Natural History of Dengue Virus (DENV)–1 and DENV‐4 Infections: Reanalysis of Classic Studies

BACKGROUND: The natural history of wild-type dengue virus (DENV) infections of humans, including incubation and infectious periods, requires further study. METHODS: Two experimental studies in the Philippines of DENV-4 (1924-1925) and DENV-1 (1929-1930) were reexamined. The intrinsic incubation periods were fitted to log-normal distribution using the maximum likelihood method, and the infectious and extrinsic incubation periods were assessed by proportions of successful transmissions causing clinically apparent dengue. Correlations between the intrinsic incubation period and other variables and univariate associations between clinical severity and serotype were also examined. RESULTS: Mean+/-SD incubation periods were 6.0+/-1.4 and 5.7+/-1.5 days for DENV-4 and DENV-1, respectively. Significant negative correlations were observed between the incubation period and duration of fever (r=-0.43 and -0.33). Even 1 and 2 days before the onset of fever, 80.0% (95% confidence interval CI, 44.9%-100%) and 25.0% (CI, 0%-67.4%) of biting experiments caused clinically apparent dengue. DENV-1 infections resulted in a significantly longer duration of fever than DENV-4 infections (P<.01). CONCLUSIONS: Incubation period was negatively correlated with disease severity, potentially reflecting a dose-response mechanism. The historical data provided useful details concerning serotype differences in the natural history of primary DENV infections.