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The immunopathogenesis of dengue severity is convoluted. The primary objective of the research was to examine the dynamics of cytokine storm and its correlation with disease development in individuals affected by DENV infection. Additionally, the study aimed to discover potential biomarkers that could indicate severe dengue infection and determine the most suitable timeframe for predicting the severity of these biomarkers during the acute stage of dengue infections. We conducted a temporal analysis of the daily viral load and cytokine levels in 60 hospitalized dengue patients until discharge. Our findings reveal a distinct cytokine profile (elevated IL-8, IL-10, IL-6, GM-CSF, MCP-1, IL-13, and IL-4 and decreased IL-12, MIP-1ß) on the third day after symptom onset is predictive of severe dengue in secondary dengue infection. The imbalanced cytokine signature may inform clinical decision-making in treating severe dengue infections.

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BACKGROUND: The study aimed to identify predictors of severe dengue during the 2017 epidemic and to develop and validate a simple predictive score for severity. METHODS: A retrospective analytical study was conducted using clinical and laboratory data from adult dengue patients with a confirmed microbiological diagnosis. The study included patients who presented to a tertiary care centre in Kerala, India, during the febrile phase (≤4 d) between June 2017 and February 2019. Using appropriate statistical tests, we derived predictors of severe disease and computed a risk score model. RESULTS: Of the 153 patients (mean age 50±17 y; 64% males), 31 (20%) had severe dengue and 4 (3%) died. Petechial lesions, hypoalbuminemia (<3.5 g/dl), elevated alanine aminotransferase (>40 IU/l) and urea >40 IU/l were significant predictors. Our scoring system (cut-off: 2) showed excellent performance, with an area under the receiver operating characteristics curve of 0.9741, sensitivity of 100%, specificity of 96% and accuracy of 98%. The risk score was secondarily validated on 48 patients hospitalized from March 2019 to June 2019. CONCLUSION: Our scoring system is easy to implement and will help primary healthcare practitioners in promptly identifying severe dengue cases upon hospital presentation.

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The genetic diversity of the dengue virus is characterized by four circulating serotypes, several genotypes, and an increasing number of existing lineages that may have differences in the potential to cause epidemics and disease severity. Accurate identification of the genetic variability of the virus is essential to identify lineages responsible for an epidemic and understanding the processes of virus spread and virulence. Here, we characterize, using portable nanopore genomic sequencing, different lineages of dengue virus 2 (DENV-2) detected in 22 serum samples from patients with and without dengue warning signs attended at Hospital de Base of São José do Rio Preto (SJRP) in 2019, during a DENV-2 outbreak. Demographic, epidemiological, and clinical data were also analyzed. The phylogenetic reconstruction and the clinical data showed that two lineages belonging to the American/Asian genotype of DENV-2-BR3 and BR4 (BR4L1 and BR4L2)-were co-circulating in SJRP. Although preliminary, these results indicate no specific association between clinical form and phylogenetic clustering at the virus consensus sequence level. Studies with larger sample sizes and which explore single nucleotide variants are needed. Therefore, we showed that portable nanopore genome sequencing could generate quick and reliable sequences for genomic surveillance to monitor viral diversity and its association with disease severity as an epidemic unfolds.

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A systematic review was conducted to investigate the relationship between aminotransferases and the severity of dengue infection, which is a prevalent and significant infection in tropical and subtropical regions. Aminotransferases are enzymes that are often elevated in dengue due to the liver's physiological and immunological response to the infection. This review focused on analyzing various studies that examined the correlation between aminotransferase levels and the severity of dengue. Extensive literature searches were performed using ("dengue*" OR "dengue fever*" OR "dengue haemorrhagic fever*" OR "dengue shock syndrome*") AND ("alanine aminotransferase*" OR "aspartate aminotransferase*") on PubMed. The selected articles were thoroughly reviewed, encompassing epidemiology, pathogenesis, and clinical manifestations of dengue. The consistent findings across the studies indicated that aminotransferases can serve as predictive markers for dengue severity. Therefore, early assessment of liver enzyme levels is crucial in dengue cases, and elevated levels should be closely monitored to prevent adverse outcomes.

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Dengue is an emerging illness in India, where it is endemic in some areas and sometimes causes yearly epidemics. Each dengue outbreak starts with high death and morbidity, which has a significant socioeconomic impact. As of September 30, 2022, India had 63,280 dengue cases, according to information provided by the National Centre for Vector Borne Diseases Control. North India is most severely impacted by each outbreak. In Uttar Pradesh, the state with the most population in India, there have been 2060 confirmed cases of dengue and 1 mortality till September 2022 reported. Patients are being reported from semi-urban, rural, and urban areas. It is essential to properly monitor disease cases through disease surveillance in order to ensure prompt case management if dengue outbreak control is to be achieved. An efficient diagnostic approach for early diagnosis is urgently required to reduce the severity of the sickness, the length of the hospital stay, and clinical consequences.

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BACKGROUND: Obesity is associated with unfavorable outcomes for infectious diseases. Most researches exploring the association between nutritional status and dengue severity have focused on pediatric populations, with only few studies assessing adult patients. METHODS: Adult patients with laboratory-confirmed dengue admitted to a tertiary hospital in southern Taiwan between 2014 and 2015 were enrolled retrospectively. Demographics, comorbidities, clinical presentation, laboratory findings, and outcomes were obtained from case-record forms. Patients were categorized into obese group and nonobese group. The obese group comprised patients with a body mass index of ≥27.5 kg/m2. RESULTS: A total of 1417 hospitalized patients with dengue were evaluated. The mean age was 57.9 years (range: 18-92 years). The obese and nonobese groups comprised 333 (23.5%) and 1084 (76.5%) patients, respectively. The obese group included more patients with hypertension (85%, p < 0.001), diabetes mellitus (33%, p < 0.001), and congestive heart failure (6.3%, p = 0.049). Multivariate analysis revealed that the obese group had more petechiae (AOR: 1.353, 95% CI: 1.025-1.786, p = 0.033), more dyspnea (AOR: 1.380, 95% CI: 1.015-1.876, p = 0.040), and more severe hepatitis (AOR: 2.061, 95% CI: 1.050-4.048, p = 0.036). The obese group also had higher peak hematocrit values (44.1%, p < 0.001) and lower nadir platelet count (45.3 × 103/µL, p = 0.049) than the nonobese group. CONCLUSION: In adult patients with dengue, obese group had more petechiae, dyspnea, severe hepatitis, lower nadir of platelet count, and higher peak hematocrit level. We observed no difference in severe dengue or mortality between obese and nonobese group.

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BACKGROUND: Severe dengue is associated with a considerable risk of mortality, and there is currently a lack of appropriate prognostic biomarkers to predict its severity. Pathogenesis of severe dengue is characterized by overt inflammation, endothelial activation, and increased vascular permeability. The current study investigates the utility of endothelial, inflammatory, and vascular permeability factors as biomarkers to identify dengue severity, which could improve disease prognosis and management. METHODS: The dengue-positive subjects were classified based on seropositivity for NS1, IgM, and IgG. The samples in each group were quantified for basic clinical investigations. The levels of Interleukin-6 (IL-6), Tumor necrosis factor receptor 1 (TNFR1), EOTAXIN, Monocyte chemoattractant protein-1 (MCP-1), Monokine induced by interferon-gamma (MIG), Intercellular adhesion molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1), Thrombomodulin, and Angiopoietin-2 were estimated in all serum samples using the multiplex bead-based assay. RESULTS: IgG seropositive dengue patients showed abnormal laboratory characteristics and severe dengue symptoms. Among the studied markers, only IL-6, TNFR1, ICAM-1, VCAM-1, Thrombomodulin, and Angiopoietin-2 were significantly elevated in IgG seropositive patients compared to healthy controls. Increased IL-6 and TNFR1 levels were associated with decreased platelet count and elevated Hematocrit levels in IgG seropositive patients. Furthermore, ROC curve analysis indicated that IL-6, TNFR1, Thrombomodulin, and Angiopoietin-2 showed good potential for predicting dengue severity. CONCLUSION: Inflammatory markers IL-6 and TNFR1, and endothelial factors Angiopoietin-2 and Thrombomodulin, could serve as prognostic markers for severe dengue. These findings also encourage the future study of these biomarkers in the pathogenesis of severe dengue infection.

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BACKGROUND: Plasma leakage is a major pathogenic manifestation of severe dengue and is a precursor of life-threatening complications associated with dengue. Accumulating evidence indicates the role of Matrix Metalloproteinases (MMPs) in mediating vascular permeability and plasma leakage following induction by the dengue virus. This study aims to investigate the utility of MMP-2, MMP-3, and MMP-9 in predicting the severity of dengue infection and further explore the relationship of these markers with the pathogenic factors associated with plasma leakage. METHODS: The dengue-positive subjects were classified into mild and severe dengue groups based on the manifestation of warning signs. The samples in each group and healthy controls were quantified for basic laboratory characteristics. The levels of MMP-2, MMP-3, MMP-9, and Macrophage migration inhibitory factor (MIF) were estimated in all serum samples using a multiplex bead-based assay. RESULTS: MMP-2 and MMP-9 were markedly elevated in severe dengue patients compared to mild dengue patients and healthy controls. No alteration in the circulating levels of MMP-3 was observed between the study groups. ROC curve analysis indicated that MMP-2 and MMP-9 exhibited good potential for predicting severe dengue. Notably, an increase in MMP-9 was associated with increased MIF and Hematocrit levels in severe dengue patients. CONCLUSION: MMP-2 and MMP-9 could serve as prognostic biomarkers for severe dengue. These findings also identify the association of MMP-9 with markers of plasma leakage, thereby encouraging further studies to explore the therapeutic potential of targeting MMP-9 in managing plasma leakage in severe dengue.

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Killer immunoglobulin-like receptors (KIRs) are a family of receptors expressed on Natural killer (NK) cells. The extensive polymorphism of KIR is involved in the immune responses of NK cells and influences dengue infections. We investigated the diversity of KIR copy numbers in dengue-infected patients from northeastern Thailand. Copy numbers of KIRs were determined by quantitative polymerase chain reaction in 137 dengue-infected patients, comprising 63 dengue fever (DF) and 74 dengue hemorrhagic fever (DHF). The distribution of KIRs was observed to be between 0 and 4 copies. The KIR AA genotype with heterozygous KIR2DS4D/WT was the most common in dengue patients, 25.4% DF and 23% DHF. Forty KIR profiles were determined in dengue patients, including 31 usual, 6 expanded, and 3 contracted profiles. Investigation of KIR copy number and dengue severity indicated that two copies of KIR2DL3 combined with HLA-C1C1 associated with an increased risk of DHF (OR 2.32, 95% CI 1.159-4.624, P = 0.016), whereas one copy of KIR2DL2 and KIR2DL3 together with HLA-C1C1 associated with a reduced risk of DHF (OR 0.17, 95% CI 0.058-0.482, P < 0.001). The outcomes of this study will contribute to the understanding of KIR complexity and innate immune responses in dengue infections.

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OBJECTIVES: Dengue viral infection is an ongoing epidemic in Sri Lanka, causing significant mortality and morbidity. A descriptive-analytical study was carried out using serologically confirmed Dengue patients during a 6 month period. The relationship between the elevation of hepatic enzymes and severity of Dengue was assessed after stratifying recorded maximum AST/ALT (SGOT/SGPT) values 2-15 times elevated and by the phases of the illness. Sensitivity, specificity, predictive values, and ROC curves were assessed using maximum values for AST and ALT. RESULTS: Out of 255 patients, 107(42%) were females. The majority (52.9%) were in the 20-39 year age group. Only 19.6% had DHF. No statistically significant difference was noticed in the values of maximum transaminases during the febrile phase among DF and DHF patients. Higher sensitivity and low specificity with the 1-5 times elevation range was noticed, and a higher cut-off level of more than 5 times elevation showed low sensitivity and higher specificity. The combination of both transaminases cut-offs with age and sex also does not show clinically significant predictability of severe disease. The AST and ALT elevations are not showing discriminatory predictive value on dengue severity. As different serotypes cause different epidemics, it is important to carry out large-scale specific studies considering the serotypes.

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BACKGROUND & OBJECTIVES: Presence of dengue is reported from India since 1960s. Secondary dengue infection may be more severe than primary, hence, distinction between primary and secondary dengue is essential. A way to detect secondary dengue is demonstration of anti DV IgG in patients' serum. In this study we explored the association of dengue severity with anti DV IgG positivity. METHODS: Laboratory confirmed cases of dengue (positive for anti DV IgM/ NS-1 Antigen/ DV -RNA), presenting to the hospital within 7 days of illness, were consecutively enrolled for a period of one month (September 1-30, 2018) and were tested for anti DV IgG in their serum. All PCR positive samples were serotyped. Cases positive for anti-dengue IgG were labeled as secondary cases. Clinical details were collected to assess the severity of illness. Association of dengue severity with anti DV IgG positivity was calculated. RESULTS: Of the 128 dengue positive cases, 89 (69.5%) were anti DV IgM positive, 72 (56.3%) were Dengue NS-1 positives and 37 (28.9%) were DV-RNA positive. Only 39 (30.5%) cases were having detectable anti-dengue IgG in their serum (secondary dengue). Anti-dengue IgM positivity was significantly higher in secondary dengue cases. No association of anti DV IgG positivity was seen with severity of dengue illness. INTERPRETATION & CONCLUSION: No association of IgG positivity with severity of illness was seen. D4 serotype is first time reported from Uttar Pradesh, India.

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OBJECTIVE: To review the diagnostic test accuracy and predictive value of statistical models in differentiating the severity of dengue infection. METHODS: Electronic searches were conducted in the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE (complete), PubMed and Scopus. Eligible studies to be included in this review were cohort studies with participants confirmed by laboratory test for dengue infection and comparison among the different severity of dengue infection by using statistical models. The methodological quality of the paper was assessed by independent reviewers using QUADAS-2. RESULTS: Twenty-six studies published from 1994 to 2017 were included. Most diagnostic models produced an accuracy of 75% to 80% except one with 86%. Two models predicting severe dengue according to the WHO 2009 classification have 86% accuracy. Both of these logistic regression models were applied during the first three days of illness, and their sensitivity and specificity were 91-100% and 79.3-86%, respectively. Another model which evaluated the 30-day mortality of dengue infection had an accuracy of 98.5%. CONCLUSION: Although there are several potential predictive or diagnostic models for dengue infection, their limitations could affect their validity. It is recommended that these models be revalidated in other clinical settings and their methods be improved and standardised in future.

OBJECTIF: Analyser la précision des tests de diagnostic et la valeur prédictive des modèles statistiques pour différencier la sévérité de l'infection par la dengue. MÉTHODES: Des recherches électroniques ont été effectuées dans la base de données de revues systématiques Cochrane, le registre central des essais contrôlés Cochrane, MEDLINE (complète), PUBMED et Scopus. Les études éligibles à inclure dans cette revue étaient des études de cohorte avec des participants confirmés par un test de laboratoire pour l'infection par la dengue et une comparaison entre les différentessévérités de l'infection par la dengue à l'aide de modèles statistiques. La qualité méthodologique des articles a été évaluée par des scientifiques indépendants à l'aide de QUADAS-2. RÉSULTATS: 26 études publiées de 1994 à 2017 ont été incluses. La plupart des modèles de diagnostic ont produit une précision de 75% à 80%, sauf un avec 86%. Selon la classification de l'OMS 2009, deux modèles prédisant la dengue sévère présentent une précision de 86%. Ces deux modèles de régression logistique ont été appliqués au cours des trois premiers jours de la maladie. Leur sensibilité et leur spécificité étaient respectivement de 91% à 100% et de 79,3% à 86%. Un autre modèle évaluant la mortalité à 30 jours de la dengue présentait une précision de 98,5%. CONCLUSION: Bien qu'il existe plusieurs modèles prédictifs ou diagnostiques potentiels de l'infection par la dengue, leurs limites pourraient affecter leur validité. Il est recommandé que ces modèles soient revalidées dans d'autres milieux cliniques et leurs méthodes améliorées et normalisées dans le futur.

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BACKGROUND: We study the association between prior yellow fever immunization and clinical outcomes of dengue infections in individuals of varying sexes and ages. Serological interactions between dengue virus and other flaviviruses could drive antibody dependent enhancement, which is associated with disease severity in dengue infections. This effect may influence disease severity in individuals subsequently affected by related flaviviruses, such as dengue. We compare the severity of dengue episodes between patients vaccinated and non-vaccinated against yellow fever. METHODS: We evaluated the severity of 11,448 lab-confirmed dengue cases reported in São José do Rio Preto, Brazil, in 7370 YF vaccinated patients compared to 4043 unvaccinated patients. We regressed dengue severity against YF vaccine status and a number of demographic, clinical, and laboratory variables as controls. We also evaluated the association between YF vaccination status and the clinical and laboratory symptoms of dengue patients. RESULTS: We did not find any evidence of increased risk for severe dengue in patients vaccinated against YF (odds ratio = 1.00; 95% confidence interval = 0.87-1.14). Most of the variables analyzed did not have a statistically significant association with YF vaccination status. CONCLUSIONS: We found no evidence that YF vaccination in dengue-endemic areas increases the risk of severe dengue fever.

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BACKGROUND: Considerable progress has been made in dengue management, however the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs. Apoptosis related mediators, among others, are known to correlate with severe dengue (SD) although no predictive validity is established. The objective of this study was to investigate the association of plasma cell-free DNA (cfDNA) with SD, and evaluate its prognostic value in SD prediction at acute phase. METHODS: This was a hospital-based prospective cohort study conducted in Vietnam. All the recruited patients were required to be admitted to the hospital and were strictly monitored for various laboratory and clinical parameters (including progression to SD) until discharged. Plasma samples collected during acute phase (6-48 h before defervescence) were used to estimate the level of cfDNA. RESULTS: Of the 61 dengue patients, SD patients (n = 8) developed shock syndrome in 4.8 days (95% CI 3.7-5.4) after the fever onset. Plasma cfDNA levels before the defervescence of SD patients were significantly higher than the non-SD group (p = 0.0493). From the receiver operating characteristic (ROC) curve analysis, a cut-off of > 36.9 ng/mL was able to predict SD with a good sensitivity (87.5%), specificity (54.7%), and area under the curve (AUC) (0.72, 95% CI 0.55-0.88; p = 0.0493). CONCLUSIONS: Taken together, these findings suggest that cfDNA could serve as a potential prognostic biomarker of SD. Studies with cfDNA kinetics and its combination with other biomarkers and clinical parameters would further improve the diagnostic ability for SD.

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OBJECTIVES: Dengue viral infection ranges from dengue fever to dengue haemorrhagic fever and lethal dengue shock syndrome. Currently no means are available to monitor the progression of disease. Real time PCR based gene expression analyses are used to find potential molecular markers for effective prediction of dengue clinical outcome. The accuracy of qPCR analysis is strongly dependent on transcript normalization using stably expressed endogenous genes, which if selected imprecisely can lead to misinterpreted results. We aimed to determine the best fit for endogenous gene among six genes namely COX, ACTB, GAPDH, HMBS, HPRT and B2M for dengue viral infection cases. Gene stability was inferred from qPCR data by normalizing with two algorithms geNorm and Normfinder and the rankings generated were validated by gene expression analysis against target gene IL-6. RESULTS: Both the algorithms showed ACTB, HPRT, GAPDH as most stable genes. Normalizing with the stable genes revealed a significant fold change (p < .05) in IL-6 levels of .32, .52, .69, and .62 in non-dengue febrile illness, non severe, severe and All Dengue groups respectively compared to healthy controls. based on our study, we suggest ACTB with HPRT/GAPDH combination for normalization in qPCR for precise quantification of transcripts in dengue infected studies.

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SUMMARYThe role of trace elements in dengue virulence is not yet known. The present study assessed the serum levels of two micronutrients, copper and iron, in cases of dengue fever. The study involved 96 patients of whom 48 had either severe or non-severe forms of dengue (with and without warning signs), and the remaining 48 were patients with other febrile illnesses (OFI), used as controls. Serum levels of copper and iron were evaluated at admission and by the time of defervescence using commercially available kits. At admission, no difference in the level of serum copper was observed between cases and controls. In the group of dengue cases, the copper level was found to be significantly decreased in severe and non-severe cases with warning signs, compared to non-severe cases without warning signs. In contrast, by the time of defervescence the copper level was found to be increased in all dengue cases compared to OFI controls, but no difference was observed among dengue cases. Unlike OFI controls, dengue cases showed an increasing pattern of copper levels from admission until defervescence. On the other hand, no such significant differences were observed in the serum level of iron in the clinical groups, except for a decreased iron level found in severe cases, compared to non-severe dengue without warning signs. The results show that copper is associated with dengue severity and this finding emphasizes the need to investigate the involvement of trace elements in disease severity so as to improve the prognosis of dengue.

RESUMOO papel dos elementos-traço na virulência da dengue não é ainda conhecido. O presente estudo avaliou os níveis séricos de dois micronutrientes, cobre e ferro, em casos de dengue. O estudo envolveu 96 pacientes dos quais 48 apresentavam dengue grave ou não grave (com ou sem sinais de alerta), e outros 48 pacientes com outras doenças febris (OFI) representaram os controles. Níveis séricos de cobre e ferro foram avaliados na admissão e no momento da defervescência usando kits comerciais disponíveis. À admissão, nenhuma diferença nos níveis séricos de cobre foi observada entre casos e controles. No grupo com dengue, os níveis de cobre se encontravam significativamente reduzidos nos casos graves e não graves com sinais de alerta, em comparação aos casos não graves sem sinais de alerta. Contrariamente, no momento da defervescência os níveis de cobre se encontravam aumentados em todos os casos de dengue em relação aos controles com outras doenças febris (OFI), no entanto, nenhuma diferença foi observada entre os casos de dengue. Diferentemente dos pacientes com outras doenças febris, os casos de dengue mostraram um padrão de elevação dos níveis de cobre do dia da admissão até a defervescência. Por outro lado, estas diferenças não foram observadas em relação aos níveis de ferro entre os dois grupos, com exceção de níveis de ferro reduzidos encontrados nos casos graves, em comparação aos não graves com sinais de alerta. Os resultados mostram que o cobre está associado à gravidade da dengue e esta observação enfatiza a necessidade de investigação do envolvimento de elementostraço na gravidade da doença para melhorar o prognóstico da dengue.

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The wide variation in severity displayed during Dengue Virus (DENV) infection may be influenced by host susceptibility. In several epidemiological approaches, differences in disease outcomes have been found between some ethnic groups, suggesting that human genetic background has an important role in disease severity. In the Caribbean, It has been reported that populations of African descent present considerable less frequency of severe forms compared with Mestizo and White self-reported groups. Admixed populations offer advantages for genetic epidemiology studies due to variation and distribution of alleles, such as those involved in disease susceptibility, as well to provide explanations of individual variability in clinical outcomes. The current study analysed three Colombian populations, which like most of Latin American populations, are made up of the product of complex admixture processes between European, Native American and African ancestors; having as a main goal to assess the effect of genetic ancestry, estimated with 30 Ancestry Informative Markers (AIMs), on DENV infection severity. We found that African ancestry has a protective effect against severe outcomes under several systems of clinical classification: Severe Dengue (OR: 0.963 for every 1% increase in African ancestry, 95% confidence interval (0.934-0.993), p-value: 0.016), Dengue Haemorrhagic Fever (OR: 0.969, 95% CI (0.947-0.991), p-value: 0.006), and occurrence of haemorrhages (OR: 0.971, 95% CI (0.952-0.989), p-value: 0.002). Conversely, decrease from 100% to 0% African ancestry significantly increases the chance of severe outcomes: OR is 44-fold for Severe Dengue, 24-fold for Dengue Haemorrhagic Fever, and 20-fold for occurrence of haemorrhages. Furthermore, several warning signs also showed statistically significant association given more evidences in specific stages of DENV infection. These results provide consistent evidence in order to infer statistical models providing a framework for future genetic epidemiology and clinical studies.

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