The Fatal Strain (51 page)

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.

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 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.