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Their demographic, serological, and clinical characteristics are shown in Table?1

Their demographic, serological, and clinical characteristics are shown in Table?1. was used for continuous variables. Multivariate logistic regression was used to assess risk factors for contamination outcomes. Results Of 38,740 DENV infections, two or more infections were detected in 502 individuals; 14 had three infections. The mean ages at the time of the first and second detected infections were 7.6??3.0 and 11.2??3.0?years. The shortest time between sequential infections was 66?days. A longer time interval between sequential infections 4-Hydroxyisoleucine was associated with dengue hemorrhagic fever (DHF) in the second detected contamination (OR 1.3, 95% CI 1.2-1.4). All possible sequential serotype pairs were observed among 201 subjects with DHF at the second detected contamination, except DENV-4 followed 4-Hydroxyisoleucine by DENV-3. Among DENV infections detected in cohort subjects by active study surveillance and subsequent non-study hospital-based passive surveillance, hospitalization at the first detected contamination increased the likelihood of hospitalization at the second detected contamination. Conclusions Increasing time between sequential DENV infections was associated with greater severity of the second detected contamination, supporting the role of heterotypic immunity in both protection and enhancement. Hospitalization was positively associated between 4-Hydroxyisoleucine the first and second detected infections, suggesting a possible predisposition in some individuals to more severe dengue disease. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-1590-z) contains supplementary material, which is available to authorized users. Background Dengue is usually a globally important, re-emerging infectious disease caused by one 4-Hydroxyisoleucine of four dengue computer virus serotypes (DENV-1 to DENV4) with a high degree of antigenic cross-reactivity. It is estimated that 390 million infections occur annually, with approximately 96 million resulting in clinically apparent disease [1]. DENV infections can lead to diverse outcomes, including subclinical 4-Hydroxyisoleucine contamination, clinically non-specific illness, dengue fever (DF), and dengue hemorrhagic fever (DHF). Many studies have shown that the risk of DHF in non-infant patients is greater when an initial DENV contamination is followed by a second contamination with a different serotype [2-7]. All possible orders of infecting serotypes have been documented in patients with DHF except DENV-4 followed by DENV-1 or DENV-3 [8]. In some populations, reports indicate that DHF occurs more frequently with DENV-2 or DENV-3 infections in DENV-1 uncovered individuals [9,10]. One mechanism underlying this observation has been postulated to be antibody-dependent enhancement (ADE) during the second contamination mediated by non-protective heterotypic antibodies arising from the first contamination. However, the timing of the second contamination seems to be important since some degree of short-term protection may be conferred against subsequent heterologous contamination by the preceding contamination [11]. In a populace model of children hospitalized with dengue in Bangkok, Thailand, the length of this short-term heterologous protection was estimated to be one to three years [12]. Longer intervals between heterologous infections seem to increase susceptibility to DHF. An evaluation of dengue cases from outbreaks in Cuba in 1981 and 1997 suggest that a longer period between infections increases the risk of DHF [13]. In an analysis of repeat DENV infections from a prospective cohort study of children in Kamphaeng Phet, Thailand, the ratio of symptomatic to subclinical infections was found to be higher when the time from first to second contamination was longer [14]. Some studies have suggested that sequential contamination with two Alas2 different serotypes may induce sufficient cross-immunity to confer some degree of protection from a third or fourth serotype. Primate studies have suggested that multivalent neutralizing antibodies after two DENV infections reduce the risk of detectable viremia from subsequent heterologous contamination [15-18]. Among thousands of children hospitalized with dengue in Bangkok, Thailand, the number of known third and fourth infections was found to be less than the number of known second infections indicating some level of multivalent protection after two heterologous infections [8]. Interestingly, in this same populace of hospitalized children, the ratio of DHF to DF with known second infections was no different than with known third or fourth infections. In an analysis of a prospective cohort from Iquitos, Peru, presumed second infections.