Dengue virus infections and maternal antibody decay in a prospective birth cohort study of Vietnamese infants.

Dengue hemorrhagic fever can occur in primary dengue virus (DENV) infection of infants. The decay of maternally derived DENV immunoglobulin (Ig) G and the incidence of DENV infection were determined in a prospectively studied cohort of 1244 Vietnamese infants. Higher concentrations of total IgG and DENV-reactive IgG were found in cord plasma relative to maternal plasma. Maternally derived DENV-neutralizing and E protein-reactive IgG titers declined to below measurable levels in >90% of infants by 6 months of age. In contrast, IgG reactive with whole DENV virions persisted until 12 months of age in 20% of infants. Serological surveillance identified 10 infants with asymptomatic DENV infection for an incidence of 1.7 cases per 100 person-years. DENV-neutralizing antibodies remained measurable for > or = 1 year after infection. These results suggest that whereas DENV infection in infants is frequently subclinical, there is a window between 4 and 12 months of age where virion-binding but nonneutralizing IgG could facilitate antibody-dependent enhancement

Clinical and virological features of Dengue in Vietnamese infants

BACKGROUND: Infants account for a small proportion of the overall dengue case burden in endemic countries but can be clinically more difficult to manage. The clinical and laboratory features in infants with dengue have not been extensively characterised. METHODOLOGY/PRINCIPAL FINDINGS: This prospective, cross-sectional descriptive study of infants hospitalized with dengue was conducted in Vietnam from November 2004 to December 2007. More than two-thirds of 303 infants enrolled on clinical suspicion of dengue had a serologically confirmed dengue virus (DENV) infection. Almost all were primary dengue infections and 80% of the infants developed DHF/DSS. At the time of presentation and during hospitalization, the clinical signs and symptoms in infants with dengue were difficult to distinguish from those with other febrile illnesses, suggesting that in infants early laboratory confirmation could assist appropriate management. Detection of plasma NS1 antigen was found to be a sensitive marker of acute dengue in infants with primary infection, especially in the first few days of illness. CONCLUSIONS/SIGNIFICANCE: Collectively, these results provide a systematic description of the clinical features of dengue in infants and highlight the value of NS1 detection for diagnosis

Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.

The pathogenesis of severe dengue is not well understood. Maternally derived subneutralizing levels of dengue virus-reactive IgG are postulated to be a critical risk factor for severe dengue during infancy. In this study, we found that, in healthy Vietnamese infants, there was a strong temporal association between the Fc-dependent, dengue virus infection-enhancing activity of neat plasma and the age-related epidemiology of severe dengue. We then postulated that disease severity in infants with primary infections would be associated with a robust immune response, possibly as a consequence of higher viral burdens in vivo. Accordingly, in infants hospitalized with acute dengue, the activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells correlated with overall disease severity, but HLA-A*1101-restricted NS3(133-142)-specific CD8+ T cells were not measurable until early convalescence. Plasma levels of cytokines/chemokines were generally higher in infants with dengue shock syndrome. Collectively, these data support a model of dengue pathogenesis in infants whereby antibody-dependent enhancement of infection explains the age-related case epidemiology and could account for antigen-driven immune activation and its association with disease severity. These results also highlight potential risks in the use of live attenuated dengue vaccines in infants in countries where dengue is endemic

Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23–1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75–0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue. </p