Time Lines of Infection and Disease in Human Influenza
Time Lines of Infection and Disease in Human Influenza
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.
The threat of a human influenza pandemic has dramatically increased in recent years, and many countries have now developed pandemic preparedness plans following World Health Organization guidelines. Measures to reduce the spread of influenza within a given population, based on treatment or prophylaxis with antiviral medications, isolation, quarantine, or other social-distancing measures, are considered at various phases of the plans, as they might play a major role by reducing transmissibility. The effectiveness of these measures would depend greatly on the possibility of identifying infectious individuals and on how or when influenza virus is transmitted between individuals.
One critical question is whether the latent period overlaps the incubation period or, in other words, how onset of infectiousness overlaps onset of symptoms, if any. Another critical issue is the duration of infectiousness, which determines, among other things, the duration of treatment, prophylaxis, or isolation.
Influenza infectiousness is usually equated to the presence of virus shedding. A recent report from the World Health Organization concluded that influenza virus shedding can be detected 24–48 hours before clinical onset, and that it peaks during the first 24 hours of illness. Shedding usually lasts less than 5 days, but it may be higher and longer in children. The incubation period is reported to average 2 days (range: 1–4 days). These data are derived from expert opinions or may have involved observational and experimental studies without any attempt to use systematic review; they are not supported by high-quality evidence.
The frequency of asymptomatic infection is also a critical parameter for interventions involving contact tracing. Modeling studies used frequencies of between 30 percent and 50 percent. However, these percentages come from pre- and post-influenza-season serologic studies, and they may therefore be subject to recall bias when individuals were asked whether they had had influenza-like illness during winter or to classification bias due to lack of sensitivity of laboratory tests.
Experimental influenza virus infection of healthy volunteers provides a unique opportunity to describe the natural history, as 1) the date of infection is known with certainty, 2) shedding and symptoms are recorded prospectively, and 3) participants are usually selected with low pre-hemagglutination inhibition (HAI) antibody titers.
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.
The threat of a human influenza pandemic has dramatically increased in recent years, and many countries have now developed pandemic preparedness plans following World Health Organization guidelines. Measures to reduce the spread of influenza within a given population, based on treatment or prophylaxis with antiviral medications, isolation, quarantine, or other social-distancing measures, are considered at various phases of the plans, as they might play a major role by reducing transmissibility. The effectiveness of these measures would depend greatly on the possibility of identifying infectious individuals and on how or when influenza virus is transmitted between individuals.
One critical question is whether the latent period overlaps the incubation period or, in other words, how onset of infectiousness overlaps onset of symptoms, if any. Another critical issue is the duration of infectiousness, which determines, among other things, the duration of treatment, prophylaxis, or isolation.
Influenza infectiousness is usually equated to the presence of virus shedding. A recent report from the World Health Organization concluded that influenza virus shedding can be detected 24–48 hours before clinical onset, and that it peaks during the first 24 hours of illness. Shedding usually lasts less than 5 days, but it may be higher and longer in children. The incubation period is reported to average 2 days (range: 1–4 days). These data are derived from expert opinions or may have involved observational and experimental studies without any attempt to use systematic review; they are not supported by high-quality evidence.
The frequency of asymptomatic infection is also a critical parameter for interventions involving contact tracing. Modeling studies used frequencies of between 30 percent and 50 percent. However, these percentages come from pre- and post-influenza-season serologic studies, and they may therefore be subject to recall bias when individuals were asked whether they had had influenza-like illness during winter or to classification bias due to lack of sensitivity of laboratory tests.
Experimental influenza virus infection of healthy volunteers provides a unique opportunity to describe the natural history, as 1) the date of infection is known with certainty, 2) shedding and symptoms are recorded prospectively, and 3) participants are usually selected with low pre-hemagglutination inhibition (HAI) antibody titers.
