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 Epizooties 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 prospect”: 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
