Liver involvement in dengue: A systematic review.

Liver involvement is an unusual yet frequently overlooked dengue complication. Pivotal for an efficient clinical management, the early diagnosis of dengue-associated liver involvement relies on an accurate description of its clinical and biological characteristics, its prognosis factors, its association with severe dengue and its clinical management. We conducted a systematic review by searching PubMed and Web of Science databases for original case reports, cohort and cross-sectional studies reporting the clinical and/or biological features of dengue-associated liver involvement. The study was registered in PROSPERO (CRD42021262657). Of the 2552 articles identified, 167 were included. Dengue-associated liver involvement was characterised by clinical features including abdominal pain, hepatomegaly, jaundice, nausea/vomiting, and an echogenic liver exhibiting hepatocellular necrosis and minimal inflammation. Elevated Aspartate Aminotransferase and Alanine Aminotransferase but also elevated bilirubin, Alkaline Phosphatase, gamma-glutamyl transferase, increased International Normalised Ratio, creatinine and creatine kinase, lower albumin and prolonged prothrombin and activated partial thromboplastin time were prevalent in dengue-associated liver involvement. Cardiovascular and haematological systems were frequently affected, translating in a strong association with severe dengue. Liver involvement was more common in males and older adults. It was associated with dengue virus serotype-2 and secondary infections. Early paracetamol intake increased the risk of liver involvement, which clinical management was mostly conservative. In conclusion, this systematic review demonstrates that early monitoring of transaminases, clinical assessment, and ultrasound examination allow an efficient diagnosis of dengue-associated liver involvement, enabling the early identification and management of severe dengue.

Comparison of predictive models using logistic regression, classification tree, and structural equation model for severe dengue.

BACKGROUND: The aim of this study was to compare the predictive performance of three statistical models-logistic regression, classification tree, and structural equation model (SEM)-in predicting severe dengue illness. METHODS/FINDINGS: We adopted modified classification of dengue illness severity based on WHO 1997 guideline. Predictive models were constructed using demographic factors and laboratory indicators on the day of fever occurrence. We developed statistical predictive models using data from two hospital cohorts in Thailand, consisting of 257 Thai children. Different predictive models for each category of severe dengue illness were developed employing logistic regression, classification tree, and SEM. The probability of discrimination of each model for severe output of disease was analyzed with external validation data sets from 55 and 700 patients not used in model development. From external validation using predictors on the day of presentation to the hospital, the area under the receiver operating characteristic curve was between 0.65 and 0.84 for the regression model. It was between 0.73 and 0.85 for SEM models. Classification tree models showed good results of sensitivity, ranging from 0.95 to 0.99. However, they showed poor specificity ranging from 0.10 to 0.44. CONCLUSIONS: Our study showed that SEM is comparable to logistic regression or classification tree, which was widely used for more severe form of dengue prediction.

Differential Proteomic Profiling at Different Phases of Dengue Infection: An Intricate Insight from Proteins to Pathogenesis.

Dengue fever is a rapidly emerging tropical disease and an important cause of morbidity in its severe form worldwide. A wide spectrum of the pathophysiology is associated with the transition of dengue fever to severe dengue, which is driven by the host immune response and might reflect in patients' proteome profile. This study aims to analyze the plasma from different phases of dengue-infected patients at two time points. A mass-spectrometry-based proteomic approach was utilized to understand the involvement of probable candidate proteins toward developing a more severe, hemorrhagic form of dengue fever. Dengue-infected hospital-admitted patients with <5 days of fever were included in this study. Patient samples from the acute phase were screened for the presence of NS1 antigen using ELISA and subjected to molecular serotyping. Dengue molecular serotype-confirmed patient samples, pairwise from acute and critical phases with healthy control were subjected to qualitative and quantitative proteomic analysis, and then pathway analysis was performed. The protein-protein interaction network between the dengue virus and host proteins was depicted in the search for proteins associated with severe dengue pathophysiology. An array of apolipoprotein, cytokines, and endothelial proteins in association with virus replication and endothelial dysfunction were validated as biomolecules involved in severe dengue pathophysiology.

Febrile Phase Soluble Urokinase Plasminogen Activator Receptor and Olfactomedin 4 as Prognostic Biomarkers for Severe Dengue in Adults.

BACKGROUND: Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor (suPAR) and olfactomedin 4, and mast cell mediators, chymase and tryptase, have not been measured longitudinally across the dengue phases. The utility of these proteins as prognostic biomarkers for severe dengue has also not been assessed in an older adult population. METHODS: We prospectively enrolled 99 adults with dengue-40 dengue fever, 46 dengue with warning signs and 13 severe dengue, along with 30 controls. Plasma levels of suPAR, olfactomedin 4, chymase and tryptase were measured at the febrile, critical and recovery phases in dengue patients. RESULTS: The suPAR levels were significantly elevated in severe dengue compared to the other dengue severities and controls in the febrile (P < .001), critical (P < .001), and recovery (P = .005) phases. In the febrile phase, suPAR was a prognostic biomarker of severe dengue, with an AUROC of 0.82. Using a cutoff derived from Youden's index (5.4 ng/mL) and an estimated prevalence of severe dengue (16.5%) in our healthcare institution, the sensitivity was 71.4% with a specificity of 87.9% in the febrile phase, and the positive and negative predictive values were 54.7% and 95.8%, respectively. Olfactomedin 4 was elevated in dengue patients but not in proportion to disease severity in the febrile phase (P = .04) There were no significant differences in chymase and tryptase levels between dengue patients and controls. CONCLUSIONS: In adult dengue, suPAR may be a reliable prognostic biomarker for severe dengue in the febrile phase.

Genotype of dengue virus serotype 1 in relation to severe dengue in Guangzhou, China.

Guangzhou has been the city most affected by the dengue virus (DENV) in China, with a predominance of DENV serotype 1 (DENV-1). Viral factors such as dengue serotype and genotype are associated with severe dengue (SD). However, none of the studies have investigated the relationship between DENV-1 genotypes and SD. To understand the association between DENV-1 genotypes and SD, the clinical manifestations of patients infected with different genotypes were investigated. A total of 122 patients with confirmed DENV-1 genotype infection were recruited for this study. The clinical manifestations, laboratory tests, and levels of inflammatory mediator factors were statistically analyzed to investigate the characteristics of clinical manifestations and immune response on the DENV-1 genotype. In the case of DENV-1 infection, the incidence of SD with genotype V infection was significantly higher than that with genotype I infection. Meanwhile, patients infected with genotype V were more common in ostealgia and bleeding significantly. In addition, levels of inflammatory mediator factors including IFN-γ, TNF-α, IL-10, and soluble vascular cell adhesion molecule 1 were higher in patients with SD infected with genotype V. Meanwhile, the concentrations of regulated upon activation normal T-cell expressed and secreted and growth-related gene alpha were lower in patients with SD infected with genotype V. The higher incidence of SD in patients infected with DENV-1 genotype V may be attributed to elevated cytokines and adhesion molecules, along with decreased chemokines.

Serum ferritin level as a prognostic biomarker for predicting dengue disease severity: A systematic review and meta-analysis.

Serum ferritin levels serves as biomarkers in many inflammatory and infectious diseases. This current systematic review and meta-analysis evaluated whether serum ferritin levels are associated with severe dengue and its utility as a biomarker of disease severity. Literature searches were conducted in PubMed, Scopus, ScienceDirect, the Cochrane library, and Google Scholar. A total of 18 studies examining the serum ferritin levels in dengue cases in the context of disease severity (nine studies having dengue classification as non-severe vs. severe dengue cases, and nine studies having dengue classification as dengue without warning signs (DwoWS), dengue with warning signs (DwWS), and severe dengue cases) were included and the quality of the studies was assessed using the Quality in Prognostic Factor Studies tool. The meta-analysis was performed using STATA software to calculate the effect size as a standardized mean difference (SMD) or Hedges 'g' for the continuous outcome. Higher serum ferritin levels were found in severe dengue cases compared to non-severe cases [SMD (Hedges 'g') 4.05 (95% C.I. 2.09-6.00), (I2  = 98.8%)]. In the second group, DwWS cases showed high serum ferritin levels compared to DwoWS [SMD 2.01 (95% C.I. 0.92-3.10), (I2  = 97.89%)], and severe dengue cases showed higher levels of serum ferritin compared to DwWS [SMD 2.66 (95% C.I. 1.72-4.48), (I2  = 98.78%)] and DwoWS cases [SMD 6.65 (95% C.I. 1.72-11.59), (I2  = 99.78%]. Subgroup analysis for the country of study (India vs. others), ferritin testing methods, and ferritin measurement day revealed testing method as a significant contributor to heterogeneity. To conclude, the present study suggests serum ferritin as a prognostic marker for dengue disease severity. Multi-centric studies involving a large number of dengue patients with a uniform case definition accounting for all the confounding variables might help in determining a universal cut-off value to discriminate between non-severe and severe dengue.

Evaluation of clinical and laboratory characteristics of dengue viral infection and risk factors of dengue hemorrhagic fever: a multi-center retrospective analysis.

BACKGROUND: Dengue Viral Infection (DVI) has become endemic in Pakistan since the first major outbreak in Karachi in 1996. Despite aggressive measures taken by relevant authorities, Pakistan has been dealing with a worsening dengue crisis for the past two decades. DHF is severe form of dengue infection which is linked with significant morbidity and mortality. Early identification of severe dengue infections can reduce the morbidity and mortality. In this context we planned current study in which we find out the different factors related with DHF as well as clinical laboratory features of DHF and compare them to DF so that patients can be best evaluated for DHF and managed accordingly at admission. METHODS: Retrospective study conducted over a period of 6 years (2013-2018) in two tertiary care hospitals in Pakistan. Data were collected by using a pre-structured data collection form. Data were statistically analyzed to determine the clinical and laboratory characteristics of DVI and risk factors of dengue hemorrhagic fever (DHF). RESULTS: A total 512 dengue cases (34.05 ± 15.08 years; Male 69.53%) were reviewed. Most common clinical manifestations of DVI were fever (99.60%), headache (89.1%), chills (86.5%), rigors (86.5%), myalgia (72.3%). Less common clinical manifestations were vomiting (52.5%), arthralgia (50.2%) and skin rashes (47.5%). Furthermore, nasal bleeding (44.1%), gum bleeding (32.6%), pleural effusion (13.9%) and hematuria (13.1%) were more profound clinical presentations among DHF patients. Mortality rate was 1.5% in this study. Logistic regression analysis indicated that delayed hospitalization (OR: 2.30) and diabetes mellitus (OR:2.71), shortness of breath (OR:2.21), association with risk groups i.e., living near stagnant water, travelling to endemic areas, living in endemic regions (OR:1.95), and presence of warning signs (OR:2.18) were identified as risk factors of DHF. Statistically we found that there is strong association of diabetes mellitus (DM) with DHF while the patient suffering from DM individually had higher odds (2.71) of developing DHF than patients without disease. CONCLUSIONS: The current study demonstrated that the clinical and laboratory profiles of DF and DHF are significantly distinct. Significant predictors of DHF were advanced age, diabetes mellitus, ascites, pleural effusion, thick gallbladder and delayed hospitalization. The identification of these factors at early stage provides opportunities for the clinicians to identify high risk patients and to reduce dengue-related morbidity and mortality.

Early-phase factors associated with pediatric severe dengue in the Thai-Myanmar cross-border region.

BACKGROUND: Dengue disease is caused by dengue virus, which is transmitted by Aedes mosquitoes in tropical and subtropical regions worldwide. Although most infected individuals have benign febrile illness or no apparent symptoms, a small percentage develop severe dengue, a potentially fatal condition that occurs after a febrile stage. Many studies have identified factors predicting dengue severity among different populations and time courses. To help find practical approaches applicable in remote settings, we focused on the investigation of early factors associated with severe dengue in Thai-Myanmar cross-border region. METHODS: This retrospective case-control study was performed to determine factors contributing to severe dengue in the pediatric population. We reviewed the hospital records of patients with dengue infection aged 0-19 years who were admitted to Maesot General Hospital, situated near the Thai-Myanmar cross-border region, between 2017 and 2022. Medical data during the first 5 days of illness and outcomes were collected and analyzed. RESULTS: This study included 144 patients with a serologically confirmed diagnosis of dengue infection, with 43 severe and 101 non-severe cases. Among biological factors, being an infant and belonging to an ethnic group in Myanmar showed a significant association with severe dengue in the univariable analysis. Multivariable logistic regression revealed that the presence of mucosal bleeding (adjusted OR 5.39, 95% CI 1.06-27.52, P = 0.043), a change in hematocrit ≥ 10% (adjusted OR 3.68, 95% CI 1.15-11.74, P = 0.028), and serum albumin < 35 g/L (adjusted OR 8.10, 95% CI 2.55-25.72, P < 0.001) during the first 5 days of illness were significantly associated with developing severe dengue. CONCLUSIONS: This study supports the use of certain WHO warning signs and hematocrit change during febrile phase to predict pediatric severe dengue in low-resource settings. Potential factors such as very young age and ethnic groups warrant further exploration to identify risks contributing to severe dengue infection.

Utility of the WHO dengue guidelines in pediatric immunological studies.

Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.

Impact of apoptotic biomarkers for prognosis of dengue disease severity among eastern Indian patients.

Dengue virus (DENV) induced severe manifestations is a precursor for fatality among infected patients. Previous autopsy examinations of severe dengue (SD) patients reported presence of apoptotic cells in liver, brain, intestinal and lung tissues. Thus, serum-level of major apoptotic proteins of dengue patients was evaluated in the current study, along with their biochemical parameters. Patients were categorized according to World Health Organization (WHO)-defined classification. DENV-infection was screened among 165 symptomatic patients by quantitative reverse transcription polymerase chain reaction, antidengue IgM, and IgG ELISA. Serum levels of apoptotic (Capase-3,7,8, Bcl-2 and FasL) and hepatic-markers, lipid profile, hematological parameters of 78 dengue-positive patients were determined by sandwich-ELISA/immunoturbidimetry/auto-analyzer. Significantly higher levels of caspase-3,7,8 and FasL was detected among SD patients compared to those without warning (WOW) signs. Amongst biochemical parameters, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase serum concentrations significantly increased among severe patients. Principal component analysis followed by hierarchical clustering differentiated severe and with warning dengue patient groups from those WOW using caspase-3,7,8 and FasL biomarkers-thus clearly distinguishing severe-dengue group. Correlation analyses also established strong positive correlation between caspase-3,7,8 and FasL. Thus, serum level of caspase-3,7,8 and FasL during early stage of infection could be used as biomarkers for WHO-defined dengue disease severity.

Clinical significance of differential serum-signatures for early prediction of severe dengue among Eastern Indian patients.

Dengue infection can result in simple dengue fever or life-threatening severe dengue. Early identification of severe patients is needed for proper disease management. Dengue infection was screened among 168 symptomatic patients by qRT-PCR, anti-dengue IgM, and IgG ELISA. Dengue patients were categorized according to WHO classification. Viral load and dengue serotypes were determined by qRT-PCR. Levels of acute-phase-proteins (SAP, SAA2; CRP and ApoA1), endothelial (Ang2, VEGF), coagulation (fibrinogen) markers were determined by sandwich ELISA/immunoturbidimetry/western-blotting. Hepatic (ALT, AST, ALP) and other blood biochemical parameters were studied by autoanalyzer and haematology cell counter. Statistical analysis and protein-protein-interaction network were performed by GraphPad-Prism and STRINGS database, respectively. Among 87 dengue patients, significantly higher levels of Ang2, VEGF, CRP, SAA2, ApoA1, AST, ALT, and AST/ALT ratio and low level of fibrinogen were detected in severe-dengue cases compared to dengue without warning-signs, with seven of them severely altered during febrile-phase. Higher fold-change of Ang2 and VEGF as well as decreased fibrinogen were observed among patients with haemorrhagic-manifestation, clinical-fluid accumulation and thrombocytopenia. Functional network analysis predicted Ang2, VEGF, and CRP to be functionally and physically connected and SAA2 and ApoA1 to be functioning together. Correlation analyses also validated this connectivity by a strong positive correlation between Ang2, VEGF, and CRP. PCA analysis followed by hierarchical clustering heatmap analysis segregated severe-dengue patients from the rest, with VEGF, Ang2, ApoA1, AST, and ALT clearly distinguishing the severe-dengue group. Thus, serum levels of VEGF, Ang2, ApoA1, AST, and ALT might act as potential biomarkers for predicting dengue severity during the early stage.

Polymorphisms in immune-mediator genes and the risk of dengue virus infection: Lights from a systematic revaluation by Bayesian approaches.

Dengue fever is a clinical manifestation of dengue virus (DENV) infection well defined by the intense host immune response with the development of high fever, anorexia, headache and muscle pain. Several immune mediators are involved in the pathophysiology of DENV infection, in which polymorphisms in immune molecule genes contribute with the susceptibility and severity of the infection. Several meta-analyses are available with significant findings in the association between genetic variants in immune-mediator genes and dengue, though the results may be false positive. Hence, to solve this issue, we have performed a systematic revaluation with Bayesian approaches to verify the false positive rate in these results. A systematic search was performed for meta-analytic studies on the aforementioned issue. The calculations of false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP) at the prior probability of 10-3 and 10-6 have been performed. To verify the methodological quality of the studies included, the evaluation by the Venice criteria was applied. In addition, gene-gene and protein-protein networks were designed. As results, seven meta-analyses on genetic variants in several immune-inflammatory mediator genes and DENV infection comprise the results. Only the polymorphisms in the TNF, MICB, PLCE1, VDR, CD32 and HLA-A genes were considered as noteworthy. There was a heterogeneity profile for the results on Venice criteria indicating variability in the methodological quality. The gene-gene and protein-protein networks showed these immune mediators as relevant players in the disease. We suggest these polymorphisms as potential biomarkers for the pathogenesis and immune response against DENV.

Integrated view of molecular diagnosis and prognosis of dengue viral infection: future prospect of exosomes biomarkers.

Dengue viruses (DENVs) are the viruses responsible for dengue infection which affects lungs, liver, heart and also other organs of individuals. DENVs consist of the group of four serotypically diverse dengue viruses transmitted in tropical and sub-tropical countries of world. Aedes mosquito is the principal vector which spread the infection from infected person to healthy humans. DENVs can cause different syndromes depending on serotype of virus which range from undifferentiated mild fever to dengue hemorrhagic fever resulting in vascular leakage due to release of cytokine and Dengue shock syndrome with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. Increase in dengue cases in pediatric population is a major concern. Transmission of dengue depends on various factors like temperature, rainfall, and distribution of Aedes aegypti mosquitoes. The present review describes a comprehensive overview of dengue, pathophysiology, diagnosis, treatment with an emphasis on potential of exosomes as biomarkers for early prediction of dengue in pediatrics.

Clinical outcomes of dengue virus infection in pregnant and non-pregnant women of reproductive age: a retrospective cohort study from 2016 to 2019 in Paraná, Brazil.

BACKGROUND: The increasing number of dengue cases worldwide implies a greater exposure of at-risk groups, such as pregnant women. DENV infection during pregnancy has been increasingly associated with unfavorable outcomes, but the evolution of the disease and its clinical outcomes remain unclear. The objective of this study was to characterize dengue cases in reproductive aged women by comparing the development of the disease in pregnant and non-pregnant women. METHODS: A population based retrospective cohort study that used data reported in the Brazilian Mandatory Notifiable Diseases Information System from 2016 to 2019 in Paraná, Brazil. We compared sociodemographic, clinical, and laboratory variables between pregnant and non-pregnant women. Hospitalization and disease severity classification (Dengue, Dengue with warning signs, Severe Dengue) were considered outcome variables. RESULTS: The two groups had differences in the year of notification, age distribution, and region of residence. Laboratory investigation was more frequent among pregnant women, and DENV-2 prevailed in both groups. The risks of hospitalization and development of Severe Dengue were higher in pregnant women. There were no deaths observed among pregnant women. CONCLUSION: This study identified pregnancy as a risk factor for an increase in the severity of DENV infection. It reinforces the importance of identifying early signs of complication, close monitoring, and adequate treatment for pregnant women.

Severe dengue associated with Staphylococcus aureus sepsis in pediatric patients: a case series.

BACKGROUND: Staphylococcus aureus co-infection is seldom reported in children with severe dengue. METHODOLOGY: In this retrospective study, we reported five children with severe dengue and S. aureus co-infection admitted to pediatric intensive care unit (PICU) during July-December 2021. RESULTS: All children had prolonged fever, persistence of bilateral pleural effusion beyond the critical phase, thrombocytopenia and raised inflammatory markers [C-reactive protein (CRP) and procalcitonin]. S. aureus was isolated from pleural fluid (n = 2, 40%), blood (n = 2, 40%) and endotracheal aspirate (n = 1, 20%). Four children (80%) grew methicillin-sensitive S. aureus, while 1 (20%) had methicillin-resistant S. aureus. Two children (40%) had septic thromboemboli in skin, and 1 (20%) had limb cellulitis. One child required anterior thoracotomy, pericardiectomy and bilateral pleural decortication, while all other children required intercostal chest tube drainage. All children required prolonged targeted antibiotics, invasive mechanical ventilation and had prolong stay in PICU and all of them survived. CONCLUSION: In children with severe dengue, persistence of fever, persistence of pleural effusion beyond critical phase and raised CRP and procalcitonin should raise suspicion of bacterial/S. aureus co-infection.

Rescue therapy with intravenous immunoglobulin in severe refractory dengue: A pilot study.

Background: Severe dengue causes more than 22,000 deaths annually worldwide. Complicated dengue has high mortality of 44-72%. Disordered immune system with capillary leak and thrombocytopenia are hallmark of complicated dengue. Intravenous immunoglobulin (IV Ig) therapy has shown to be effective in complicated dengue in pediatric age group with refractory shock, but studies in adults are lacking. Its immunoresuscitative role is not yet fully explored in critically ill patients with severe dengue. Methods: This is retrospective observational study of patients with complicated dengue fever who were administered IV Ig therapy in a tertiary care hospital of southern India from 01 Jan 2018 to 31 Dec 2019. Results: A total of 999 patients with dengue were admitted; 754 (75.47%) were males, and 245 (24.53%) were females. A total of 402 (40.24%) patients presented with warning signs. Bleeding was seen in 121 patients (12.11%); 102 (10.21%) had shock; 29 (2.90%) had acute kidney injury and 24 (2.40%) had adult respiratory distress syndrome. Overall, four people died (mortality rate: 0.40%). IV Ig in the dose of 0.4 g/kg for 5 days was used in 13 critically ill patients where standard therapy failed, 9 patients with refractory shock (which included three with myocarditis with refractory shock), 2 with encephalitis, 2 in hemophagocytic lymphohistiocytosis. Two patients died, one with myocarditis with refractory shock and another with refractory shock. Conclusion: IV Ig therapy in critically ill patients with complicated dengue can be used as a rescue therapy.

Higher Plasma Viremia in the Febrile Phase Is Associated With Adverse Dengue Outcomes Irrespective of Infecting Serotype or Host Immune Status: An Analysis of 5642 Vietnamese Cases.

BACKGROUND: One of the generally accepted constructs of dengue pathogenesis is that clinical disease severity is at least partially dependent upon plasma viremia, yet data on plasma viremia in primary versus secondary infections and in relation to clinically relevant endpoints remain limited and contradictory. METHODS: Using a large database comprising detailed clinical and laboratory characterization of Vietnamese participants enrolled in a series of research studies executed over a 15-year period, we explored relationships between plasma viremia measured by reverse transcription-polymerase chain reaction and 3 clinically relevant endpoints-severe dengue, plasma leakage, and hospitalization-in the dengue-confirmed cases. All 4 dengue serotypes and both primary and secondary infections were well represented. In our logistic regression models we allowed for a nonlinear effect of viremia and for associations between viremia and outcome to differ by age, serotype, host immune status, and illness day at study enrollment. RESULTS: Among 5642 dengue-confirmed cases we identified 259 (4.6%) severe dengue cases, 701 (12.4%) patients with plasma leakage, and 1441 of 4008 (40.0%) patients recruited in outpatient settings who were subsequently hospitalized. From the early febrile phase onwards, higher viremia increased the risk of developing all 3 endpoints, but effect sizes were modest (ORs ranging from 1.12-1.27 per 1-log increase) compared with the effects of a secondary immune response (ORs, 1.67-7.76). The associations were consistent across age, serotype, and immune status groups, and in the various sensitivity and subgroup analyses we undertook. CONCLUSIONS: Higher plasma viremia is associated with increased dengue severity, regardless of serotype or immune status.

Use of intravenous N-acetylcysteine in acute severe hepatitis due to severe dengue infection: a case series.

BACKGROUND: Dengue fever is a common mosquito borne viral infection. Severe dengue fever associated severe hepatitis carries high mortality. Based on the beneficial effect of N-acetylcysteine (NAC) in paracetamol poisoning and non-acetaminophen induced liver failure, it is used in dengue fever associated hepatitis in clinical practice. We aim to study the reversal of liver enzymes with NAC in the setting of severe hepatitis due to severe dengue infection. METHODS: A retrospective analysis was conducted on hospitalized 30 adults with severe dengue fever with severe hepatitis. These 30 patients had aspartate transaminase (AST) and alanine transaminases (ALT) more than 500 U/L and/or PT INR (prothrombin time and international normalized ratio) more than 1.5. They were treated with NAC infusion of 100 mg/h for 3 to 5 days. RESULTS: The mean age of the group was 49.9 ± 11.46 years and 18 (60%) patients were males. Nineteen patients (63%) developed dengue shock. Of them 12 patients (40%) developed hepatic encephalopathy. Median AST on the day of administration of NAC was 1125 U/L interquartile range (IQR) 1653.25 while median ALT was 752 (IQR 459.25). There was a statistically significant reduction of both ALT (p = 0.034) and AST (p = 0.049) from day 1 to 4 after NAC infusion. Rise of platelet count between day 1 and day 4 also showed statistically significant difference (p = 0.011) but the reduction of prothrombin time and international normalized ratio (PT/INR) from 1 to day 4 did not show statistical significance difference. Mean duration of treatment with NAC was 3.61 ± 0.75 days while mean length of hospital stay was 6.2 ± 1.27 days. Only one patient died (3.3%). None of the patients reported adverse drug reaction due to NAC. CONCLUSION: Majority of patients demonstrated marked clinical and biochemical improvements and they recovered fully. We observed faster and significant recovery of liver enzymes following administration of NAC. Based on the above findings, this study provides preliminary evidence for the beneficial effect of NAC in severe hepatitis in dengue infection with greater survival benefits.

A Case Study of Dual Infection of Dengue and COVID-19: Presenting as Multiorgan Dysfunction in an Infant.

Dengue is a major health concern in South Asian countries transmitted by bite of day breeder mosquitoes Aedes aegypti and Aedes albopictus. Severity of plasma leak, shock, bleeding tendency and other organ dysfunction can be more pronounced in infants. The management becomes further complicated in the presence of a co-existing COVID-19 infection. Although COVID-19 infection is usually asymptomatic or has mild manifestations in children, however in presence of serious co-infection like dengue it can modify the course of the illness and lead to drastic consequences. Here, we present one such case of a 9-month-old female child who tested positive for dengue as well as COVID-19 during the ongoing corona pandemic and went on to develop shock, encephalopathy with deranged liver enzymes but managed to overcome all odds and recover from the disease by day 14 of illness.

Cytokine Signature of Dengue Patients at Different Severity of the Disease.

Clinical presentations of dengue fever (DF) are diverse and non-specific, causing unpredictable progression and outcomes. Its progression and severity have been associated with cytokine levels alteration. In this study, dengue patients were classified into groups following the 2009 WHO dengue classification scheme to investigate the cytokine signature at different severity of the disease: dengue without warning sign symptoms (A); dengue with warning signs (B); severe dengue (C); other fever (OF) and healthy (Healthy). We analyzed 23 different cytokines simultaneously, namely IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-33, CD14, CD54, CD62E, CD62L, CD62p, CD106, CD121b, CD154, CD178, GM-CSF, IFN-g, MIF, ST2 and TNF from patients admitted to National Cheng Kung University Hospital during the 2015 Taiwan dengue outbreak. Cytokines TNF, CD54, CD62E, CD62L, CD62P, GM-CSF, IL-1b, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, INF-g and MIF were elevated while CD106, CD154, IL-4 and L-33 were decreased when compared to the control. IL-10 demonstrated to be a potential diagnostic marker for DF (H and A group; AUC = 0.944, H and OF group; AUC = 0.969). CD121b demonstrated to be predictive of the SD (A and B group; AUC = 0.744, B and C group; AUC = 0.775). Our results demonstrate the cytokine profile changes during the progression of dengue and highlight possible biomarkers for optimizing effective intervention strategies.