http://www.who.int/csr/don/2004_12_30/en/</ext-link>. Disease Outbreak News</comment></element-citation></ref><ref id="pone.0014582-WHO5"><label>15</label><element-citation publication-type="other"><collab>WHO</collab><year>2006</year><article-title>World Health Organization. Avian influenza: situation in Indonesia, update 21 August 2006.</article-title><comment>Available at: <ext-link ext-link-type="uri" xlink:href="http://www.searo.who.int/en/Section10/Section1027/Section2095/Section2176_12077.htm">http://www.searo.who.int/en/Section10/Section1027/Section2095/Section2176_12077.htm. Disease</ext-link> Outbreak News</comment></element-citation></ref><ref id="pone.0014582-Rabinowitz1"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rabinowitz</surname><given-names>P</given-names></name><name><surname>Perdue</surname><given-names>M</given-names></name><name><surname>Mumford</surname><given-names>E</given-names></name></person-group><year>2009</year><article-title>Contact Variables for Exposure to Avian Influenza H5N1 Virus at the Human-Animal Interface.</article-title><source>Zoonoses Public Health 2009: Mar</source><volume>26</volume></element-citation></ref><ref id="pone.0014582-Mounts1"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mounts</surname><given-names>A</given-names></name><name><surname>Kwong</surname><given-names>H</given-names></name><name><surname>Izurieta</surname><given-names>H</given-names></name><name><surname>Ho</surname><given-names>Y</given-names></name><name><surname>Au</surname><given-names>T</given-names></name><etal></etal></person-group><year>1999</year><article-title>Case-control study of risk factors for avian influenza A (H5N1) disease, Hong Kong, 1997.</article-title><source>J Infect Dis</source><volume>180</volume><fpage>505</fpage><lpage>508</lpage><pub-id pub-id-type="pmid">10395870</pub-id></element-citation></ref><ref id="pone.0014582-Katz1"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>Wilina</surname><given-names>Lim</given-names></name><name><surname>Bridges</surname><given-names>CB</given-names></name><name><surname>Rowe</surname><given-names>T</given-names></name><name><surname>Hu-Primmer</surname><given-names>J</given-names></name><etal></etal></person-group><year>1999</year><article-title>Antibody Response in Individuals Infected with Avian Influenza A (H5N1) Viruses and Detection of Anti-H5 Antibody among Household and Social Contacts.</article-title><source>The Journal of Infectious Diseases</source><volume>180</volume><fpage>1763</fpage><lpage>1770</lpage><pub-id pub-id-type="pmid">10558929</pub-id></element-citation></ref><ref id="pone.0014582-Bridges1"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bridges</surname><given-names>C</given-names></name><name><surname>Katz</surname><given-names>J</given-names></name><name><surname>Seto</surname><given-names>W</given-names></name><name><surname>Chan</surname><given-names>P</given-names></name><name><surname>Tsang</surname><given-names>D</given-names></name><etal></etal></person-group><year>2000</year><article-title>Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong.</article-title><source>J Infect Dis</source><volume>181</volume><fpage>344</fpage><lpage>348</lpage><pub-id pub-id-type="pmid">10608786</pub-id></element-citation></ref><ref id="pone.0014582-Bridges2"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bridges</surname><given-names>C</given-names></name><name><surname>Lim</surname><given-names>W</given-names></name><name><surname>Hu-Primmer</surname><given-names>J</given-names></name><name><surname>Sims</surname><given-names>L</given-names></name><name><surname>Fukuda</surname><given-names>K</given-names></name><etal></etal></person-group><year>2002</year><article-title>Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997-1998.</article-title><source>J Infect Dis</source><volume>185</volume><fpage>1005</fpage><lpage>1010</lpage><pub-id pub-id-type="pmid">11930308</pub-id></element-citation></ref><ref id="pone.0014582-Apisarnthanarak1"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Apisarnthanarak</surname><given-names>A</given-names></name><name><surname>Erb</surname><given-names>S</given-names></name><name><surname>Stephenson</surname><given-names>I</given-names></name><name><surname>Katz</surname><given-names>JM</given-names></name><name><surname>Chittaganpitch</surname><given-names>M</given-names></name><etal></etal></person-group><year>2005</year><article-title>Seroprevalence of Anti-H5 Antibody among Thai Health Care Workers after Exposure to Avian Influenza (H5N1) in a Tertiary Care Ce<italic>nter</italic>.</article-title><source>Clin Infect Dis</source><volume>40</volume><fpage>e16</fpage><lpage>e18</lpage><pub-id pub-id-type="pmid">15655735</pub-id></element-citation></ref><ref id="pone.0014582-Areechokchai1"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Areechokchai</surname><given-names>D</given-names></name><name><surname>Jiraphongsa</surname><given-names>C</given-names></name><name><surname>Laosiritaworn</surname><given-names>Y</given-names></name><name><surname>Hanshaoworakul</surname><given-names>W</given-names></name><name><surname>O'Reilly</surname><given-names>M</given-names></name><etal></etal></person-group><year>2006</year><article-title>Investigation of avian influenza (H5N1) outbreak in humans–Thailand, 2004.</article-title><source>MMWR</source><volume>55</volume><fpage>3</fpage><lpage>6</lpage></element-citation></ref><ref id="pone.0014582-Dinh1"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dinh</surname><given-names>P</given-names></name><name><surname>Long</surname><given-names>H</given-names></name><name><surname>Tien</surname><given-names>N</given-names></name><name><surname>Hien</surname><given-names>N</given-names></name><name><surname>Mai</surname><given-names>L</given-names></name><etal></etal></person-group><year>2006</year><article-title>and the World Health Organization/Global Outbreak Alert and Response Network Avian Influenza Investigation Team in Vietnam. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004.</article-title><source>Emerg Infect Dis</source><volume>12</volume><fpage>1841</fpage><lpage>1847</lpage><pub-id pub-id-type="pmid">17326934</pub-id></element-citation></ref><ref id="pone.0014582-Hinjoy1"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hinjoy</surname><given-names>S</given-names></name><name><surname>Puthavathana</surname><given-names>P</given-names></name><name><surname>Laosiritaworn</surname><given-names>Y</given-names></name><name><surname>Limpakarnjanarat</surname><given-names>K</given-names></name><name><surname>Pooruk</surname><given-names>P</given-names></name><etal></etal></person-group><year>2008</year><article-title>Low Frequency of Infection With Avian Influenza Virus (H5N1) Among Poultry Farmers, Thailand, 2004.</article-title><source>Emerg Infect Dis</source><volume>14</volume><fpage>499</fpage><lpage>450</lpage><pub-id pub-id-type="pmid">18325273</pub-id></element-citation></ref><ref id="pone.0014582-Lu1"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>C</given-names></name><name><surname>Lu</surname><given-names>J</given-names></name><name><surname>Chen</surname><given-names>W</given-names></name><name><surname>Jiang</surname><given-names>L</given-names></name><name><surname>Tan</surname><given-names>B</given-names></name><etal></etal></person-group><year>2008</year><article-title>Potential infections of H5N1 and H9N2 avian influenza do exist in Guangdong populations of China.</article-title><source>Chin Med J (Engl)</source><volume>121</volume><fpage>2050</fpage><lpage>2053</lpage><pub-id pub-id-type="pmid">19080274</pub-id></element-citation></ref><ref id="pone.0014582-Ortiz1"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ortiz</surname><given-names>J</given-names></name><name><surname>Katz</surname><given-names>M</given-names></name><name><surname>Mahmoud</surname><given-names>M</given-names></name><name><surname>Ahmed</surname><given-names>S</given-names></name><name><surname>Bawa</surname><given-names>S</given-names></name><etal></etal></person-group><year>2007</year><article-title>Lack of Evidence of Animan-to-Human Transmission of Avian Influenza A (H5N1) Virus among Poultry Workers, Kano, Nigeria, 2006.</article-title><source>J Infect Dis</source><volume>196</volume><fpage>1685</fpage><lpage>1691</lpage><pub-id pub-id-type="pmid">18008254</pub-id></element-citation></ref><ref id="pone.0014582-Schultsz1"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schultsz</surname><given-names>C</given-names></name><name><surname>Vo</surname><given-names>C</given-names></name><name><surname>Nguyen</surname><given-names>V</given-names></name><name><surname>Nguyen</surname><given-names>T</given-names></name><name><surname>Lim</surname><given-names>W</given-names></name><etal></etal></person-group><year>2005</year><article-title>Avian Influenza H5N1 and Healthcare Workers.</article-title><source>Emerg Infect Dis</source><volume>11</volume><fpage>1158</fpage><lpage>1159</lpage><pub-id pub-id-type="pmid">16032802</pub-id></element-citation></ref><ref id="pone.0014582-ThanhLiem1"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thanh Liem</surname><given-names>N</given-names></name><name><surname>Lim</surname><given-names>W</given-names></name></person-group><collab>World Health Organization International Avian Influenza Investigation Team V</collab><year>2005</year><article-title>Lack of H5N1 avian influenza transmission to hospital employees, Hanoi, 2004.</article-title><source>Emerg Infect Dis</source><volume>11</volume><fpage>210</fpage><lpage>215</lpage><pub-id pub-id-type="pmid">15752437</pub-id></element-citation></ref><ref id="pone.0014582-Vong1"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vong</surname><given-names>S</given-names></name><name><surname>Goghlan</surname><given-names>B</given-names></name><name><surname>Mardy</surname><given-names>S</given-names></name><name><surname>Holl</surname><given-names>D</given-names></name><name><surname>Seng</surname><given-names>H</given-names></name><etal></etal></person-group><year>2006</year><article-title>Low Frequency of Avian-to-Human Transmission of H5N1 in Southern Cambodia, 2005.</article-title><source>Emerg Infect Dis</source><volume>12</volume><fpage>1542</fpage><lpage>1547</lpage><pub-id pub-id-type="pmid">17176569</pub-id></element-citation></ref><ref id="pone.0014582-Santhia1"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Santhia</surname><given-names>K</given-names></name><name><surname>Ramy</surname><given-names>A</given-names></name><name><surname>Jayaningsih</surname><given-names>P</given-names></name><name><surname>Samaan</surname><given-names>G</given-names></name><name><surname>Putra</surname><given-names>A</given-names></name><etal></etal></person-group><year>2009</year><article-title>Avian influenza A H5N1 infections in Bali province, Indonesia: a behavioral, virological andseroepidemiological study.</article-title><source>Influenza and Other Respiratory Diseases</source><volume>3</volume><fpage>81</fpage><lpage>89</lpage></element-citation></ref><ref id="pone.0014582-Cai1"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cai</surname><given-names>W</given-names></name><name><surname>Schweiger</surname><given-names>B</given-names></name><name><surname>Buchholz</surname><given-names>U</given-names></name><name><surname>Buda</surname><given-names>S</given-names></name><name><surname>Littmann</surname><given-names>M</given-names></name><etal></etal></person-group><year>2009</year><article-title>Protective measures and H5N1-seroprevalence among personnel tasked with bird collection during an outbreak of avian influenza A/H5N1 in wild birds, Ruegen, Germany, 2006.</article-title><source>BMC Infectious Diseases</source><volume>9</volume><fpage>170</fpage><pub-id pub-id-type="pmid">19835632</pub-id></element-citation></ref><ref id="pone.0014582-Wang1"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>M</given-names></name><name><surname>Fu</surname><given-names>C</given-names></name><name><surname>Zheng</surname><given-names>B</given-names></name></person-group><year>2009</year><article-title>Antibodies against H5 and H9 avian influenza among poultry workers in China.</article-title><source>N Engl J Med</source><volume>360</volume><fpage>2583</fpage><lpage>2584</lpage><pub-id pub-id-type="pmid">19516044</pub-id></element-citation></ref><ref id="pone.0014582-World1"><label>33</label><element-citation publication-type="journal"><collab>World Health Organization</collab><year>2006</year><article-title>Human avian influenza in Azerbaijan, February–March 2006.</article-title><source>Weekly Epidemiological Record (WER) 5 May 2006</source><volume>81</volume><fpage>183</fpage><lpage>188</lpage></element-citation></ref><ref id="pone.0014582-Dejpichai1"><label>34</label><element-citation publication-type="other"><person-group person-group-type="author"><name><surname>Dejpichai</surname><given-names>R</given-names></name><name><surname>Laosiritaworn</surname><given-names>Y</given-names></name><name><surname>Phuthavathana</surname><given-names>P</given-names></name><name><surname>Uyeki</surname><given-names>T</given-names></name><name><surname>O'Reilly</surname><given-names>M</given-names></name><etal></etal></person-group><year>2009</year><article-title>Seroprevalence of antibodies to avian influenza virus A (H5N1) among residents of villages with human cases, Thailand. Emerg Infect Dis 15: 756-60.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.cdc.gov/EID/content/15/5/756.htm">http://www.cdc.gov/EID/content/15/5/756.htm</ext-link></comment></element-citation></ref><ref id="pone.0014582-Wang2"><label>35</label><element-citation publication-type="other"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>M</given-names></name><name><surname>Di</surname><given-names>B</given-names></name><name><surname>Zhou</surname><given-names>D</given-names></name><name><surname>Zheng</surname><given-names>B</given-names></name><name><surname>Jing</surname><given-names>H</given-names></name><etal></etal></person-group><year>2006</year><article-title>Food Markets with Live Brids as Source of Avian Influenza. Emerg Infect Dis 12 (Nov).</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.cdc.gov/ncidod/EID/vol12no11/06-0675.htm">http://www.cdc.gov/ncidod/EID/vol12no11/06-0675.htm</ext-link></comment></element-citation></ref><ref id="pone.0014582-Vong2"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vong</surname><given-names>S</given-names></name><name><surname>Ly</surname><given-names>S</given-names></name><name><surname>Van Kerkhove</surname><given-names>MD</given-names></name><name><surname>Achenbach</surname><given-names>J</given-names></name><name><surname>Holl</surname><given-names>D</given-names></name><etal></etal></person-group><year>2009</year><article-title>Risk Factors Associated with Subclinical Human Infection with Avian Influenza A (H5N1) Virus- Cambodia, 2006.</article-title><source>Journal of Infectious Diseases</source><volume>199</volume><fpage>1744</fpage><lpage>1752</lpage><pub-id pub-id-type="pmid">19416078</pub-id></element-citation></ref><ref id="pone.0014582-Cavailler1"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cavailler</surname><given-names>P</given-names></name><name><surname>Chu</surname><given-names>S</given-names></name><name><surname>Ly</surname><given-names>S</given-names></name><name><surname>Garcia</surname><given-names>J</given-names></name><name><surname>Ha</surname><given-names>D</given-names></name><etal></etal></person-group><year>2010</year><article-title>Seroprevalence of anti-H5 antibody in rural Cambodia, 2007.</article-title><source>J Clin Virol Mar </source><volume>29</volume><comment>[Epub ahead of print]</comment></element-citation></ref><ref id="pone.0014582-Gilsdorf1"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gilsdorf</surname><given-names>A</given-names></name><name><surname>Boxall</surname><given-names>N</given-names></name><name><surname>Gasimov</surname><given-names>V</given-names></name><name><surname>Agayev</surname><given-names>I</given-names></name><name><surname>Mammadzade</surname><given-names>F</given-names></name><etal></etal></person-group><year>2006</year><article-title>Two clusters of human infection with influenza A. Human avian influenza in Azerbaijan, February-March 2006.</article-title><source>Euro Surveill</source><volume>11</volume><fpage>122</fpage><lpage>126</lpage><pub-id pub-id-type="pmid">16757853</pub-id></element-citation></ref><ref id="pone.0014582-Zhou1"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>L</given-names></name><name><surname>Liao</surname><given-names>Q</given-names></name><name><surname>Dong</surname><given-names>L</given-names></name><name><surname>Huai</surname><given-names>Y</given-names></name><name><surname>Bai</surname><given-names>T</given-names></name><etal></etal></person-group><year>2009</year><article-title>Risk Factors for Human Illness with Avian Influenza A (H5N1) Virus Infection in China.</article-title><source>The Journal of Infectious Diseases</source><volume>199</volume><fpage>1726</fpage><lpage>1734</lpage><pub-id pub-id-type="pmid">19416076</pub-id></element-citation></ref><ref id="pone.0014582-Wang3"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>Y</given-names></name><name><surname>Liu</surname><given-names>Y</given-names></name><name><surname>Jiang</surname><given-names>L</given-names></name><name><surname>Liu</surname><given-names>Y</given-names></name><name><surname>Yang</surname><given-names>Z</given-names></name><etal></etal></person-group><year>2009</year><article-title>Risk assessment of H5N1 human infection after an outbreak of avian influenza in water fowl.</article-title><source>Zhonghua Yu Fang Yi Xue Za Zhi</source><volume>43</volume><fpage>41</fpage><lpage>44</lpage><pub-id pub-id-type="pmid">19534879</pub-id></element-citation></ref><ref id="pone.0014582-Schultsz2"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schultsz</surname><given-names>C</given-names></name><name><surname>Van Dung</surname><given-names>N</given-names></name><name><surname>Hai</surname><given-names>LT</given-names></name><name><surname>Quang Ha</surname><given-names>D</given-names></name><name><surname>Peiris</surname><given-names>JSM</given-names></name><etal></etal></person-group><year>2009</year><article-title>Prevalence of Antibodies against Avian Influenza A (H5N1) Virus among Cullers and Poultry Workers in Ho Chi Minh City, 2005.</article-title><source>PLoS One</source><volume>4</volume><fpage>e7948</fpage><pub-id pub-id-type="pmid">19956765</pub-id></element-citation></ref><ref id="pone.0014582-Olsen1"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Olsen</surname><given-names>S</given-names></name><name><surname>Ungchusak</surname><given-names>K</given-names></name><name><surname>Sovann</surname><given-names>L</given-names></name><name><surname>Uyeki</surname><given-names>T</given-names></name><name><surname>Dowell</surname><given-names>SF</given-names></name><etal></etal></person-group><year>2005</year><article-title>Family Clustering of Avian Influenza A (H5N1).</article-title><source>Emerg Infect Dis</source><volume>11</volume><fpage>1799</fpage><lpage>1801</lpage><pub-id pub-id-type="pmid">16422010</pub-id></element-citation></ref><ref id="pone.0014582-Oner1"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oner</surname><given-names>AF</given-names></name><name><surname>Bay</surname><given-names>A</given-names></name><name><surname>Arslan</surname><given-names>S</given-names></name><name><surname>Akdeniz</surname><given-names>H</given-names></name><name><surname>Sahin</surname><given-names>HA</given-names></name><etal></etal></person-group><year>2006</year><article-title>Avian Influenza A (H5N1) Infection in Eastern Turkey in 2006.</article-title><source>N Engl J Med</source><volume>355</volume><fpage>2179</fpage><lpage>2185</lpage><pub-id pub-id-type="pmid">17124015</pub-id></element-citation></ref><ref id="pone.0014582-Ungchusak1"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ungchusak</surname><given-names>K</given-names></name><name><surname>Auewarakul</surname><given-names>P</given-names></name><name><surname>Dowell</surname><given-names>SF</given-names></name><name><surname>Kitphati</surname><given-names>R</given-names></name><name><surname>Auwanit</surname><given-names>W</given-names></name><etal></etal></person-group><year>2005</year><article-title>Probable Person-to-Person Transmission of Avian Influenza A (H5N1).</article-title><source>N Engl J Med</source><volume>352</volume><fpage>333</fpage><lpage>340</lpage><pub-id pub-id-type="pmid">15668219</pub-id></element-citation></ref><ref id="pone.0014582-Kandun1"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kandun</surname><given-names>IN</given-names></name><name><surname>Wibisono</surname><given-names>H</given-names></name><name><surname>Sedyaningsih</surname><given-names>ER</given-names></name><name><surname>Yusharmen</surname></name><name><surname>Hadisoedarsuno</surname><given-names>W</given-names></name><etal></etal></person-group><year>2006</year><article-title>Three Indonesian Clusters of H5N1 Virus Infection in 2005.</article-title><source>N Engl J Med</source><volume>355</volume><fpage>2186</fpage><lpage>2194</lpage><pub-id pub-id-type="pmid">17124016</pub-id></element-citation></ref><ref id="pone.0014582-Wang4"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>H</given-names></name><name><surname>Feng</surname><given-names>Z</given-names></name><name><surname>Shu</surname><given-names>Y</given-names></name><name><surname>Yu</surname><given-names>H</given-names></name><name><surname>Zhou</surname><given-names>L</given-names></name><etal></etal></person-group><year>2008</year><article-title>Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China.</article-title><source>The Lancet</source><volume>371</volume><fpage>1427</fpage><lpage>1434</lpage></element-citation></ref><ref id="pone.0014582-Kandun2"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kandun</surname><given-names>I</given-names></name><name><surname>Tresnaningsih</surname><given-names>E</given-names></name><name><surname>Purba</surname><given-names>W</given-names></name><name><surname>Lee</surname><given-names>V</given-names></name><name><surname>Samaan</surname><given-names>G</given-names></name><etal></etal></person-group><year>2008</year><article-title>Factors associated with case fatality of human H5N1 virus infections in Indonesia: a case series.</article-title><source>The Lancet</source><volume>372</volume><fpage>744</fpage><lpage>749</lpage></element-citation></ref><ref id="pone.0014582-WHO6"><label>48</label><element-citation publication-type="other"><collab>WHO</collab><year>2010</year><article-title>Summary of human infection with highly pathogenic avian infl uenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases. WER 85: 13-20.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/wer/2010/wer8503.pdf">http://www.who.int/wer/2010/wer8503.pdf</ext-link></comment></element-citation></ref><ref id="pone.0014582-deJong1"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Jong</surname><given-names>MD</given-names></name><name><surname>Cam</surname><given-names>BV</given-names></name><name><surname>Qui</surname><given-names>PT</given-names></name><name><surname>Hien</surname><given-names>VM</given-names></name><name><surname>Thanh</surname><given-names>TT</given-names></name><etal></etal></person-group><year>2005</year><article-title>Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma.</article-title><source>N Engl J Med</source><volume>352</volume><fpage>686</fpage><lpage>91</lpage><pub-id pub-id-type="pmid">15716562</pub-id></element-citation></ref><ref id="pone.0014582-FAO1"><label>50</label><element-citation publication-type="other"><collab>FAO</collab><year>2004</year><article-title>FAO Recommendations on the Prevention, Control and Eradication of Highly Pathogenic Avian Influenza (HPAI) in Asia.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.fao.org/AG/AGAINFO/SUBJECTS/en/health/diseases-cards/27septrecomm.pdf">http://www.fao.org/AG/AGAINFO/SUBJECTS/en/health/diseases-cards/27septrecomm.pdf</ext-link></comment></element-citation></ref><ref id="pone.0014582-Vong3"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vong</surname><given-names>S</given-names></name><name><surname>Ly</surname><given-names>S</given-names></name><name><surname>Sek</surname><given-names>M</given-names></name><name><surname>Holl</surname><given-names>D</given-names></name><name><surname>Buchy</surname><given-names>P</given-names></name></person-group><year>2008</year><article-title>Environmental Contamination during Influenza A Virus (H5N1) Outbreaks in Cambodia, 2006.</article-title><source>Emerg Infect Dis</source><volume>14</volume><fpage>1303</fpage><lpage>1305</lpage><pub-id pub-id-type="pmid">18680663</pub-id></element-citation></ref><ref id="pone.0014582-WHO7"><label>52</label><element-citation publication-type="other"><collab>WHO</collab><year>2006</year><article-title>World Health Organization: Review of latest available evidence on potential transmission of avian influenza (H5N1) through water and sewage and ways to reduce the risks to human health.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/water_sanitation_health/emerging/h5n1background.pdf">http://www.who.int/water_sanitation_health/emerging/h5n1background.pdf</ext-link> p</comment></element-citation></ref><ref id="pone.0014582-Kandun3"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kandun</surname><given-names>I</given-names></name><name><surname>Samaan</surname><given-names>G</given-names></name><name><surname>Harun</surname><given-names>S</given-names></name><name><surname>Purba</surname><given-names>W</given-names></name><name><surname>Sariwati</surname><given-names>E</given-names></name><etal></etal></person-group><year>2009</year><article-title>Chicken Faeces Garden Fertilizer: Possible Source of Human Avian Influenza H5N1 Infection.</article-title><source>Zoonoses Public Health</source><volume>57</volume><fpage>285</fpage><lpage>90</lpage><pub-id pub-id-type="pmid">19912615</pub-id></element-citation></ref><ref id="pone.0014582-Greiner1"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Greiner</surname><given-names>M</given-names></name><name><surname>Muller-Graf</surname><given-names>C</given-names></name><name><surname>Hiller</surname><given-names>P</given-names></name><name><surname>Schrader</surname><given-names>C</given-names></name><name><surname>Gervelmeyer</surname><given-names>A</given-names></name><etal></etal></person-group><year>2007</year><article-title>Expert opinion based modelling of the risk of human infections iwth H5N1 through the consumption of poultry meat in Germany.</article-title><source>Berl Munch Tierarztl Wochenschr Heft 3/</source><volume>4</volume><fpage>98</fpage><lpage>107</lpage></element-citation></ref><ref id="pone.0014582-Beigel1"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Beigel</surname><given-names>J</given-names></name><name><surname>Farrar</surname><given-names>J</given-names></name><name><surname>Han</surname><given-names>A</given-names></name><name><surname>Hayden</surname><given-names>F</given-names></name><name><surname>Hyer</surname><given-names>R</given-names></name><etal></etal></person-group><year>2005</year><article-title>Avian influenza A (H5N1) infection in humans.</article-title><source>N Engl J Med</source><volume>353</volume><fpage>1374</fpage><lpage>1385</lpage><pub-id pub-id-type="pmid">16192482</pub-id></element-citation></ref><ref id="pone.0014582-WHO8"><label>56</label><element-citation publication-type="other"><collab>WHO</collab><year>2010</year><article-title>Situation updates - Avian influenza.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/avian_influenza/updates/en/index.html">http://www.who.int/csr/disease/avian_influenza/updates/en/index.html</ext-link></comment></element-citation></ref><ref id="pone.0014582-Yu1"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>H</given-names></name><name><surname>Feng</surname><given-names>Z</given-names></name><name><surname>Zhang</surname><given-names>X</given-names></name><name><surname>Xiang</surname><given-names>N</given-names></name><name><surname>Huai</surname><given-names>Y</given-names></name><etal></etal></person-group><year>2007</year><article-title>Human influenza A (H5N1) cases, urban areas of People's Republic of China, 2005-2006.</article-title><source>Emerg Infect Dis</source><volume>13</volume><fpage>1061</fpage><lpage>1064</lpage><pub-id pub-id-type="pmid">18214180</pub-id></element-citation></ref><ref id="pone.0014582-VanKerkhove1"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Kerkhove</surname><given-names>M</given-names></name><name><surname>Ly</surname><given-names>S</given-names></name><name><surname>Holl</surname><given-names>D</given-names></name><name><surname>Guitian</surname><given-names>J</given-names></name><name><surname>Mangtani</surname><given-names>P</given-names></name><etal></etal></person-group><year>2008</year><article-title>Frequency and patterns of contact with domestic poultry and potential risk of H5N1 transmission to humans living in rural Cambodia.</article-title><source>Influenza and Other Respiratory Viruses</source><volume>2</volume><fpage>155</fpage><lpage>163</lpage><pub-id pub-id-type="pmid">19453420</pub-id></element-citation></ref><ref id="pone.0014582-Neumann1"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Neumann</surname><given-names>G</given-names></name><name><surname>Chen</surname><given-names>H</given-names></name><name><surname>Gao</surname><given-names>GF</given-names></name><name><surname>Shu</surname><given-names>Y</given-names></name><name><surname>Kawaoka</surname><given-names>Y</given-names></name></person-group><year>2010</year><article-title>H5N1 influenza viruses: outbreaks and biological properties.</article-title><source>Cell Res</source><volume>20</volume><fpage>51</fpage><lpage>61</lpage><pub-id pub-id-type="pmid">19884910</pub-id></element-citation></ref><ref id="pone.0014582-Horby1"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Horby</surname><given-names>P</given-names></name><name><surname>Sudoyo</surname><given-names>H</given-names></name><name><surname>Viprakasit</surname><given-names>V</given-names></name><name><surname>Fox</surname><given-names>A</given-names></name><name><surname>Thai</surname><given-names>PQ</given-names></name><etal></etal></person-group><year>2010</year><article-title>What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?</article-title><source>Epidemiology and Infection First View</source><fpage>1</fpage><lpage>9</lpage></element-citation></ref><ref id="pone.0014582-Indriani1"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Indriani</surname><given-names>R</given-names></name><name><surname>Samaan</surname><given-names>G</given-names></name><name><surname>Gultom</surname><given-names>A</given-names></name><name><surname>Loth</surname><given-names>L</given-names></name><name><surname>Indryani</surname><given-names>S</given-names></name><etal></etal></person-group><year>2010</year><article-title>Environmental contamination with avian influenza A H5N1 in live bird markets, Indonesia.</article-title><source>Emerg Infect Dis. In press</source></element-citation></ref><ref id="pone.0014582-Bird1"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bird</surname><given-names>S</given-names></name><name><surname>Farrar</surname><given-names>J</given-names></name></person-group><year>2008</year><article-title>Minimum dataset needed for confirmed human H5N1 cases.</article-title><source>The Lancet</source><volume>372</volume><fpage>696</fpage><lpage>697</lpage></element-citation></ref><ref id="pone.0014582-WHO9"><label>63</label><element-citation publication-type="other"><collab>WHO</collab><year>2006</year><article-title>World Health Organization: Avian Influenza.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/avian_influenza/en/">http://www.who.int/csr/disease/avian_influenza/en/</ext-link>. Accessed 27 October 2008</comment></element-citation></ref><ref id="pone.0014582-Biswas1"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Biswas</surname><given-names>P</given-names></name><name><surname>Christensen</surname><given-names>J</given-names></name><name><surname>Ahmed</surname><given-names>S</given-names></name><name><surname>Barua</surname><given-names>H</given-names></name><name><surname>Das</surname><given-names>A</given-names></name><etal></etal></person-group><year>2008</year><article-title>Avian influenza outbreaks in chickens, Bangladesh.</article-title><source>Emerg Infect Dis</source><volume>14</volume><fpage>1909</fpage><lpage>1912</lpage><pub-id pub-id-type="pmid">19046518</pub-id></element-citation></ref><ref id="pone.0014582-WER1"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>WER</surname></name></person-group><year>2008</year><article-title>Human cases of avian infl uenza A(H5N1) in North-West Frontier Province, Pakistan, October–November 2007.</article-title><source>Weekly Epidemiological Record (WER) 3 October 2008</source><volume>83</volume><fpage>357</fpage><lpage>364</lpage></element-citation></ref><ref id="pone.0014582-Fasina1"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fasina</surname><given-names>F</given-names></name><name><surname>Ifende</surname><given-names>V</given-names></name><name><surname>Ajibade</surname><given-names>A</given-names></name></person-group><year>2010</year><article-title>Avian influenza A(H5N1) in humans: lessons from Egypt.</article-title><source>Euro Surveill</source><volume>15</volume><fpage>19473</fpage><pub-id pub-id-type="pmid">20122384</pub-id></element-citation></ref><ref id="pone.0014582-Otte1"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Otte</surname><given-names>M</given-names></name><name><surname>Pfeiffer</surname><given-names>D</given-names></name><name><surname>Roland-Holst</surname><given-names>D</given-names></name><name><surname>Inui</surname><given-names>K</given-names></name><name><surname>Tung</surname><given-names>N</given-names></name><etal></etal></person-group><year>2010</year><article-title>Implications of Global and Regional Patterns of HPAI H5N1 Virus Clades for Risk Management.</article-title><source>In press</source></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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