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How Prevalent Is Mild H5N1?

A Detailed Assessment of the Evidence from H5N1 Serosurveys 

FEBRUARY 6, 2013—Baltimore, MD—In an article posted online, senior scholars at the Center for Biosecurity of UPMC and the University of Pittsburgh Graduate School of Public Health report on the results of a comprehensive survey and detailed analysis of all English-language serological surveys that sought evidence of prior asymptomatic or mild H5N1 influenza infections in humans. The article, “Assessment of Serosurveys for H5N1,” was posted ahead of print on the website of the journal Clinical Infectious Diseases.

The review was conducted because part of the recent debate about research on modified highly pathogenic avian influenza (HPAI) H5N1 viruses has centered on the true case fatality rate of human H5N1 infection. Some have suggested that the case fatality rate of approximately 60%, which is based on official World Health Organization (WHO) case reports, is too high because many mild or asymptomatic cases may have been missed. Over the past 15 years, a number of sero-epidemiologic studies have been conducted to try to identify such missed cases. But previous reviews of these studies have come to widely divergent conclusions about the likely prevalence of such asymptomatic infections.

To better understand these differing analyses, the research team carefully examined each of the studies to determine:

  • The laboratory methodology used (including whether investigators used laboratory criteria set by WHO to define positive serology results for prior H5N1 infection);

  • The laboratory controls used; and

  • The geographic areas and specific viral clade and genotype involved.

The researchers looked at 29 studies and found that none of the studies was designed to determine the prevalence of H5 seropositivity across a general population; most of the studies used titer thresholds and research designs that would make the results susceptible to false-positive cross reactions with other influenza viruses; and no study that used WHO criteria showed any evidence of seropositivity to the clade 2 H5N1 viruses that have spread throughout Eurasia and Africa. 

This review suggests that the frequency of positive H5 serology results is likely to be low and that, because of the methodologies used, many of the studies conducted to date may be subject to misinterpretation due to false-positive cross-reaction with other viruses. Therefore, the researchers conclude, it is essential that future studies adhere to WHO criteria and include unexposed controls in their laboratory assays to limit the likelihood of false-positive results.

“The result of this analysis is clear: The serosurveys done to date do not provide evidence that the oft-quoted 60% case fatality rate of human H5N1 infections is an overestimation,” said lead author Eric Toner. “These serosurveys do not give us the true incidence of clinically mild cases of H5N1, but it looks to be very low. To determine this, we will need better tests and more rigorous methodologies.”

The research team consisted of Eric Toner, MD; Jennifer Nuzzo, SM; and Amesh Adalja, MD, all senior associates at the Center for Biosecurity of UPMC; Thomas Inglesby, MD, director and CEO of the Center for Biosecurity of UPMC; D. A. Henderson, MD, MPH, Distinguished Scholar at the Center for Biosecurity of UPMC; and Donald Burke, MD, dean of the Graduate School of Public Health at the University of Pittsburgh.

The article, titled “Assessment of Serosurveys for H5N1,” appears online ahead of print in Clinical Infectious Diseases, a peer-reviewed journal published by Oxford University Press. The article is available online at




The Center for Biosecurity is an independent, nonprofit organization of UPMC whose mission is to strengthen US national security and resilience by reducing dangers posed by epidemics, biothreats, nuclear disasters, and other destabilizing events.



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