Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project

Abstract

BackgroundDengue has emerged as the most important vector-borne viral disease in tropical areas. Evaluations of the burden and severity of dengue disease have been hindered by the frequent lack of laboratory confirmation and strong selection bias toward more severe cases.MethodologyA multinational, prospective clinical study was carried out in South-East Asia (SEA) and Latin America (LA), to ascertain the proportion of inapparent dengue infections in households of febrile dengue cases, and to compare clinical data and biological markers from subjects with various dengue disease patterns. Dengue infection was laboratory-confirmed during the acute phase, by virus isolation and detection of the genome. The four participating reference laboratories used standardized methods.Principal FindingsAmong 215 febrile dengue subjects—114 in SEA and 101 in LA—28 (13.0%) were diagnosed with severe dengue (from SEA only) using the WHO definition. Household investigations were carried out for 177 febrile subjects. Among household members at the time of the first home visit, 39 acute dengue infections were detected of which 29 were inapparent. A further 62 dengue cases were classified at early convalescent phase. Therefore, 101 dengue infections were found among the 408 household members. Adding these together with the 177 Dengue Index Cases, the overall proportion of dengue infections among the study participants was estimated at 47.5% (278/585; 95% CI 43.5–51.6). Lymphocyte counts and detection of the NS1 antigen differed significantly between inapparent and symptomatic dengue subjects; among inapparent cases lymphocyte counts were normal and only 20% were positive for NS1 antigen. Primary dengue infection and a specific dengue virus serotype were not associated with symptomatic dengue infection.ConclusionHousehold investigation demonstrated a high proportion of household members positive for dengue infection, including a number of inapparent cases, the frequency of which was higher in SEA than in LA.

Comparison of Seven Commercial Antigen and Antibody Enzyme-Linked Immunosorbent Assays for Detection of Acute Dengue Infection

“…Previous studies examining variation in serotype detection by the Standard Diagnostics (24) and Panbio/Bio-Rad Platelia (12) NS1 ELISAs reported generally higher sensitivities than those presented here. Interestingly, the Bio-Rad and Standard Diagnostics NS1 antigen ELISAs had relatively low sensitivities for dengue virus serotype 2 compared to previously reported sensitivities of the Bio-Rad assay for the other serotypes (7), which is significant as serotype 2 is highly prevalent in both the Americas and Asia (1,8,10,21).…”

Dengue and Other Common Causes of Acute Febrile Illness in Asia: An Active Surveillance Study in Children

“…Sensitivity of NS1 testing is directly related to the viral load, and thus the time since the start of viral replication: the mean duration of fever at the time of sampling was 2.4 days. Although the NS1 antigen test used in this study to test for laboratory-confirmed dengue has high specificity [18], [27], DENV-2 infections have been associated with significantly lower plasma NS1 levels relative to DENV-1 or DENV-3 infections [28]. In addition, a lower sensitivity for this test has been reported for secondary infections and, in dengue-endemic areas (such as those where this study was conducted), a higher proportion of patients have secondary infections [27].…”

Symptomatic Versus Inapparent Outcome in Repeat Dengue Virus Infections Is Influenced by the Time Interval between Infections and Study Year

“…In one of the first prospective dengue cohort studies in Bangkok, Thailand [9], and in a multinational index cluster study with four sites in South-East Asia and Latin America [14], the inapparent-to-symptomatic ratio was similar in primary and secondary infections. We also previously reported similar ratios in primary and secondary DENV infections in Managua, Nicaragua [15].…”