Different Associations between DC-SIGN Promoter-336G/A (rs4804803) Polymorphism with Severe Dengue in Asians and South-Central Americans: a Meta-Analysis.

Objective: This study was conducted to identify the association between rs4804803 polymorphism in DC-SIGN with the susceptibility of severe dengue. Methods: A comprehensive search was conducted to identify all eligible papers in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Google Scholar. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were used to assess the association. Subgroup analyses were performed by ethnicity. Sensitivity analyses were performed through employing different statistical models (fixed versus random effect model). Results: A total of nine papers and 12 studies, with 1520 severe dengue and 1496 clinical dengue infection were included. The overall meta-analysis revealed significant associations between rs4804803 and severe dengue under the recession (GG versus GA/AA: OR = 0.44, 95%CI, 0.23-0.82) and a codominant model (GG versus AA: OR = 0.43, 95%CI, 0.23-0.81), but sensitivity analysis indicated that the significant pooled ORs were not robust. The subgroup analysis suggested that the carrier of G in rs4804803 was a risk factor for severe dengue under dominant (GG/GA versus AA: OR = 1.86,95%CI, 1.01-3.45), superdominant (GA versus GG/AA: OR = 1.81,95%CI, 1.02-3.21) and a codominant (GA versus AA: OR=1.82,95%CI, 1.02-3.26) models in Asians, while it was a protective factor for severe dengue in South-central Americans under recessive (GG versus GA/AA: OR = 0.27,95%CI, 0.10-0.70) and codominant (GG versus AA: OR=0.24,95%CI, 0.09-0.64) models. The results from subgroup analysis were robust. Conclusions: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) promoter-336G/A (rs4804803) polymorphism is association with severe dengue, and it acts in different directions for Asians and South-central Americans.

Dengue fever in Dar es Salaam, Tanzania: clinical features and outcome in populations of black and non-black racial category.

BACKGROUND: Although the incidence of dengue across Africa is high, severe dengue is reported infrequently. We describe the clinical features and the outcome of dengue according to raceduring an outbreak in Dar es Salaam, Tanzania that occurred in both native and expatriate populations. METHODS: Adults with confirmed dengue (NS1 and/or IgM on rapid diagnostic test and/or PCR positive) were included between December 2013 and July 2014 in outpatient clinics. Seven-day outcome was assessed by a visit or a call. Association between black race and clinical presentation, including warning signs, was assessed by logistic regression adjusted for age, malaria coinfection, secondary dengue and duration of symptoms at inclusion. The independent association between demographic and comorbidities characteristics of the patients and severe dengue was evaluated by multivariate logistic regression that included potential confounders. RESULTS: After exclusion of 3 patients of mixed race, 431 patients with dengue (serotype 2, genotype Cosmopolitan) were included: 241 of black and 190 of non-black race. Black patients were younger (median age 30 versus 41 years; p < 0.001) and attended care after a slightly longer duration of symptoms (median of 2.9 versus 2.7 days; p = 0.01). Malaria coinfection was not significantly different between black (5%) and non-black (1.6%) patients (p = 0.06). The same proportion of patients in both group had secondary dengue (13 and 14%; p = 0.78). Among warning signs, only mucosal bleed was associated with race, black race being protective (adjusted OR 0.44; 95% CI 0.21-0.92). Overall, 20 patients (4.7%) presented with severe dengue. Non-black race (adjusted OR 3.9; 95% CI 1.3-12) and previously known diabetes (adjusted OR 43; 95% CI 5.2-361) were independently associated with severe dengue. CONCLUSIONS: Although all patients were infected with the same dengue virus genotype, black race was independently protective against a severe course of dengue, suggesting the presence of protective genetic or environmental host factors among people of African ancestry. The milder clinical presentation of dengue in black patients might partly explain why dengue outbreaks are under-reported in Africa and often mistaken for malaria. These results highlight the need to introduce point-of-care tests, beside the one for malaria, to detect outbreaks and orientate diagnosis. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01947075 , retrospectively registered on the 13 of September 2014.

Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome.

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS.

Predicción de mortalidad en pacientes con dengue grave en Unidad de Cuidados Intensivos / Prediction of mortality in severe dengue in the Intensive Care Unit

Introducción: el dengue constituye un importante problema de salud pública para las regiones endémicas. Objetivo: identificar variables clínicas, biológicas e imaginológicas asociadas a la probabilidad de morir en pacientes con dengue grave ingresados en la unidad de cuidados intensivos del Hospital General Docente Dr Agostinho Neto entre enero y noviembre de 2014. Método: se realizó un estudio epidemiológico, caso-control, retrospectivo en el que se incluyen todos los pacientes ingresados en el escenario investigacional con diagnóstico de dengue grave y que fueron confirmados serológicamente, en dicho período de estudio. Se emplearon estadígrafos descriptivos y análisis univariado, bivariado y de regresión logística para determinar la asociación de las variables seleccionadas con la mortalidad. Se analizaron 90 casos, 10 fallecidos y 80 egresados vivos. Resultados: En el análisis univariado resultaron tener diferencias significativas la presión arterial media, el gasto urinario y el conteo plaquetario, la glicemia, la acidosis metabólica y el derrame pericárdico. En el análisis multivariado, mostraron asociación con la mortalidad el gasto urinario y la presión arterial media, la glicemia, la acidosis metabólica y el derrame pericárdico. El derrame pericárdico y la acidosis metabólica tienen aceptables medidas de validez y seguridad diagnósticas de la probabilidad de morir. Conclusiones: La presión arterial media y el gasto urinario 3, la glicemia 2 y 3, ¿la acidosis metabólica con DB? -8 mmol/l en el momento 1 y 2, y el derrame pericárdico en el momento 3 resultaron ser variables con capacidad predictiva de mortalidad en pacientes con dengue grave(AU)

Introduction: dengue is an important public health problem for endemic regions. Objective: to identify clinical, biological and imaging variables associated with the probability of dying in patients with severe dengue admitted to the intensive care unit of the General Teaching Hospital Dr. Agostinho Neto between January and November 2014. Method: a study was conducted epidemiological, case-control, retrospective study in which all patients were admitted to the research scenario with a diagnosis of severe dengue and whom were confirmed serologically in this studied period. Descriptive statistics and univariate, bivariate and logistic regression were used to determine the association of the selected variables with mortality. It were analyzed 90 cases, 10 deaths and 80 alive. Results: In the univariate analysis, mean blood pressure, urinary output and platelet count, glycaemia, metabolic acidosis and pericardial effusion were found to have significant differences. In the multivariate analysis, that shown an association with mortality, urinary output and mean arterial pressure, glycemia, metabolic acidosis and pericardial effusion. Pericardial effusion and metabolic acidosis have acceptable measures of diagnostic validity and safety of the probability of dying. Conclusions: Mean arterial pressure and urinary output 3, glycemia 2 and 3, metabolic acidosis with DB?8 mmol / l at time 1 and 2 and pericardial effusion at time 3 were found to be variables with predictive capacity of mortality in patients with severe dengue(AU)

OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans.

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.

HLA Class I Supertype Associations With Clinical Outcome of Secondary Dengue Virus Infections in Ethnic Thais.

BACKGROUND: Human leukocyte antigen (HLA) supertypes are groups of functionally related alleles that present structurally similar antigens to the immune system. OBJECTIVES: To analyze HLA class I supertype associations with clinical outcome in hospitalized Thai children with acute dengue illness. METHODS: Seven hundred sixty-two patients and population-matched controls recruited predominantly in Bangkok were HLA-A and -B typed. HLA supertype frequencies were compared and tested for significant dengue disease associations using logistic regression analyses. Multivariable models were built by conducting forward stepwise selection procedures. RESULTS: In the final logistic regression model, the HLA-B44 supertype was protective against dengue hemorrhagic fever (DHF) in secondary infections (odds ratio [OR] = 0.46, 95% confidence interval [CI], .30-.72), while the HLA-A02 supertype (OR = 1.92, 95% CI, 1.30-2.83) and the HLA-A01/03 supertype (OR = 3.01, 95% CI, 1.01-8.92) were associated with susceptibility to secondary dengue fever. The B07 supertype was associated with susceptibility to secondary DHF in the univariate analysis (OR = 1.60, 95% CI, 1.05-2.46), whereas that was not retained in the final model. CONCLUSIONS: As the HLA-B44 supertype is predicted to target conserved epitopes in dengue, our results suggest that B44 supertype-restricted immune responses to highly conserved regions of the dengue proteome may protect against secondary DHF.

A 47-year-old returning traveler with shock.

A 47-year-old man with no significant past medical history, originally from Indonesia, was brought to the ED of an urban US medical center after being found collapsed on the sidewalk in respiratory distress and with an altered sensorium. Upon arrival to the ED, he was tachypneic, with increased work of breathing and an oxygen saturation of 88% on 100% nonrebreather mask, so he was immediately intubated. Following intubation, he became profoundly hypotensive, requiring aggressive crystalloid resuscitation and vasopressor support. Broad-spectrum antimicrobials were administered, including ceftriaxone, vancomycin, levofloxacin, and oseltamivir. Further history elicited subsequently from family members revealed that the patient had returned from a 2-week vacation in Indonesia 6 days prior to presentation. According to relatives, he appeared to be in his usual state of health upon his return and was not seen by anyone thereafter, but in the interim he reportedly had an episode of epistaxis, and text messages received from him became progressively more bizarre.

Dengue hemorrhagic fever is associated with polymorphisms in JAK1.

To identify genes associated with the clinical presentation of dengue, 50 cases of probable or possible dengue hemorrhagic fever (DHF), 236 dengue fever (DF), and 236 asymptomatic infections were genotyped for 593 single-nucleotide polymorphisms (SNPs) in 56 genes across the type 1 interferon (IFN) response pathway as well as other important candidate genes. By single locus analysis comparing DHF with DF, 11 of the 51 markers with P<0.05 were in the JAK1 gene. Five markers were significantly associated by false discovery rate criteria (q<0.20 when P<6 × 10(-4)). The JAK1 SNPs showed differential distribution by ethnicity and ancestry consistent with epidemiologic observations in the Americas. The association remained significant after controlling for ancestry and income. No association was observed with markers in the gene encoding CD209 (DC-SIGN). An association between DHF and JAK1 polymorphisms is in agreement with expression profiles showing generalized decreased type 1 IFN-stimulated gene expression in these patients.