Review Article: The Fraction of Influenza Virus Infections That Are Asymptomatic: A Systematic Review and Meta-analysis

Abstract

Background: The fraction of persons with influenza virus infection, who do not report any signs or symptoms throughout the course of infection is referred to as the asymptomatic fraction.

Methods: We conducted a systematic review and meta-analysis of published estimates of the asymptomatic fraction of influenza virus infections. We found that estimates of the asymptomatic fraction were reported from two different types of studies: first, outbreak investigations with short-term follow-up of potentially exposed persons and virologic confirmation of infections; second, studies conducted across epidemics typically evaluating rates of acute respiratory illness among persons with serologic evidence of infection, in some cases adjusting for background rates of illness from other causes.

Results: Most point estimates from studies of outbreak investigations fell in the range 4%-28% with low heterogeneity (I = 0%) with a pooled mean of 16% (95% confidence interval = 13%, 19%). Estimates from the studies conducted across epidemics without adjustment were very heterogeneous (point estimates 0%-100%; I = 97%), while estimates from studies that adjusted for background illnesses were more consistent with point estimates in the range 65%-85% and moderate heterogeneity (I = 58%). Variation in estimates could be partially explained by differences in study design and analysis, and inclusion of mild symptomatic illnesses as asymptomatic in some studies.

Conclusions: Estimates of the asymptomatic fraction are affected by the study design, and the definitions of infection and symptomatic illness. Considerable differences between the asymptomatic fraction of infections confirmed by virologic versus serologic testing may indicate fundamental differences in the interpretation of these two indicators.

Figure 1

Flow diagram of the process and results of study selection.

Figure 2

Forest plot of estimates of the asymptomatic fraction (‘Estimate’), stratified by study design. Panel A: estimates from outbreak investigations in which potentially exposed individuals were followed intensively for a short time and infections were typically confirmed by virologic methods. Panel B and C: estimates from cohort studies in which individuals were followed across entire influenza seasons, and numbers of illnesses assessed in individuals with serologic evidence of infection. Estimates in Panel B were adjusted for rates of symptomatic illness in uninfected persons, and not adjusted in Panel C. Footnotes: The values for 95% confidence interval (“95% CI”) were either supplied from the articles (black) or derived from the point estimates (grey). We cannot derive the 95% CI for Monto et al. (34) as the number of individuals who were asymptomatic among infected was not provided. If individual estimates for different subtypes of influenza A virus (a–d) or populations (i–ii) from the same study were provided, they were presented separately. Studies by Thai et al. (27) and Horby et al. (35) were conducted in the same cohort of subjects (#). For some of the studies estimates of the asymptomatic fractions and counts were extracted differently from what was reported (``) and justifications were given in Table 1. Some studies reported estimates of the asymptomatic fractions with denominator based on person-season of follow up (^). The column “Adjusted” indicates whether estimate of the asymptomatic fraction was adjusted (Y) for rates of symptomatic illness in uninfected persons or not (N), or although not adjusted a separate estimate of the asymptomatic fraction was reported for individuals without evidence of laboratory-confirmed influenza virus infections (C). Remarks for each individual study are included in Table 1. Abbreviations. PCR: reverse transcriptase polymerase chain reaction; HI: hemagglutination-inhibition assay; MN: microneutralization assay; CF: complement fixation assay; culture: viral culture; paired sera: the corresponding serologic assay (HI, MN or CF as indicated) was conducted in baseline and convalescent sera; single serum: the corresponding serologic assay was conducted in a single serum specimen; +ve: positive.