Analysis of Repeat Hospital Admissions for Dengue to Estimate the Frequency of Third or Fourth Dengue Infections Resulting in Admissions and Dengue Hemorrhagic Fever, and Serotype Sequences

Abstract

Immunity to a single dengue virus (DENV) infection does not provide heterologous immunity to subsequent infection. In fact, the greatest risk for dengue hemorrhagic fever (DHF) is with a second DENV serotype exposure. The risk for DHF with a third or fourth dengue infection relative to a first or second exposure is not known. An analysis of our database of children admitted to the Queen Sirikit National Institute of Child Health and Kamphaeng Phet Provincial Hospital with suspected dengue illness revealed that the number of dengue admissions caused by a third or fourth DENV infection was extremely low (0.08-0.8%). Once admitted, the risk for DHF relative to dengue fever was not different for those experiencing third or fourth DENV infections over those experiencing a second DENV infection. We document new dengue serotype infection sequences leading to DHF of 1-4, 2-3, 3-1, and 3-4.

Variation in Inflammatory/Regulatory Cytokines in Secondary, Tertiary, and Quaternary Challenges with Dengue Virus

“…20 However, there are few studies on the incidence of dengue disease after a third or fourth dengue infection. [21][22][23] Data presented compare the inflammatory/anti-inflammatory response after primary, secondary, tertiary, and quaternary challenge. Our results confirm that primary dengue challenge induces TNF-α, IFN-γ, IL-10, and TGF-β expression at early stages after infection, but notably lower than the secondary exposure.…”

“…It is believed that after a secondary dengue infection, a heterologous protective immunity is raised and the threat of dengue is reduced, although there are reports of possible tertiary infection resulting in DHF. 21,22 Havana has a unique epidemiologic dengue situation in which residents could have had immunity to two of the four dengue viruses before the DENV-3 epidemic in 2001-2002. DENV-1 circulated in 1977-1979 7 and DENV-2 infections occurred in 1981.…”

The pathogenesis of dengue

“…[34][35][36][37][38] Third, or even fourth infections also probably occur in endemic settings, but hospital data and the age-related burden of dengue (children) suggests the vast majority of these tertiary or quaternary infections are clinically silent or very mild. 39 The leading explanation for increased risk of disease in secondary infection is that non-neutralising, crossreactive antibodies elicited by a primary infection bind the virus which then have greater potential to infect Fc-receptor bearing cells. This phenomenon, called antibody-dependent enhancement (ADE), potentially increases the risks of developing severe disease by virtue of increasing the number of virus infected cells and therefore the viral biomass in vivo.…”

Environmental influences on antibody-enhanced dengue disease outcomes

“…In addition, an analysis of repeated hospital admissions for dengue showed that at least 10% of repeat dengue admission patients may correspond to a third or fourth infection with all secondary admissions due to secondary dengue infection (Gibbons et al 2007). Because most DENV infections are asymptomatic, it is reasonable to assume that a number of patients from endemic areas hospitalised with severe dengue disease may have been exposed to multiple infections.…”