by Alan Sipress
49 a counterattack so furious: This aggressive response has been much discussed. The following is a sampling of the research: M. C. W. Chan et al., “Proinflammatory Cytokine Responses Induced by Influenza A (H5N1) Viruses in Primary Human Alveolar and Bronchial Epithelial Cells,” Respiratory Research 6 (Nov. 11, 2005): 135; C. Y. Cheung et al., “Induction of Proinflammatory Cytokines in Human Macrophages by Influenza A (H5N1) Viruses: A Mechanism for the Unusual Severity of Human Disease?” Lancet 360, no. 9348 (Dec. 7, 2002): 1831-37; Menno D. de Jong et al., “Fatal Outcome of Human Influenza A (H5N1) Is Associated with High Viral Load and Hypercytokinemia,” Nature Medicine 12, no. 10 (Oct. 2006): 1203-07; J. S. Malik Peiris et al., “Re-emergence of Fatal Human Influenza A Subtype H5N1 Disease,” Lancet 363, no. 9409 (Feb. 21, 2004): 617-19; Ka-Fai To et al., “Pathology of Fatal Human Infection Associated with Avian Influenza A H5N1 Virus,” Journal of Medical Virology 63 (2001): 242-46; and Jianfang Zhou et al., “Differential Expression of Chemokines and Their Receptors in Adult and Neonatal Macrophages Infected with Human or Avian Influenza Viruses,” Journal of Infectious Diseases 194 (2006): 61-70.
50 inviting a suicidal counterattack: There has been debate about whether the immune response or the virus itself is more directly responsible for death. See, for instance, Kristy J. Szretter et al., “Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice,” Journal of Virology 81, no. 6 (Mar. 2007): 2736-44; and Rachelle Salomon, Erich Hoffman, and Robert G. Webster, “Inhibition of the Cytokine Response Does Not Protect Against Lethal H5N1 Influenza Infection,” PNAS 104, no. 30 (July 24, 2007): 12479-81.
50 enters the human body: For an overview of how the microbe operates, see J. S. Malik Peiris, Menno D. de Jong, and Yi Guan, “Avian Influenza Virus (H5N1): A Threat to Human Health,” Clinical Microbiology Review 20, no. 2 (Apr. 2007): 243-67; and R. G. Webster and D. J. Hulse, “Microbial Adaption and Change: Avian Influenza,” Revue Scientifique et Technique, Office International des Épizooties 23, no. 2 (2004): 453-65.
52 receptors in the human respiratory tract: There has also been extensive discussion about the preferences that different strains have for human and avian receptors and the crucial role these play in transmission. The following is a sampling of the research: Susan J. Baigent and John W. McCauley, “Influenza Type A in Humans, Mammals and Birds: Determinants of Virus Virulence, Host-Range and Interspecies Transmission,” BioEssays 25, no. 7 (2003): 657-71; Aarthi Chandrasekaran et al., “Glycan Topology Determines Human Adaptation of Avian H5N1 Virus Hemagglutinin,” Nature Biotechnology 26, no. 1 (Jan. 2008): 107-13; A. Gambaryan et al., “Evolution of the Receptor Binding Phenotype of Influenza A (H5) Viruses,” Virology 344, no. 2 (Jan. 20, 2006): 432-38; Thijs Kuiken et al., “Host Species Barriers to Influenza Virus Infections,” Science 312, no. 5772 (Apr. 21, 2006): 394-97; Masato Hatta et al., “Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice,” PLoS Pathogens 3, no. 10 (Oct. 2007): 1374-79; John M. Nicholls et al., “Sialic Acid Receptor Detection in the Human Respiratory Tract: Evidence for Widespread Distribution of Potential Binding Sites for Human and Avian Influenza Viruses,” Respiratory Research 8 (2007): 73; J. M. Nicholls et al., “Tropism of Avian Influenza A (H5N1) in the Upper and Lower Respiratory Tract,” Nature Medicine 13 (2007): 147-49; Kyoko Shinya et al., “Influenza Virus Receptors in the Human Airway,” Nature 440 (Mar. 23, 2006): 435-36; Debby van Riel et al., “H5N1 Virus Attachment to Lower Respiratory Tract,” Science 312, no. 5772 (Apr. 23, 2006): 399; Terrence M. Tumpey et al., “A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza Virus Abolishes Transmission,” Science 315, no. 5812 (Feb. 2, 2007): 655-59; Shinya Yamada et al., “Haemagglutinin Mutations Responsible for the Binding of H5N1 Influenza A Viruses to Human-type Receptors,” Nature 444 (Nov. 16, 2006): 378-82 and Influenza Research at the Human and Animal Interface: Report of a WHO Working Group, WHO, Geneva, Sept. 21-22, 2006.
52 a few other genetic tweaks: For discussion of possible changes in viral proteins that can lead to an avian virus attacking humans and becoming more lethal, see Christopher F. Basler and Patricia V. Aguilar, “Progress in Identifying Virulence Determinants of the 1918 H1N1 and the Southeast Asian H5N1 Influenza A Viruses,” Antiviral Research 79 (2008): 166-78; Andrea Gambotto et al., “Human Infection with Highly Pathogenic H5N1 Influenza Virus,” Lancet 371, no. 9622 (Apr. 26, 2008): 1464-75; and Neal Van Hoeven et al., “Human HA and Polymerase Subunit PB2 Proteins Confer Transmission of an Avian Influenza Virus Through Air,” PNAS, published online before print February 11, 2009, doi: 10.1073/pnas.0813172106.
55 Growing up in Hong Kong: Miriam Shuchman, “Improving Global Health—Margaret Chan at the WHO,” NEJM 356, no. 7 (Feb. 15, 2007): 653-56; and Lawrence K. Altman, “Her Job: Helping Save the World from Bird Flu,” New York Times, Aug. 9, 2005.
56 a baffling plague: On the connection between Hoi-ka’s case with the earlier poultry outbreak, see Eric C. J. Claas et al., “Human Influenza A H5N1 Virus Related to a Highly Pathogenic Avian Influenza Virus,” Lancet 351, no. 9101 (Feb. 14, 1998): 472-77; and David L. Suarez et al., “Comparisons of Highly Virulent H5N1 Influenza A Viruses Isolated from Humans and Chickens from Hong Kong,” Journal of Virology 72, no. 8 (Aug. 1998): 6678-88.
58 The Spanish flu: For a scientific investigation of the 1918 pandemic, see Jeffrey K. Taubenberger and David M. Morens, “1918 Influenza: The Mother of All Pandemics,” Emerging Infectious Diseases 12, no. 1 (Jan. 2006): 15-22.
58 two subsequent pandemics: On flu pandemics of the last century, see Edwin D. Kilbourne, “Influenza Pandemics of the 20th Century,” Emerging Infectious Diseases 12, no. 1 (Jan. 2006): 9-14. WHO estimates that the 1957 pandemic killed two million and the 1968 pandemic one million.
60 If two different flu strains: For a discussion of the compatibility of genes from H5N1 and human viruses, see Li-Mei Chen et al., “Genetic compatibility and Virulence of Reassortants Derived from Contemporary Avian H5N1 and Human H3N2 Influenza A Viruses,” PLoS Pathogens 4, no. 5: e1000072.
60 the recent, seemingly improbable encounter: For early discussions of the H1N1 swine flu virus, see Rebecca J. Garten et al., “Antigenic and Genetic Characteristics of Swine-Origin 2009 A (H1N1) Influenza Viruses Circulating in Humans,” Science, published online before print May 22, 2009, doi: 10.1126/ science.1176225; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, “Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans,” NEJM, published online before print May 7, 2009, doi: 10.1056/ NEJMoa0903810; and Robert B. Belshe, “Implications of the Emergence of a Novel H1 Influenza Virus,” NEJM, published online before print May 7, 2009, doi: 10.1056/NEJMe0903995. On the triple reassortant virus, see Vivek Shinde, et al., “Triple-reassortant swine influenza A (H1) in Humans in the United States, 2005-2009,” NEJM, published online before print May 7, 2009, doi: 10.1056/NEJMoa0903812.
60 even infecting mammals: See, for example, Juthatip Keawcharoen et al., “Avian Influenza H5N1 in Tigers and Leopards,” Emerging Infectious Diseases 10, no. 12 (Dec. 2004): 2189-91; and Guus F. Rimmelzwaan et al., “Influenza A Virus (H5N1) Infection in Cats Causes Systemic Disease with Potential Novel Routes of Virus Spread Within and Between Hosts,” American Journal of Pathology 168, no. 1 (Jan. 2006): 176-83.
60 The dice were being rolled: Alice Croisier et al., “Highly Pathogenic Avian Influenza A (H5N1) and Risks to Human Health,” Background Paper at the Technical Meeting on Highly Pathogenic Avian Influenza and Human H5N1 Infection, June 27-29, 2007, Rome.
60 “appear out of control”: I. Capua and S. Marangon, “Control and Prevention of Avian Influenza in an Evolving Scenario,” Vaccine 25, no. 30 (July 26, 2007): 5645-52.
60 it returns: Antonio Petrini, “Global Situation: HPAI Outbreaks in Poultry—A Synthesis of Country Reports to the OIE,” Background Paper at the Technical Meeting on Highly Pathogenic Avian Influenza and Human H5N1 Infection, June 27-29, 2007, Rome.
60 “a distant and unlikely pro
spect”: Joseph Domenech et al., “Trends of Dynamics of HPAI—Epidemiological and Animal Health Risks,” Background Paper at the Technical Meeting on Highly Pathogenic Avian Influenza and Human H5N1 Infection, June 27-29, 2007, Rome.
60 not the only avian virus menacing humanity: J. S. Malik Peiris, Menno D. de Jong, and Yi Guan, “Avian Influenza Virus (H5N1): A Threat to Human Health,” Clinical Microbiology Review 20, no. 2 (April 2007): 243-67.
60 avian strain called H9N2: K. M. Xu et al., “Evolution and Molecular Epidemiology of H9N2 Influenza A Viruses from Quail in Southern China, 2000 to 2005,” Journal of Virology 81, no. 6 (Mar. 2007): 2635-45; and K. M. Xu et al., “The Genesis and Evolution of H9N2 Influenza Viruses in Poultry from Southern China, 2000 to 2005,” Journal of Virology 81 no. 19 (Oct. 2007): 10389-10401.
61 “The establishment and prevalence”: Hongquan Wan et al., “Replication and Transmission of H9N2 Influenza Viruses in Ferrets: Evaluation of Pandemic Potential,” PLoS One 3, no. 8 (Aug. 2008): e2923.
61 “continued surveillance and study”: Jessica A. Belser et al., “Contemporary North American Influenza H7 Viruses Possess Human Receptor Specificity: Implications for Virus Transmissibility,” PNAS 105 no. 21 (May 27, 2008): 7558-63.
61 Some medical scholars dissent: Dennis Normile, “Avian Influenza: Pandemic Skeptics Warn Against Crying Wolf,” Science 310, no. 5751 (Nov. 18, 2005): 1112-13; and Declan Butler, “Yes, But Will It Jump?” Nature 439, no. 12 (Jan. 2006): 124-25.
62 “Such complacency”: Robert G. Webster et al., “H5N1 Outbreaks and Enzootic Influenza,” Emerging Infectious Diseases 12, no. 1 (Jan. 2006): 3-8.
62 “The virus has evolved”: Remarks in a speech tape for Business Preparedness for Pandemic Influenza, Second Annual Summit, sponsored by the University of Minnesota Center for Infectious Disease Research and Policy, Feb. 5, 2007.
62 “If you put a burglar”: Margaret Chan, “Pandemics: Working Together for an Effective and Equitable Response,” address to the Pacific Health Summit, Seattle, June 13, 2007.
66 “There’s a possibility”: Cindy Sui, “Hospital Staff Ill After Treating Bird Flu Victims,” Hong Kong Standard, Dec. 8, 1997.
66 reached double digits: For a clinical discussion of the Hong Kong cases, see K. Y. Yuen et al., “Clinical Features and Rapid Viral Diagnosis of Human Disease Associated with Avian Influenza A H5N1 Virus,” Lancet 351, no. 9101 (Feb. 14, 1998): 467-71; and Paul K. S. Chan, “Outbreak of Avian Influenza A (H5N1) Virus Infection in Hong Kong in 1997,” Clinical Infectious Diseases 34 (2002): S58-S64.
68 The parallels were eerie: David M. Morens and Anthony S. Fauci, “The 1918 Influenza Pandemic: Insights for the 21st Century,” Journal of Infectious Diseases 195 (2007): 1018-28; Jeffrey K. Taubenberger, “The Origin and Virulence of the 1918 ‘Spanish’ Influenza Virus,” Proceedings of the American Philosophical Society 150, no. 1 (Mar. 2006); Jeffrey K. Taubenberger and David M. Morens, “1918 Influenza: The Mother of All Pandemics,” Emerging Infectious Diseases 12, no. 1 (Jan. 2006): 15-22; and L. Simonsen et al., “Pandemic Versus Epidemic Influenza Mortality: A Pattern of Changing Age Distribution,” Journal of Infectious Diseases 178, no. 1 (July 1998): 53-60.
68 this disquieting pattern: “Epidemiology of WHO-Confirmed Human Cases of Avian Influenza A (H5N1) Infection,” Weekly Epidemiological Record 81, no. 26 (June 30, 2006): 249-57; and “Update: WHO-Confirmed Human Cases of Avian Influenza A (H5N1) Infection, 25 November 2003-24 November 2006,” Weekly Epidemiological Record, 82, no. 6 (Feb. 9, 2007): 41-47.
68 “most important unsolved mystery”: David M. Morens and Anthony S. Fauci, “The 1918 Influenza Pandemic: Insights for the 21st Century,” Journal of Infectious Diseases 195 (2007): 1018-28.
69 tremendous cytokine storms: See, for example, John C. Kash, et al., “Genomic Analysis of Increased Host Immune and Cell Death Responses Induced by 1918 Influenza Virus,” Nature 443 (Oct. 5, 2006): 578-81; Darwyn Kobasa et al., “Enhanced Virulence of Influenza A Viruses with the Hemagglutinin of the 1918 Pandemic Virus,” Nature 431, no. 7009 (Oct. 7, 2004): 703-7; and Darwyn Kobasa et al., “Aberrant Innate Immune Response in Lethal Infection of Ma caques with the 1918 Influenza Virus,” Nature 445 (Jan. 18, 2007): 319-23. A study in 2008 comparing the immune response to H5N1 and the 1918 virus in mice showed “considerable similarities” but found that the H5N1 strain actually elicited significantly higher levels of cytokines and macrophages. See Lucy A. Perrone et al., “H5N1 and 1918 Pandemic Influenza Virus Infection Results in Early and Excessive Infiltration of Macrophages and Neutrophils in the Lungs of Mice,” PLoS Pathogens 4, no. 8 (2008): e1000115.
69 “kissing cousin”: Remarks at Business Preparedness for Pandemic Influenza, Second Annual Summit, University of Minnesota Center for Infectious Disease Research and Policy, Feb. 5, 2007.
69 a wholly avian virus: Jeffrey K. Taubenberger et al., “Characterization of the 1918 Influenza Virus Polymerase Genes,” Nature 437 (Oct. 6, 2005): 889-93; and Terrence M. Tumpey et al., “Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus,” Science 310, no. 5745 (Oct. 7, 2005): 77-80.
69 “a number of the same changes”: Jeffrey K. Taubenberger et al., “Characterization of the 1918 Influenza Virus Polymerase Genes,” Nature 437 (Oct. 6, 2005): 889-93.
69 more like the Spanish flu strain: For example, see James Stevens et al., “Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus,” Science 312, no. 5772 (Apr. 21, 2006): 404-10.
69 A series of studies: H. Chen et al., “The Evolution of H5N1 Influenza Viruses in Ducks in Southern China,” PNAS 101, no. 28 (July 13, 2004): 10452-57; Taronna R. Maines et al., “Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals,” Journal of Virology 79, no. 18 (Sept. 2005): 11788-11800; Hui-Ling Yen et al., “Virulence May Determine the Necessary Duration and Dosage of Oseltamivir Treatment for Highly Pathogenic A/Vietnam/1203/04 Influenza Virus in Mice,” Journal of Infectious Diseases 192 (2005): 665-72; and Adrianus C. M. Boon et al., “Role of Terrestrial Wild Birds in Ecology of Influenza A Virus (H5N1),” Emerging Infectious Diseases 13, no. 11 (Nov. 2007): 1720-24.
69 “a process of rapid evolution”: “Mouse Studies of Oseltamivir Show Promise Against H5N1 Influenza Virus,” NIH News, July 18, 2005.
69 already become more ferocious: Carole R. Baskin et al., “Early and Sustained Innate Immune Response Defines Pathology and Death in Nonhuman Primates Infected by Highly Pathogenic Influenza Virus,” PNAS, Published online before print February 13, 2009, doi 10.1073/pnas.0813234106.
70 If the virus continued to develop: J. S. Malik Peiris, “H5N1 Pathogenesis in Humans: An Update,” Power Point presentation to the WHO working group, Sept. 21-22, 2006.
70 though later reported : WHO, “Influenza Research at the Human and Animal Interface: Report of a WHO Working Group,” Geneva, September 21-22, 2006.
70 62 million: Christopher J. L. Murray et al., “Estimation of Potential Global Pandemic Influenza Mortality on the Basis of Vital Registry Data from the 1918- 1920 Pandemic: A Quantitative Analysis,” Lancet 368, no. 9554 (Dec. 23, 2006): 2211-18.
70 $3.13 trillion during the first year: The figures for severe, mild, and moderate pandemics are based on numbers included in Andrew Burns, Dominique van der Mensbrugghe, and Hans Timmer, “Evaluating the Economic Consequences of Avian Influenza,” updated in September 2008. An earlier version of this report, which had calculated the costs using a lower figure for global GDP, put the toll of a severe pandemic at $2.38 trillion. The study was originally published in a slightly different form in the World Bank’s June 2006 edition of Global Development Finance. For further discussion, see Milan Brahmbatt, “Economic Impacts of Avian Influenza Propagation,” speech at the First International Conference on Avian Influenza in Humans, June 29, 2006.
71 “It’s a possibility in this case”: Jane Moir, “Cousins of Child Victim in Flu Alert: Human Transmission Suspected,” South China Morning Post, Dec.
17, 1997.
71 “They live together at Grandma’s”: Edward A. Gargan, “Chicken-Borne Flu Virus Puts Hong Kong on Alert,” New York Times, Dec. 17, 1997.
71 “working at breakneck pace”: Jane Moir, “Cousins of Child Victim in Flu Alert: Human Transmission Suspected,” South China Morning Post, Dec. 17, 1997.
71 barely three hundred square feet: Rhonda Lam Wan, “Bird Flu Cousins’ Flat Behind Pile of Rubbish,” South China Morning Post, Dec. 19, 1997.
71 they were rebuffed: Ibid.
72 a city under siege: See, for example, the following accounts, all from the South China Morning Post: Rhonda Lam Wan and Billy Wong Wai-Yuk, “Doctors Scramble for Special Drug,” Dec. 13, 1997; Andrea Li and Alex Lo, “Fears Force Changes to Menus,” Dec. 16, 1997; Stella Lee, “18 Private Doctors to Join Bird Flu Probe,” Dec. 18, 1997; Rhonda Lam Wan, “Flood of Requests Prompts Promise of A-Strain Testing,” Dec. 20, 1997; and Ng Kang-Chung, “Rush for Bird Flu Tests As Seven More Suspected Victims Found,” Dec. 26, 1997.
73 Fukuda had never before missed: Patricia Guthrie, “Focus on Hong Kong Flu,” Atlanta Journal and Constitution, Dec. 25, 1997.
73 “will stop or spread”: “Hong Kong Tests Show Human-to-Human Transmission of Bird Flu Difficult,” Agence France Presse, Dec. 27, 1997.
73 “measures are sufficient”: Keith B. Richburg, “Hong Kong Killing All Chickens in Fight Against ‘Bird Flu’ Virus,” Washington Post, Dec. 29, 1997.
73 more bad news: For discussion of the poultry outbreaks in late December 1997, see L. D. Sims et al., “Avian Influenza in Hong Kong 1997-2002,” Avian Diseases 47, no. s3 (2003): 832-38; and Kennedy F. Shortridge, “Poultry and the Influenza H5N1 Outbreak in Hong Kong, 1997: Abridged Chronology and Virus Isolation,” Vaccine 17 (1999): s26-s29.
75 would kill every last chicken: For an overview of the 1997 poultry outbreaks and government response, see Kennedy F. Shortridge et al., “Interspecies Transmission of Influenza Viruses: H5N1 Virus and a Hong Kong SAR Perspective,” Veterinary Microbiology 74 (2000): 141-47.
