Exposure source unclear in 25% of human H5N1 cases

Jan 16, 2008 (CIDRAP News) – In at least 25% of human infections with the H5N1 avian influenza virus, just how the person was exposed to the virus remains a mystery, according to a report by an expert panel set up by the World Health Organization (WHO).

"In one quarter or more of patients with influenza A (H5N1) infection virus infection, the source of exposure is unclear, and environment-to-human transmission remains possible," says the report, which appears today in the New England Journal of Medicine.

The predominant source of exposure in H5N1 cases is contact with infected poultry in the week before onset of illness, the article notes. But in cases involving no such contact, patients might have touched contaminated objects (fomites) or fertilizer containing poultry feces or have inhaled aerosolized infectious material. The only known risk factor for some patients was visiting a live-poultry market, the article says.

The discussion of exposure sources is part of a review of all aspects of human H5N1 cases, including epidemiology, clinical features, diagnosis, treatment, and prevention. The report is based on the WHO's Second Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1), a meeting held in Antalya, Turkey, in March 2007.

About a quarter of all human cases have occurred in clusters of two or more that were epidemiologically linked, the report says. More than 90% of the clusters have involved blood relatives, suggesting a possible genetic susceptibility to the infection. Most people in the clusters probably were infected through common exposure to poultry, "but limited, nonsustained human-to-human transmission has probably occurred during very close, unprotected contact with a severely ill patient," the article states.

Regarding the virus's evolution, the report has a chart that shows a total of 10 different clades (including the original 1997 strain from Hong Kong), or lineages, plus five subclades in clade 2.

"Changes in multiple viral genes"—not just the surface protein known as hemagglutinin—"are probably required to generate a potentially pandemic influenza A (H5N1) virus," the article says. So far, the virus is not transmissible among ferrets or swine, and reassortment (hybridization) between an H5N1 virus and an H3N2 (human-adapted) virus did not produce a virus transmissible among ferrets.

Concerning host responses, the report does not fully endorse the "cytokine storm" theory: the proposition that the severe disease in H5N1 cases is a result of an overly intense immune response. The tissue damage "probably results from the combined effects of unrestrained viral infection and inflammatory responses" induced by the infection, it says.

Further, the current understanding of the immune response to the infection is not adequate to guide efforts to treat the disease by modifying the immune response, the panel says.

In line with that, the report repeats previous WHO advice against the routine use of corticosteroids in H5N1 patients. Corticosteroid therapy has not been effective, and prolonged or high-dose corticosteroids can lead to serious adverse events.

As for antiviral drugs, the panel says that clade 1 viruses and most clade 2 viruses from Indonesia are fully resistant to M2 inhibitors (amantadine and rimantadine), but the other clade 2 viruses from other parts of Eurasia and Africa are usually susceptible to these older drugs.

The article repeats the standard recommendation for early treatment with oseltamivir, a neuraminidase inhibitor. The panel also reiterates previous WHO statements that doubling the standard oseltamivir dose and duration of treatment may be reasonable. Resistance to the drug has been seen in a few patients, and clade 1 viruses seem to be more susceptible than some clade 2 viruses, though the clinical relevance of this difference is unclear.

Concerning H5N1 vaccines, the panel writes that certain proprietary adjuvants seem to be highly effective in antigen sparing (reducing the amount of antigen needed to generate an immune response) and inducing cross-reactive antibody responses. However, the antibody levels needed for protection against the virus are unknown.

The report stops short of endorsing prepandemic vaccination—giving an existing H5N1 vaccine before a pandemic in the hope that it will yield some protection against a later H5N1-based pandemic strain or will at least prime the immune system so that just one dose of a specific pandemic vaccine would be necessary.

Decisions about prepandemic vaccination require complex risk-benefit and cost-benefit analyses because of likely effects on seasonal vaccine production and the chance that mass vaccinations would trigger adverse events, the article says.

Some other observations in the report:

  • The median age of H5N1 case-patients is about 18, and 90% of patients have been 40 years or younger.
  • While the disease typically leads to severe pneumonia, febrile upper respiratory illnesses without pneumonia have been seen in children, particularly since 2005.
  • About 15% to 20% of older adults have some antibodies to H5N1 and might respond to a single dose of vaccine.

See also:

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. N Engl J Med 2008 Jan 17;358(3) [Full text]

Apr 20, 2007, CIDRAP News story "WHO warns against steroids for H5N1 patients"

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