Risk Factor For Severe Dengue Research Articles

Risk factors associated with severe dengue in Latin America: A systematic review and meta-analysis.

Severe dengue is a significant health problem in Latin America, with children being the most affected. Understanding risk factors for severe dengue is crucial for enhancing patient care. Therefore, this study aims to systematically review the literature to identify the risk factors associated with severe dengue in Latin America through systematic review and meta-analysis. PubMed, SciELO, LILACS and EMBASE databases were used to search for eligible scientific articles for the review. The outcomes considered were symptoms of severe dengue, hospitalisation and death. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the quality of the studies. Data analysis was performed using STATA v 13.0 software. The degree of heterogeneity between studies was quantified using the I2 measure, and statistically significant results were defined as those with p values <0.05. Of the 1876 articles screened, 47 articles were included in the systematic review and 45 articles were analysed through meta-analysis. Identified risk factors associated with severe dengue included secondary dengue infection, female sex, white or Caucasian ethnicity and specific signs and symptoms such as headache, myalgia and/or arthralgia, vomiting/nausea, abdominal pain or tenderness, diarrhoea, prostration, lethargy, fatigue or similar. For the death outcome, respiratory symptoms and age <18 years were identified as risk factors. On the other hand, in women, the diagnosis of positive tourniquet test, platelet count <100,000 per μL and symptoms of capillary fragility were associated with a lower probability of death. These data highlight the importance of early screening of patients, to identify possible haemorrhagic signs and reduce deaths from dengue. This study has limitations, including possible publication bias, heterogeneity of results and study design biases. These findings are significant for shaping strategies, management approaches and identifying high-risk groups, which will help establish future guidelines.

Recombinant Protein Mimicking the Antigenic Structure of the Viral Surface Envelope Protein Reinforces Induction of an Antigen-Specific and Virus-Neutralizing Immune Response Against Dengue Virus.

Dengue virus (DENV), belonging to the family Flaviviridae, is the causative agent of dengue and comprises four serotypes. A second heterologous DENV infection is a critical risk factor for severe dengue, and no effective vaccine is available to prevent infection by all four DENV serotypes. Recombinant DENV vaccines are primarily based on the envelope proteins, prM and E. The E protein and its envelope domain III (EDIII) have been investigated as candidate antigens (Ags) for recombinant subunit vaccines. However, most EDIII-based Ags are monomers that do not display the cognate antigenic structure of E protein, which is essential for induction of virus-neutralizing immunity. Here, we developed recombinant DENV-2 envelope domain (r2ED) protein as an Ag that mimics the quaternary structure of E protein on the DENV surface. We confirmed that r2ED retained the conformational epitope displayed at the E-dimer interface, which reportedly exhibits broad virus-neutralizing capacity, without displaying the fusion loop epitope that causes antibody (Ab)-dependent enhancement. Furthermore, compared with EDIII alone, r2ED elicited stronger Ag-specific and cross-reactive neutralizing Ab and T cell-mediated immune responses in mice. This Ag-specific immunity was maintained at an elevated level 6months after the last immunization, suggesting sustained Ag-specific immune memory. Taken together, these observations suggest that r2ED could be used to develop an improved subunit vaccine capable of inducing a broadly cross-reactive and long-lasting immune response against DENV infection.

Association between serum albumin levels and disease severity in adult patients with dengue: A 7-year retrospective cohort study in mainland China

Objective: To identify the association between serum albumin levels and disease severity among adult patients with dengue in mainland China. Methods: This retrospective cohort study analyzed the data of adult patients (aged ≥ 18 years) hospitalized with laboratory-confirmed dengue in a tertiary center for infectious diseases from 2013 to 2019 in mainland China. Serum albumin levels were estimated and compared between patients with severe dengue and non-severe dengue. Additionally, the association between serum albumin levels and severe dengue was evaluated using a generalized linear model [relative risks (RR)]. Multivariate logistic regression analysis was performed to identify the potential predictors of severe dengue. Results: Overall, 1568 patients were included in this study. Of these patients, 34 (2.17%) developed severe dengue. The median serum albumin levels were significantly lower in patients with severe dengue than that in those with non-severe dengue (33 g/L vs. 37 g/L, P<0.001). After adjustment for age, sex, and comorbidities, hypoalbuminemia (RR 4.877, 95% CI 2.193-11.461, P<0.001) was found to be a predictor of severe dengue. Serum albumin levels (OR 1.303, 95% CI 1.161-1.462, P<0.001)] and age (OR 1.038, 95% CI 1.017-1.061, P<0.001) were significant risk factors for severe dengue. The area under the curve for serum albumin levels to distinguish severe dengue was 0.787. Conclusions: Lower serum albumin levels were significantly associated with disease severity in adult patients with dengue. Hypoalbuminemia on admission resulted in at least a four-fold increased risk of severe dengue.

Clinical Presentation with Predictors of Severity of Dengue Fever in Children of 2019, Endemic in Bangladesh

Background: Dengue fever is a serious public health problem with a wide range of clinical manifestations. In 2019, the clinical presentation of dengue infection was novel in relation to the conventional features of the previous years and also in degree of severity. So the study was done to see the varied clinical presentation, predictors of severity and outcome in pediatric population in 2019 endemic. Methods: It was a cross sectional, descriptive study conducted among 100 cases of serologically positive dengue patients from department of Paediatrics of Shaheed Suhrawardy Medical College Hospital, Dhaka from July to October, 2019.The data were collected by preformed semi-structured questionnaires and analyzed using SPSS version 16.0. Results: The mean age of the patients was 7.4 ± 3.4 years with equal male and female ratio. Children between 5-12 years were most (72%) commonly affected. Mean duration of fever was 4.5 ± 1.8 days and fever was present in 63% cases on presentation. Features of shock were present in 61% of patients who were designated as severe dengue. Most of the patients presented with abdominal pain (77%) followed by vomiting (70%), headache (35%), myalgia(32%) and retro-orbital pain(30%). Among the important clinical findings, tender hepatomegaly was present in 77% cases followed by ascites in 35% and pleural effusion in 4% cases. Melaena was found to be the most common form of bleeding manifestation. Risk factors for severe dengue were vomiting, abdominal pain, melaena, ascites and low platelet count. Majority of the patients (95%) were discharged, 4% were referred to ICU and only 1% died. Conclusion: Majority of admitted pediatric dengue patients presented with severe Dengue (Dengue Shock Syndrome). Presence of vomiting, abdominal pain, ascites and low platelet count were found to be significant in predicting severity of dengue. J Shaheed Suhrawardy Med Coll 2021; 13(1): 8-14

Severe dengue in adults and children, Ouagadougou (Burkina Faso), West Africa, October 2015–January 2017

Although dengue is the most common arbovirus infection worldwide, studies of severe dengue in Africa are lacking, and risk factors for severe dengue have been insufficiently described. This study was conducted in the context of the 2016 dengue epidemic in Burkina Faso to determine the prevalence of severe dengue, identify factors associated with severe dengue, and perform mapping of dengue cases in the country's capital, Ouagadougou. This cross-sectional study was conducted from November 2015 to January 2017. Data were collected in 15 public and private health centres, and included sociodemographic, clinical and patient outcome variables. Dengue was diagnosed using SD Bioline Dengue Duo rapid diagnostic tests. Data were analysed using Epi-Info Version 7. Logistic regression was used to identify predictors of severe dengue. P<0.05 was considered significant. Dengue case mapping was performed using Geographic Information System software (ArcGIS). Of the 811 patients who tested positive for dengue, 609 (75%) had early dengue (AgNS1 positive) and 272 (33.5%) had severe dengue. Patient age ranged from 1 to 83 years (median 30.5 years) and 393 (48.3%) were female. Renal failure (13.1%) and severe bleeding (10.6%) were the most common signs of severe dengue. Risk factors for severe dengue included age, male sex, haemoglobin S, diabetes, hypertension, and primary dengue.Dengue cases weremore concentratedin sectors located in the centre of the city and close to the health centres. Dengue is increasingly common in Africa and factors associated with severity should be sought systematically as soon as a patient tests positive. Additional studies are needed to determine if the factors found to be associated with severity can be used to identify patients at risk for dengue-related complications, and to provide early and specialized management to reduce morbidity and mortality related to dengue in Africa.

Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO).

Background: Dengue is a disease of major global importance. While most symptomatic infections are mild, a small proportion of patients progress to severe disease with risk of hypovolaemic shock, organ dysfunction and death. In the absence of effective antiviral or disease modifying drugs, clinical management is solely reliant on supportive measures. Obesity is a growing problem among young people in Vietnam and is increasingly recognised as an important risk factor for severe dengue, likely due to alterations in host immune and inflammatory pathways. Metformin, a widely used anti-hyperglycaemic agent with excellent safety profile, has demonstrated potential as a dengue therapeutic in vitro and in a retrospective observational study of adult dengue patients with type 2 diabetes. This study aims to assess the safety and tolerability of metformin treatment in overweight and obese dengue patients, and investigate its effects on several clinical, immunological and virological markers of disease severity. Methods: This open label trial of 120 obese/overweight dengue patients will be performed in two phases, with a metformin dose escalation if no safety concerns arise in phase one. The primary endpoint is identification of clinical and laboratory adverse events. Sixty overweight and obese dengue patients aged 10-30 years will be enrolled at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Participants will complete a 5-day course of metformin therapy and be compared to a non-treated group of 60 age-matched overweight and obese dengue patients. Discussion: Previously observed antiviral and immunomodulatory effects of metformin make it a promising dengue therapeutic candidate in appropriately selected patients. This study will assess the safety and tolerability of adjunctive metformin in the management of overweight and obese young dengue patients, as well as its effects on markers of viral replication, endothelial dysfunction and host immune responses. Trial registration: ClinicalTrials.gov: NCT04377451 (May 6 th 2020).

Risk factors of severe dengue in children: A nested case-control study

Background: Dengue is a mosquito-borne viral disease whose severity varies from a mild undifferentiated fever to severe fatal form. The objectives of this study were to determine the prevalence and risk factors of severe dengue. Subjects and Methods: This nested case–control study was done in a medical college hospital in South India from October 2019 to January 2020. Children between 1 month and 12 years of age who presented with fever without focus and tested positive for dengue serology were included. Demographic data, anthropometry, clinical features, and laboratory parameters were noted down from all children. Severity of illness was classified according to the World Health Organization dengue guidelines 2009. Prevalence of severe dengue was expressed in proportion with 95% confidence interval (CI). Bivariate analysis was performed using Chi-square test, Fisher's test, and Student's t-test, and a P Results: Out of 370 children, 192 (51.9%) had dengue without warning signs, 168 (45.4%) had dengue with warning signs, and 10 had severe dengue. The prevalence (95% CI) of severe dengue was 2.7% (1.3%–4.9%). Abdominal pain/tenderness (odd's ratio [OR] - 7.429), facial puffiness (OR - 4.333), hepatomegaly (OR - 3.857), and pleural effusion (OR - 13.222) were the significant risk factors for severe dengue. Conclusions: The significant risk factors for severe dengue were abdominal pain/tenderness, facial puffiness, hepatomegaly, and pleural effusion.

Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO)

Background: Dengue is a disease of major global importance. While most symptomatic infections are mild, a small proportion of patients progress to severe disease with risk of hypovolaemic shock, organ dysfunction and death. In the absence of effective antiviral or disease modifying drugs, clinical management is solely reliant on supportive measures. Obesity is a growing problem among young people in Vietnam and is increasingly recognised as an important risk factor for severe dengue, likely due to alterations in host immune and inflammatory pathways. Metformin, a widely used anti-hyperglycaemic agent with excellent safety profile, has demonstrated potential as a dengue therapeutic in vitro and in a retrospective observational study of adult dengue patients with type 2 diabetes. This study aims to assess the safety and tolerability of metformin treatment in overweight and obese dengue patients, and investigate its effects on several clinical, immunological and virological markers of disease severity. Methods: This open label trial of 120 obese/overweight dengue patients will be performed in two phases, with a metformin dose escalation if no safety concerns arise in phase one. The primary endpoint is identification of clinical and laboratory adverse events. Sixty overweight and obese dengue patients aged 10-30 years will be enrolled at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Participants will complete a 5-day course of metformin therapy and be compared to a non-treated group of 60 age-matched overweight and obese dengue patients. Discussion: Previously observed antiviral and immunomodulatory effects of metformin make it a promising dengue therapeutic candidate in appropriately selected patients. This study will assess the safety and tolerability of adjunctive metformin in the management of overweight and obese young dengue patients, as well as its effects on markers of viral replication, endothelial dysfunction and host immune responses. Trial registration: ClinicalTrials.gov: NCT04377451 (May 6 th 2020).

Clinical and laboratory profile of dengue fever in children in a tertiary care hospital of Navi Mumbai, India

Background: Dengue fever is a mosquito born arboviral illness endemic in tropical countries and causes significant mortality and morbidity due to lack of definitive treatment. The objective of this study was to assess the clinical and laboratory profile of confirmed cases of dengue in children up to 12 years of age and also to charactrise the risk factors for severe dengue.Methods: This is a descriptive, observational, retrospective study done in the Department of Pediatrics, Terna Medical College, Nerul, Navi Mumbai, India. Medical records of all children up to 12 years of age diagnosed to have dengue were reviewed. Their clinical and laboratory profile were recorded in a pro forma and analyzed. All cases were classified as per WHO guidelines into non severe and severe dengue cases.Results: Among the 117 confirmed dengue cases, (84.6%) had non severe dengue and (15.4%) had severe dengue. The most common age group affected was 9-12 years (45.3%) with a male to female ratio of 2.4:1. Fever was the most common clinical feature seen in all cases followed by headache (83%), myalgia (81%), ascites (24.7%), vomiting (17.9%). Clinical signs of ascitis, hepatomegally, gastrointestinal bleeding, pleural effusion and shock were predominantly associated with severe dengue cases. Laboratory parameters showed leukopenia in 58.1% and thrombocytopenia (platelet counts &lt;20,000/cumm3) in16.2% cases. Elevated liver enzymes, raised hematocrit (36.3%) and coagulation abnormalities were seen in over 50% dengue cases and were significantly associated with severe dengue dengue.Conclusions: Knowledge of clinical and laboratory profile of dengue cases of a particular area will help in early prediction of risk factors for severe dengue resulting in favourable outcome of such cases.

Metformin as adjunctive therapy for dengue in overweight and obese patients: a protocol for an open-label clinical trial (MeDO).

Background: Dengue is a disease of major global importance. While most symptomatic infections are mild, a small proportion of patients progress to severe disease with risk of hypovolaemic shock, organ dysfunction and death. In the absence of effective antiviral or disease modifying drugs, clinical management is solely reliant on supportive measures. Obesity is a growing problem among young people in Vietnam and is increasingly recognised as an important risk factor for severe dengue, likely due to alterations in host immune and inflammatory pathways. Metformin, a widely used anti-hyperglycaemic agent with excellent safety profile, has demonstrated potential as a dengue therapeutic in vitro and in a retrospective observational study of adult dengue patients with type 2 diabetes. This study aims to assess the safety and tolerability of metformin treatment in overweight and obese dengue patients, and investigate its effects on several clinical, immunological and virological markers of disease severity. Methods: This open label trial of 120 obese/overweight dengue patients will be performed in two phases, with a metformin dose escalation if no safety concerns arise in phase one. The primary endpoint is identification of clinical and laboratory adverse events. Sixty overweight and obese dengue patients aged 10-30 years will be enrolled at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. Participants will complete a 5-day course of metformin therapy and be compared to a non-treated group of 60 age-matched overweight and obese dengue patients. Discussion: Previously observed antiviral and immunomodulatory effects of metformin make it a promising dengue therapeutic candidate in appropriately selected patients. This study will assess the safety and tolerability of adjunctive metformin in the management of overweight and obese young dengue patients, as well as its effects on markers of viral replication, endothelial dysfunction and host immune responses. Trial registration: ClinicalTrials.gov: NCT04377451 (May 6 th 2020).

The spectrum of disease severity, the burden of hospitalizations and associated risk factors in confirmed dengue among persons of all ages: findings from a population based longitudinal study from Barbados

Background: Dengue can be severe and potentially fatal in a small proportion. Risk factors for severe dengue have been highlighted but long term population based study is lacking. We assesses the severity and hospitalization in dengue.Methods: This is a longitudinal population based prospective study of all persons with confirmed dengue in Barbados during the years 2006 through 2015. Most recent WHO criteria were used for classifying dengue severity. Disease severity and hospitalization need were two main outcomes.Results: There were 2939 ambulatory and 1234 hospitalized cases. Compared to those in the age group 16–60 years, the risk of hospitalization was higher among persons over 61 years (RR = 1.8) and those under 16 years (RR = 1.7). Overall, 190 (4.4%), 771 (17.8%) and 3202 (73.7%) were classified as severe and dengue with and without warning signs respectively. The risk of severe dengue was higher in the over 60 years age group compared to the 16–60 years (RR = 1.97). Primary infection was at a lower risk of severe dengue compared to secondary infection (RR = 0.46).Conclusions: Less than 5% of dengue presents with severe disease, the risk being highest among the elderly and those with previous dengue.

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.

2016 dengue outbreak in Buenos Aires: A case series

Background: In 2016, the Metropolitan Area of Buenos Aires suffered the largest dengue outbreak ever recalled with 12495 cases assisted in the city. The main circulating serotype was DEN-1 and affected a population predominantly non-immune. Methods & Materials: Description of clinical and biochemical characteristics of suspected dengue cases (as defined by argentinian guidelines), in adults attended on a specialized hospital between the 11th and the 18th epidemiological week of 2016, when the outbreak was officially announced. Results: 1728 adults with an acute febrile illness were assisted; 1468 fulfilled the inclusion criteria. 57 cases had recently travelled to areas with active circulation of dengue and 124 had risk factors for severe dengue. The median age was 34 (range 18-80) and 50% were women. The symptoms most frequently associated were headache (87%), myalgia or arthralgia (83%), nausea or vomiting (55%), diarrhea (24%), abdominal pain (29%), rash or pruritus (36%). 7.5% presented with bleeding, mainly epistaxis (28%), gingival hemorrhage (29%) and metrorrhagia (22%). Blood tests were performed in 1300 patients. Before the fifth day of symptoms (n = 924), 66% of patients presented with laboratory findings suggestive of dengue: hematocrit > 47 (11%), leucopenia (44%) and thrombocytopenia (41%). During the overall follow-up period (median of 2 consults, range 1-10), 82% showed laboratory findings suggestive of dengue, mainly thrombocytopenia (64%), leucopenia (54%) and relative lymphocytosis (32%). 222 patients required IV fluids and 49 of them were hospitalized. Conclusion: In these series, there was a high frequency of gastrointestinal symptoms, supposing a challenge for the differential diagnosis. The course of the illness was benign in most cases. A normal CBC before the fifth day of symptoms should not exclude the diagnosis of dengue. In the context of an outbreak, a close follow up is essential for the diagnosis and the early detection of alarm signs, in order to prevent the progression to severe dengue.

Abstract PD-011: RISK FACTORS FOR SEVERE DENGUE: RETROSPECTIVE OBSERVATIONAL STUDY FROM A PICU IN SOUTHERN INDIA

Aims & Objectives: To describe clinical pattern of dengue fever (DF) and find out risk factors for severe dengue. Methods A retrospective study covering calendar year 2017 was done in a tertiary care centre in south India. Case records of children (1 month-13 years) admitted to pediatric emergency with suspected DF were screened and data analyzed. Results In 2017, 160 cases were screened of which 121(75.6%) were dengue proven (revised WHO case definition) and 22(13.8%) had probable dengue. Cases were classified as DF (9.1%), dengue fever with warning signs (66.4%) and severe dengue (24.5%). Median age was 8 years (IQR 4.8–10 years) and 54.5% were males. Fever (100%), vomiting (76.2%) and pain abdomen (54.3%) were the most common presenting symptoms. Hepatomegaly (64.3%) and thrombocytopenia (86.5%) were the commonest sign and investigation findings. There were 2 deaths (0.01%) and shock (23.8%) and massive pleural effusion (14.7%) were most frequent complications (Figure). Demographic parameters, symptoms, signs and investigations were studied as possible risk factors for severity. Female sex was associated with severe dengue (OR=1.6; 95% C.I. [0.74–3.45]). Among symptoms, bleeding tendency had significant association with severe dengue (OR=5.7; 95% C.I. [2.16–15.23]). Hepatomegaly (OR=3.5; 95% C.I. [1.32–9.0]) and severe thrombocytopenia (OR=3.63; 95% C.I. [1.5–8.8]) had significant association with severe dengue among signs and investigations (Table).Conclusions Studies on pattern of DF from different regions should help in mapping global trends. The key to management in severe dengue is meticulous monitoring and supportive care. Identification of risk factors could streamline specific protocols for actionable outcomes in Pediatric Intensive Care Units.

Metformin Use and Severe Dengue in Diabetic Adults

Diabetes mellitus is a risk factor for severe dengue in adults, but few studies have examined the association between metformin use and disease severity in dengue. In addition to its effect on glucose control, metformin has been associated with pleiotropic properties in preclinical studies. Using a cohort of laboratory-confirmed adult (≥21 years) dengue patients with diabetes mellitus admitted to Tan Tock Seng Hospital, we conducted a retrospective cohort study involving 131 (58.7%) metformin users and 92 (41.3%) non-users. Dengue severity was categorized as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in World Health Organization (WHO) 1997 criteria and severe dengue (SD) in WHO 2009 criteria. Multivariable Poisson regression with robust error variance was used to estimate risk ratio (RR). Compared with non-use, metformin use was associated with a decreased risk of developing severe dengue (adjusted risk ratio [aRR] = 0.60, 95% confidence interval [CI]: 0.37–0.98, P = 0.04). Additionally, there was an inverse dose-response relationship (aRR = 0.69, 95% CI: 0.49–0.98, P = 0.04) with dengue severity as classified by WHO 2009 criteria. Use of metformin, however, was not associated with dengue severity based on WHO 1997 criteria; and no dose-response relationship was noted. Our results suggest metformin use could attenuate disease severity in dengue-infected diabetes mellitus individuals.

Clinical profile and outcome of children admitted with dengue fever in a tertiary care hospital in South India

Objective: The objective is to study the clinical profile and outcome of patients admitted with dengue fever and to identify the risk factors for severe dengue (SD). Materials and Methods: This is a descriptive study of children admitted with a diagnosis of dengue fever from January 2013 to June 2014 in a tertiary care Medical College Hospital in South India. Results: A total of 306 children were admitted with dengue fever during the study period with a mean age of 7.8±3.2 years and male:female ratio of 1.06:1. The most common symptoms apart from fever were vomiting (54.9%) and abdominal pain (36.3%). Tender hepatomegaly and narrow pulse pressure were the most common signs. 131 (42.8%) were classified as dengue fever without warning signs, 119 (38.8%) as dengue fever with warning signs (DWS), and 56 (18.4%) as severe dengue (SD) according to the WHO guidelines 2012. A significant difference in aspartate aminotransferase’ and alanine aminotransferase elevation was noted among dengue fever without warning signs, DWS, and SD. Hemoconcentration, thrombocytopenia, hypoproteinemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hepatic derangement, elevated urea, and creatinine were significantly associated with SD. The mean values of prothrombin time, international normalized ratio, and activated partial thromboplastin time in SD were 19±3.7 s, 1.5±0.3 s, and 46±7 s, respectively. The finding of thalamic hypodensity in one patient with dengue encephalopathy was only rarely described in literature. Conclusion: Bleeding manifestations altered coagulation profile as well as deranged liver functions can be used as predictors of severe dengue fever.

Proposal of a Clinical Decision Tree Algorithm Using Factors Associated with Severe Dengue Infection

BackgroundWHO’s new classification in 2009: dengue with or without warning signs and severe dengue, has necessitated large numbers of admissions to hospitals of dengue patients which in turn has been imposing a huge economical and physical burden on many hospitals around the globe, particularly South East Asia and Malaysia where the disease has seen a rapid surge in numbers in recent years. Lack of a simple tool to differentiate mild from life threatening infection has led to unnecessary hospitalization of dengue patients.MethodsWe conducted a single-centre, retrospective study involving serologically confirmed dengue fever patients, admitted in a single ward, in Hospital Kuala Lumpur, Malaysia. Data was collected for 4 months from February to May 2014. Socio demography, co-morbidity, days of illness before admission, symptoms, warning signs, vital signs and laboratory result were all recorded. Descriptive statistics was tabulated and simple and multiple logistic regression analysis was done to determine significant risk factors associated with severe dengue.Results657 patients with confirmed dengue were analysed, of which 59 (9.0%) had severe dengue. Overall, the commonest warning sign were vomiting (36.1%) and abdominal pain (32.1%). Previous co-morbid, vomiting, diarrhoea, pleural effusion, low systolic blood pressure, high haematocrit, low albumin and high urea were found as significant risk factors for severe dengue using simple logistic regression. However the significant risk factors for severe dengue with multiple logistic regressions were only vomiting, pleural effusion, and low systolic blood pressure. Using those 3 risk factors, we plotted an algorithm for predicting severe dengue. When compared to the classification of severe dengue based on the WHO criteria, the decision tree algorithm had a sensitivity of 0.81, specificity of 0.54, positive predictive value of 0.16 and negative predictive of 0.96.ConclusionThe decision tree algorithm proposed in this study showed high sensitivity and NPV in predicting patients with severe dengue that may warrant admission. This tool upon further validation study can be used to help clinicians decide on further managing a patient upon first encounter. It also will have a substantial impact on health resources as low risk patients can be managed as outpatients hence reserving the scarce hospital beds and medical resources for other patients in need.

Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

The four dengue virus serotypes (DENV1-4) are mosquito-borne flaviviruses that infect ∼ 390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.

Clinical profile of dengue among children according to revised WHO classification: analysis of a 2012 outbreak from Southern India.

To study the clinical profile of dengue fever and its outcome in children with application of revised WHO classification and to identify risk factors for severe dengue. This study was a prospective observational study of children diagnosed with dengue from July 2012 through February 2013 at a tertiary care hospital in Bangalore, Karnataka (South India). Eighty one children including 55(67.9 %) boys and 26(32.1 %) girls were diagnosed with dengue. Mean age of presentation was 8 y. Vomiting (60.5 %), pain abdomen (32 %), headache (30.9 %), myalgia (23.5 %) and bleeding manifestations (16 %) were the common presenting complaints. Facial puffiness (63 %), hepatomegaly (51.9 %), ascites (48.1 %), pleural effusion (39.5 %) and petechiae (14.8 %) were noted during examination. Dengue NS1 antigen, IgM, IgG were positive in 66.7 %, 29.6 % and 18.5 % of cases respectively. Investigations showed hemoconcentration in 72.8 %, leucopenia (34.5 %), thrombocytopenia (82.7 %), abnormal liver function test (LFT) (33.3 %). USG abdomen was suggestive of dengue in 66.7 % and gall bladder edema was noted in 53.1 %. Two patients died out of the total 81 patients with mortality rate of 2.5 %. Number of cases classified as Dengue without warning signs (D), Dengue with warning signs (DW) and Severe Dengue (SD) were 48.1 %, 27.2 % and 24.7 % respectively. Children between 5 and 15 y were most affected by dengue fever. Pain abdomen and vomiting were most common presenting symptoms. Ascites, plerural effusion, hepatomegaly, gall bladder wall thickening and abnormal LFT were found significantly high in severe dengue cases.

A tetravalent alphavirus-vector based dengue vaccine provides effective immunity in an early life mouse model

Dengue viruses (DENV1-4) cause 390 million clinical infections every year, several hundred thousand of which progress to severe hemorrhagic and shock syndromes. Preexisting immunity resulting from a previous DENV infection is the major risk factor for severe dengue during secondary heterologous infections. During primary infections in infants, maternal antibodies pose an analogous risk. At the same time, maternal antibodies are likely to prevent induction of endogenous anti-DENV antibodies in response to current live, attenuated virus (LAV) vaccine candidates. Any effective early life dengue vaccine has to overcome maternal antibody interference (leading to ineffective vaccination) and poor induction of antibody responses (increasing the risk of severe dengue disease upon primary infection). In a previous study, we demonstrated that a non-propagating Venezuelan equine encephalitis virus replicon expression vector (VRP), expressing the ectodomain of DENV E protein (E85), overcomes maternal interference in a BALB/c mouse model. We report here that a single immunization with a tetravalent VRP vaccine induced NAb and T-cell responses to each serotype at a level equivalent to the monovalent vaccine components, suggesting that this vaccine modality can overcome serotype interference. Furthermore, neonatal immunization was durable and could be boosted later in life to further increase NAb and T-cell responses. Although the neonatal immune response was lower in magnitude than responses in adult BALB/c mice, we demonstrate that VRP vaccines generated protective immunity from a lethal challenge after a single neonatal immunization. In summary, VRP vaccines expressing DENV antigens were immunogenic and protective in neonates, and hence are promising candidates for safe and effective vaccination in early life.