Background: It has been suggested that the true case-fatality rate of human H5N1 influenza infection is appreciably less than the figure of approximately 60% that is based on official World Health Organization (WHO)-confirmed case reports because asymptomatic cases may have been missed. A number of seroepidemiologic studies have been conducted in an attempt to identify such missed cases.

Methods: We conducted a comprehensive literature review of all English-language H5N1 human serology surveys with detailed attention to laboratory methodology used (including whether investigators used criteria set by the WHO to define positive cases), laboratory controls used, and the clades/genotypes involved.

Results: Twenty-nine studies were included in the analysis. Few reported using unexposed control groups and one-third did not apply WHO criteria. Of studies that used WHO criteria, only 4 found any seropositive results to clades/genotypes of H5N1 that are currently circulating. No studies reported seropositive results to the clade 2/genotype Z viruses that have spread throughout Eurasia and Africa.

Conclusions: This review suggests that the frequency of positive H5 serology results is likely to be low; therefore, 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.