Debate over H5N1 fatality rate flares again

In the latest chapter in an ongoing debate over the true case-fatality ratio (CFR) for human H5N1 influenza infections, a group of leading flu experts has written a Science article rejecting the idea that millions of H5N1 infections have gone undetected.

The debate was sparked by the controversy over publication of two studies involving lab-created H5N1 viruses with airborne transmissibility (both of which have now been published in full). Some proponents of publishing the full details of the studies argued that the true H5N1 case-fatality ratio (CFR) is probably much lower than the nearly 60% observed in confirmed cases, because in their view many mild or asymptomatic cases have likely been missed.

In February, Science published a meta-analysis by a team from Mount Sinai School of Medicine in New York City who said that on the basis of seroprevalence studies, the infection rate in populations exposed to H5N1 could be 1% to 2%, which would probably translate into millions of infections globally. The authors were Taia T. Wang, PhD, Michael K. Parides, PhD, and Peter Palese, PhD.

In the article published today, flu experts write that Wang and colleagues "overinterpret the results of seroprevalence studies and take too little account of underlying uncertainties. Although the true risk of death from H5N1 infection will likely be lower than the 60% of reported laboratory-confirmed cases, there is little evidence of millions of missed infections."

The article is accompanied by a response from the Mount Sinai group, who observe that the combined rural population of countries where H5N1 outbreaks occur is about 1 billion and assert that the tests used in seroprevalence studies probably miss many cases.

The first author of the article published today is Maria D. Van Kerkhove, PhD, and the senior author is Neil M. Ferguson, D Phil, both of the Medical Research Council Centre for Outbreak Analysis and Modeling at Imperial College London. Several other widely known flu experts are co-authors.

The main way to detect asymptomatic or subclinical cases is to conduct seroprevalence studies, looking for H5N1 antibodies in people who weren't sick but may have been exposed to the virus, such as contacts of confirmed case-patients, poultry cullers, or residents of an area where poultry outbreaks occurred. In nearly all such studies conducted since 2003, few people tested positive, if any.

The Van Kerkhove article says that H5N1 cases in both the numerator and denominator of the CFR are undoubtedly being missed, since in some disease-related deaths the cause remains undetermined and some sick people never seek medical care. But it notes that in a recent systematic review by Van Kerkhove and others, most studies found no seropositive individuals, and the seropositive rate in the rest was less than 3%.

That review and others have pointed up the limitations of seroprevalence studies and cautioned against overinterpreting low levels of seroprevalnece as signaling actual infection, the authors write. They note that findings are clouded by a lack of standardized serologic assays, variable criteria for seropositivity, and cross-reactions in people who have been exposed to seasonal flu or vaccines.

"Populations with no known exposure to highly pathogenic H5N1 viruses also manifest low, but detectable, levels of seroprevalnece, and it is unwise to infer aymptomatic H5N1 infection on the basis of such low levels of seroprevalence," Van Kerkhove and colleagues write.

For these reasons and others, the article says, the suggestion by the Mount Sinai group that millions of H5N1 infections may have gone undetected "represents an incautious overinterpretation of limited and uncertain data."

Even if the true number of infections were 60 times as great as the official number, the authors add, "natural H5N1 viruses would still be 100 times as lethal as the 2009 H1N1 pandemic virus. The precautionary principle dictates that we continue to assume that natural H5N1 infection in humans carries a high risk of death."

In a short response to the Van Kerkhove article, Wang and Palese of Mount Sinai write that four of the countries that have H5N1 outbreaks—Vietnam, Indonesia, Egypt, and China—have a total rural populaton of about 1 billion, and each year, "some fraction of those people is exposed to H5N1," with studies suggesting 1% to 3% have been infected.

"Recent reports of human antibodies or of T cells specific for H5N1 viruses support the 1 to 3% rate of infection or provide evidence for infections without detectable antibodies," Wang and Palese write. "Over the many decades that H5N1 viruses have been circulating in poultry, millions of people have likely been infected."

Further, they assert that serologic tests used in seroprevalence studies are more likely to underestimate than overestimate the number of positives: "The lack of sensitivity of H5N1 seroassays is well documented, as is the short period in which serum H5N1 antibodies can be detected in infected individuals. The high rate of false negative results from serum-based assays is exemplified by the rate of only ~70% seropositive findings from patients with polymerase chain reaction–confirmed H5N1 disease—and this is under the best of circumstances, when the time of infection is known."

Finally, Wang and Palese dismiss as "arbitrary" the statement that if H5N1 infections were underestimated by a factor of 60, the virus would still be 100 times as lethal as the 2009 H1N1 virus.

Jun 22, 2102 (CIDRAP News) –Robert Roos News Editor

Van Kerkhove MD, Riley S, Lipsitch M, et al. Comment on "Seroprevalence for H5N1 influenza virus infections in humans: meta-analysis." Science 2012 Jun 22;336(6088) [Full text]

Wang TT, Palese P. Response to comment on "Seroprevalence for H5N1 influenza infections in humans: meta-analysis." Science 2012 Jun 22; 336(6088):1506 [Full text]

Wang TT, Parides M, Palese P. Seroevidence for H5N1 influenza infections in humans: meta-analysis. Science 2012 Mar 23;335(6075):1463 [Full text]

See also:

Feb 24 CIDRAP News story "Debate on H5N1 death rate and missed cases continues"

Feb 9 CIDRAP News story "Undetected H5N1 cases seem few, but questions persist"