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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 ⩾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

Dengue is a well-documented public-health burden in many developing countries [1, 2]. Any of the 4 serotypes of dengue virus (DENV)—DENV1-DENV4—can cause a spectrum of outcomes in humans, ranging from asymptomatic infection to clinically significant disease. Severe disease is called “dengue hemorrhagic fever” (DHF) and is characterized by systemic capillary leakage, thrombocytopenia, and, in severe cases, hypovolemic shock. Substantial epidemiological evidence indicates that DHF in children and adults is typically associated with secondary infection caused by a DENV serotype distinct from that present when an individual is first exposed to DENV [3-6]. In contrast, DHF also occurs in primary DENV infections in infants born to dengue-immune mothers [7, 8]. A unifying hypothesis that explains the age-related epidemiology of DHF is a process called “antibody-dependent enhancement” (ADE) of disease [9]. The ADE model postulates that cross-reactive but subneutralizing levels of DENV-reactive IgG, acquired either passively or because of a previous infection, enhance DENV’s infectivity of Fc receptor-bearing cells. ADE could conceptually result in higher viral burdens in vivo and thereby precipitate some of the clinical events in dengue. Consistent with this model, children with secondary infections and DHF have higher initial plasma viral loads [10-12]. DHF in secondary infections is also associated with both significantly greater plasma concentrations of inflammatory cytokines [13-15] and increased frequencies of activated lymphocytes, compared with those in patients with milder disease [16, 17], presumably in response to higher viral burdens in DHF. Although much less is known about the pathogenesis of dengue in infants, previous studies by our group have suggested that, at least at the time of study enrollment, viral parameters are not associated with disease severity [8]. A critical challenge in dengue pathogenesis and vaccinology is to determine whether the biological character of ADE when measured in vitro can be correlated with disease outcomes and/or epidemiology. Previous prospective studies of children that have attempted to link the ADE phenomenon with disease outcomes in secondary infection but that have employed different methodologies have yielded conflicting results [18, 19]. Kliks et al. have described, in primary infections, a correlation between ADE activity in diluted maternal serum and the age at DHF onset in 13 Thai infants [20]. Against this backdrop, the aim of the present study was to correlate ADE with disease epidemiology in infants and to determine whether innate or acquired immune responses in infants with dengue, responses possibly triggered by ADE-mediated DENV infection, would correlate with disease severity. Our findings are consistent with the notion that infection-enhancing antibody plays a role in the pathogenesis of DHF in infants. Furthermore, we identified aspects of the infant innate and acquired immune response that are associated with disease severity.

Dengue hemorrhagic fever (DHF) is a serious public health problem. Increased vascular permeability and thrombocytopenia are the hallmarks of DHF. The mechanisms involved in DHF/Dengue shock syndrome (DSS) pathogenesis is not fully understood. This study gives evidence of the presence of antibodies which cross-reacted with platelets, and endothelial cells in the sera of Vietnamese infants and children with DHF/DSS. The anti-platelet, anti-endothelial cell IgM levels were higher in the sera of DHF/DSS infants and children, compared with controls. However, the levels of these autoantibodies were not correlated with the severity of DHF (non-shock DHF vs DSS). The antiplatelet, and anti-endothelial cell autoantibodies may play a role in the pathogenesis of DHF/DSS in infants and children with predominantly primary, and secondary dengue infections, respectively. The epitopes shared by surface molecules of platelets and endothelial cells and dengue virus antigens need to be identified and avoided in designing the safe candidate vaccines.

Supplemental Digital Content is available in the text., Background: Understanding viral etiology and age-specific incidence of acute respiratory infections in infants can help identify risk groups and inform vaccine delivery, but community-based data is lacking from tropical settings. Methods: One thousand four hundred and seventy-eight infants in urban Ho Chi Minh City and 981 infants in a semi-rural district in southern Vietnam were enrolled at birth and followed to 1 year of age. Acute respiratory infection (ARI) episodes were identified through clinic-based illness surveillance, hospital admissions and self-reports. Nasopharyngeal swabs were collected from infants with respiratory symptoms and tested for 14 respiratory pathogens using multiplex reverse transcription-polymerase chain reaction. Results: Estimated incidence of ARI was 542 and 2691 per 1000 infant-years, and hospitalization rates for ARI were 81 and 138 per 1000 infant-years, in urban and semi-rural cohorts, respectively, from clinic- and hospital-based surveillance. However self-reported ARI episodes were just 1.5-fold higher in the semi-rural versus urban cohort, indicating that part of the urban–rural difference was explained by under-ascertainment in the urban cohort. Incidence was higher in infants ≥6 months of age than

A prospective study of clinical and cytokine profiles of 107 infants with dengue hemorrhagic fever (DHF)/ dengue shock syndrome (DSS) was conducted. Fever petechiae on the skin and hepatomegaly were the most common clinical findings associated with DHF/DSS in infants. DSS occurred in 20.5% of the patients. Hemoconcentration and thrombocytopenia were observed in 91.5% and 92.5% of the patients respectively. Serologic testing revealed that almost all of the patients (95.3%) had primary dengue virus infections. These data demonstrate that clinical and laboratory findings of DHF/DSS in infants are compatible with the World Health Organization’s clinical diagnostic criteria for pediatric DHF. The present study is the first to report evidence of production of cytokines in infants with DHF/DSS and to describe the difference between the cytokine profile of infants with primary dengue virus infections and children with secondary infections. Overproduction of both proinflammatory cytokines (interferon-t and tumor necrosis factor–a) and anti-inflammatory cytokines (interleukin-10 and -6) may play a role in the pathogenesis of DHF/DSS in infants. (authors)

BACKGROUND: In Ho Chi Minh City, Vietnam, more than one-third of admissions to the two paediatric hospitals are attributable to four infectious syndromes: dengue, diarrhoeal disease, acute respiratory infection, and hand, foot and mouth disease. We have established a large prospective birth cohort study to investigate individual, environmental, virological, and immunological determinants of infection and disease in infants. Specific research questions are focused on the role of maternal antibody in protection against infection in infancy, and the adaptive immune response to vaccination and natural infection. This paper presents the cohort design, methods, and baseline characteristics of the participants enrolled in the first two years. METHODS/DESIGN: Women are enrolled prior to delivery at one hospital in each of two catchment areas: an urban district in central HCMC, and a mixed urban/rural district in the Mekong Delta 150 km southwest of HCMC. Infants are enrolled within 3 days of birth, and maternal and cord blood samples are collected. Routine blood samples and data on growth, health status and vaccinations are collected from infants at scheduled visits at 4, 9 and 12 months. Clinical data and specimens are collected from infants presenting at a study clinic, or admitted to hospital, with any of the the four infectious syndromes of interest. DISCUSSION: In four years since since the study began in July 2009, >6400 infants have been enrolled, and enrolment is ongoing. Attrition is low: 84% of participants have completed the full 12-month follow-up period. Baseline characteristics of the first 4300 enrollees are presented here. We have demonstrated the feasibility of establishing a large prospective study of infectious diseases in infancy in a resource-limited setting, with minimal loss to follow-up. Our linked socio-demographic, clinical and laboratory data will help elucidate the viral aetiology and epidemiology of common infectious diseases of infancy, and can inform the implemention of existing and future vaccines. This study furthermore provides a platform to which additional endpoints could be added in the future.

The paper by Thac et al. is an important paper from the point of view of health care providers and policy makers in the context of Integrated Management of Childhood Illnesses (IMCI) in developing countries like India [1]. IMCI is an integrated approach which includes three main components [2]: Improving case management skills of health-care staff. Improving overall health systems. Improving family and community health practices. The paper highlights the importance of the third and valuable component of IMCI, that is, “improving family and community health practices” by health education of mothers of under-five children. The figures mentioned in the paper clearly show that it is successful in achieving this third component. India has made notable strides in tackling neonatal and childhood illnesses through a number of initiatives. These are in the form of addition of neonatal component in IMCI (IMNCI), training of community level grass-root workers such as Accredited Social Health Activists (ASHA) and Anganwadi Workers (AWW), Home Based Neonatal Care (HBNC), facility based IMNCI, infant and young child feeding practices (IYCF), and Rashtriya Bal Swasthya Karyakram (RBSK) to name a few [3]. Health education and training of grass-root workers are being done in India, but organized component of health education of mothers needs to be incorporated for improving health practices at family and community level. This can be systematically introduced at national level using the community based platforms of Village Health Sanitation and Nutrition Committees (VHSNC) and Mahila Arogya Samitis (MAS) in India.

The pathogenesis of dengue in infants is poorly understood. We postulated that dengue severity in infants would be positively associated with markers of viral burden and that maternally derived, neutralizing anti-dengue antibody would have decayed before the age at which infants with dengue presented to the hospital. In 75 Vietnamese infants with primary dengue, we found significant heterogeneity in viremia and NS1 antigenemia at hospital presentation, and these factors were independent of disease grade or continuous measures of disease severity. Neutralizing antibody titers, predicted in each infant at the time of their illness, suggested that the majority of infants (65%) experienced dengue hemorrhagic fever when the maternally derived neutralizing antibody titer had declined to