No abstract

Dengue, a mosquito-borne virus of humans, infects over 50 million people annually. Infection with any of the four dengue serotypes induces protective immunity to that serotype, but does not confer long-term protection against infection by other serotypes. The immunological interactions between serotypes are of central importance in understanding epidemiological dynamics and anticipating the impact of dengue vaccines. We analysed a 38-year time series with 12 197 serotyped dengue infections from a hospital in Bangkok, Thailand. Using novel mechanistic models to represent different hypothesized immune interactions between serotypes, we found strong evidence that infection with dengue provides substantial short-term cross-protection against other serotypes (approx. 1–3 years). This is the first quantitative evidence that short-term cross-protection exists since human experimental infection studies performed in the 1950s. These findings will impact strategies for designing dengue vaccine studies, future multi-strain modelling efforts, and our understanding of evolutionary pressures in multi-strain disease systems.

Please cite this paper as: Simmerman et al. (2011) Findings from a household randomized controlled trial of hand washing and face masks to reduce influenza transmission in Bangkok, Thailand. Influenza and Other Respiratory Viruses 5(4), 256–267 Background  Evidence is needed on the effectiveness of non‐pharmaceutical interventions (NPIs) to reduce influenza transmission. Methodology  We studied NPIs in households with a febrile, influenza‐positive child. Households were randomized to control, hand washing (HW), or hand washing plus paper surgical face masks (HW + FM) arms. Study nurses conducted home visits within 24 hours of enrollment and on days 3, 7, and 21. Respiratory swabs and serum were collected from all household members and tested for influenza by RT‐PCR or serology. Principal Findings  Between April 2008 and August 2009, 991 (16·5%) of 5995 pediatric influenza‐like illness patients tested influenza positive. Four hundred and forty‐two index children with 1147 household members were enrolled, and 221 (50·0%) were aged <6 years. Three hundred and ninety‐seven (89·8%) households reported that the index patient slept in the parents’ bedroom. The secondary attack rate was 21·5%, and 56/345 (16·3%; 95% CI 12·4–20·2%) secondary cases were asymptomatic. Hand‐washing subjects reported 4·7 washing episodes/day, compared to 4·9 times/day in the HW + FM arm and 3·9 times/day in controls (P = 0·001). The odds ratios (ORs) for secondary influenza infection were not significantly different in the HW arm (OR = 1·20; 95% CI 0·76–1·88; P‐0.442), or the HW + FM arm (OR = 1·16; 95% CI .0·74–1·82; P = 0.525). Conclusions  Influenza transmission was not reduced by interventions to promote hand washing and face mask use. This may be attributable to transmission that occurred before the intervention, poor facemask compliance, little difference in hand‐washing frequency between study groups, and shared sleeping arrangements. A prospective study design and a careful analysis of sociocultural factors could improve future NPI studies.

Analyzing data from Thailand's 72 provinces, Derek Cummings and colleagues find that decreases in birth and death rates can explain the shift in age distribution of dengue hemorrhagic fever.

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to two years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogenous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV.

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.

BackgroundIt is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention in Bangkok, Thailand.Methodology/Principal FindingsProspective studies were conducted from 1994 to 2006. Univariate and multivariate logistic and multinomial logistic regressions were used to determine if dengue hemorrhagic fever (DHF) and signs of severe clinical disease (pleural effusion, ascites, thrombocytopenia, hemoconcentration) were associated with serotype. Crude and adjusted odds ratios were calculated. There were 162 (36%) cases with DENV-1, 102 (23%) with DENV-2, 123 (27%) with DENV-3, and 64 (14%) with DENV-4. There was no significant difference in the rates of DHF by serotype: DENV-2 (43%), DENV-3 (39%), DENV-1 (34%), DENV-4 (31%). DENV-2 was significantly associated with increased odds of DHF grade I compared to DF (OR 2.9 95% CI 1.1, 8.0), when using DENV-1 as the reference. Though not statistically significant, DENV-2 had an increased odds of total DHF and DHF grades II, III, and IV. Secondary serologic response was significantly associated with DHF (OR 6.2) and increased when considering more severe grades of DHF. DENV-2 (9%) and -4 (3%) were significantly less often associated with primary disease than DENV-1 (28%) and -3 (33%). Restricting analysis to secondary cases, we found DENV-2 and DENV-3 to be twice as likely to result in DHF as DEN-4 (p = 0.05). Comparing study years, we found the rate of DHF to be significantly less in 1999, 2000, 2004, and 2005 than in 1994, the study year with the highest percentage of DHF cases, even when controlling for other variables.Conclusions/SignificanceAs in other studies, we find secondary disease to be strongly associated with DHF and with more severe grades of DHF. DENV-2 appears to be marginally associated with more severe dengue disease as evidenced by a significant association with DHF grade I when compared to DENV-1. In addition, we found non-significant trends with other grades of DHF. Restricting the analysis to secondary disease we found DENV-2 and -3 to be twice as likely to result in DHF as DEN-4. Differences in severity by study year may suggest that other factors besides serotype play a role in disease severity.

BackgroundDengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Inapparent dengue is an important component of the overall burden of dengue infection. It provides a source of infection for mosquito transmission during the course of an epidemic, yet by definition is undetected by health care providers. Previous studies of inapparent or subclinical infection have reported varying ratios of symptomatic to inapparent dengue infection.Methodology/Principal FindingsIn a prospective study of school children in Northern Thailand, we describe the spatial and temporal variation of the symptomatic to inapparent (S:I) dengue illness ratio. Our findings indicate that there is a wide fluctuation in this ratio between and among schools in a given year and within schools over several dengue seasons. The most important determinants of this S:I ratio for a given school were the incidence of dengue infection in a given year and the incidence of infection in the preceding year. We found no association between the S:I ratio and age in our population.Conclusions/SignificanceOur findings point to an important aspect of virus-host interactions at either a population or individual level possibly due to an effect of heterotypic cross-reactive immunity to reduce dengue disease severity. These findings have important implications for future dengue vaccines.