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INFLUENZA A VIRUS SUBTYPES H5, H7 AND H9

PATHOGEN SAFETY DATA SHEET - INFECTIOUS SUBSTANCES

SECTION I - INFECTIOUS AGENT

NAME: Influenza A virus subtypes H5, H7 and H9.

SYNONYM OR CROSS REFERENCE: Orthomyxovirus Footnote 1-Footnote 3, influenza virus type A Footnote 1-Footnote 3, influenzavirus A Footnote 1-Footnote 3, avian influenza Footnote 1-Footnote 3, and pandemic influenza Footnote 4.

CHARACTERISTICS: Influenza virus subtypes H5, H7 and H9 are members of the Orthomyxoviridae family of segmented, negative sense single-stranded RNA viruses. Type A influenza viruses are subdivided on the basis of the antigenic nature of their membrane-bound surface glycoproteins, haemagglutinin (HA) and neuraminidase (NA). To date, 16 HA, and 9 NA subtypes have been detected in wild birds and poultry Footnote 5-Footnote 9. Antigenic alterations occur frequently in the antigenic sites of HA and NA and are the mechanism for virus adaptation and survival. Small alterations are referred to as antigenic drift, whereas larger alterations caused by reassortment are referred to as antigenic shift. Influenza pandemics may occur as a result of antigenic shifts if the virus is able to maintain efficient human-to-human transmission Footnote 1-Footnote 3.

SECTION II - HAZARD IDENTIFICATION

PATHOGENICITY/TOXICITY: Avian influenza A viruses are referred to as low pathogenic avian influenza (LPAI) and highly pathogenic avian influenza (HPAI), based on the severity of illness caused in poultry. To date, only H5 and H7 subtypes have been shown to be HPAI, although not all H5 and H7 viruses are highly virulent Footnote 2, Footnote 3, Footnote 10. Furthermore, it appears that HPAI viruses arise by mutation after LPAI viruses have been introduced to poultry Footnote 2.

Human infections from influenza A virus subtypes H5, H7 and H9 range from eye infections (conjunctivitis) to influenza-like illness (ILI) symptoms to severe respiratory illness Footnote 11-Footnote 13. Symptoms of H5N1 range from typical flu-like symptoms (e.g., fever, sore throat, cough, and muscle aches) to pneumonia, acute respiratory distress syndrome, multiple organ failure, lymphopenia, elevated liver enzyme levels and abnormal clotting profiles, diarrhoea, vomiting, abdominal pain, pleuritic pain, and bleeding from the nose and gums Footnote 11, Footnote 14, Footnote 15.

EPIDEMIOLOGY: Influenza can occur in pandemics, epidemics, localized outbreaks, and as sporadic cases. Many strains of avian influenza virus can cause varying degrees of disease in domestic poultry. Avian influenza usually does not make wild birds sick, but can cause serious illness and death in poultry Footnote 10. HPAI is a fatal form of avian influenza that can spread rapidly in flocks, causing high mortalities. Outbreaks of HPAI have led to human infections, some of which resulted in deaths Footnote 11. Lack of previous exposure to the virus and high virulence of avian influenza H5N1 is a key determinant of the high fatality rate Footnote 11. LPAI can also cause disease in humans. For example, H7N7 (1996, conjunctivitis); H9N2 (1999, ILI); H7N2 (2002, ILI); H9N2 (2003, ILI) and H7N2 (2003, ILI) Footnote 16. Continuous existence of LPAI virus in an avian population may provide opportunities for the virus to undergo mutation and convert to a highly pathogenic strain Footnote 2.

Animal influenza A virus subtypes that have infected humans include H5N1, H7N2, H7N3, H7N7, H9N2, H10N7 and swine and avian H1 viruses.

Human cases of H5 were first reported in 1997 in Hong Kong, where avian-to-human transmission of H5N1 resulted in 18 cases of human infection and 6 deaths Footnote 15, Footnote 17. In 2003 another outbreak in Hong Kong led to 2 cases of human infection and one death Footnote 15, Footnote 17. In December 2003, a further outbreak of H5N1 occurred among poultry in South Korea and then later in Vietnam, Japan, Thailand, Laos, Cambodia, China, Indonesia and Malaysia Footnote 1, Footnote 18. Since the outbreak in 2003, the World Health Organization (WHO) has reported a number of waves of avian-to-human transmission starting in Southeast Asia and spreading to areas North and West of China reaching as far as Eastern Europe and Northern Africa Footnote 19-Footnote 21. The cumulative number of human H5N1 cases reported to WHO from 2003 to May 6, 2010 is 498 cases with 294 deaths (59% mortality rate) Footnote 21.

H7 infection in humans is rare, but can occur in persons who have been in direct contact with infected birds Footnote 12, Footnote 22, Footnote 23, or in one case, seals Footnote 24. In 2003, H7N7 was responsible for the death of a veterinarian and extensive conjunctivitis among those employed in the disposal of diseased birds in the Netherlands Footnote 12. An outbreak of H7N3 in 2004 also led to two cases of human infection in British Columbia, Canada Footnote 23.

Since 1998, a number of human cases of H9N2 have been reported in Asia and are generally associated with mild illness Footnote 25, Footnote 26. Transmission of H9N2 appears to be exclusively avian-to-human Footnote 26, Footnote 27.

HOST RANGE: Domestic and wild avian species. H5 and H7 are generally non-pathogenic in their natural waterfowl hosts but may become highly pathogenic once introduced into domestic poultry Footnote 3, Footnote 15. Viral transmission of H5N1 to mammals has been reported in domestic cats, dogs, tigers and also in a stone marten (reviewed in Footnote 1, Footnote 20).

INFECTIOUS DOSE: Unknown.

MODE OF TRANSMISSION: Influenza A infections (H5, H7, H9) in humans result predominantly from direct transmission of the virus from birds to humans. Transmission occurs primarily through contact of the mucous membranes with infectious secretions or excreta from infected wild birds or poultry. Exposure to sick poultry and the butchering of birds is associated with seropositivity for H5N1 Footnote 28, Footnote 29. Slaughtering, de-feathering, or preparing sick poultry for cooking, playing with or handling diseased or dead poultry, handling fighting cocks or ducks that appear asymptomatic, and consuming raw or uncooked poultry or poultry products, have all been implicated as potential risk factors Footnote 14, Footnote 20. Oral ingestion of contaminated water during swimming and direct intranasal or conjunctival inoculation during exposure to water are other potential modes of transmission, as is contamination of hands from infected fomites and subsequent self-inoculation Footnote 20, Footnote 28. The widespread use of untreated poultry feces as fertilizer is another possible risk factor Footnote 14. Non-sustained human-to-human spread has only been documented in a few cases Footnote 30-Footnote 32; however, the continued circulation of virulent influenza virus H5N1 increases the potential for a new influenza virus to arise through reassortment with other circulating influenza viruses, thus increasing the threat of an influenza virus that is transmissible from person-to-person that could lead to a global influenza pandemic Footnote 1, Footnote 18, Footnote 32.

INCUBATION PERIOD: Most cases of influenza A (H5N1) occurred within two to four days after exposure Footnote 15, Footnote 18-Footnote 20. In clusters in which limited human-to-human transmission may have occurred, the incubation period appeared to be approximately 3 to 5 days, although in one cluster it was estimated to be 8 to 9 days Footnote 30, Footnote 31.

COMMUNICABILITY: Limited human-to-human transmission reported, whereby transmission probably occurred during close unprotected contact with a severely ill patient Footnote 30-Footnote 32.

SECTION III - DISSEMINATION

RESERVOIR: Wild aquatic birds, predominantly ducks, geese, and shorebirds. Avian influenza viruses are generally non-pathogenic in wild birds, sometimes causing significant morbidity and mortality upon transmission to other species, including domestic birds and mammals Footnote 3, Footnote 5, Footnote 18, Footnote 20.

ZOONOSIS: Yes, from various avian species Footnote 3, Footnote 11, Footnote 12, Footnote 14, Footnote 15, Footnote 18, Footnote 20, Footnote 23, Footnote 28, Footnote 31.

VECTORS: Wild birds Footnote 3, Footnote 5, Footnote 18, Footnote 20.

SECTION IV - STABILITY AND VIABILITY

DRUG SUSCEPTIBILITY: Various subtypes of H5 (H5N1), H7 (H7N3, H7N7) and H9 (N9N2) are susceptible to the neuraminidase inhibitors, oseltamivir Footnote 4, Footnote 23, Footnote 33-Footnote 36, zanamivir Footnote 4, Footnote 23, Footnote 33-Footnote 36, and peramivir (RWJ-270201) Footnote 34. In the past, influenza viruses have been shown to be sensitive to M2 inhibitors, amantadine and rimantadine, although to a lesser extent than the neuraminidase inhibitors Footnote 1, Footnote 4, Footnote 35. There is evidence of increasing resistance to M2 inhibitors by H5N1 Footnote 1, Footnote 4, Footnote 35, Footnote 36.

SUSCEPTIBILITY TO DISINFECTANTS: Susceptible to the following disinfectants: 1% sodium hypochlorite, 70% ethanol, glutaraldehyde, formalin and iodine compounds (reviewed in Footnote 37). Also susceptible to a number of commercially available disinfectants (reviewed in Footnote 37).

PHYSICAL INACTIVATION: Incubation at 56ºC to 60ºC for 60 min will inactivate various subtypes of H5, H7 and H9 (reviewed in Footnote 37). Incubations in low (1 to 3) or high (10 to 14) pH solutions has also been shown to be effective at inactivating H5, H7 and H9, although the medium in which the virus is suspended may interfere with the effect of pH on virus infectivity (reviewed in Footnote 37).

SURVIVAL OUTSIDE HOST: Influenza virus may remain infective in lake water for 4 days, in water at 22ºC, and for 30 days at 0ºC Footnote 2. Survival in feces is likely to be influenced by the strain of the virus, type of faeces and temperature Footnote 37.

SECTION V – FIRST AID / MEDICAL

SURVEILLANCE: Identify potential exposure to H5, H7 or H9 through recent travel to or from areas with known influenza activity Footnote 1. Monitor for symptoms of influenza. Confirm by viral culture Footnote 12, Footnote 14, Footnote 15, Footnote 18, Footnote 23, RT-PCR with strain specific primers Footnote 12, Footnote 14, Footnote 15, Footnote 18, Footnote 20, Footnote 22, Footnote 23, Footnote 31, immunostaining (Western blot, ELISA) with subtype specific antibodies Footnote 11, Footnote 15, Footnote 17, Footnote 27, Footnote 28, Footnote 30, Footnote 31, molecular sequencing Footnote 30, Footnote 31, antiviral resistance testing Footnote 30, and/or microneutralization Footnote 27, Footnote 30.

FIRST AID/TREATMENT: Antivirals must be administered early after the onset of symptoms to be effective Footnote 14, Footnote 20. Oseltamivir is recommended for the treatment of avian influenza viruses. Oseltamivir is an oral preparation (capsule or liquid suspension), whereas zanamivir is delivered by inhalation Footnote 4, Footnote 20, Footnote 35. Amantadine and rimantadine are also administered in countries where they are licensed if oseltamivir and zanamivir are unavailable Footnote 1, Footnote 35.

IMMUNIZATION: A vaccine for humans against the H5N1 influenza virus was approved by the Food and Drug Administration (FDA) in the United States. The immunization consists of two intramuscular injections, given approximately one month apart Footnote 38. A vaccine for H9N2 is currently in clinical trials Footnote 1. It is a cold-adapted, live, attenuated virus vaccine administered intranasally Footnote 1. There are currently no human vaccines for H7 viruses, although, avian vaccines for H7 viruses are being investigated as a method to prevent outbreaks Footnote 39, Footnote 40.

PROPHYLAXIS: Chemoprophylaxis with of oseltamivir once daily for 7 days after the last known exposure is warranted for persons who have had a possible unprotected exposure H5N1 Footnote 4, Footnote 35, Footnote 38, Footnote 41. Zanamivir (10mg twice daily) Footnote 1, Footnote 4, Footnote 35 and the M2 inhibitors, amantadine (100 mg twice daily) Footnote 1, Footnote 4, Footnote 35 and rimantadine (100 mg twice daily Footnote 1, Footnote 4, Footnote 35 are also used; however, amantadine and rimantadine are documented to be less effective as a first-line mono-therapy Footnote 1, Footnote 4, Footnote 35. The use of human or humanized antibodies for prophylaxis and therapy are currently being investigated Footnote 32.

SECTION VI - LABORATORY HAZARDS

LABORATORY-ACQUIRED INFECTIONS: None reported.

SOURCES/SPECIMENS: Tissues, secretions and/or excretions from infected birds Footnote 1, Footnote 4, Footnote 14, Footnote 35.

PRIMARY HAZARDS: Inhalation of virus from aerosols generated when aspirating, dispensing, or mixing virus-infected samples from infected animals, especially birds Footnote 1, Footnote 4, Footnote 14, Footnote 35.

SPECIAL HAZARDS: Possible risk to people who have contact with surfaces that have been contaminated with secretions or excretions from infected birds Footnote 1, Footnote 20, Footnote 28. Accidental inoculation is also a risk Footnote 1, Footnote 20, Footnote 28.

SECTION VII – EXPOSURE CONTROLS / PERSONAL PROTECTION

RISK GROUP CLASSIFICATION: Risk Group 2 or 3, depending on specific virus.

CONTAINMENT REQUIREMENTS: Containment Level 2 facilities, equipment, and operational practices for work involving clinical or diagnostic specimens. Containment Level 3 facilities, equipment, and operational practices are recommended for virus isolation and laboratory manipulation of highly pathogenic H5, H7 and H9 strains of avian influenza Footnote 42

PROTECTIVE CLOTHING: Protective solid-front gowns, gloves, shoe covers, eye protection with face seal, and N95 respiratory protection Footnote 1, Footnote 42, Footnote 43.

OTHER PRECAUTIONS: Manipulations with autopsy material or infectious material in open vessels to be carried out in a certified biological safety cabinet. Centrifugation of respiratory specimens or tissue samples to be carried out using sealed centrifuge cups or rotors,both of which are to be loaded and unloaded in a biological safety cabinet Footnote 1, Footnote 42, Footnote 43.

SECTION VIII – HANDLING AND STORAGE

SPILLS: Allow aerosols to settle, and while wearing protective clothing, gently cover the spill with paper towels and apply 1% sodium hypochlorite or other proven effective disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time and then clean the area.

DISPOSAL: Decontaminate before disposal by steam sterilization, chemical disinfection, or incineration.

STORAGE: In sealed containers that are appropriately labelled Footnote 43.

SECTION IX - REGULATORY AND OTHER INFORMATION

UPDATED: December 2011

PREPARED BY: Pathogen Regulation Directorate, Public Health Agency of Canada.

Although the information, opinions and recommendations contained in this Pathogen Safety Data Sheet are compiled from sources believed to be reliable, we accept no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information. Newly discovered hazards are frequent and this information may not be completely up to date.

Copyright ©
Public Health Agency of Canada, 2011
Canada

REFERENCES:

Footnote 1
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Footnote 2
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Footnote 3
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Footnote 4
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Footnote 5
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Footnote 6
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Footnote 7
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Footnote 8
Kawaoka, Y., Yamnikova, S., Chambers, T. M., Lvov, D. K., & Webster, R. G. (1990). Molecular characterization of a new hemagglutinin, subtype H14, of influenza A virus. Virology, 179(2), 759-767.

Footnote 9
Röhm, C., Zhou, N., Süss, J., Mackenzie, J., & Webster, R. G. (1996). Characterization of a novel influenza hemagglutinin, H15: Criteria for determination of influenza A subtypes. Virology, 217(2), 508-516.

Footnote 10
Senne, D. A., Panigrahy, B., Kawaoka, Y., Pearson, J. E., Suss, J., Lipkind, M., Kida, H., & Webster, R. G. (1996). Survey of the hemagglutinin (HA) cleavage site sequence of H5 and H7 avian influenza viruses: amino acid sequence at the HA cleavage site as a marker of pathogenicity potential. Avian Diseases, 40(2), 425-437.

Footnote 11
Chan, P. K. (2002). Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 34 Suppl 2, S58-64. doi:10.1086/338820

Footnote 12
Koopmans, M., Wilbrink, B., Conyn, M., Natrop, G., van der Nat, H., Vennema, H., Meijer, A., van Steenbergen, J., Fouchier, R., Osterhaus, A., & Bosman, A. (2004). Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet, 363(9409), 587-593. doi:10.1016/S0140-6736(04)15589-X

Footnote 13
Lin, Y. P., Shaw, M., Gregory, V., Cameron, K., Lim, W., Klimov, A., Subbarao, K., Guan, Y., Krauss, S., Shortridge, K., Webster, R., Cox, N., & Hay, A. (2000). Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates. Proceedings of the National Academy of Sciences of the United States of America, 97(17), 9654-9658. doi:10.1073/pnas.160270697

Footnote 14
Beigel, J. H., Farrar, J., Han, A. M., Hayden, F. G., Hyer, R., de Jong, M. D., Lochindarat, S., Nguyen, T. K., Nguyen, T. H., Tran, T. H., Nicoll, A., Touch, S., Yuen, K. Y., & Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. (2005). Avian influenza A (H5N1) infection in humans. The New England Journal of Medicine, 353(13), 1374-1385. doi:10.1056/NEJMra052211

Footnote 15
Yuen, K. Y., Chan, P. K., Peiris, M., Tsang, D. N., Que, T. L., Shortridge, K. F., Cheung, P. T., To, W. K., Ho, E. T., Sung, R., & Cheng, A. F. (1998). Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet, 351(9101), 467-471.

Footnote 16
Alexander, D. J. (2006). Avian influenza viruses and human health. Developments in Biologicals, 124, 77-84.

Footnote 17
Peiris, J. S., Yu, W. C., Leung, C. W., Cheung, C. Y., Ng, W. F., Nicholls, J. M., Ng, T. K., Chan, K. H., Lai, S. T., Lim, W. L., Yuen, K. Y., & Guan, Y. (2004). Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet, 363(9409), 617-619. doi:10.1016/S0140-6736(04)15595-5

Footnote 18
Tran, T. H., Nguyen, T. L., Nguyen, T. D., Luong, T. S., Pham, P. M., Nguyen, V. C., Pham, T. S., Vo, C. D., Le, T. Q., Ngo, T. T., Dao, B. K., Le, P. P., Nguyen, T. T., Hoang, T. L., Cao, V. T., Le, T. G., Nguyen, D. T., Le, H. N., Nguyen, K. T., Le, H. S., Le, V. T., Christiane, D., Tran, T. T., Menno de, J., Schultsz, C., Cheng, P., Lim, W., Horby, P., Farrar, J., & World Health Organization International Avian Influenza Investigative Team. (2004). Avian influenza A (H5N1) in 10 patients in Vietnam. The New England Journal of Medicine, 350(12), 1179-1188. doi:10.1056/NEJMoa040419

Footnote 19
Chotpitayasunondh, T., Ungchusak, K., Hanshaoworakul, W., Chunsuthiwat, S., Sawanpanyalert, P., Kijphati, R., Lochindarat, S., Srisan, P., Suwan, P., Osotthanakorn, Y., Anantasetagoon, T., Kanjanawasri, S., Tanupattarachai, S., Weerakul, J., Chaiwirattana, R., Maneerattanaporn, M., Poolsavathitikool, R., Chokephaibulkit, K., Apisarnthanarak, A., & Dowell, S. F. (2005). Human disease from influenza A (H5N1), Thailand, 2004. Emerging Infectious Diseases, 11(2), 201-209.

Footnote 20
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, Abdel-Ghafar, A. N., Chotpitayasunondh, T., Gao, Z., Hayden, F. G., Nguyen, D. H., de Jong, M. D., Naghdaliyev, A., Peiris, J. S., Shindo, N., Soeroso, S., & Uyeki, T. M. (2008). Update on avian influenza A (H5N1) virus infection in humans. The New England Journal of Medicine, 358(3), 261-273. doi:10.1056/NEJMra0707279

Footnote 21
World Health Organization (WHO). (2010). Cumulative Number of Confirmed Cases of Avian Influenza A/(H5N1) Reported to WHO.

Footnote 22
Kurtz, J., Manvell, R. J., & Banks, J. (1996). Avian influenza virus isolated from a woman with conjunctivitis. Lancet, 348(9031), 901-902. doi:10.1016/S0140-6736(05)64783-6

Footnote 23
Tweed, S. A., Skowronski, D. M., David, S. T., Larder, A., Petric, M., Lees, W., Li, Y., Katz, J., Krajden, M., Tellier, R., Halpert, C., Hirst, M., Astell, C., Lawrence, D., & Mak, A. (2004). Human illness from avian influenza H7N3, British Columbia. Emerging Infectious Diseases, 10(12), 2196-2199.

Footnote 24
Webster, R. G., Geraci, J., Petursson, G., & Skirnisson, K. (1981). Conjunctivitis in human beings caused by influenza A virus of seals. The New England Journal of Medicine, 304(15), 911.

Footnote 25
Peiris, M., Yuen, K. Y., Leung, C. W., Chan, K. H., Ip, P. L., Lai, R. W., Orr, W. K., & Shortridge, K. F. (1999). Human infection with influenza H9N2. Lancet, 354(9182), 916-917.

Footnote 26
Butt, K. M., Smith, G. J., Chen, H., Zhang, L. J., Leung, Y. H., Xu, K. M., Lim, W., Webster, R. G., Yuen, K. Y., Peiris, J. S., & Guan, Y. (2005). Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. Journal of Clinical Microbiology, 43(11), 5760-5767. doi:10.1128/JCM.43.11.5760-5767.2005

Footnote 27
Uyeki, T. M., Chong, Y. H., Katz, J. M., Lim, W., Ho, Y. Y., Wang, S. S., Tsang, T. H., Au, W. W., Chan, S. C., Rowe, T., Hu-Primmer, J., Bell, J. C., Thompson, W. W., Bridges, C. B., Cox, N. J., Mak, K. H., & Fukuda, K. (2002). Lack of evidence for human-to-human transmission of avian influenza A (H9N2) viruses in Hong Kong, China 1999. Emerging Infectious Diseases, 8(2), 154-159.

Footnote 28
Bridges, C. B., Lim, W., Hu-Primmer, J., Sims, L., Fukuda, K., Mak, K. H., Rowe, T., Thompson, W. W., Conn, L., Lu, X., Cox, N. J., & Katz, J. M. (2002). Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997-1998. The Journal of Infectious Diseases, 185(8), 1005-1010. doi:10.1086/340044

Footnote 29
Schultsz, C., Nguyen, V. D., Hai le, T., Do, Q. H., Peiris, J. S., Lim, W., Garcia, J. M., Nguyen, D. T., Nguyen, T. H., Huynh, H. T., Phan, X. T., van Doorn, H. R., Nguyen, V. V., Farrar, J., & de Jong, M. D. (2009). Prevalence of antibodies against avian influenza A (H5N1) virus among Cullers and poultry workers in Ho Chi Minh City, 2005. PloS One, 4(11), e7948. doi:10.1371/journal.pone.0007948

Footnote 30
Kandun, I. N., Wibisono, H., Sedyaningsih, E. R., Yusharmen, Hadisoedarsuno, W., Purba, W., Santoso, H., Septiawati, C., Tresnaningsih, E., Heriyanto, B., Yuwono, D., Harun, S., Soeroso, S., Giriputra, S., Blair, P. J., Jeremijenko, A., Kosasih, H., Putnam, S. D., Samaan, G., Silitonga, M., Chan, K. H., Poon, L. L., Lim, W., Klimov, A., Lindstrom, S., Guan, Y., Donis, R., Katz, J., Cox, N., Peiris, M., & Uyeki, T. M. (2006). Three Indonesian clusters of H5N1 virus infection in 2005. The New England Journal of Medicine, 355(21), 2186-2194. doi:10.1056/NEJMoa060930

Footnote 31
Ungchusak, K., Auewarakul, P., Dowell, S. F., Kitphati, R., Auwanit, W., Puthavathana, P., Uiprasertkul, M., Boonnak, K., Pittayawonganon, C., Cox, N. J., Zaki, S. R., Thawatsupha, P., Chittaganpitch, M., Khontong, R., Simmerman, J. M., & Chunsutthiwat, S. (2005). Probable person-to-person transmission of avian influenza A (H5N1). The New England Journal of Medicine, 352(4), 333-340. doi:10.1056/NEJMoa044021

Footnote 32
Sambhara, S., & Poland, G. A. (2010). H5N1 Avian influenza: preventive and therapeutic strategies against a pandemic. Annual Review of Medicine, 61, 187-198. doi:10.1146/annurev.med.050908.132031

Footnote 33
Leneva, I. A., Roberts, N., Govorkova, E. A., Goloubeva, O. G., & Webster, R. G. (2000). The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Antiviral Research, 48(2), 101-115.

Footnote 34
Govorkova, E. A., Leneva, I. A., Goloubeva, O. G., Bush, K., & Webster, R. G. (2001). Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrobial Agents and Chemotherapy, 45(10), 2723-2732. doi:10.1128/AAC.45.10.2723-2732.2001

Footnote 35
World Health Organization (WHO). (2006). WHO Rapid Advice Guidelines on Pharmacological Management of Humans Infected with Avian Influenza A (H5N1) Virus. Retrieved from http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf

Footnote 36
World Health Organization Global Influenza Program Surveillance Network. (2005). Evolution of H5N1 avian influenza viruses in Asia. Emerging Infectious Diseases, 11(10), 1515-1521.

Footnote 37
De Benedictis, P., Beato, M. S., & Capua, I. (2007). Inactivation of avian influenza viruses by chemical agents and physical conditions: a review. Zoonoses and Public Health, 54(2), 51-68. doi:10.1111/j.1863-2378.2007.01029.x

Footnote 38
Welliver, R., Monto, A. S., Carewicz, O., Schatteman, E., Hassman, M., Hedrick, J., Jackson, H. C., Huson, L., Ward, P., Oxford, J. S., & Oseltamivir Post Exposure Prophylaxis Investigator Group. (2001). Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA : The Journal of the American Medical Association, 285(6), 748-754.

Footnote 39
van der Goot, J. A., Engel, B., van de Water, S. G., Buist, W., de Jong, M. C., Koch, G., van Boven, M., & Stegeman, A. (2010). Validation of diagnostic tests for detection of avian influenza in vaccinated chickens using Bayesian analysis. Vaccine, 28(7), 1771-1777. doi:10.1016/j.vaccine.2009.12.009

Footnote 40
van der Goot, J. A., Koch, G., de Jong, M. C., & van Boven, M. (2005). Quantification of the effect of vaccination on transmission of avian influenza (H7N7) in chickens. Proceedings of the National Academy of Sciences of the United States of America, 102(50), 18141-18146. doi:10.1073/pnas.0505098102

Footnote 41
Hayden, F. G., Belshe, R., Villanueva, C., Lanno, R., Hughes, C., Small, I., Dutkowski, R., Ward, P., & Carr, J. (2004). Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. The Journal of Infectious Diseases, 189(3), 440-449. doi:10.1086/381128

Footnote 42
Public Health Agency of Canada. (2004). In Best M., Graham M. L., Leitner R., Ouellette M. and Ugwu K. (Eds.), Laboratory Biosafety Guidelines (3rd ed.). Canada: Public Health Agency of Canada.

Footnote 43
Office of Laboratory Security, Public Health Agency of Canada. (Ed.). (2004). Laboratory Biosafety Guidelines. (3rd ed.)