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WHO Update on Human H5N1 Infections

By Eric Toner, M.D., January 18, 2008

On January 17, 2008, the Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus published a review article in the New England Journal of Medicine providing updated information on human cases of highly pathogenic avian influenza A (H5N1) infection.1 Highlights are summarized below.

The Continuing Epizootic and Evolution of H5N1 Viruses

The article indicates that highly pathogenic avian influenza A (H5N1) viruses, herein referred to simply as H5N1, continue to evolve. Eight distinct clades (0-8), or subgroups, of H5N1 are now recognized based on the phylogeny of the H5 hemagglutinin. Clade 1 viruses caused the 2004 outbreaks in Southeast Asia. Clade 2 viruses have caused outbreaks in Indonesia, western China, Europe and Africa. Clade 2 is now recognized to have 5 subclades (2.1-2.5). Six of these clades/subclades (0, 1, 2.1, 2.2, 2.3 and 7) have caused human infections.  Although the introduction of H5N1 into some new geographic regions may have occurred as a result of wild bird migration, the authors conclude that the principal mechanism of spread of H5N1 has been the movement of poultry and poultry products. The authors judge that there is a low risk of H5N1 being introduced to North America by wild bird migration through Alaska.

Epidemiology of Human Infections

Although human cases of H5N1 continue, primarily in Indonesia and Egypt, they remain rare relative to the frequency of human exposure to infected poultry. The overall case fatality ratio remains at approximately 60%, but varies with age: it is highest in those aged 10 to 19 years and lowest in those older than 50, with 90% of human cases occurring in those under age 40. The reason for the age differences is unclear. There continues to be little evidence of mild or asymptomatic human infections. Eight relatively small-scale serological surveys of individuals at high risk of H5N1 exposure are summarized in a table included in the article’s supplementary information. Of 1,232 people sampled, only one person was found to be seropositive.

Most human cases continue to be associated with close, recent poultry exposure. Usually, but not always, the birds were ill or had died. The consumption of raw or undercooked poultry products has been associated with some cases. The source of infection in approximately one quarter of cases is unclear, and in some patients, the only poultry exposure has been a visit to a live-poultry market.

Many clusters (two or more epidemiologically linked cases) of human H5N1 infections have been identified in 10 countries, representing approximately 25% of all the human cases, and 90% of the clusters involve only blood relatives. While most clusters probably represent common-source exposures, several appear to have resulted from non-sustained person-to-person transmission within a family.


Despite new knowledge about respiratory tract viral attachment receptors and mutations of the viral polymerase, the barriers to both poultry-to-human and human-to-human transmission are still not fully understood. The evidence of infectious virus in multiple organs of some patients indicates that, in contrast to other types of human influenza infections, H5N1 can cause a systemic infection. H5N1 is known to cause a systemic infection in birds.

Although high levels of cytokines and chemokines are found in patients with H5N1 infection and correlate with viral load, the authors judge that there is insufficient knowledge about the mechanisms of the hypercytokinemia to guide immunomodulatory therapy. (See July 30, 2007 CBN Report for more information on this topic.)

Clinical Features

Pneumonia continues to be the predominant clinical manifestation of H5N1 infection, although, since 2005, there has been some increase in the incidence of febrile upper respiratory infection without pneumonia in children. This is especially true in Egypt, where only half the infected children developed pneumonia. This may be due to early antiviral treatment.

Diarrhea, which occurred with 16 of 32 (52%) clade 1 infections, has occurred less frequently with clade 2 infections in each involved country (5% to 29%). Because H5N1 infections present with nonspecific symptoms, approximately 90% of H5N1 patients are misdiagnosed initially. The most common mistaken diagnoses are community acquired pneumonia, dengue fever, and upper respiratory infection.

Diagnostic Testing

Polymerase chain reaction is still the best initial test for H5N1 infection, but due to continual genetic change of the virus, the primers must be updated frequently. Throat swabs are a more reliable source of specimens than nasal swabs, but tracheal aspirates are better still. Because specimens are often inadequate, a single negative test does not rule out H5N1. To date, rapid antigen assays using nasal or throat swabs have proven to be insensitive for H5N1.

Antiviral Treatment

Most clade 1 viruses as well as clade 2 viruses from Indonesia are resistant to amantadine; however, clade 2 viruses from other counties are usually susceptible. Early treatment with oseltamivir appears to improve survival. Clade 1 viruses are 15 to 30 times more sensitive to oseltamivir than clade 2 viruses. Variants that are highly resistant to oseltamivir can emerge during the course of therapy and have been associated with subsequent death. Two Egyptians who died had been infected with H5N1 viruses that were relatively resistant to oseltamivir even before oseltamivir therapy was initiated (see November 1, 2007 CBN Report for more information on this topic). The authors state that a higher than normal dose of oseltamivir and a longer course of treatment may be indicated, although data to support this is limited. Combination therapy with M2 inhibitors (e.g. amantadine) may be reasonable in some areas. Corticosteroids do not seem to be efficacious in patients with H5N1 infection and may worsen outcomes.


Safe inactivated H5 vaccines have been developed, but their potential utility is limited by relatively poor immunogenicity  and by the continual antigenic drift of the virus. Two large doses of antigen are required to induce an adequate response. The use of whole virus vaccines or the use of some adjuvants can reduce the required dose of antigen. Multiple clinical studies are underway. The antibody level needed for protection against H5N1 is unclear, as is the duration of protection. Priming with a pre-pandemic vaccine may allow a single dose of a pandemic-specific vaccine.


Significant advances have occurred in the understanding of H5N1 and H5N1 infection in humans. The increasing incidence of cases without obvious poultry contact and the increasing number of clusters of human cases is of concern. The optimal treatment regimen remains unclear, and the emergence of neuraminidase resistance is ominous. Continued advances in vaccine research hold out the promise of more effective and perhaps cross-protective vaccines.


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 2008;358:261-273. Accessed January 17, 2008.