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Avian Influenza: a global threat needing a global solution

Avian Influenza: a global threat needing a global solution There have been three influenza pandemics since the 1900s, of which the 1919–1919 flu pandemic had the highest mortality rates. The influenza virus infects both humans and birds, and mutates using two mechanisms: antigenic drift and antigenic shift. Currently, the H5N1 avian flu virus is limited to outbreaks among poultry and persons in direct contact to infected poultry, but the mortality rate among infected humans is high. Avian influenza (AI) is endemic in Asia as a result of unregulated poultry rearing in rural areas. Such birds often live in close proximity to humans and this increases the chance of genetic re-assortment between avian and human influenza viruses which may produce a mutant strain that is easily transmitted between humans. Once this happens, a global pandemic is likely. Unlike SARS, a person with influenza infection is contagious before the onset of case-defining symptoms which limits the effectiveness of case isolation as a control strategy. Researchers have shown that carefully orchestrated of public health measures could potentially limit the spread of an AI pandemic if implemented soon after the first cases appear. To successfully contain and control an AI pandemic, both national and global strategies are needed. National strategies include source surveillance and control, adequate stockpiles of anti-viral agents, timely production of flu vaccines and healthcare system readiness. Global strategies such as early integrated response, curbing the disease outbreak at source, utilization of global resources, continuing research and open communication are also critical. appears that the immune system in young persons para- Background Since the 1700s, there have been ten to thirteen influenza doxically went into over-drive while battling the influenza outbreaks or probable pandemics, of which three have virus and progressed into an immunologic storm that th occurred since the beginning of the 20 century: the killed the victims [2]. This was in contrast to the pandem- 1918–1919 Spanish flu pandemic, the 1957–1958 Asian ics of 1957–1958 and 1968–1969 which were much flu pandemic and the 1968–1969 Hong Kong flu pan- milder. There were several reasons for this: the influenza demic [1]. Of the three pandemics, the 1918–1919 pan- strains were less virulent, the patterns of mortality were demic was the most severe. The 1918–1919 strain of more typical of a usual seasonal influenza outbreak (i.e. it influenza was unusual because of the high rate of mortal- was concentrated among the very young and very old) and ity among victims between the ages of 15 and 35 years. doctors were able to use antibiotics to treat secondary bac- Deaths from influenza are usually due to secondary bacte- terial infections. The Attack Rate is the percentage of the rial infection but many deaths during the 1918–1919 population that becomes ill from an infection while case pandemic were caused directly by the virus itself. It fatality rate refers to the percentage of infected people who Page 1 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 die from the infection. Experts generally agree that the enza outbreak among poultry. The cross-infection was attack rates of the past 3 influenza outbreaks in the last confirmed by molecular studies which showed that the century did not differ markedly and is estimated to be genetic makeup of the virus in humans were identical to 25% to 30%. Using similar evidence, experts estimate the those found in poultry. The H5N1 virus caused severe ill- case fatality rate during the 1918 outbreak to be about ness and high mortality among humans: among 18 per- 2.5% whereas the case fatality rates during the 1957–1958 sons who were infected, 6 died. The outbreak ended after and 1968–1969 episodes were below 0.2% [3]. authorities slaughtered Hong Kong's entire stock of 1.5 million poultry. Since then, AI among birds has been The genes of the influenza virus can mutate in 2 main reported all over the world [9] and one of the factors ways: (1) antigenic drift which involves small errors being responsible for the spread is the trans-oceanic and trans- incorporated into a virus gene sequence when the virus continental migration of wild birds [10]. Most deaths makes copies of itself and (2) antigenic shift involving an from AI have occurred in Indonesia to date [11] and exchange of genes between two types of viruses (e.g. nearly all of the human cases resulted from close contact between avian and human forms of influenza virus) when with infected birds [12]. However, there has been a both viruses are present in the same animal or human [4]. reported cluster of plausible human-to-human transmis- As a result of these mutations, the influenza virus changes sion of the H5N1 virus within an extended family in the its protein coat (antigens) and allows them to find new village of Kubu Sembelang in north Sumatra, Indonesia, susceptible non-immune populations to infect. Both in May 2006 [13]. mechanisms of genetic mutation have the possibility of producing a new virus that can be easily transmitted Strains of influenza virus are classified into subtypes by between humans and initiate a pandemic. Scientists think their protein coat antigens, namely haemagglutin (HA) that the 1918 influenza pandemic virus was a result of and neuramidase (NA). Of the 15 HA subtypes known, antigenic drift while the 1957–1958 and 1968–1969 H1, H2 and H3 are known to have circulated among influenza pandemic virus was a result of antigenic shift humans in the past century and hence, most people have [5]. gained immunity to interrupt the transmission of the virus. However, the H5N1 strain is unfamiliar to most Avian Influenza humans and our low herd immunity to it poses a pan- The influenza virus has been in existence for centuries and demic threat. There are thought to be three pre-requisites has been constantly infecting both humans and animals for a viral pandemic to occur: (1) the infectious strain is a (including birds). The avian influenza (AI) virus (also new virus subtype which the population has little or no called avian flu or bird flu virus) is a subtype that causes herd immunity; (2) the virus is able to replicate and cause contagious respiratory disease mainly in birds [6]. Wild serious illness and (3) the virus has the ability to be trans- waterfowls, especially ducks, are natural reservoirs and mitted efficiently from human to human. The H5N1 virus can carry the virus without manifesting symptoms of the satisfies the first two pre-requisites of a pandemic but has disease and spread the virus over great distances. Domes- not developed the ability to be transmitted easily from ticated poultry are also susceptible to avian flu and can human to human, yet. cause varying symptoms ranging from reduced egg pro- duction to rapid death. The severe form of the disease is Lessons from the SARS Outbreak The recent Severe Acute Respiratory Syndrome (SARS) called "highly pathogenic avian influenza" (sometimes abbreviated as HPAI) and is associated with near 100% virus outbreak in Asia saw another type of virus called the mortality rates among domesticated birds. AI has become coronavirus spread widely in a short time. However, the endemic in several parts of Asia and it is believed that this SARS outbreak is considered to be "minor" when com- is a result of unregulated poultry rearing practices in rural pared to the 1918–1919 influenza outbreak because less areas of developing countries. This is of concern because than 800 persons died from SARS worldwide whereas 40 such birds often live in close proximity to humans and to 50 million people died worldwide in the 1918 influ- this increases the chance of genetic re-assortment between enza pandemic [14]. However, the rapid spread of SARS to avian and human influenza viruses which may produce a Asia, Australia, Europe and North America during the first mutant strain that is easily transmitted between humans two quarters of 2003 illustrates the speed that an AI pan- [7,8]. demic can spread across the world. The major reason why SARS was quickly contained was that people with SARS In the past, avian influenza viruses have rarely caused were not contagious before the onset of case-defining severe disease in humans. However, in Hong Kong during symptoms which allowed effective control measures 1997, a highly pathogenic strain of avian influenza of based on case-identification [15]. However, a person with H5N1 subtype crossed from birds to humans who were in influenza infection is contagious before the onset of case- direct contact with diseased birds during an avian influ- Page 2 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 defining symptoms, which limits the effectiveness of iso- countries. Unfortunately, total global capacity for flu vac- lation of cases as a control strategy for this illness [16]. cine manufacture in the first 12 months is estimated at only 500 million doses. Moreover, flu vaccine production The Feasibility of Early Containment Measures faces many constraints: the vaccine is cultured in eggs and The endemic nature of the avian flu among domestic birds this is a lengthy process which cannot be speeded up [20]. and their close co-existence with humans in rural areas of Fortunately, alternative sources of virus culture cells are Asia makes this part of world a likely epicenter of an AI being investigated. With avian flu affecting poultry and pandemic. Two international teams of researchers used eggs, the egg supply required for vaccine production may computer modeling to simulate what may happen if avian itself be disrupted. Intellectual property rights and liabil- flu were to start being transmitted efficiently between peo- ity from adverse effects from vaccines are other issues that ple in Southeast Asia [17,18]. Both groups showed that a impede manufacturers from increasing vaccine produc- carefully selected and orchestrated combination of public tion. It should also be noted that if the influenza pan- health measures could potentially stop the spread of an demic strain turns out not to be the H5N1 variety, then avian flu pandemic if implemented soon after the first the stockpiled vaccines would be useless and wasted. cases appear. Interventional strategies simulated include Deciding who to vaccinate is another challenge. Cur- an international stockpile to 3 million courses of flu anti- rently, influenza vaccination is recommended to the eld- viral drugs, treating infected individuals and everyone in erly and those with medical conditions which put them at their social networks, closure of schools and workplaces, higher risk for hospitalization and death if they become vaccinating (even with a low-efficacy vaccine) half the infected with influenza. However, some critics have population before the start of a pandemic and quarantine argued that younger and healthier individuals should be measures. Targeted anti-viral treatment was a crucial com- given priority because they are more mobile than older, ponent of all combined strategies and increasing public less healthy people and are therefore more likely to spread health measures needed to be greatly increased as the the flu to others. Another factor in favour of giving priority virus became more contagious. While the researchers said to younger people is that the seasonal flu vaccine pro- that implementing such a combination of approaches was duces a weaker immune response in the elderly. Moreo- challenging because it required a coordinated interna- ver, if the flu pandemic has characteristics of the 1918– tional response, the models did show that containing an 1919 pandemic, then the young and healthy are at higher avian flu pandemic at its source was theoretically feasible. risk of death. Even if supplies were adequate for all age groups, mass immunization for a potential pandemic still Strategies to Contain and Cope with an Avian Flu has its risks. In 1976, four US soldiers developed swine flu Pandemic in an army camp and there was concern that it could To successfully contain and control an AI pandemic, both become a pandemic like the 1918 Spanish flu. Although national and global strategies are needed [19]. National some health officials expressed doubts about the likeli- strategies need multi-pronged approaches and involve hood of an epidemic, the government initiated a mass source surveillance and control, adequate stockpiles of inoculation programme for the entire US population. anti-viral agents, timely production of flu vaccines and After hundreds of people receiving the vaccine came down healthcare system readiness. with Guillian-Barre syndrome, the US government termi- nated the campaign and indemnified manufacturers, ulti- Source Surveillance and Control mately paying $93 million in claims [21]. When the H5N1 flu virus becomes easily transmissible from human to human, the earlier this fact is known, the There is a light at the end of the tunnel. The WHO recently more time there will be to gather and deploy available announced plans to stockpile H5 influenza vaccine and public health resources. Currently, the World Health create a policy framework for vaccine allocation and rec- Organisation (WHO), United Nations and other interna- ommendations for its use [22]. Several recent develop- tional agencies are trying to contain the H5N1 epidemic ments in H5 vaccines have made this stockpile feasible: among poultry flocks in Asia and have set up monitoring the development of H5N1 vaccines with adjuvants that systems to detect new outbreaks (especially human-to- reduce the required dose as much as fourfold [23] and the human cases) early. finding that adjuvant-enhanced vaccines may provide cross-protection against strains that have undergone up to Flu Vaccines seven years of genetic drift [24]. Furthermore, the manu- Currently, there are ongoing efforts to mass produce and facturing capacity of 500 million doses is calculated on a stockpile vaccines against the H5N1 strain. Recent models requirement for three strains of flu virus for standard vac- built on data from the 1918 flu pandemic predict that 50 cinations; in crisis mode, three times as much monovalent million-80 million people could die and the overwhelm- pandemic flu vaccine could be produced. ing majority of deaths are likely to occur in the developing Page 3 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 Antiviral Drugs priority on curbing the disease "at source" in the agricul- Anti-viral drugs are thought to be backbone of a manage- tural sector, thereby reducing the probability of a human ment plan of an avian flu pandemic [25]. Only two anti- epidemic. International resources are also needed for sur- viral drugs have shown promise in treating avian influ- veillance on avian influenza outbreaks and human-to- ® ® enza: oseltamivir (Tamiflu ) and zanamivir (Relenza ). A human transmission. It is also important to strike a bal- treatment of Tamiflu includes 10 pills taken over five ance between short and long term measures. Avian flu is days while Relenza is administered by oral inhalation. becoming endemic in parts of East Asia and will require a The US Food and Drug Administration has approved both long effort to suppress it. Meanwhile, a human pandemic anti-viral drugs for treating influenza but only Tamiflu may still emerge from a different strain of flu virus. Thus has been approved to prevent influenza infection. Because it makes sense for the international community to also antivirals can be stored without refrigeration and for undertake broader long-term measures to strengthen the longer periods than vaccines, developing a stockpile of institutional, regulatory and technical capacity of the ani- antivirals has advantages as part of an overall strategy to mal health, human health and other relevant sectors in control a flu epidemic. However, there are limitations to Asia. While country-level preparedness and leadership is needs to be taken within 2 the use of antivirals: Tamiflu essential for success, it must be backed by global days of initial flu symptoms for it to be effective, but many resources. Even though the benefits of containing a pan- people may not be aware that they have the flu early in the demic are overwhelming, individual governments may disease. Some research in animals and recent experience still be daunted by the social, political and economic costs in the use of the drug to treat human cases have also found of various policy measures. Richer countries may have to that Tamiflu may be less effective against the recent strains support poorer countries in financial and non-financial for the current H5N1 virus than the 1997 strain [26]. means in the fight against a flu pandemic, for the sake of Improper compliance to antivirals by irresponsible indi- international good. The Global Outbreak Alert & viduals during an outbreak may results in the emergence Response Network (GOARN), a technical collaboration of of a drug-resistant strain. Lastly, there are current concerns existing institutions and networks who pool human and about the safety of Tamiflu which has been associated technical resources for the rapid identification, confirma- with increased psychiatric symptoms among Japanese tion and response to disease outbreaks, is one such inter- adolescents [27]. national body that supports global preparedness against bird flu. However, for such an organization to succeed, Healthcare System Readiness open communication and international cooperation is Every country's healthcare system would be stretched to essential. Lastly, there is a critical need to share informa- the limit in the event of a global pandemic of bird flu. The tion rapidly with experts, policymakers and the world- ability of healthcare facilities to maintain strict infection wide community at large. Honest public communication control measures would be challenged. The sudden surge will be critical as evidenced by China's denial of a local in health manpower and facility need would be acutely SARS outbreak initially which delayed early containment felt among healthcare workers, epidemiologists and labo- measures. ratory technicians. Countries must set up AI pandemic contingency plans and high-level coordinating commit- Recently, the Bill & Melinda Gates Foundation, the Pas- tees comprising of representatives from multiple minis- teur Institute and the Wellcome Trust, began planning, tries and agencies. with major medical-research funders and other stakehold- ers, several projects to enhance the research effort and International Strategies reduce the risks from the threat of pandemic influenza An avian flu that is easily transmissible between humans over coming decades [22]. In the next few years, they plan would spread rapidly all over the world. The economic to develop, maintain and disseminate a central inventory cost of an avian pandemic to all countries would be phe- of funded research activities that are relevant to human nomenal and, if allowed to last for months, become expo- influenza to ensure that stakeholders are well-informed. nential [28-30]. Early detection and control of an AI They will also coordinate road-mapping exercises to iden- pandemic will also require a coordinated international tify knowledge gaps to assist funders and researchers in response. Controlling avian flu is for the good of global establishing research-funding priorities, with specific public health and all countries have an interest and obli- focus on vaccines, drug therapies and epidemiology/pop- gation to do so. Firstly, the response to the influenza ulation science (for example, diagnostics, surveillance, threat would need an integrated cross-sector approach, transmission and modelling), in the hope of developing a bringing together animal and human health, areas of rural cohesive health-research agenda for pandemic influenza. development and agriculture, economics, finance, plan- ning and others. Partnerships are needed at both interna- tional and national levels. Next, there is certainly a Page 4 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 4. Webster RG, Govorkova EA: H5N1 influenza – continuing evo- Conclusion lution and spread. N Eng J Med 2006, 21:2174-7. In the words of the late Director General of World Health 5. Reid AH, Fanning TG, Janczewski TA, Taubenberger JK: Character- Organization, Dr Lee Jong Wook, '"it is only a matter of ization of the 1918 "Spanish" influenza virus neuraminidase gene. Proc Natl Acad Sci USA 2000, 97:6785-90. time before an avian flu virus acquires the ability to be 6. Chai LYA: Avian influenza: basic science, potential for muta- transmitted from human to human, sparking the out- tion, transmission, illness symptomatology and vaccines. In Bird flu: a rising pandemic in Asia and beyond? 1st edition. Edited by: break of human pandemic influenza...we don't know Tambyah P, Leung PC. Singapore: World Scientific Publishing; when this will happen but we do know that it will hap- 2006:1-13. pen"[31]. Factors that suggest that an AI pandemic would 7. Normille D: Epidemiology: Indonesia taps village wisdom to fight bird flu. Science 2007, 315:50. be less severe than past influenza pandemics include 8. Abikusno N: Bird flu in Indonesia. In Bird flu: a rising pandemic in advances in medicine such as the availability of antiviral Asia and beyond? 1st edition. Edited by: Tambyah P, Leung PC. Singa- medications and vaccines, and international surveillance pore: World Scientific Publishing; 2006:85-97. 9. Food and Agriculture Organisation (FAO): Latest HPAI cumula- systems. However, there are also factors that suggest than tive maps (24 Jul 06 – 24 Jan 07). [http://www.fao.org/ag/againfo/ an avian influenza pandemic could be worse than the programmes/en/empres/maps.html]. 25 Apr 07 10. H5N1 outbreaks in 2005 and major flyways of migratory 1918 pandemic, such as a more densely populated world, birds. United Nations Food and Agriculture Organisation a larger immunocompromised population of elderly and [http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/ AIDS patients, and faster air travel and interconnections migrationmap.html]. 25 Apr 07 11. Normille D, Enserink M: Avian influenza: with change in the sea- between countries and continents which will accelerate sons, bird flu returns. Science 2007, 315:448. the spread of disease. Nevertheless, unlike the past, we 12. World Health Organisation: Avian Influenza ("bird flu") and the significance of its transmission to humans. [http:// have the prior knowledge of a possible impending pan- www.who.int/mediacentre/factsheets/avian_influenza/en/print.html]. demic and the knowledge of how to contain and control 15 Jan 2004, 25 Apr 07 it. Preparedness, vigilance and cooperation, on local, 13. Declan B: Pandemic 'dry run' cause for concern. Nature 2006, 441:554-5. national and international levels, are our best weapons 14. World Health Organization: Summary of probable SARS cases against a deadly bird flu pandemic. with onset of illness from 1 November 2002 to 31 July 2003. [http://www.who.int/csr/sars/country/table2004_04_21/en/ index.html]. 26 Apr 07 Summary of Implications for GPs 15. Anderson RM, Fraser C, Ghani AC, et al.: Epidemiology, transmis- Currently, the H5N1 avian flu virus is limited to outbreaks sion dynamics and control of SARS: the 2002–2003 epidemic. among poultry and persons in direct contact to infected Philos Trans R Soc Lond B Biol Sci 2004, 359:1091-105. 16. Chowell G, Ammon CE, Hengartner NW, Hyman JM: Transmissioj poultry. Avian influenza (AI) is endemic in Asia where dynamics of the great influenza pandemic of 1918 in Geneva, birds often live in close proximity to humans. This Switzerland: Assessing the effects of hypothetical interven- tions. J Theor Biol 2006, 241:193-204. increases the chance of genetic re-assortment between 17. Ferguson NM, Cummings DAT, Cauchemez S, et al.: Strategies for avian and human influenza viruses which may produce a containing an emerging influenza pandemic in Southeast mutant strain that is easily transmitted between humans, Asia. Nature 2005, 437:209-14. 18. Longini IM, Nizam A, Xu S, et al.: Containing pandemic influenza resulting in a pandemic. Unlike SARS, a person with influ- at the source. Science 2005, 309:1083-7. enza infection is contagious before the onset of case- 19. US Congressional Budget Office: A potential influenza pandemic: possible macroeconomic effects and policy issues. [http:// defining symptoms. Researchers have shown that care- www.cbo.gov/showdoc.cfm?index=6946&sequence=0]. 25 Apr 07 fully orchestrated of public health measures could poten- 20. Morse SS, Garwin RL, Olsiewski PJ: Next flu pandemic: what to tially limit the spread of an AI pandemic if implemented do until the vaccine arrives? Science 2006, 314:929. 21. Sencer DJ, Millar JD: Reflections on the 1976 swine flu vaccina- soon after the first cases appear. Both national and inter- tion program. Emerg Infect Dis 2006, 12:29-33. national strategies are needed: National strategies include 22. Yamada T, Dautry A, Walport M: Ready for avian flu? Nature 2008, source surveillance and control, adequate anti-viral agents 454:162. 23. Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement and vaccines, and healthcare system readiness; interna- F, Hons E, Devaster JM, Leroux-Roels G: Antigen sparing and tional strategies include early integrated response, curbing cross-reactive immunity with an adjuvanted rH5N1 proto- type pandemic influenza vaccine: a randomised controlled disease outbreak at source, utilization of global resources, trial. Lancet 2007, 370:580-9. continuing research and open communication. 24. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, Zambon MC, Katz JM: Cross-reactivity to highly pathogenic avian influ- enza H5N1 viruses after vaccination with nonadjuvanted and Authors' contributions MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) All authors contributed to development of the paper, writ- vaccine: a potential priming strategy. J Infect Dis 2005, 191:1210-5. ing of the manuscript and final approval for submission. 25. Schünemann HJ, Hill SR, Kakad M, et al.: WHO Rapid Advice Guidelines for pharmacological management of sporadic References human infection with avian influenza (H5N1) virus. Lancet th Infct Dis 2007, 7:21-31. 1. Kilbourne ED: Influenza pandemics of the 20 century. Emerg 26. Beigel JH, Farrar J, Han AM, et al.: (The Writing Committee of Infect Dis 2006, 12:9-14. the World Health Organisation (WHO) Consultation on 2. Kobasa D, Jones SM, Shinya K, et al.: Aberrant innate immune Human Influenza A/H5). Avian influenza A(H5N1) infection response in lethal infection of macaques with the 1918 influ- in humans. N Eng J Med 2005, 353:373-85. enza virus. Nature 2007, 445:319-23. 27. Fuyuno I: Tamiflu side effects come under scrutiny. Nature 3. Brundage JF: Cases and deaths during influenza pandemics in 2007, 446:358-9. the United States. Am J Prev Med 2006, 31:252-6. Page 5 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 28. Bloom E, de Wit V, Carangal-San Jose MJ: Economics and Research Department Policy Brief: Potential economic impact of an avian flu pandemic on Asia. 2005 [http://www.asia- studies.com/policybrief.html]. 25 Apr 07 29. Smith S: The economic and social impacts of avianinfluenza. [http://www.avianinfluenza.org/economic-social-impacts-avian-influ enza.php]. 12 Dec 2005, 25 Apr 07 30. Koh GCH, Koh DSQ: The socioeconomic effects of an avian influenza pandemic. In Bird flu: a rising pandemic in Asia and beyond? 1st edition. Edited by: Tambyah P, Leung PC. Singapore: World Scien- tific Publishing; 2006:127-46. 31. Lee JW: Opening remarks at the meeting on avian influenza and pandemic human influenza. [http://www.who.int/dg/lee/ speeches/2005/flupandemicgeneva/en/print.html]. 9 Nov 05 Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Asia Pacific Family Medicine Springer Journals

Avian Influenza: a global threat needing a global solution

Avian Influenza: a global threat needing a global solution

There have been three influenza pandemics since the 1900s, of which the 1919–1919 flu pandemic had the highest mortality rates. The influenza virus infects both humans and birds, and mutates using two mechanisms: antigenic drift and antigenic shift. Currently, the H5N1 avian flu virus is limited to outbreaks among poultry and persons in direct contact to infected poultry, but the mortality rate among infected humans is high. Avian influenza (AI) is endemic in Asia as a result of unregulated poultry rearing in rural areas. Such birds often live in close proximity to humans and this increases the chance of genetic re-assortment between avian and human influenza viruses which may produce a mutant strain that is easily transmitted between humans. Once this happens, a global pandemic is likely. Unlike SARS, a person with influenza infection is contagious before the onset of case-defining symptoms which limits the effectiveness of case isolation as a control strategy. Researchers have shown that carefully orchestrated of public health measures could potentially limit the spread of an AI pandemic if implemented soon after the first cases appear. To successfully contain and control an AI pandemic, both national and global strategies are needed. National strategies include source surveillance and control, adequate stockpiles of anti-viral agents, timely production of flu vaccines and healthcare system readiness. Global strategies such as early integrated response, curbing the disease outbreak at source, utilization of global resources, continuing research and open communication are also critical. appears that the immune system in young persons para- Background Since the 1700s, there have been ten to thirteen influenza doxically went into over-drive while battling the influenza outbreaks or probable pandemics, of which three have virus and progressed into an immunologic storm that th occurred since the beginning of the 20 century: the killed the victims [2]. This was in contrast to the pandem- 1918–1919 Spanish flu pandemic, the 1957–1958 Asian ics of 1957–1958 and 1968–1969 which were much flu pandemic and the 1968–1969 Hong Kong flu pan- milder. There were several reasons for this: the influenza demic [1]. Of the three pandemics, the 1918–1919 pan- strains were less virulent, the patterns of mortality were demic was the most severe. The 1918–1919 strain of more typical of a usual seasonal influenza outbreak (i.e. it influenza was unusual because of the high rate of mortal- was concentrated among the very young and very old) and ity among victims between the ages of 15 and 35 years. doctors were able to use antibiotics to treat secondary bac- Deaths from influenza are usually due to secondary bacte- terial infections. The Attack Rate is the percentage of the rial infection but many deaths during the 1918–1919 population that becomes ill from an infection while case pandemic were caused directly by the virus itself. It fatality rate refers to the percentage of infected people who Page 1 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 die from the infection. Experts generally agree that the enza outbreak among poultry. The cross-infection was attack rates of the past 3 influenza outbreaks in the last confirmed by molecular studies which showed that the century did not differ markedly and is estimated to be genetic makeup of the virus in humans were identical to 25% to 30%. Using similar evidence, experts estimate the those found in poultry. The H5N1 virus caused severe ill- case fatality rate during the 1918 outbreak to be about ness and high mortality among humans: among 18 per- 2.5% whereas the case fatality rates during the 1957–1958 sons who were infected, 6 died. The outbreak ended after and 1968–1969 episodes were below 0.2% [3]. authorities slaughtered Hong Kong's entire stock of 1.5 million poultry. Since then, AI among birds has been The genes of the influenza virus can mutate in 2 main reported all over the world [9] and one of the factors ways: (1) antigenic drift which involves small errors being responsible for the spread is the trans-oceanic and trans- incorporated into a virus gene sequence when the virus continental migration of wild birds [10]. Most deaths makes copies of itself and (2) antigenic shift involving an from AI have occurred in Indonesia to date [11] and exchange of genes between two types of viruses (e.g. nearly all of the human cases resulted from close contact between avian and human forms of influenza virus) when with infected birds [12]. However, there has been a both viruses are present in the same animal or human [4]. reported cluster of plausible human-to-human transmis- As a result of these mutations, the influenza virus changes sion of the H5N1 virus within an extended family in the its protein coat (antigens) and allows them to find new village of Kubu Sembelang in north Sumatra, Indonesia, susceptible non-immune populations to infect. Both in May 2006 [13]. mechanisms of genetic mutation have the possibility of producing a new virus that can be easily transmitted Strains of influenza virus are classified into subtypes by between humans and initiate a pandemic. Scientists think their protein coat antigens, namely haemagglutin (HA) that the 1918 influenza pandemic virus was a result of and neuramidase (NA). Of the 15 HA subtypes known, antigenic drift while the 1957–1958 and 1968–1969 H1, H2 and H3 are known to have circulated among influenza pandemic virus was a result of antigenic shift humans in the past century and hence, most people have [5]. gained immunity to interrupt the transmission of the virus. However, the H5N1 strain is unfamiliar to most Avian Influenza humans and our low herd immunity to it poses a pan- The influenza virus has been in existence for centuries and demic threat. There are thought to be three pre-requisites has been constantly infecting both humans and animals for a viral pandemic to occur: (1) the infectious strain is a (including birds). The avian influenza (AI) virus (also new virus subtype which the population has little or no called avian flu or bird flu virus) is a subtype that causes herd immunity; (2) the virus is able to replicate and cause contagious respiratory disease mainly in birds [6]. Wild serious illness and (3) the virus has the ability to be trans- waterfowls, especially ducks, are natural reservoirs and mitted efficiently from human to human. The H5N1 virus can carry the virus without manifesting symptoms of the satisfies the first two pre-requisites of a pandemic but has disease and spread the virus over great distances. Domes- not developed the ability to be transmitted easily from ticated poultry are also susceptible to avian flu and can human to human, yet. cause varying symptoms ranging from reduced egg pro- duction to rapid death. The severe form of the disease is Lessons from the SARS Outbreak The recent Severe Acute Respiratory Syndrome (SARS) called "highly pathogenic avian influenza" (sometimes abbreviated as HPAI) and is associated with near 100% virus outbreak in Asia saw another type of virus called the mortality rates among domesticated birds. AI has become coronavirus spread widely in a short time. However, the endemic in several parts of Asia and it is believed that this SARS outbreak is considered to be "minor" when com- is a result of unregulated poultry rearing practices in rural pared to the 1918–1919 influenza outbreak because less areas of developing countries. This is of concern because than 800 persons died from SARS worldwide whereas 40 such birds often live in close proximity to humans and to 50 million people died worldwide in the 1918 influ- this increases the chance of genetic re-assortment between enza pandemic [14]. However, the rapid spread of SARS to avian and human influenza viruses which may produce a Asia, Australia, Europe and North America during the first mutant strain that is easily transmitted between humans two quarters of 2003 illustrates the speed that an AI pan- [7,8]. demic can spread across the world. The major reason why SARS was quickly contained was that people with SARS In the past, avian influenza viruses have rarely caused were not contagious before the onset of case-defining severe disease in humans. However, in Hong Kong during symptoms which allowed effective control measures 1997, a highly pathogenic strain of avian influenza of based on case-identification [15]. However, a person with H5N1 subtype crossed from birds to humans who were in influenza infection is contagious before the onset of case- direct contact with diseased birds during an avian influ- Page 2 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 defining symptoms, which limits the effectiveness of iso- countries. Unfortunately, total global capacity for flu vac- lation of cases as a control strategy for this illness [16]. cine manufacture in the first 12 months is estimated at only 500 million doses. Moreover, flu vaccine production The Feasibility of Early Containment Measures faces many constraints: the vaccine is cultured in eggs and The endemic nature of the avian flu among domestic birds this is a lengthy process which cannot be speeded up [20]. and their close co-existence with humans in rural areas of Fortunately, alternative sources of virus culture cells are Asia makes this part of world a likely epicenter of an AI being investigated. With avian flu affecting poultry and pandemic. Two international teams of researchers used eggs, the egg supply required for vaccine production may computer modeling to simulate what may happen if avian itself be disrupted. Intellectual property rights and liabil- flu were to start being transmitted efficiently between peo- ity from adverse effects from vaccines are other issues that ple in Southeast Asia [17,18]. Both groups showed that a impede manufacturers from increasing vaccine produc- carefully selected and orchestrated combination of public tion. It should also be noted that if the influenza pan- health measures could potentially stop the spread of an demic strain turns out not to be the H5N1 variety, then avian flu pandemic if implemented soon after the first the stockpiled vaccines would be useless and wasted. cases appear. Interventional strategies simulated include Deciding who to vaccinate is another challenge. Cur- an international stockpile to 3 million courses of flu anti- rently, influenza vaccination is recommended to the eld- viral drugs, treating infected individuals and everyone in erly and those with medical conditions which put them at their social networks, closure of schools and workplaces, higher risk for hospitalization and death if they become vaccinating (even with a low-efficacy vaccine) half the infected with influenza. However, some critics have population before the start of a pandemic and quarantine argued that younger and healthier individuals should be measures. Targeted anti-viral treatment was a crucial com- given priority because they are more mobile than older, ponent of all combined strategies and increasing public less healthy people and are therefore more likely to spread health measures needed to be greatly increased as the the flu to others. Another factor in favour of giving priority virus became more contagious. While the researchers said to younger people is that the seasonal flu vaccine pro- that implementing such a combination of approaches was duces a weaker immune response in the elderly. Moreo- challenging because it required a coordinated interna- ver, if the flu pandemic has characteristics of the 1918– tional response, the models did show that containing an 1919 pandemic, then the young and healthy are at higher avian flu pandemic at its source was theoretically feasible. risk of death. Even if supplies were adequate for all age groups, mass immunization for a potential pandemic still Strategies to Contain and Cope with an Avian Flu has its risks. In 1976, four US soldiers developed swine flu Pandemic in an army camp and there was concern that it could To successfully contain and control an AI pandemic, both become a pandemic like the 1918 Spanish flu. Although national and global strategies are needed [19]. National some health officials expressed doubts about the likeli- strategies need multi-pronged approaches and involve hood of an epidemic, the government initiated a mass source surveillance and control, adequate stockpiles of inoculation programme for the entire US population. anti-viral agents, timely production of flu vaccines and After hundreds of people receiving the vaccine came down healthcare system readiness. with Guillian-Barre syndrome, the US government termi- nated the campaign and indemnified manufacturers, ulti- Source Surveillance and Control mately paying $93 million in claims [21]. When the H5N1 flu virus becomes easily transmissible from human to human, the earlier this fact is known, the There is a light at the end of the tunnel. The WHO recently more time there will be to gather and deploy available announced plans to stockpile H5 influenza vaccine and public health resources. Currently, the World Health create a policy framework for vaccine allocation and rec- Organisation (WHO), United Nations and other interna- ommendations for its use [22]. Several recent develop- tional agencies are trying to contain the H5N1 epidemic ments in H5 vaccines have made this stockpile feasible: among poultry flocks in Asia and have set up monitoring the development of H5N1 vaccines with adjuvants that systems to detect new outbreaks (especially human-to- reduce the required dose as much as fourfold [23] and the human cases) early. finding that adjuvant-enhanced vaccines may provide cross-protection against strains that have undergone up to Flu Vaccines seven years of genetic drift [24]. Furthermore, the manu- Currently, there are ongoing efforts to mass produce and facturing capacity of 500 million doses is calculated on a stockpile vaccines against the H5N1 strain. Recent models requirement for three strains of flu virus for standard vac- built on data from the 1918 flu pandemic predict that 50 cinations; in crisis mode, three times as much monovalent million-80 million people could die and the overwhelm- pandemic flu vaccine could be produced. ing majority of deaths are likely to occur in the developing Page 3 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 Antiviral Drugs priority on curbing the disease "at source" in the agricul- Anti-viral drugs are thought to be backbone of a manage- tural sector, thereby reducing the probability of a human ment plan of an avian flu pandemic [25]. Only two anti- epidemic. International resources are also needed for sur- viral drugs have shown promise in treating avian influ- veillance on avian influenza outbreaks and human-to- ® ® enza: oseltamivir (Tamiflu ) and zanamivir (Relenza ). A human transmission. It is also important to strike a bal- treatment of Tamiflu includes 10 pills taken over five ance between short and long term measures. Avian flu is days while Relenza is administered by oral inhalation. becoming endemic in parts of East Asia and will require a The US Food and Drug Administration has approved both long effort to suppress it. Meanwhile, a human pandemic anti-viral drugs for treating influenza but only Tamiflu may still emerge from a different strain of flu virus. Thus has been approved to prevent influenza infection. Because it makes sense for the international community to also antivirals can be stored without refrigeration and for undertake broader long-term measures to strengthen the longer periods than vaccines, developing a stockpile of institutional, regulatory and technical capacity of the ani- antivirals has advantages as part of an overall strategy to mal health, human health and other relevant sectors in control a flu epidemic. However, there are limitations to Asia. While country-level preparedness and leadership is needs to be taken within 2 the use of antivirals: Tamiflu essential for success, it must be backed by global days of initial flu symptoms for it to be effective, but many resources. Even though the benefits of containing a pan- people may not be aware that they have the flu early in the demic are overwhelming, individual governments may disease. Some research in animals and recent experience still be daunted by the social, political and economic costs in the use of the drug to treat human cases have also found of various policy measures. Richer countries may have to that Tamiflu may be less effective against the recent strains support poorer countries in financial and non-financial for the current H5N1 virus than the 1997 strain [26]. means in the fight against a flu pandemic, for the sake of Improper compliance to antivirals by irresponsible indi- international good. The Global Outbreak Alert & viduals during an outbreak may results in the emergence Response Network (GOARN), a technical collaboration of of a drug-resistant strain. Lastly, there are current concerns existing institutions and networks who pool human and about the safety of Tamiflu which has been associated technical resources for the rapid identification, confirma- with increased psychiatric symptoms among Japanese tion and response to disease outbreaks, is one such inter- adolescents [27]. national body that supports global preparedness against bird flu. However, for such an organization to succeed, Healthcare System Readiness open communication and international cooperation is Every country's healthcare system would be stretched to essential. Lastly, there is a critical need to share informa- the limit in the event of a global pandemic of bird flu. The tion rapidly with experts, policymakers and the world- ability of healthcare facilities to maintain strict infection wide community at large. Honest public communication control measures would be challenged. The sudden surge will be critical as evidenced by China's denial of a local in health manpower and facility need would be acutely SARS outbreak initially which delayed early containment felt among healthcare workers, epidemiologists and labo- measures. ratory technicians. Countries must set up AI pandemic contingency plans and high-level coordinating commit- Recently, the Bill & Melinda Gates Foundation, the Pas- tees comprising of representatives from multiple minis- teur Institute and the Wellcome Trust, began planning, tries and agencies. with major medical-research funders and other stakehold- ers, several projects to enhance the research effort and International Strategies reduce the risks from the threat of pandemic influenza An avian flu that is easily transmissible between humans over coming decades [22]. In the next few years, they plan would spread rapidly all over the world. The economic to develop, maintain and disseminate a central inventory cost of an avian pandemic to all countries would be phe- of funded research activities that are relevant to human nomenal and, if allowed to last for months, become expo- influenza to ensure that stakeholders are well-informed. nential [28-30]. Early detection and control of an AI They will also coordinate road-mapping exercises to iden- pandemic will also require a coordinated international tify knowledge gaps to assist funders and researchers in response. Controlling avian flu is for the good of global establishing research-funding priorities, with specific public health and all countries have an interest and obli- focus on vaccines, drug therapies and epidemiology/pop- gation to do so. Firstly, the response to the influenza ulation science (for example, diagnostics, surveillance, threat would need an integrated cross-sector approach, transmission and modelling), in the hope of developing a bringing together animal and human health, areas of rural cohesive health-research agenda for pandemic influenza. development and agriculture, economics, finance, plan- ning and others. Partnerships are needed at both interna- tional and national levels. Next, there is certainly a Page 4 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 4. Webster RG, Govorkova EA: H5N1 influenza – continuing evo- Conclusion lution and spread. N Eng J Med 2006, 21:2174-7. In the words of the late Director General of World Health 5. Reid AH, Fanning TG, Janczewski TA, Taubenberger JK: Character- Organization, Dr Lee Jong Wook, '"it is only a matter of ization of the 1918 "Spanish" influenza virus neuraminidase gene. Proc Natl Acad Sci USA 2000, 97:6785-90. time before an avian flu virus acquires the ability to be 6. Chai LYA: Avian influenza: basic science, potential for muta- transmitted from human to human, sparking the out- tion, transmission, illness symptomatology and vaccines. In Bird flu: a rising pandemic in Asia and beyond? 1st edition. Edited by: break of human pandemic influenza...we don't know Tambyah P, Leung PC. Singapore: World Scientific Publishing; when this will happen but we do know that it will hap- 2006:1-13. pen"[31]. Factors that suggest that an AI pandemic would 7. Normille D: Epidemiology: Indonesia taps village wisdom to fight bird flu. Science 2007, 315:50. be less severe than past influenza pandemics include 8. Abikusno N: Bird flu in Indonesia. In Bird flu: a rising pandemic in advances in medicine such as the availability of antiviral Asia and beyond? 1st edition. Edited by: Tambyah P, Leung PC. Singa- medications and vaccines, and international surveillance pore: World Scientific Publishing; 2006:85-97. 9. Food and Agriculture Organisation (FAO): Latest HPAI cumula- systems. However, there are also factors that suggest than tive maps (24 Jul 06 – 24 Jan 07). [http://www.fao.org/ag/againfo/ an avian influenza pandemic could be worse than the programmes/en/empres/maps.html]. 25 Apr 07 10. H5N1 outbreaks in 2005 and major flyways of migratory 1918 pandemic, such as a more densely populated world, birds. United Nations Food and Agriculture Organisation a larger immunocompromised population of elderly and [http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/ AIDS patients, and faster air travel and interconnections migrationmap.html]. 25 Apr 07 11. Normille D, Enserink M: Avian influenza: with change in the sea- between countries and continents which will accelerate sons, bird flu returns. Science 2007, 315:448. the spread of disease. Nevertheless, unlike the past, we 12. World Health Organisation: Avian Influenza ("bird flu") and the significance of its transmission to humans. [http:// have the prior knowledge of a possible impending pan- www.who.int/mediacentre/factsheets/avian_influenza/en/print.html]. demic and the knowledge of how to contain and control 15 Jan 2004, 25 Apr 07 it. Preparedness, vigilance and cooperation, on local, 13. Declan B: Pandemic 'dry run' cause for concern. Nature 2006, 441:554-5. national and international levels, are our best weapons 14. World Health Organization: Summary of probable SARS cases against a deadly bird flu pandemic. with onset of illness from 1 November 2002 to 31 July 2003. [http://www.who.int/csr/sars/country/table2004_04_21/en/ index.html]. 26 Apr 07 Summary of Implications for GPs 15. Anderson RM, Fraser C, Ghani AC, et al.: Epidemiology, transmis- Currently, the H5N1 avian flu virus is limited to outbreaks sion dynamics and control of SARS: the 2002–2003 epidemic. among poultry and persons in direct contact to infected Philos Trans R Soc Lond B Biol Sci 2004, 359:1091-105. 16. Chowell G, Ammon CE, Hengartner NW, Hyman JM: Transmissioj poultry. Avian influenza (AI) is endemic in Asia where dynamics of the great influenza pandemic of 1918 in Geneva, birds often live in close proximity to humans. This Switzerland: Assessing the effects of hypothetical interven- tions. J Theor Biol 2006, 241:193-204. increases the chance of genetic re-assortment between 17. Ferguson NM, Cummings DAT, Cauchemez S, et al.: Strategies for avian and human influenza viruses which may produce a containing an emerging influenza pandemic in Southeast mutant strain that is easily transmitted between humans, Asia. Nature 2005, 437:209-14. 18. Longini IM, Nizam A, Xu S, et al.: Containing pandemic influenza resulting in a pandemic. Unlike SARS, a person with influ- at the source. Science 2005, 309:1083-7. enza infection is contagious before the onset of case- 19. US Congressional Budget Office: A potential influenza pandemic: possible macroeconomic effects and policy issues. [http:// defining symptoms. Researchers have shown that care- www.cbo.gov/showdoc.cfm?index=6946&sequence=0]. 25 Apr 07 fully orchestrated of public health measures could poten- 20. Morse SS, Garwin RL, Olsiewski PJ: Next flu pandemic: what to tially limit the spread of an AI pandemic if implemented do until the vaccine arrives? Science 2006, 314:929. 21. Sencer DJ, Millar JD: Reflections on the 1976 swine flu vaccina- soon after the first cases appear. Both national and inter- tion program. Emerg Infect Dis 2006, 12:29-33. national strategies are needed: National strategies include 22. Yamada T, Dautry A, Walport M: Ready for avian flu? Nature 2008, source surveillance and control, adequate anti-viral agents 454:162. 23. Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement and vaccines, and healthcare system readiness; interna- F, Hons E, Devaster JM, Leroux-Roels G: Antigen sparing and tional strategies include early integrated response, curbing cross-reactive immunity with an adjuvanted rH5N1 proto- type pandemic influenza vaccine: a randomised controlled disease outbreak at source, utilization of global resources, trial. Lancet 2007, 370:580-9. continuing research and open communication. 24. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, Zambon MC, Katz JM: Cross-reactivity to highly pathogenic avian influ- enza H5N1 viruses after vaccination with nonadjuvanted and Authors' contributions MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) All authors contributed to development of the paper, writ- vaccine: a potential priming strategy. J Infect Dis 2005, 191:1210-5. ing of the manuscript and final approval for submission. 25. Schünemann HJ, Hill SR, Kakad M, et al.: WHO Rapid Advice Guidelines for pharmacological management of sporadic References human infection with avian influenza (H5N1) virus. Lancet th Infct Dis 2007, 7:21-31. 1. Kilbourne ED: Influenza pandemics of the 20 century. Emerg 26. Beigel JH, Farrar J, Han AM, et al.: (The Writing Committee of Infect Dis 2006, 12:9-14. the World Health Organisation (WHO) Consultation on 2. Kobasa D, Jones SM, Shinya K, et al.: Aberrant innate immune Human Influenza A/H5). Avian influenza A(H5N1) infection response in lethal infection of macaques with the 1918 influ- in humans. N Eng J Med 2005, 353:373-85. enza virus. Nature 2007, 445:319-23. 27. Fuyuno I: Tamiflu side effects come under scrutiny. Nature 3. Brundage JF: Cases and deaths during influenza pandemics in 2007, 446:358-9. the United States. Am J Prev Med 2006, 31:252-6. Page 5 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 28. Bloom E, de Wit V, Carangal-San Jose MJ: Economics and Research Department Policy Brief: Potential economic impact of an avian flu pandemic on Asia. 2005 [http://www.asia- studies.com/policybrief.html]. 25 Apr 07 29. Smith S: The economic and social impacts of avianinfluenza. [http://www.avianinfluenza.org/economic-social-impacts-avian-influ enza.php]. 12 Dec 2005, 25 Apr 07 30. Koh GCH, Koh DSQ: The socioeconomic effects of an avian influenza pandemic. In Bird flu: a rising pandemic in Asia and beyond? 1st edition. Edited by: Tambyah P, Leung PC. Singapore: World Scien- tific Publishing; 2006:127-46. 31. Lee JW: Opening remarks at the meeting on avian influenza and pandemic human influenza. [http://www.who.int/dg/lee/ speeches/2005/flupandemicgeneva/en/print.html]. 9 Nov 05 Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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Copyright © 2008 by Koh et al; licensee BioMed Central Ltd.
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Medicine & Public Health; General Practice / Family Medicine; Primary Care Medicine
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Abstract

There have been three influenza pandemics since the 1900s, of which the 1919–1919 flu pandemic had the highest mortality rates. The influenza virus infects both humans and birds, and mutates using two mechanisms: antigenic drift and antigenic shift. Currently, the H5N1 avian flu virus is limited to outbreaks among poultry and persons in direct contact to infected poultry, but the mortality rate among infected humans is high. Avian influenza (AI) is endemic in Asia as a result of unregulated poultry rearing in rural areas. Such birds often live in close proximity to humans and this increases the chance of genetic re-assortment between avian and human influenza viruses which may produce a mutant strain that is easily transmitted between humans. Once this happens, a global pandemic is likely. Unlike SARS, a person with influenza infection is contagious before the onset of case-defining symptoms which limits the effectiveness of case isolation as a control strategy. Researchers have shown that carefully orchestrated of public health measures could potentially limit the spread of an AI pandemic if implemented soon after the first cases appear. To successfully contain and control an AI pandemic, both national and global strategies are needed. National strategies include source surveillance and control, adequate stockpiles of anti-viral agents, timely production of flu vaccines and healthcare system readiness. Global strategies such as early integrated response, curbing the disease outbreak at source, utilization of global resources, continuing research and open communication are also critical. appears that the immune system in young persons para- Background Since the 1700s, there have been ten to thirteen influenza doxically went into over-drive while battling the influenza outbreaks or probable pandemics, of which three have virus and progressed into an immunologic storm that th occurred since the beginning of the 20 century: the killed the victims [2]. This was in contrast to the pandem- 1918–1919 Spanish flu pandemic, the 1957–1958 Asian ics of 1957–1958 and 1968–1969 which were much flu pandemic and the 1968–1969 Hong Kong flu pan- milder. There were several reasons for this: the influenza demic [1]. Of the three pandemics, the 1918–1919 pan- strains were less virulent, the patterns of mortality were demic was the most severe. The 1918–1919 strain of more typical of a usual seasonal influenza outbreak (i.e. it influenza was unusual because of the high rate of mortal- was concentrated among the very young and very old) and ity among victims between the ages of 15 and 35 years. doctors were able to use antibiotics to treat secondary bac- Deaths from influenza are usually due to secondary bacte- terial infections. The Attack Rate is the percentage of the rial infection but many deaths during the 1918–1919 population that becomes ill from an infection while case pandemic were caused directly by the virus itself. It fatality rate refers to the percentage of infected people who Page 1 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 die from the infection. Experts generally agree that the enza outbreak among poultry. The cross-infection was attack rates of the past 3 influenza outbreaks in the last confirmed by molecular studies which showed that the century did not differ markedly and is estimated to be genetic makeup of the virus in humans were identical to 25% to 30%. Using similar evidence, experts estimate the those found in poultry. The H5N1 virus caused severe ill- case fatality rate during the 1918 outbreak to be about ness and high mortality among humans: among 18 per- 2.5% whereas the case fatality rates during the 1957–1958 sons who were infected, 6 died. The outbreak ended after and 1968–1969 episodes were below 0.2% [3]. authorities slaughtered Hong Kong's entire stock of 1.5 million poultry. Since then, AI among birds has been The genes of the influenza virus can mutate in 2 main reported all over the world [9] and one of the factors ways: (1) antigenic drift which involves small errors being responsible for the spread is the trans-oceanic and trans- incorporated into a virus gene sequence when the virus continental migration of wild birds [10]. Most deaths makes copies of itself and (2) antigenic shift involving an from AI have occurred in Indonesia to date [11] and exchange of genes between two types of viruses (e.g. nearly all of the human cases resulted from close contact between avian and human forms of influenza virus) when with infected birds [12]. However, there has been a both viruses are present in the same animal or human [4]. reported cluster of plausible human-to-human transmis- As a result of these mutations, the influenza virus changes sion of the H5N1 virus within an extended family in the its protein coat (antigens) and allows them to find new village of Kubu Sembelang in north Sumatra, Indonesia, susceptible non-immune populations to infect. Both in May 2006 [13]. mechanisms of genetic mutation have the possibility of producing a new virus that can be easily transmitted Strains of influenza virus are classified into subtypes by between humans and initiate a pandemic. Scientists think their protein coat antigens, namely haemagglutin (HA) that the 1918 influenza pandemic virus was a result of and neuramidase (NA). Of the 15 HA subtypes known, antigenic drift while the 1957–1958 and 1968–1969 H1, H2 and H3 are known to have circulated among influenza pandemic virus was a result of antigenic shift humans in the past century and hence, most people have [5]. gained immunity to interrupt the transmission of the virus. However, the H5N1 strain is unfamiliar to most Avian Influenza humans and our low herd immunity to it poses a pan- The influenza virus has been in existence for centuries and demic threat. There are thought to be three pre-requisites has been constantly infecting both humans and animals for a viral pandemic to occur: (1) the infectious strain is a (including birds). The avian influenza (AI) virus (also new virus subtype which the population has little or no called avian flu or bird flu virus) is a subtype that causes herd immunity; (2) the virus is able to replicate and cause contagious respiratory disease mainly in birds [6]. Wild serious illness and (3) the virus has the ability to be trans- waterfowls, especially ducks, are natural reservoirs and mitted efficiently from human to human. The H5N1 virus can carry the virus without manifesting symptoms of the satisfies the first two pre-requisites of a pandemic but has disease and spread the virus over great distances. Domes- not developed the ability to be transmitted easily from ticated poultry are also susceptible to avian flu and can human to human, yet. cause varying symptoms ranging from reduced egg pro- duction to rapid death. The severe form of the disease is Lessons from the SARS Outbreak The recent Severe Acute Respiratory Syndrome (SARS) called "highly pathogenic avian influenza" (sometimes abbreviated as HPAI) and is associated with near 100% virus outbreak in Asia saw another type of virus called the mortality rates among domesticated birds. AI has become coronavirus spread widely in a short time. However, the endemic in several parts of Asia and it is believed that this SARS outbreak is considered to be "minor" when com- is a result of unregulated poultry rearing practices in rural pared to the 1918–1919 influenza outbreak because less areas of developing countries. This is of concern because than 800 persons died from SARS worldwide whereas 40 such birds often live in close proximity to humans and to 50 million people died worldwide in the 1918 influ- this increases the chance of genetic re-assortment between enza pandemic [14]. However, the rapid spread of SARS to avian and human influenza viruses which may produce a Asia, Australia, Europe and North America during the first mutant strain that is easily transmitted between humans two quarters of 2003 illustrates the speed that an AI pan- [7,8]. demic can spread across the world. The major reason why SARS was quickly contained was that people with SARS In the past, avian influenza viruses have rarely caused were not contagious before the onset of case-defining severe disease in humans. However, in Hong Kong during symptoms which allowed effective control measures 1997, a highly pathogenic strain of avian influenza of based on case-identification [15]. However, a person with H5N1 subtype crossed from birds to humans who were in influenza infection is contagious before the onset of case- direct contact with diseased birds during an avian influ- Page 2 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 defining symptoms, which limits the effectiveness of iso- countries. Unfortunately, total global capacity for flu vac- lation of cases as a control strategy for this illness [16]. cine manufacture in the first 12 months is estimated at only 500 million doses. Moreover, flu vaccine production The Feasibility of Early Containment Measures faces many constraints: the vaccine is cultured in eggs and The endemic nature of the avian flu among domestic birds this is a lengthy process which cannot be speeded up [20]. and their close co-existence with humans in rural areas of Fortunately, alternative sources of virus culture cells are Asia makes this part of world a likely epicenter of an AI being investigated. With avian flu affecting poultry and pandemic. Two international teams of researchers used eggs, the egg supply required for vaccine production may computer modeling to simulate what may happen if avian itself be disrupted. Intellectual property rights and liabil- flu were to start being transmitted efficiently between peo- ity from adverse effects from vaccines are other issues that ple in Southeast Asia [17,18]. Both groups showed that a impede manufacturers from increasing vaccine produc- carefully selected and orchestrated combination of public tion. It should also be noted that if the influenza pan- health measures could potentially stop the spread of an demic strain turns out not to be the H5N1 variety, then avian flu pandemic if implemented soon after the first the stockpiled vaccines would be useless and wasted. cases appear. Interventional strategies simulated include Deciding who to vaccinate is another challenge. Cur- an international stockpile to 3 million courses of flu anti- rently, influenza vaccination is recommended to the eld- viral drugs, treating infected individuals and everyone in erly and those with medical conditions which put them at their social networks, closure of schools and workplaces, higher risk for hospitalization and death if they become vaccinating (even with a low-efficacy vaccine) half the infected with influenza. However, some critics have population before the start of a pandemic and quarantine argued that younger and healthier individuals should be measures. Targeted anti-viral treatment was a crucial com- given priority because they are more mobile than older, ponent of all combined strategies and increasing public less healthy people and are therefore more likely to spread health measures needed to be greatly increased as the the flu to others. Another factor in favour of giving priority virus became more contagious. While the researchers said to younger people is that the seasonal flu vaccine pro- that implementing such a combination of approaches was duces a weaker immune response in the elderly. Moreo- challenging because it required a coordinated interna- ver, if the flu pandemic has characteristics of the 1918– tional response, the models did show that containing an 1919 pandemic, then the young and healthy are at higher avian flu pandemic at its source was theoretically feasible. risk of death. Even if supplies were adequate for all age groups, mass immunization for a potential pandemic still Strategies to Contain and Cope with an Avian Flu has its risks. In 1976, four US soldiers developed swine flu Pandemic in an army camp and there was concern that it could To successfully contain and control an AI pandemic, both become a pandemic like the 1918 Spanish flu. Although national and global strategies are needed [19]. National some health officials expressed doubts about the likeli- strategies need multi-pronged approaches and involve hood of an epidemic, the government initiated a mass source surveillance and control, adequate stockpiles of inoculation programme for the entire US population. anti-viral agents, timely production of flu vaccines and After hundreds of people receiving the vaccine came down healthcare system readiness. with Guillian-Barre syndrome, the US government termi- nated the campaign and indemnified manufacturers, ulti- Source Surveillance and Control mately paying $93 million in claims [21]. When the H5N1 flu virus becomes easily transmissible from human to human, the earlier this fact is known, the There is a light at the end of the tunnel. The WHO recently more time there will be to gather and deploy available announced plans to stockpile H5 influenza vaccine and public health resources. Currently, the World Health create a policy framework for vaccine allocation and rec- Organisation (WHO), United Nations and other interna- ommendations for its use [22]. Several recent develop- tional agencies are trying to contain the H5N1 epidemic ments in H5 vaccines have made this stockpile feasible: among poultry flocks in Asia and have set up monitoring the development of H5N1 vaccines with adjuvants that systems to detect new outbreaks (especially human-to- reduce the required dose as much as fourfold [23] and the human cases) early. finding that adjuvant-enhanced vaccines may provide cross-protection against strains that have undergone up to Flu Vaccines seven years of genetic drift [24]. Furthermore, the manu- Currently, there are ongoing efforts to mass produce and facturing capacity of 500 million doses is calculated on a stockpile vaccines against the H5N1 strain. Recent models requirement for three strains of flu virus for standard vac- built on data from the 1918 flu pandemic predict that 50 cinations; in crisis mode, three times as much monovalent million-80 million people could die and the overwhelm- pandemic flu vaccine could be produced. ing majority of deaths are likely to occur in the developing Page 3 of 6 (page number not for citation purposes) Asia Pacific Family Medicine 2008, 7:5 http://www.apfmj.com/content/7/1/5 Antiviral Drugs priority on curbing the disease "at source" in the agricul- Anti-viral drugs are thought to be backbone of a manage- tural sector, thereby reducing the probability of a human ment plan of an avian flu pandemic [25]. Only two anti- epidemic. International resources are also needed for sur- viral drugs have shown promise in treating avian influ- veillance on avian influenza outbreaks and human-to- ® ® enza: oseltamivir (Tamiflu ) and zanamivir (Relenza ). A human transmission. It is also important to strike a bal- treatment of Tamiflu includes 10 pills taken over five ance between short and long term measures. Avian flu is days while Relenza is administered by oral inhalation. becoming endemic in parts of East Asia and will require a The US Food and Drug Administration has approved both long effort to suppress it. Meanwhile, a human pandemic anti-viral drugs for treating influenza but only Tamiflu may still emerge from a different strain of flu virus. Thus has been approved to prevent influenza infection. Because it makes sense for the international community to also antivirals can be stored without refrigeration and for undertake broader long-term measures to strengthen the longer periods than vaccines, developing a stockpile of institutional, regulatory and technical capacity of the ani- antivirals has advantages as part of an overall strategy to mal health, human health and other relevant sectors in control a flu epidemic. However, there are limitations to Asia. While country-level preparedness and leadership is needs to be taken within 2 the use of antivirals: Tamiflu essential for success, it must be backed by global days of initial flu symptoms for it to be effective, but many resources. Even though the benefits of containing a pan- people may not be aware that they have the flu early in the demic are overwhelming, individual governments may disease. Some research in animals and recent experience still be daunted by the social, political and economic costs in the use of the drug to treat human cases have also found of various policy measures. Richer countries may have to that Tamiflu may be less effective against the recent strains support poorer countries in financial and non-financial for the current H5N1 virus than the 1997 strain [26]. means in the fight against a flu pandemic, for the sake of Improper compliance to antivirals by irresponsible indi- international good. The Global Outbreak Alert & viduals during an outbreak may results in the emergence Response Network (GOARN), a technical collaboration of of a drug-resistant strain. Lastly, there are current concerns existing institutions and networks who pool human and about the safety of Tamiflu which has been associated technical resources for the rapid identification, confirma- with increased psychiatric symptoms among Japanese tion and response to disease outbreaks, is one such inter- adolescents [27]. national body that supports global preparedness against bird flu. However, for such an organization to succeed, Healthcare System Readiness open communication and international cooperation is Every country's healthcare system would be stretched to essential. Lastly, there is a critical need to share informa- the limit in the event of a global pandemic of bird flu. The tion rapidly with experts, policymakers and the world- ability of healthcare facilities to maintain strict infection wide community at large. Honest public communication control measures would be challenged. The sudden surge will be critical as evidenced by China's denial of a local in health manpower and facility need would be acutely SARS outbreak initially which delayed early containment felt among healthcare workers, epidemiologists and labo- measures. ratory technicians. Countries must set up AI pandemic contingency plans and high-level coordinating commit- Recently, the Bill & Melinda Gates Foundation, the Pas- tees comprising of representatives from multiple minis- teur Institute and the Wellcome Trust, began planning, tries and agencies. with major medical-research funders and other stakehold- ers, several projects to enhance the research effort and International Strategies reduce the risks from the threat of pandemic influenza An avian flu that is easily transmissible between humans over coming decades [22]. In the next few years, they plan would spread rapidly all over the world. The economic to develop, maintain and disseminate a central inventory cost of an avian pandemic to all countries would be phe- of funded research activities that are relevant to human nomenal and, if allowed to last for months, become expo- influenza to ensure that stakeholders are well-informed. nential [28-30]. Early detection and control of an AI They will also coordinate road-mapping exercises to iden- pandemic will also require a coordinated international tify knowledge gaps to assist funders and researchers in response. Controlling avian flu is for the good of global establishing research-funding priorities, with specific public health and all countries have an interest and obli- focus on vaccines, drug therapies and epidemiology/pop- gation to do so. Firstly, the response to the influenza ulation science (for example, diagnostics, surveillance, threat would need an integrated cross-sector approach, transmission and modelling), in the hope of developing a bringing together animal and human health, areas of rural cohesive health-research agenda for pandemic influenza. development and agriculture, economics, finance, plan- ning and others. Partnerships are needed at both interna- tional and national levels. 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Morse SS, Garwin RL, Olsiewski PJ: Next flu pandemic: what to tially limit the spread of an AI pandemic if implemented do until the vaccine arrives? Science 2006, 314:929. 21. Sencer DJ, Millar JD: Reflections on the 1976 swine flu vaccina- soon after the first cases appear. Both national and inter- tion program. Emerg Infect Dis 2006, 12:29-33. national strategies are needed: National strategies include 22. Yamada T, Dautry A, Walport M: Ready for avian flu? Nature 2008, source surveillance and control, adequate anti-viral agents 454:162. 23. Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement and vaccines, and healthcare system readiness; interna- F, Hons E, Devaster JM, Leroux-Roels G: Antigen sparing and tional strategies include early integrated response, curbing cross-reactive immunity with an adjuvanted rH5N1 proto- type pandemic influenza vaccine: a randomised controlled disease outbreak at source, utilization of global resources, trial. Lancet 2007, 370:580-9. continuing research and open communication. 24. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, Zambon MC, Katz JM: Cross-reactivity to highly pathogenic avian influ- enza H5N1 viruses after vaccination with nonadjuvanted and Authors' contributions MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) All authors contributed to development of the paper, writ- vaccine: a potential priming strategy. J Infect Dis 2005, 191:1210-5. ing of the manuscript and final approval for submission. 25. Schünemann HJ, Hill SR, Kakad M, et al.: WHO Rapid Advice Guidelines for pharmacological management of sporadic References human infection with avian influenza (H5N1) virus. Lancet th Infct Dis 2007, 7:21-31. 1. Kilbourne ED: Influenza pandemics of the 20 century. Emerg 26. Beigel JH, Farrar J, Han AM, et al.: (The Writing Committee of Infect Dis 2006, 12:9-14. the World Health Organisation (WHO) Consultation on 2. 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Koh GCH, Koh DSQ: The socioeconomic effects of an avian influenza pandemic. In Bird flu: a rising pandemic in Asia and beyond? 1st edition. Edited by: Tambyah P, Leung PC. Singapore: World Scien- tific Publishing; 2006:127-46. 31. Lee JW: Opening remarks at the meeting on avian influenza and pandemic human influenza. [http://www.who.int/dg/lee/ speeches/2005/flupandemicgeneva/en/print.html]. 9 Nov 05 Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes)

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Asia Pacific Family MedicineSpringer Journals

Published: Nov 13, 2008

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