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      Serotype-Specific Differences in the Risk of Dengue Hemorrhagic Fever: An Analysis of Data Collected in Bangkok, Thailand from 1994 to 2006


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          It 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 Findings

          Prospective 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.


          As 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.

          Author Summary

          The four dengue viruses (DENV) represent the most common human arbovirus infections in the world and are currently a challenging problem, particularly in the tropical and subtropical regions of Asia and the Americas. Infection with DENV may produce symptoms of varying severity. While access to care, appropriate interventions, host genetic factors, and previous exposure to DENV are all known to affect the outcome of the infection, it is not entirely understood why some individuals develop more severe disease. It has been hypothesized that the four dengue serotypes differ in disease severity and clinical manifestations. This analysis assessed whether there were significant differences in severity of disease caused by the dengue serotypes in a pediatric population in Thailand. We found significant and non-significant correlations between dengue serotype 2 infection and more severe dengue disease. We also found that individual serotypes varied in disease severity between study years, perhaps supporting the hypothesis that the particular sequences of primary and secondary DENV infections influence disease severity.

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          Most cited references24

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          Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak.

          In January 1980, the municipal area of Rayong, Thailand, and contiguous suburban villages were chosen for a long-term study on dengue epidemiology. From 3,185 children randomly sampled in schools and households, the population prevalence of neutralizing antibody to the four dengue serotypes was estimated. To estimate the incidence of infection with each dengue virus serotype (dengue seroconversions), first grade children were re-bled in January 1981 (cohort study). Children admitted to hospital were studied for dengue virus isolation and antibody responses in paired sera. An epidemic of dengue occurred in 1980. Plaque reduction neutralization tests of 1,009 pre-epidemic sera from children aged less than 1-10 years of age determined that 3.3% were immune to dengue 1, 13.2% to dengue 2, 6.4% to dengue 3, and 5.8% to dengue 4. Examination of pre- and post-epidemic cohort blood samples revealed that the incidence of dengue infection in 251 seronegative children was 39.4% (15.1% dengue 1, 11.1% dengue 2, 2.0% dengue 3, 4.8% dengue 4, and 6.4% two or more dengue viruses). Among the 52,935 residents of the study area, there were 22 cases of virologically and clinically confirmed dengue shock syndrome, in children 15 years or younger. All 22 shock syndrome cases had secondary type antibody responses. Eight of 22 had been included in the random serologic sample prior to onset of shock; five had been immune to dengue 1, two to dengue 3, one to dengue 4, and none to dengue 2. Despite the high rate of dengue 1 infections in 1980, only dengue 2 viruses were recovered from dengue shock syndrome cases, including two dengue 1 immune children with pre-illness serum specimens. Although the pre-epidemic prevalence of antibodies to dengue 1 was the lowest to any type, children with this immunologic background contributed disproportionately to shock cases. In descending order of magnitude, risk factors for dengue shock syndrome in Rayong were secondary infections with dengue 2 which followed primary infections with dengue 1, dengue 3, or dengue 4.
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            Early clinical and laboratory indicators of acute dengue illness.

            A prospective observational study was conducted to identify early indicators of acute dengue virus infection. Children with fever for <72 h without obvious cause were studied at hospitals in Bangkok and Kamphaeng Phet, Thailand, until resolution of fever. Of 172 evaluable subjects (91% of enrollees), 60 (35%) had dengue, including 32 with dengue fever (DF) and 28 with dengue hemorrhagic fever (DHF). At enrollment, children with dengue were more likely than children with other febrile illnesses (OFI) to report anorexia, nausea, and vomiting and to have a positive tourniquet test, and they had lower total white blood cell counts, absolute neutrophil and absolute monocyte counts, and higher plasma alanine and aspartate (AST) aminotransferase levels than children with OFI. Plasma AST levels were higher in children who developed DHF than in those with DF. These data identify simple clinical and laboratory parameters that help to identify children with DF or DHF.
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              Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand.

              T Endy (2002)
              Dengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Knowledge about the epidemiology and host determinants of inapparent and severe dengue virus infections is limited. In this paper, the authors report findings from the first 3 years of a prospective study of dengue virus transmission and disease severity conducted in a cohort of 2,119 elementary school children in northern Thailand. A total of 717,106 person-school days were observed from 1998 to 2000. The incidence of inapparent and of symptomatic dengue virus infection was 4.3% and 3.6% in 1998, 3.2% and 3.3% in 1999, and 1.4% and 0.8% in 2000, respectively. Symptomatic dengue virus infection was responsible for 3.2%, 7.1%, and 1.1% of acute-illness school absences in 1998, 1999, and 2000, respectively. The early symptom complex of acute dengue virus infection is protean and difficult to distinguish from other causes of febrile childhood illnesses. The authors' results illustrate the spatial and temporal diversity of dengue virus infection and the burden of dengue disease in schoolchildren in Thailand. Their findings increase understanding of dengue virus transmission and disease severity in a well-defined cohort population and offer a study design in which to test the efficacy of potential dengue vaccines.

                Author and article information

                Role: Editor
                PLoS Negl Trop Dis
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                March 2010
                2 March 2010
                : 4
                : 3
                : e617
                [1 ]Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [2 ]Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok, Thailand
                [3 ]Queen Sirikit National Institute of Child Health, Bangkok, Thailand
                [4 ]University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
                [5 ]Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                Pediatric Dengue Vaccine Initiative, United States of America
                Author notes

                Analyzed the data: JRF. Wrote the paper: JRF. Analyzed and interpreted data: JRF. Drafted and revised manuscript: JRF. Contributed to original study design and interpretation of data, and manuscript revision: DVG SK. Participated in the interpretation of data and manuscript revision: SJT AS I-KY RGJ SG ALR. Participated in the analysis, interpretation of data, and manuscript revision: DATC.

                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                : 10 August 2009
                : 13 January 2010
                Page count
                Pages: 6
                Research Article
                Infectious Diseases
                Public Health and Epidemiology

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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