Alan Sipress - The Fatal Strain

42 also onto a third:Politics long prevented researchers from publishing their analysis of human-to-human-to-human spread in the Sumatra cluster. But half a year later, another instance of third-generation transmission was confirmed in Pakistan and later described in a publication. See: “Human Cases of Avian influenza A (H5N1) in North-West Frontier Province, Pakistan, October-November 2007,” Weekly Epidemiological Record, no. 40 (October 3, 2008): 359-64.

This chapter draws on interviews with current and former public health, infectious-disease, and laboratory specialists at the Hong Kong Department of Health and the CDC, as well as animal health researchers in Hong Kong and the United States.

45 a three-year-old boy:The case is described in J. C. de Jong et al., “A Pandemic Warning?” Nature 389, no. 6651 (Oct. 9, 1997): 554; and in Kanta Subbarao et al., “Characterization of an Avian Influenza A (H5N1) Virus Isolated from a Child with a Fatal Respiratory Disease,” Science 279, no. 5349 (Jan. 16, 1998): 393-96.

48 far more than a runny nose and chills:A thorough overview of the clinical spectrum is provided in 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 in K. Y. Yuen and S. S. Y. Wong, “Human Infection by Avian Influenza A H5N1,” Hong Kong Medical Journal 11, no. 3 (June 2005): 189-99. WHO has described the symptoms and clinical course of the disease in reports by the agency’s writing committee. See Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, “Update on Avian Influenza A (H5N1) Virus Infection in Humans,” NEJM 358 no. 3 (Jan. 17, 2008): 261-73. The cases in individual countries have also been surveyed and described. See, for example, Hongjie Yu et al., “Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China,” PLoS One 3, no. 8 (Aug. 21, 2008): e2985; and Sardikin Giriputro et al., “Clinical and Epidemiological Features of Patients with Confirmed Avian Influenza Presenting to Sulianti Saroso Infectious Diseases Hospital, 2005–2007,” Annals of the Academy of Medicine (Singapore) 37 (2008): 454-57.

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.