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American Journal of Epidemiology Advance Access originally published online on January 29, 2008
American Journal of Epidemiology 2008 167(7):775-785; doi:10.1093/aje/kwm375
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American Journal of Epidemiology © 2008 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Fabrice Carrat1,2,3, Elisabeta Vergu1,2,4, Neil M. Ferguson5, Magali Lemaitre1,2, Simon Cauchemez5, Steve Leach6 and Alain-Jacques Valleron1,2,3

1 Université Pierre et Marie Curie-Paris6, UMR-S 707, Paris, France
2 INSERM, UMR-S 707, Paris, France
3 Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
4 Mathématiques et Informatique Appliqués Unit, Institut National de la Recherche Agronomique, Jouy-en-Josas, France
5 Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, United Kingdom
6 Health Protection Agency, Centre for Emergency Preparedness and Response, Porton Down, Salisbury, Wiltshire, United Kingdom

Correspondence to Dr. F. Carrat, Epidémiologie, Systèmes d'Information, Modélisation, UMR-S 707, Faculté de médecine Saint-Antoine, 27, rue Chaligny, 75571, Paris Cedex 12, France (e-mail: carrat{at}u707.jussieu.fr).

Received for publication September 20, 2007. Accepted for publication November 30, 2007.

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.

influenza, human; signs and symptoms; virus shedding

Abbreviations: CI, confidence interval; GEE, generalized estimating equations; HAI, hemagglutination inhibition; SD, standard deviation

Editor's note: References 83–111 are cited in the Web-only Supplementary Material posted on the Journal's website (http://aje.oxfordjournals.org/).


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