Time Lines of Infection and Disease in Human Influenza: A Review of Volunteer Challenge Studies

Abstract

The dynamics of viral shedding and symptoms following influenza virus infection are key factors when considering epidemic control measures. The authors reviewed published studies describing the course of influenza virus infection in placebo-treated and untreated volunteers challenged with wild-type influenza virus. A total of 56 different studies with 1,280 healthy participants were considered. Viral shedding increased sharply between 0.5 and 1 day after challenge and consistently peaked on day 2. The duration of viral shedding averaged over 375 participants was 4.80 days (95% confidence interval: 4.31, 5.29). The frequency of symptomatic infection was 66.9% (95% confidence interval: 58.3, 74.5). Fever was observed in 37.0% of A/H1N1, 40.6% of A/H3N2 (p = 0.86), and 7.5% of B infections (p = 0.001). The total symptoms scores increased on day 1 and peaked on day 3. Systemic symptoms peaked on day 2. No such data exist for children or elderly subjects, but epidemiologic studies suggest that the natural history might differ. The present analysis confirms prior expert opinion on the duration of viral shedding or the frequency of asymptomatic influenza infection, extends prior knowledge on the dynamics of viral shedding and symptoms, and provides original results on the frequency of respiratory symptoms or fever.

Estimation of influenza‐attributable medically attended acute respiratory illness by influenza type/subtype and age, Germany, 2001/02–2014/15

“…What this study adds is the additional information of the comprehensive burden of all‐influenza cases in primary care, be they mild or more severe, not only by age, but also by type/subtype, over a long time period. It is interesting that the “typical” pattern of influenza B shows a substantially higher relative iMAARI attack rate among school‐age children5, 6, 7, 8, 9, 10, 11, 12, 13, 14 compared to that in age group 0‐4 (Figure 5, right panel), although in absolute terms the attack rate among 5‐ to 14‐year‐old children is comparable to that caused by A(H3N2). This striking characteristic of influenza B concurs with data from two serological studies, one from the Netherlands and one from Germany, which investigated the seroprevalence of antibodies against influenza virus types and subtypes by year of age among children 17, 18.…”

“…Similarly, in the three seasons following the pandemic, influenza‐associated consultations by patients with ILI were estimated in a population‐based surveillance project in 13 US health jurisdictions as 0.7%, 0.2% and 1.1% 16. Given that only between 30% and 80% of all influenza cases manifest themselves as ILI5, 6, 7, 8 and in the same year influenza seasons may be quite different in different countries, the estimated 2.6%, 1.0% and 8.9% in our study lie in a comparable magnitude as the US data. We believe that our combination of surveillance (using ARI data) followed by modelling estimates the population impact of influenza more realistically than sentinel systems that use ILI data.…”

“…As a result, ILI case definitions are more specific, but less sensitive compared to ARI, and as a corollary surveillance systems using ILI see more pronounced illness waves and peaks during influenza epidemics. However, because only a portion of all symptomatic influenza cases are captured by ILI case definitions,1, 5, 6, 7, 8, 9 ILI surveillance systems are less well suited to describe and capture the burden of disease of influenza.…”

Estimating influenza incidence and rates of influenza‐like illness in the outpatient setting

“…Patient records with missing RT‐PCR results or no report of fever were excluded from analysis. Patients with specimens collected more than 5 days after onset were also excluded due to a loss of viral detectability after 5 days 7 , 8 …”

Epidemiology of influenza B in Australia: 2001‐2014 influenza seasons

“…Studies have shown controversial findings of clinical features in cases infected with A and B infections 21, 22, 23. In both paediatric and adult populations, patients with influenza B infection showed similar clinical features compared with influenza A 22, 24, 25, 26.…”