COMMENTARY

Infectious Diseases: May 15, 2004

John Bartlett, MD

Disclosures

May 14, 2004

In This Article

Influenza

Zambon M. The inexact science of influenza prediction. Lancet. 2004;363:582-585. The study author reviews some of the recent experiences with avian influenza and compares the experience with the H7N7 strain in The Netherlands and the H5N1 strain in Asia. The subtypes of influenza A are classified by viral hemagglutinin and neuraminidase which are surface proteins. The only strains that circulate in mammalian hosts are H1N1, H1N2, and H3N2; however, all subtypes circulate in the natural hosts, which are wild birds, in which there is substantial mixing and exchanging of gene segments to promote new combinations. Both H5 and H7 subtypes cause serious disease in domestic poultry, which presumably is acquired by contact with wild birds. These strains have all avian genes and have receptors that are specific for alpha-2,3-galactosidase (in contrast to the human receptor alpha-2,6-galactosidase). They also both have multibasic cleavage sites, but the diseases produced in humans by H7N7 and H5N1 are very different. H5N1 has a mortality rate of over 50%, a course characterized by pulmonary failure with adult respiratory distress syndrome (ARDS), and a seroprevalence in exposed persons that is low. By contrast, H7N7 is usually associated with conjunctivitis; there is only 1 death; and serologic studies indicate high rates of asymptomatic infection in those who have contact with poultry sources. These comparisons are summarized in Table 1 .

The study author concludes that the current policy for control of a human epidemic is to limit the potential for recombination with viruses that are adapted to humans by culling infected poultry and intensive surveillance. It is noted that influenza A zoonosis is rare but needs to be taken seriously on the basis of the 1918 pandemic.

Comment: 2004 has been an extraordinarily bad year for influenza in birds, including poultry. There have been multiple epidemics of highly lethal avian influenza combined with culling of millions of birds in an attempt to control the epidemics. These epidemics involve multiple avian influenza strains, and the impact or potential impact on humans is quite varied. Table 2 summarizes this point as emphasized in the review above.

Weekly Report: Influenza Summary Update. CDC. April 24, 2004. http://www.cdc.gov/flu/weekly/. The report summarizes the data for World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories for influenza testing for the period from September 28, 2003 through March 20, 2004. During this time, 24,108 out of 113,517 specimens were positive for influenza (and are summarized in Table 3 ).

Comment: This was clearly an influenza A H3N2 year. The US experience was that 85% of these were A/Fujian/4ll/2002. This breakdown is now available for the global experience from the WHO report cited here. In terms of the magnitude of the 2003-2004 epidemic in the United States, this year was the largest since 2000-2001 in terms of excess mortality attributed to influenza and pneumonia.

Stevens J, Corper AL, Basler CF, Taubenberger JK, Palese P, Wilson IA. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science. 2004;303:1866-1870. The study authors present the crystal structure of the hemagglutinin of the 1918 pandemic H1 strain. They describe previously unknown features that contribute to altered fusion properties. These changes appear to have given the virus a unique mechanism of enhanced host-cell infection properties that may account for the extraordinary epidemic of 1918.

Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science. 2004;303:1838-1842. This is a report from the Medical Research Council in London, England, that provides a description of the amino acid residues of the hemagglutinin of the 1918 pandemic influenza strain. The relevance of this work concerns the fact that receptor binding of influenza viruses is the initial event of the infection and is mediated by the hemagglutinin membrane glycoprotein. The receptors are sialic acids found in alpha-2,3 or alpha-2,6 linkages to galactose; human influenza viruses (H1, H2, and H3) recognize alpha-2,6-linked sialic acid found on cells of the human respiratory tract. By contrast, the hemagglutinins of the 15 antigenic subtypes found in avian influenza viruses preferentially bind to sialic acid in alpha-2,3 linkages, which is the predominant sialosaccharide in avian enteric tracts (the replication site). These differences account for species specificity. The analysis showed a close similarity in the structures of the human and swine hemagglutinin binding sites. The conclusion is that this unique binding capacity of the 1918 pandemic strain of influenza permitted invasion of human cells with a strain that was sufficiently different from prior strains to which the susceptible human population had no cross-immunity.

Comment: The 1918 influenza epidemic was responsible for 20 million deaths and represents the largest outbreak of infectious disease in history. The ability to study that epidemic has been fostered by the availability of viral DNA fragments recovered from a mass burial in permafrost that followed an epidemic in an Alaskan village that killed 85% of the adult population in 5 days.[1] The DNA from these strains was used to create the genetic code of H1, and this permitted production of the protein for structural analysis. The relevance of this work may apply to the recent outbreaks of avian influenza subtypes H5, H7, and H9 -- all avian influenza strains that went directly from birds to humans. In each case, the epidemics have been small and contained because there was no person-person transmission. These studies examine some of the issues related to the current concern for avian influenza and its control.

Webby RJ, Perez DR, Coleman JS, et al. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet. 2004;363:1099-1103. The study authors from St. Jude Children's Research Hospital, Memphis, Tennessee, address the issue of a potential emergent need for influenza vaccine for a unique strain. On February 19, 2003, WHO issued a pandemic alert regarding avian H5N1 influenza. There was an attempt to develop a vaccine with traditional methods, but there were no avirulent viruses that were antigenically similar to the H5N1 strain, and this strain killed embryonated eggs, which is the traditional method of cultivation. As a result, an attempt was made to produce a vaccine with reverse genetics. The technique involved plasmid-based reverse genetics to remove polybasic amino acids that confer virulence. With this technique, a reference avirulent vaccine virus containing H5 and N1 was produced in 4 weeks. This strain proved nonpathogenic to chickens and ferrets and proved stable with multiple passages.

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