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The present study was designed as an exploratory investigation to characterize the overall profile of chemokines, growth factors, and pro-inflammatory/regulatory cytokines during acute DENV infection according to DENV-1, DENV-2, DENV-4 serotypes and age: children: <1-10-year-old (yo); adolescents:11-20 yo; adults 21-40 yo; and older adults: 41-75 yo. The levels of soluble immunemediators were measured in serum by high-throughput microbeads array in 636 subjects including 317 DENV-infected and 319 age-matching non-infected control (NI). Overall, most soluble mediators were increased in DENV-infected patients as compared to NI group regardless of age and DENV serotype, with high magnitude order of increase for CCL2, CXCL10, IL-1ß, IFN-γ, IL1-Ra (fold change >3x), except PDGF in which no fold change was observed. Moreover, despite the age ranges, DENV-1 and DENV-4 presented increased levels of VEGF, IL-6, and TNF-α in serum but decreased levels of PDGF, while DENV-2 exhibited increased levels of CXCL8, CCL4, and IL-12. Noteworthy was that DENV-2 showed increased levels of IL-12, IL-15, IL-17, IL-4, IL-9, and IL-13, and maintained an unaltered levels of PDGF at younger ages (<1-10 yo and 11-20 yo), whereas in older ages (21-40 yo and 41-75 yo), the results showed increased levels of CCL2, IL-6, and TNF-α, but lower levels of PDGF. In general, DENV infection at younger age groups exhibited more complex network immunoclusters as compared to older age groups. Multivariate analysis revealed a clustering of DENV cases according to age for a set of soluble mediators especially in subjects infected with DENV-2 serotype. Altogether, our findings demonstrate that the profile of circulating soluble mediators differs substantially in acute DENV according to age and DENV serotypes suggesting the participation of serotype-associated immune response, which may represent a potential target for development of therapeutics and could be used to assist medical directive for precise clinical management of severe cases.

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An effective vaccine against the dengue virus (DENV) should induce a balanced, long-lasting antibody (Ab) response against all four viral serotypes. The burst of plasmablasts in the peripheral blood after vaccination may reflect enriched vaccine-specific Ab secreting cells. Here we characterize the acute plasmablast responses from naïve and DENV-exposed individuals following immunization with the live attenuated tetravalent (LAT) Butantan DENV vaccine (Butantan-DV). The frequency of circulating plasmablasts was determined by flow cytometric analysis of fresh whole blood specimens collected from 40 participants enrolled in the Phase II Butantan-DV clinical trial (NCT01696422) before and after (days 6, 12, 15 and 22) vaccination. We observed a peak in the number of circulating plasmablast at day 15 after vaccination in both the DENV naïve and the DENV-exposed vaccinees. DENV-exposed vaccinees experienced a significantly higher plasmablast expansion. In the DENV-naïve vaccinees, plasmablasts persisted for approximately three weeks longer than among DENV-exposed volunteers. Our findings indicate that the Butantan-DV can induce plasmablast responses in both DENV-naïve and DENV-exposed individuals and demonstrate the influence of pre-existing DENV immunity on Butantan DV-induced B-cell responses.

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A panoramic analysis of chemokines, pro-inflammatory/regulatory cytokines, and growth factors was performed in serum samples from patients with acute DENV infection (n=317) by a high-throughput microbeads array. Most soluble mediators analyzed were increased in DENV patients regardless of the DENV serotype. The substantial increase (≥10-fold) of CXCL10, IL-6, and IFN-γ, and decreased levels of PDGF (<0.4-fold) was universally identified in all DENV serotypes. Of note, increased levels of CXCL8, CCL4, and IL-12 (≥3-9-fold) were selectively observed in DENV2 as compared to DENV1 and DENV4. Heatmap and biomarker signatures further illustrated the massive release of soluble mediators observed in DENV patients, confirming the marked increase of several soluble mediators in DENV2. Integrative correlation matrices and networks showed that DENV infection exhibited higher connectivity among soluble mediators. Of note, DENV2 displayed a more complex network, with higher connectivity involving a higher number of soluble mediators. The timeline kinetics (Day 0-1, D2, D3, D4-6) analysis additionally demonstrated differences among DENV serotypes. While DENV1 triggers a progressive increase of soluble mediators towards D3 and with a decline at D4-6, DENV2 and DENV4 develop with a progressive increase towards D4-6 with an early plateau observed in DENV4. Overall, our results provided a comprehensive overview of the immune response elicited by DENV infection, revealing that infection with distinct DENV serotypes causes distinct profiles, rhythms, and dynamic network connectivity of soluble mediators. Altogether, these findings may provide novel insights to understand the pathogenesis of acute infection with distinct DENV serotypes.

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An effective vaccine against the dengue virus (DENV) should induce a balanced, long-lasting antibody (Ab) response against all four viral serotypes. The burst of plasmablasts in the peripheral blood after vaccination may reflect enriched vaccine-specific Ab secreting cells. Here we characterize the acute plasmablast responses from naïve and DENV-exposed individuals following immunization with the live attenuated tetravalent (LAT) Butantan DENV vaccine (Butantan-DV). The frequency of circulating plasmablasts was determined by flow cytometric analysis of fresh whole blood specimens collected from 40 participants enrolled in the Phase II Butantan-DV clinical trial (NCT01696422) before and after (days 6, 12, 15 and 22) vaccination. We observed a peak in the number of circulating plasmablast at day 15 after vaccination in both the DENV naïve and the DENV-exposed vaccinees. DENV-exposed vaccinees experienced a significantly higher plasmablast expansion. In the DENV-naïve vaccinees, plasmablasts persisted for approximately three weeks longer than among DENV-exposed volunteers. Our findings indicate that the Butantan-DV can induce plasmablast responses in both DENV-naïve and DENV-exposed individuals and demonstrate the influence of pre-existing DENV immunity on Butantan DV-induced B-cell responses.

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BACKGROUND: Dengue is the leading cause of mosquito-borne viral infection. It is responsible for high morbidity and mortality in children living in endemic areas. Nowadays, neurological complications are progressively referred to and include a broad spectrum of symptoms. It can be secondary to metabolic alterations, direct invasion by the virus, and enhanced autoimmune response. CASE PRESENTATION: Here, we report a rare case of hydrocephalus secondary to dengue encephalitis. A 13-day-old boy was diagnosed with dengue. He evolved with seizures and impaired consciousness being diagnosed with encephalitis. After clinical treatment, he was discharged fully recovered. Three months later, he presented with signs and symptoms of intracranial hypertension. Brain MRI revealed hydrocephalus secondary to acquired aqueduct stenosis. The patient underwent an endoscopic third ventriculocisternostomy. CONCLUSION: Dengue infection is a differential diagnosis for acute febrile neurological impairment in children from endemic areas. Follow-up should be offered after dengue encephalitis to detect possible late-onset complications, as hydrocephalus.

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BACKGROUND: We evaluated the validity of clinical diagnosis compared with laboratory diagnosis of dengue in a retrospective sample of patients in São José do Rio Preto, Brazil. METHODS: Our sample included 148 299 clinically (56.3%) or laboratory-diagnosed (43.7%) dengue cases. We compared the sensitivity, specificity, positive and negative predictive value (PPV and NPV) of dengue patients' demographic and clinical characteristics with laboratory-based diagnosis. We used logistic regressions to estimate the correlation between clinical and laboratory diagnosis of dengue and a full set of dengue signs and symptoms. RESULTS: We found substantial variability in sensitivity and specificity of signs and symptoms ranging from 0.8-81.1 and 21.5-99.6, respectively. Thrombocytopenia exhibited the highest PPV (92.0) and lowest NPV (42.2) and was the only symptom showing agreement with laboratory-confirmed dengue (φ = 0.38). The presence of exanthema and thrombocytopenia led to a greater likelihood of concordant clinical and laboratory diagnoses (exanthema: OR: 4.23; 95% CI: 2.09 to 8.57; thrombocytopenia: OR: 4.02; 95% CI: 1.32 to 12.27). CONCLUSIONS: We found substantial variation in sensitivity, specificity, PPV and NPV of dengue signs and symptoms. For accuracy, clinical and laboratory diagnosis of dengue should be performed concurrently. When laboratory tests are not available, we suggest focusing on the clinical manifestations most associated with dengue.

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We assessed a dengue IgG rapid diagnostic test (RDT) and IgG enzyme-linked immunosorbent assay (ELISA) to determine their suitability for dengue prevaccination screening. Each exhibited ≥99% specificity. The RDT demonstrated no Zika cross-reactivity, while the ELISA displayed greater sensitivity. Both could safely guide vaccination in Puerto Rico pending availability of improved serotests.

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BACKGROUND: The collapsing variant of focal segmental glomerulosclerosis (FSGS) is the most aggressive form of FSGS and is characterized by at least one glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia. Viruses can act as aetiological agents of secondary FSGS. This study aims to establish an aetiological link between dengue virus (DENV) infection and the collapsing variant of FSGS and to analyse possible influences of the apolipoprotein 1 (APOL1) gene risk alleles on the disease. METHODS: Biopsies and medical records were gathered from 700 patients of the Instituto de Nefropatologia, Belo Horizonte, Brazil. Screening for the collapsing variant of FSGS was performed and serological, immunohistochemical, tissue polymerase chain reaction (PCR) and genetic analysis were conducted. RESULTS: Eight patients were identified with positive DENV serology and negative serological and/or tissue markers for hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human immunodeficiency virus, cytomegalovirus and parvovirus B19. In PCR analysis, six patients had positive markers for DENV strain genetic material, one patient had positive markers for co-infection of Zika virus (ZIKV) and DENV and one patient had positive markers only for ZIKV infection. Six of the eight patients did not show risk alleles of the APOL1 gene. One patient had only one risk allele (G1) and the sample from another did not contain enough DNA for genetic analysis to be performed. CONCLUSIONS: This study provided strong evidence that DENV can infect renal tissue and possibly functions as a second hit to the development of the collapsing variant of FSGS. Nonetheless, this study also highlights the possible implication of ZIKV infection in FSGS and supports the argument that risk alleles of the APOL1 gene may not be implicated in the susceptibility to FSGS in these patients.

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Dengue infection has been associated with multiple renal complications, including glomerulonephritis, acute tubular necrosis, tubulointerstitial nephritis, and thrombotic microangiopathy (TMA), this last one being a rare complication of dengue, with only a few reported cases. TMA associated with dengue can be explained by an alteration in the activity of the enzyme ADAMTS13, leading to thrombotic thrombocytopenic purpura; or it can be secondary to direct or indirect endothelial injury by the virus, which leads to hemolytic uremic syndrome. Here, we present a case of severe TMA, not related to ADAMTS13, which was clearly associated with dengue infection.

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BACKGROUND: Dengue is the most important human viral disease transmitted by mosquitoes. It can be asymptomatic or it can present in any of its 3clinical forms: Dengue fever, dengue haemorrhagic fever and dengue shock syndrome. However, some atypical manifestations have been reported in surgical emergencies caused by acute appendicitis in patients with dengue fever. CLINICAL CASE: We report the case of an 18-year-old Mexican male who presented to the emergency department of the General Hospital of Culiacan, Sinaloa, with symptoms of dengue fever, accompanied by crampy abdominal pain with positive Rovsing and Dunphy signs. Dengue infection was confirmed by a positive NS1 antigen test performed by enzyme-linked immunosorbent assay. An abdominal ultrasound revealed an appendicular process; as the abdominal pain in the right side kept increasing, an open appendectomy was performed. Abundant inflammatory liquid was observed during the surgery, and the pathology laboratory reported an oedematous appendix with fibrinopurulent plaques, which agreed with acute ulcerative appendicitis. The patient was discharged fully recovered without complications during the follow-up period. CONCLUSIONS: Acute abdominal pain can be caused in some cases by dengue infection. This can be confusing, which can lead to unnecessary surgical interventions, creating additional morbidities and costs for the patient. This unusual and coincident acute appendicitis with dengue highlights the importance of performing careful clinical studies for appropriate decision making, especially in dengue endemic regions during an outbreak of this disease.

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OBJECTIVE: In this study, single nucleotide polymorphisms (SNP) of interleukin (IL) 1ß -511C>T, IL1RN VNTR 86 bp, IL6 -174G>C, IL10 -819C>T and TNFα -308G>A were analyzed by PCR-RFLP with symptoms of dengue with the clinical features. SUBJECTS: 196 individuals admitted to the São José Infectious Diseases Hospital with suspected dengue infection. Dengue was confirmed in 111 of the patients. The control group consisted of 85 other individuals confirmed without dengue. RESULTS: It was demonstrated that the presence the T allele of IL1ß (P < 0.05) was associated with susceptibility to developing the disease. Other results also suggested that the polymorphism in the combinations IL6 × IL1ß (C and T alleles, respectively), IL1ß (T allele) × IL1RN (*2/*2 genotype), IL6 (C allele) × TNFα (A allele), IL10 (C/T genotype) × TNFα (A/A genotype) (P < 0.01, P = 0.01, P < 0.05 and P = 0.03, respectively) were associated with predisposition to developing the disease and its symptoms. CONCLUSIONS: In summary, the findings of this study in a Brazilian population point out the importance of studies of combinations of polymorphisms in the development of dengue, which can increase the risk of dengue infection and its severity.

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El Salvador is a Central American country that has been affected by several dengue outbreaks. This study investigated the levels of IgM, IgA, and IgE anti-dengue antibodies in serum samples from children in El Salvador, with a clinical and serological diagnosis of dengue infection during the dengue 4 outbreak in 2002-2003. Seventy one serum samples were tested by ELISA and cases were classified in three groups: 13 primary dengue fever (PDF), 21 secondary dengue fever (SDF), and 37 secondary dengue hemorrhagic fever (SDHF). Also, the specificity of anti-dengue IgM for the different serotypes was tested. No significant differences in the IgM response were found between PDF and SDF, but these were detected between PDF and SDHF (P = 0.0053) and between SDF and SDHF (P = 0.0003). The IgA and IgE values showed a statistically significant difference between primary and secondary groups. The highest positivity percentage of IgA was between 95% (SDF) and 100% (SDHF) towards day 7 of onset of fever. All secondary cases were positive for IgE antibodies. The specificity of IgM was determined for DENV-4 virus in primary and secondary DF groups. This is the first study on dengue cases in Salvadorian children related to the immune response of different immunoglobulins to the type of infection and the clinical picture. Further prospective studies are needed to define if the pattern of immunoglobulins can determine early dengue infection and/or severity.

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Because an enriched environment (EE) enhances T-cell activity and T-lymphocytes contribute to immunopathogenesis during heterologous dengue virus (DENV) infections, we hypothesised that an EE increases dengue severity. To compare single serotype (SS) and antibody-enhanced disease (AED) infections regimens, serial intraperitoneal were performed with DENV3 (genotype III) infected brain homogenate or anti-DENV2 hyperimmune serum followed 24 h later by DENV3 (genotype III) infected brain homogenate. Compared AED for which significant differences were detected between the EE and impoverished environmental (IE) groups (Kaplan-Meyer log-rank test, p = 0.0025), no significant differences were detected between the SS experimental groups (Kaplan-Meyer log-rank test, p = 0.089). Survival curves from EE and IE animals infected with the AED regimen were extended after corticoid injection and this effect was greater in the EE than in the IE group (Kaplan-Meyer log-rank test, p = 0.0162). Under the AED regimen the EE group showed more intense clinical signs than the IE group. Dyspnoea, tremor, hunched posture, ruffled fur, immobility, pre-terminal paralysis, shock and death were associated with dominant T-lymphocytic hyperplasia and presence of viral antigens in the liver and lungs. We propose that the increased expansion of these memory T-cells and serotype cross-reactive antibodies facilitates the infection of these cells by DENV and that these events correlate with disease severity in an EE.

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BACKGROUND: Polymorphisms in the human leukocyte antigen (HLA) genes might predispose certain individuals to dengue fever (DF) and the severe forms of the disease: dengue haemorrhagic fever/ dengue shock syndrome (DHF/DSS). SUBJECTS AND METHOD: A DNA-based HLA typing method was used to determine the HLA class I and II alleles in 50 patients with dengue, including 45 cases of DF, 5 cases of DHF and 177 healthy individuals in Jamaica. RESULTS: HLA -A*24 and -DR β5*01/02 were significantly associated with dengue infection while possession of HLA -A*23, - CW*04, -DQ β1*02, -DQ β1*03 and DQ β1*06 were protective. No other significant associations were found after correction for the number of alleles tested at each HLA - locus. CONCLUSION: This is the first study to report a significant association with HLA -A*24 and DF although this allele is associated with DHF and DSS in Vietnamese patients. The other HLA associations observed in the Jamaican cohort also are different from those reported in other ethnic groups. Further studies which involve larger numbers of patients with DHF and explore functional aspects of HLA allelic associations with dengue in Jamaicans are necessary.

ANTECEDENTES: Los polimorfismos de los genes del antígeno leucocitario humano (HLA) podría predisponer a ciertos individuos a la fiebre de dengue (FD) y a las formas severas de esta enfermedad: la fiebre hemorrágica de dengue y el síndrome de choque por dengue (FHD/SCD). SUJETOS Y MÉTODO: Se usó un método de tipificación HLA basado en el ADN con el propósito de determinar los alelos HLA clase I y II en 50 pacientes con dengue, incluyendo 45 casos de FD, 5 casos de FHD y 177 individuos saludables en Jamaica. RESULTADOS: HLA -A*24 y -DR β5*01/02 estuvieron significativamente asociados con la infección de dengue en tanto que la posesión de HLA -A*23, -CW*04, -DQ β1*02, -DQ β1*03 y DQ β1*06 tenía carácter protector. No se halló ninguna otra asociación significativa tras la corrección en relación con el número de alelos probados en cada locus de HLA . CONCLUSIÓN: Este es el primer estudio que reporta una asociación significativa de HLA -A*24 y FD, aunque este alelo se halla asociado con FHD y SCD en pacientes vietnamitas. Las otras asociaciones observadas en la cohorte jamaicana son también diferentes de las que se reportan para otros grupos étnicos. Se requieren estudios ulteriores que comprendan grandes números de pacientes con FHD y exploren los aspectos funcionales de las asociaciones alélicas de HLA con el dengue en los jamaicanos.

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Meningitis and encephalitis are complications of West Nile virus (WNV) infection. Although WNV is endemic in North America, the virus has recently been reported in Colombia and Argentina. Investigation of WNV in Brazil is important since this virus has never been studied previously in this country. OBJECTIVE: To investigate the presence of WNV infection in viral encephalitis/meningitis cases of unknown etiology in the city of Rio de Janeiro, Brazil. METHOD: Thirty-seven adults with viral meningitis/encephalitis had their serum and CSF tested for WNV antibodies using the ELISA method. RESULTS: Only one case was WNV-positive, but this case was also positive for dengue. The plaque reduction neutralization test distinguished infections, and was negative for WNV. CONCLUSION: WNV can be confused with dengue infection. Their symptoms and neurological picture are similar. We did not find WNV in any patients with encephalitis and meningitis in the city of Rio de Janeiro. Up to now, it has not been detected in Brazil.

Meningite e encefalite são complicações da infecção pelo vírus do Oeste do Nilo (VON). Embora o VON seja endêmico na América do Norte, recentemente o vírus foi descrito na Colômbia e Argentina. Sua pesquisa no Brasil é importante uma vez que o vírus nunca fora estudado antes em nosso país. OBJETIVO: Investigar a presença do VON em casos de meningite e encefalite viral de etiologia desconhecida, na cidade no Rio de Janeiro, Brasil. MéTODO: Trinta e sete adultos com quadro de meningite/encefalite tiveram seu LCR e soro testados para anticorpos anti-VON, pelo método ELISA. RESULTADOS: Apenas um caso obteve sorologia positiva para VON, mas a sorologia para dengue também fora positiva. O teste da neutralização por redução de placa foi utilizado para distinção entre as infecções, sendo negativo para VON. CONCLUSÃO: A infecção por VON pode ser confundida com a infecção pelo vírus da dengue, seus sintomas e quadro neurológico são similares. Nós não encontramos o VON em pacientes com meningite/ encefalite na cidade do Rio de Janeiro. Até o momento ele ainda não foi identificado no Brasil.

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The recognition of DF (DHF Dengue Hemorrhagic Fever) is very complicated due to occurrence of a wide spectrum of clinical signs and symptoms during acute phase of illness. Moreover, presence of four serotypes further complicates the prognosis. To investigate the predictors of disease severity and elucidate the prognostic markers among four dengue serotypes, this study was conducted on 320 inpatients having acute febrile illness clinically suspected as DI, over a period of five years. Dengue serotypes were confirmed by multiplex reverse transcriptase (RT)-PCR. Eighty patients were positive for DI with presence of Den-1, Den-2, Den-3, and Den-4 in 8, 35, 27 and 10 patients, respectively. The severe clinical manifestations, abdominal pain and hepatomegaly, were comparatively higher in Den-2 patients. Liver aminotransferases levels were also higher in Den-2 patients (app. 5 fold). This study clearly indicates the hyperendemicity of all dengue serotypes. Nucleotide sequencing of Envelope region revealed that the presently emerged Den-3 belongs to type III, having high homology with genotype responsible for number of outbreaks in 1980s. The re-emergence of this deadly type can be suspected to cause more outbreaks in future and is a matter of great concern.

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