To investigate age-related differences in dengue severity, 114 infants, 1,211 children, and 346 adults with laboratory-confirmed dengue virus (DEN) infections presenting to three hospitals in major urban centers in Nicaragua were recruited from 1999 to 2001. The age distribution of dengue cases and the circulating serotype (predominantly DEN2) were representative of national data. Similar results were obtained when either dengue hemorrhagic fever/dengue shock syndrome or its principal manifestations (vascular permeability, internal hemorrhage, marked thrombocytopenia, and/or shock) were analyzed in relation to age and immune status. The burden of disease and of severe dengue was found predominantly in infants 4-9 months of age and in children 5-9 years old, and secondary DEN infection was a risk factor for severity in children. Age-related differences were identified in the prevalence of specific clinical manifestations as well as in their association with a confirmed DEN diagnosis. This represents one of the few comprehensive studies to analyze characteristics of dengue in infants, children, and adults in the same population and highlights age-related differences in dengue severity.

Abstract. From July to December 1998, a hospital-and health center-based surveillance system for dengue was established at selected sites in Nicaragua to better define the epidemiology of this disease. Demographic and clinical information as well as clinical laboratory results were obtained, and virus isolation, reverse transcriptase-polymerase chain reaction, and serologic assays were performed. World Health Organization criteria were used to classify disease severity; however, a number of patients presented with signs of shock in the absence of thrombocytopenia or hemoconcentration. Therefore, a new category was designated as ''dengue with signs associated with shock'' (DSAS). Of 1,027 patients enrolled in the study, 614 (60%) were laboratory-confirmed as positive cases; of these, 268 (44%) were classified as dengue fever (DF); 267 (43%) as DF with hemorrhagic manifestations (DFHem); 40 (7%) as dengue hemorrhagic fever (DHF); 20 (3%) as dengue shock syndrome (DSS); and 17 (3%) as DSAS. Interestingly, secondary infection was not significantly correlated with DHF/DSS, in contrast to previous studies in Southeast Asia. DEN-3 was responsible for the majority of cases, with a minority due to DEN-2; both serotypes contributed to severe disease. As evidenced by the analysis of this epidemic, the epidemiology of dengue can differ according to geographic region and viral serotype.

Dengue, the most prevalent arthropod-borne viral disease of humans, is caused by four serotypes of dengue virus (DENV 1-4). Although all four DENV serotypes cause a range of illness, defining precisely which clinical characteristics are associated with the distinct serotypes has been elusive. A cross-sectional study was conducted on 984 and 313 hospitalized children with confirmed DENV infections during two time periods, respectively, in the same hospitals in Nicaragua: a 3-year period (1999-2001) when DENV-2 accounted for 96% of the viruses identified, and the 2003 dengue season when DENV-1 predominated (87% of identified serotypes). When the two periods were compared, more shock (OR 1.91, 95% CI 1.35-2.71) and internal hemorrhage (OR 2.05, CI 1.16-3.78) were observed in the period when DENV-2 predominated, whereas increased vascular permeability was associated to a greater degree with the DENV-1 period (OR 2.36, CI 1.80-3.09). Compared with the DENV-2 period, the DENV-1 season was associated with more hospitalized primary dengue cases (OR 3.86, CI 2.72-5.48) and more primary DENV infections with severe manifestations (OR 2.93, CI 2.00-4.28). These findings provide new data to characterize the pathogenic potential of distinct DENV serotypes in human populations.

SummaryTo investigate the incidence of dengue virus (DENV) infection in Nicaragua, a 2-year prospective study was conducted in schoolchildren 4-16 years old in the capital city of Managua. Blood samples were collected before the rainy season in 2001, 2002 and 2003, and were assayed for DENV-specific antibodies. Participants were monitored for dengue-like illness, and acute and convalescent blood samples were collected from suspected dengue cases. In 2001 and 2002, 602 and 397 students were recruited, respectively, and paired annual serum samples were available from 467 and 719 participants in 2001-2002 and 2002-2003, respectively. The overall seroprevalence of anti-DENV antibodies was 91%, increasing from 75% at age 4 to 100% at age 16. The incidence of DENV infection was 12% in Year 1 and 6% in Year 2 (P < 0.001). During Year 1, four laboratory-confirmed dengue cases were detected, with one DENV2 isolate; during Year 2, there were six confirmed dengue cases, with one DENV1 isolate. These and additional circulating serotypes were confirmed by plaque reduction neutralisation test. This study demonstrates surprisingly high transmission of DENV in urban Nicaragua.

To evaluate alternative approaches to the serological diagnosis of dengue virus (DEN) infection, the detection of DEN-specific immunoglobulin M (IgM) and IgA antibodies in serum and saliva specimens was assessed in 147 patients with symptoms of DEN infection seen at the Ministry of Health in Nicaragua. Seventy-two serum samples were determined to be positive for anti-DEN antibodies by IgM capture enzymelinked immunosorbent assay, the routine diagnostic procedure. Serum and saliva specimens were obtained from 50 healthy adults as additional controls. IgM was detected in the saliva of 65 of the 72 serum IgM-positive cases, 6 of the 75 serum IgM-negative cases, and none of the control group, resulting in a sensitivity of 90.3% and a specificity of 92.0% and demonstrating that salivary IgM is a useful diagnostic marker for DEN infection. Detection of IgA in serum may be another feasible alternative for the diagnosis of DEN infection, with serum IgA found in 68 (94.4%) of the IgM-positive cases. In contrast, detection of IgA in saliva was not found to be a useful tool for DEN diagnosis in the present study. Further studies of the kinetics of antibody detection in another set of 151 paired acute-and convalescent-phase serum samples showed that DEN-specific IgA antibodies were detected in more acute-phase samples than were IgM antibodies. Thus, we conclude that DEN-specific IgA in serum is a potential diagnostic target. Furthermore, given that saliva is a readily obtainable, noninvasive specimen, detection of DEN-specific salivary IgM should be considered a useful, cheaper diagnostic modality with similar sensitivity and specificity to IgM detection in serum.

Abstract. This report presents the results of applying the reverse transcriptase-polymerase chain reaction (RT-PCR) to the analysis of clinical specimens during the 1998 dengue epidemic in Nicaragua. The RT-PCR was validated through comparison with viral isolation, resulting in a sensitivity of 100% and a specificity of 90%. In-country application of the RT-PCR permitted the rapid identification of dengue-3 virus as the cause of the epidemic at the beginning of 1998 and the detection of the reintroduction of dengue-2 virus in the middle of the year. Nineteen isolates of dengue-3 and one of dengue-2 were characterized using the restriction site-specific (RSS)-PCR technique. This showed that the dengue-3 strain belonged to the ''Sri Lanka'' subtype and that the dengue-2 strain belonged to the ''Jamaica'' subtype, both of which have been associated with hemorrhagic dengue in the Americas. The application of these simple PCR-based strain typing methods in a country endemic for dengue virus infections can help to characterize the transmission dynamics of this important emerging infectious disease problem and provide this information to local health authorities in a timely manner so that appropriate control measures can be implemented.

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