Dengue-Associated Hemophagocytic Lymphohistiocytosis: A Narrative Review of Its Identification and Treatment.

Dengue's lack of specific treatments beyond supportive care prompts a focus on uncovering additional pathophysiological factors. Dengue-associated hemophagocytic lymphohistiocytosis (HLH), characterized by dysregulated macrophage activation and cytokine storm, remains underexplored despite its potential to worsen disease severity and mortality. While rare, dengue-associated HLH disproportionately affects severe cases, significantly impacting mortality rates. To mitigate high mortality, early identification and familiarity with dengue-associated HLH are imperative for prompt treatment by clinicians. This narrative review therefore aims to examine the current clinical and therapeutic knowledge on dengue-associated HLH, and act as a resource for clinicians to improve their management of HLH associated with severe dengue. Dengue-associated HLH should be considered for all cases of severe dengue and may be suspected based on the presence of prolonged or recurrent fever for >7 days, or anemia without intravascular hemolysis or massive bleeding. Diagnosis relies on fulfilling at least five of the eight HLH-2004 criteria. Treatment predominantly involves short courses (3-4 days) of high-dose steroids (e.g., dexamethasone 10 mg/m2), with additional therapies considered in more severe presentations. Notably, outcomes can be favorable with steroid therapy alone.

APRI as a predictor of severe dengue fever.

Introduction: The AST/platelet ratio index (APRI) is a well-researched indicator of liver fibrosis. Some studies have shown that APRI can be used as a predictor of severe dengue, but the data is limited. As dengue epidemics are common in our country with limited healthcare resources, we believe APRI can help emergency physicians/primary physicians in predicting the severity of dengue and plan for the appropriate use of limited healthcare resources. Objective: 1) To determine the utility of APRI as a predictor of severe dengue. 2) To determine the association of APRI with length of hospital stay and platelet requirement. Materials and Methods: A retrospective cross-sectional study was done on patients presented to the Emergency Medicine department at Travancore Medicity Medical College with a positive Dengue NS1 antigen or IgM antibody. Results: We found from the univariate analysis results that ALT > 74.5 IU/L has a sensitivity of 59.6 and a specificity of 76.3 (AUC: 0.696; 95% CI: 0.606-0.786), AST > 160.5 IU/L has a sensitivity of 42.3 and a specificity of 93.7 (AUC: 0.747; 95% CI: 0.665-0.829), and APRI > 3.2 has a sensitivity of 69.2 and a specificity of 84.2 (AUC: 0.806; 95% CI: 0.72-0.884) to predict severe dengue. Patients with an APRI of >3.2 required a mean hospital stay of 5.47 days (P = 0.005); 27 (81.8%) requiring platelet transfusion had an APRI of > 3.2 (P = 0.00). Conclusion: APRI is a straightforward index that can be easily derived from AST and platelet values. APRI values of >3.2 can predict severe dengue with a sensitivity of 69.2 and a specificity of 84.2. APRI values of >3.2 are also associated with the length of hospital stay and requirement of platelet transfusion.

Dengue induced acute liver failure: A meta summary of case reports.

BACKGROUND: Dengue fever is the most common cause of viral hemorrhagic fever, with more than 400 million cases being reported annually, worldwide. Even though hepatic involvement is common, acute liver failure (ALF) is a rare complication of dengue fever. AIM: To analyze the demographic profile, symptomology, hospital course and outcomes of patients presenting with ALF secondary to dengue infection by reviewing the published case reports. METHODS: A systematic search was performed from multiple databases including PubMed, Reference Citation Analysis, Science Direct, and Google Scholar. The search terms used were "dengue" OR "severe dengue" OR "dengue shock syndrome" OR "dengue haemorrhagic syndrome" OR "dengue fever" AND "acute liver failure" OR "hepatic failure" OR "liver injury". The inclusion criteria were: (1) Case reports or case series with individual patient details; (2) Reported acute liver failure secondary to dengue infection; and (3) Published in English language and on adult humans. The data were extracted for patient demographics, clinical symptomatology, clinical interventions, hospital and intensive care unit course, need for organ support and clinical outcomes. RESULTS: Data from 19 case reports fulfilling the predefined inclusion criteria were included. The median age of patients was 38 years (inter quartile range: Q3-Q1 26.5 years) with a female preponderance (52.6%). The median days from diagnosis of dengue to development of ALF was 4.5 d. The increase in aspartate aminotransferase was higher than that in alanine aminotransferase (median 4625 U/L vs 3100 U/L). All the patients had one or more organ failure, with neurological failure present in 73.7% cases. 42.1% patients required vasopressor support and hepatic encephalopathy was the most reported complication in 13 (68.4%) cases. Most of the patients were managed conservatively and 2 patients were taken up for liver transplantation. Only 1 death was reported (5.3%). CONCLUSION: Dengue infection may rarely lead to ALF. These patients may frequently require intensive care and organ support. Even though most of these patients may improve with supportive care, liver transplantation may be a therapeutic option in refractory cases.

Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

Introduction: Severe dengue is thought to be caused by an excessive host immune response. Methods: To study the pathogenesis of severe dengue, we developed a novel model using LysM Cre+Ifnarflox/flox mice carrying depleted Ifnar expression only in subsets of murine myeloid cells. Results: Although dengue virus (DENV) clinical isolates were not virulent in LysM Cre+Ifnarflox/flox mice, mouse-adapted DV1-5P7Sp and DV3P12/08P4Bm, which were obtained by passaging the spleen or bone marrow of mice, demonstrated 100% lethality with severe vascular leakage in the liver and small intestine. DV1-5P7Sp and DV3P12/08P4Bm harbored five and seven amino acid substitutions, respectively. Infection also induced neutrophil infiltration in the small intestine, and increased expression of IL-6 and MMP-8 and blockade of TNF-α signaling protected the mice, as demonstrated in a previous severe dengue mouse model using C57/BL6 mice lacking both IFN-α/ß and IFN-γ receptors. Notably, the new models with DV1-5P7Sp and DV3P12/08P4Bm showed an increased proliferative capacity of the adapted viruses in the thymus and bone marrow. Discussion: These observations suggest that myeloid cell infection is sufficient to trigger cytokine storm-induced vascular leakage. This model can refine the factors involved in the pathology of severe dengue leading to vascular leakage.

Prediction of severity of dengue infection in children based on hepatic involvement.

Background and Aim: To assess the spectrum of hepatic involvement in children with dengue fever (DF) and prediction of severity of dengue infection by early detection of elevated liver enzymes. Methods: This prospective observational study was conducted at a tertiary care hospital from June 2019 to September 2019. Children admitted with DF were included. Severity of DF was graded as dengue without warning sign (DNWS), with warning sign (DWS), and severe dengue fever (SDF) according to WHO criteria. Liver injury (LI) was defined as alanine aminotransferase (ALT) more than upper limit of normal irrespective of sex. Results: Of 190 children (male, 109) with DF, 60 had DNWS, 49 had DWS, and 81 had SDF. A total of 100 children (52.6%) had LI. The distribution of hepatic involvement spectrum involves hepatomegaly (26.3%), hepatic tenderness (25.2%), features of acute liver failure (1.5%), raised level of ALT (52.6%), raised level of aspartateaminotransferase (AST) (65.8%), prolonged prothrombin time (7.3%), and reduced level of serum albumin (44.7%) in children. Of them, 5.8% and 6.8% of children had >tenfold increase in ALT and AST values. The degree of liver function derangement significantly (P < 0.05) increased with DF severity. In our study, ALT at 422 IU/L (10 times upper limit of normal [ULN]) and AST 689 IU/L (17 times ULN) had similar sensitivity and specificity as WHO recommended cutoff of 1000 IU/L (25 times of ULN) to detect SDF. Conclusion: ALT ≥10 times and AST ≥17 times of ULN are as sensitive as ≥25 times (as recommended by WHO) to detect SDF.

Reverse Takotsubo Cardiomyopathy with Severe Dengue: Case Report from Pakistan.

Takotsubo Cardiomyopathy is an established transient cardiomyopathy found predominately in females with intense emotional and physical strain. It has four notable variants: Apical, Mid-Ventricular, Basal and Focal. Mid Ventricular variant is also referred to as Reverse Takotsubo Cardiomyopathy. Dengue is a viral arthopod-borne tropical disease endemic to Pakistan, with multiple reports of cardiovascular involvement. We report an atypical presentation of a 17 year old male, suffering from Dengue Fever, who presented to a tertiary care hospital with Reverse Takotsubo Cardiomyopathy.

[Clinical Update on Diagnosis, Treatment and Prevention of Dengue]. / Atualização Clínica sobre Diagnóstico, Tratamento e Prevenção da Dengue.

Dengue is a vector-borne disease that has a significant impact on global public health. The vector mosquito belongs to the genus Aedes. Two species play a key role in human transmission: Ae. aegypti, which has adapted to the urban environment of highly populated areas in tropical and subtropical countries, leading to a dramatic increase in dengue cases over the years, and Ae. albopictus, which poses a potential threat to temperate climate countries due to its ability to adapt to colder climates. The disease is widespread across the world, posing a risk to nearly half of the world's population. Although most cases are asymptomatic, dengue causes a burden on healthcare systems and mainly affects the younger population. The disease is also spreading to temperate climate countries, thus becoming a global threat. Vector control measures and vaccine development have been the main prevention strategies, as there is still no effective treatment for the disease.

A dengue é uma doença transmitida por um vetor hematófago (mosquito) que possui um impacto significativo na saúde pública mundial. O mosquito transmissor pertence ao género Aedes. São duas as espécies responsáveis pela transmissão humana: o Ae. aegypti, que se adaptou ao ambiente urbano de áreas altamente populosas de países tropicais e subtropicais, resultando num aumento dramático dos casos de dengue ao longo dos anos; e o Ae. Albopictus, que representa uma potencial ameaça para os países de clima temperado pela sua capacidade de adaptação aos climas mais frios. A doença está presente em grande parte do mundo, colocando cerca de metade da população do planeta em risco. Embora a maioria dos casos seja assintomática, a dengue causa uma sobrecarga nos sistemas de saúde e impacta principalmente os jovens. A doença também tem vindo a alastrar-se a países de clima temperado, tornando-se uma ameaça global. As medidas de controlo vetorial e o desenvolvimento de vacinas têm sido as principais estratégias de prevenção, uma vez que não existe ainda um tratamento eficaz para a doença.

Harness risk stratification of diabetic patients with dengue in a cohort study.

BACKGROUND: Identifying predictors of severe dengue (SD) is key for triage and management of patients as well as for advising travellers to countries where dengue is endemic. In this, meta-analyses have raised diabetes mellitus as a risk factor for SD and a prognostic factor for dengue-related mortality. The purpose of this study was to assess whether diabetic patients (DPs) are at increased risk for SD in comparison to non-diabetic patients (NDPs) in a setting of high prevalence of type 2 diabetes mellitus and increasing endemicity for dengue. METHODS: In a cohort study conducted during the 2019 dengue epidemic on Reunion Island, we estimated the risk ratios (RR) of DPs for SD (WHO 2009 definition), hospitalisation, intensive care unit (ICU) admission, critical care need or death in the ICU, and scales rating severity or multiple organ dysfunction syndrome (MODS), among confirmed cases of dengue (positive RT-PCR or NS1 antigen). RESULTS: In a Poisson regression model adjusted for age, gender and comorbidity, DPs were more likely to develop SD (adjusted RR: 1.46, 95%CI 1.10-1.95), to be hospitalised, admitted to the ICU, and need critical care or die in the ICU. Subgroup analyses identified female DPs, non-elderly DPs (< 65 years) and DPs with low Charlson score (< 3) to be at higher risk for SD, the two first subgroups trough more severe presentation (higher Simplified Acute Physiology Score-2 values; higher MODS scores, respectively). Male gender, age less than 65 years and mixed comorbidity were identified as prognostic factors for critical care need or death in the ICU, male and non-elderly DPs being more likely to develop MODS than their non-diabetic counterparts. CONCLUSIONS: Together, these data highlight the role of diabetes mellitus in the progression from dengue to SD through higher severity per se or the event of MODS.

Severe dengue in the intensive care unit.

Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.

A comparison of changes in venous lactate and haematocrit during fluid resuscitation of dengue haemorrhagic fever.

BACKGROUND: Judicious fluid resuscitation and stringent monitoring of clinical parameters improve the outcome of dengue haemorrhagic fever (DHF). The usefulness of serum lactate to monitor adequate fluid therapy has not been adequately explored. METHODS: An observational study was conducted in Sri Lanka, recruiting 162 DHF patients within 12 h of diagnosis of the critical phase. Venous lactate level was measured at each time of performing haematocrit (HCT), using a prevalidated handheld lactate analyser. RESULTS: The median venous lactate level was 1.3 (range 0.3-6) mmol/L in the study population and 154 (95.2%) patients had median lactate levels of <2 mmol/L. The HCT values in the study participants ranged from 28 to 62, with a median value of 43. There was no statistically significant correlation between the lactate and HCT values obtained at the same time. A significant reduction in venous lactate was not observed following the administration of fluid boluses. The expected reduction in HCT was seen following the administration of dextran and crystalloid/dextran combination. The maximum recorded lactate level positively correlated with the duration of hospital stay. CONCLUSIONS: This study concludes that venous lactate is not an appropriate parameter with which to monitor the response to fluid therapy in uncomplicated DHF.

Assessment of the importance of platelet transfusion in patients with severe dengue: a systematic review / Evaluación de la importancia de la transfusión de plaquetas en pacientes con dengue grave: una revisión sistemática

Introduction: Dengue is one of the most important vector-borne viral diseases in subtropical and tropical regions. The World Health Organization (WHO) 2009 classified dengue into three groups: dengue without alarm signs, dengue with alarm signs, and severe dengue. According to the type of dengue, various managements have been proposed. The authors suggest that a predictive factor to avoid a poor prognosis in this disease is to keep platelet levels stable in the patient to prevent a fatal outcome. The aim of this paper is to analyze the efficacy of transfusion of platelet agents in the outcome of patients with severe dengue and thrombocytopenia. Material and methods: A bibliographic search was carried out in the Medline, OVID, and Scielo databases from January 1, 2008, to April 31, 2023, using the MeSH terms. Results: 7 articles were included in the systematic review. A wide range in age was found (18 to 79 years). A minimal number of studies detail the comorbidities of patients in their enrollment. Regarding platelet transfusion, the average number of platelet units used in the transfusion case was 5 (2 - 14). Transfusions of ABO identical and compatible pooled platelets transfusion were found to be more successful in increasing platelets. Almost all of the patients included in the studies had platelets <20,000 at enrollment. One study found a significant increase in platelets after transfusion, while the rest did not find it compelling. No mortality associated with platelet transfusion was recorded. Conclusions: Prophylactic platelet transfusion is not recommended as a routine measure in patients with severe dengue and thrombocytopenia. The uncertainty highlights need to reach a specific consensus establishing the appropriate indications for platelet transfusion and what type of patients with dengue virus would be beneficial. (AU)

Introducción: El dengue es una de las enfermedades virales transmitidas por vectores más importantes en las regiones tropicales y subtropicales. La Organización Mundial de la Salud (OMS) en 2009 clasificó el dengue en tres grupos: dengue sin signos de alarma, dengue con signos de alarma y dengue grave. Según el tipo de dengue se han propuesto diversos manejos. Los autores sugieren que un factor predictivo para evitar un mal pronóstico en esta enfermedad es mantener estables los niveles de plaquetas en el paciente para evitar un desenlace fatal. El objetivo de este trabajo es analizar la eficacia de la transfusión de plaquetas en la evolución de pacientes con dengue grave y trombocitopenia. Material y métodos: Se realizó una búsqueda bibliográfica en las bases de datos Medline, OVID y Scielo desde el 1 de enero de 2008 al 31 de abril de 2023, utilizando los términos MeSH. Resultados: Se incluyeron 7 artículos en la revisión sistemática. Se encontró un amplio rango de edad (18 a 79 años). Un número mínimo de estudios detallan las comorbilidades de los pacientes en su inscripción. En cuanto a la transfusión de plaquetas, el promedio de unidades de plaquetas utilizadas en el caso de transfusión fue de 5 (2 - 14). Se encontró que las transfusiones de plaquetas combinadas ABO idénticas y compatibles tuvieron más éxito en el aumento de plaquetas. Casi todos los pacientes incluidos en los estudios tenían plaquetas <20 000 en el momento del reclutamiento. Un estudio encontró un aumento significativo de plaquetas después de la transfusión, mientras que el resto no lo encontró convincente. No se registró mortalidad asociada con la transfusión de plaquetas. Conclusiones: La transfusión profiláctica de plaquetas no se recomienda como medida de rutina en pacientes con dengue grave y trombocitopenia. ... (AU)

Clinical profiles and predictors of survival in severe dengue cases.

Introduction: Dengue is endemic in tropical countries. Severe dengue has a high risk of morbidity and mortality. We aimed to identify factors associated with dengue survival among our intensive care unit (ICU) patients. Methods: A retrospective study was conducted among dengue cases admitted to the ICU of Hospital Sultan Abdul Halim, Kedah, Malaysia from 2016 to 2019. Results: Out of 1,852 dengue cases admitted to the hospital, 7.2% of patients required ICU admission. Survival rate was 88.6% among severe dengue cases. The majority of severe dengue patients were obese, while other notable comorbidities included hypertension and diabetes mellitus. Also, 73% of patients presented in the critical phase, at a median of Day 4 of illness. All patients admitted to the ICU had a history of fever. The predominant warning signs were lethargy, fluid accumulation and haemoconcentration with rapid platelet reduction. Among nonsurvivors, 69.2% had fulminant hepatitis, 53.8% had massive bleeding or disseminated intravascular coagulation, 38.5% had haemophagocytic lymphohistiocytosis and 30.8% had myocarditis. The predominant serotypes were DENV-3 and DENV-1. The least number of cases was seen in 2017, when all serotypes were equally presented. Multiple logistic regression showed that Sequential Organ Failure Assessment (SOFA) score, peak international normalised ratio, peak partial thromboplastin time and aspartate aminotransferase on admission were independent risk factors for survival. This model had an area under the curve of 0.98, giving an overall 98.2% accuracy. Conclusions: Specific warning signs and blood investigations in dengue patients may aid in early decision for ICU admission. Monitoring of SOFA scores plus coagulation and liver enzyme profiles could improve dengue survival rates.

Analysis of gene expression profile for identification of novel gene signatures during dengue infection.

Background: Dengue is a major arthropod-borne viral disease spreading rapidly across the globe. The absence of vaccines and inadequate vector control measures leads to further expansion of dengue in many regions globally. Hence, the identification of genes involved in the pathogenesis of dengue will help to understand the molecular basis of the disease and the genes responsible for the disease progression. Methods: In the present study, a meta-analysis was carried out using dengue gene expression data obtained from Gene Expression Omnibus repository. The differentially expressed genes such as CCNB1 and CCNB2 (G2/mitotic-specific cyclin-B2 and B1) were upregulated in dengue fever to control (DF-CO) and severe dengue (dengue hemorrhagic fever [DHF]) to control (DHF-CO) were identified as key genes for controlling the major pathways (cell cycle, oocyte meiosis, p53 signaling pathway, cellular senescence and progesterone-mediated oocyte maturation). Similarly, interferon alpha-inducible (IFI27) genes, type-I and type-III interferon (IFN) signaling genes (STAT1 and STAT2), B cell activation and survival genes (TNFSF13B, TNFRSF17) and toll like receptor (TLR7) genes were differentially up activated during DF-CO and DHF-CO. Followed by, Cytoscape was used to identify the immune system process and topological analysis. Results: The results showed that the top differentially expressed genes under the statistical significance p <0.001, which is majorly involved in Kyoto Encyclopedia of Genes and Genomes orthology K05868 and K21770 with gene names CCNB1 and CCNB2. In addition to this, the immune system profile showed up-regulation of IL12A, CXCR3, TNFSF13B, IFI27, TNFRSF17, STAT, STAT2, and TLR7 genes in DF-CO and DHF-CO act as immunological signatures for inducing the immune response towards dengue infection. Conclusions: The current study could aid in understanding of molecular pathogenesis, genes and corresponding pathway upon dengue infection, and could facilitate for identification of novel drug targets and prognostic markers.

Genetic Association Studies of MICB and PLCE1 with Severity of Dengue in Indonesian and Taiwanese Populations.

Dengue is an arboviral disease that has spread globally and become a major public health concern. A small proportion of patients may progress from symptomatic dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Findings from a previous genome-wide association study (GWAS) demonstrated that variations in the major histocompatibility complex (MHC) class I chain-related B (MICB) and the phospholipase C epsilon 1 (PLCE1) genes were related to DSS in a Vietnamese population. This study investigated associations of variations in MICB (rs3132468) and PLCE1 (rs3740360, rs3765524) with dengue severity and thrombocytopenia in both the Indonesian and Taiwanese populations. We sampled 160 patients from the Indonesian population and 273 patients from the Taiwanese population. None of the patients had DSS in the Taiwanese population. Based on age demographics, we found that dengue is more prevalent among younger individuals in the Indonesian population, whereas it has a greater impact on adults in the Taiwanese population. Our results showed the association between MICB rs3132468 and DSS. In addition, an association was identified between PLCE1 rs3740360 and DHF in secondary dengue in Indonesian patients. However, there is no association of MICB or PLCE1 variants with thrombocytopenia. This study highlights the value of genetic testing, which might be included in the clinical pathway for specific patients who can be protected from severe dengue.

Dengue virus serotype did not contribute to clinical severity or mortality in Taiwan's largest dengue outbreak in 2015.

BACKGROUND: Dengue virus serotype 2 (DENV-2) was the major serotype in the 2015 dengue outbreak in Taiwan, while DENV-1 and DENV-3 were dominant between 2005 and 2014. We aimed to investigate whether DENV-2 contributed to disease severity and mortality in the outbreak in Kaohsiung city, Taiwan. METHODS: We collected serum samples from dengue patients to detect the presence of DENV and determine the serotypes by using quantitative reverse transcription-polymerase chain reaction. Our cohorts comprised 105 DENV-1-infected cases and 1,550 DENV-2-infected cases. Demographic data, DENV serotype, and comorbidities were covariates for univariate and multivariate analyses to explore the association with severity and mortality. RESULTS: The results suggested that DENV-1 persisted and circulated, while DENV-2 was dominant during the dengue outbreak that occurred between September and December 2015. However, DENV-2 did not directly contribute to either severity or mortality. Aged patients and patients with diabetes mellitus (DM) or moderate to severe chronic kidney disease (CKD) had a higher risk of developing severe dengue. The mortality of dengue patients was related to a higher Charlson comorbidity index score and severe dengue. Among DENV-2-infected patients and older patients, preexisting anti-dengue IgG, DM, and moderate to severe CKD were associated with severe dengue. Moreover, female sex and severe dengue were associated with a significantly higher risk of death. CONCLUSIONS: Our findings highlight the importance of timely serological testing in elderly patients to identify potential secondary infections and focus on the meticulous management of elderly patients with DM or moderate to severe CKD to reduce dengue-related death.

Dengue Encephalopathy or Dengue Encephalitis? You Decide.

Awareness of neurological sequelae of dengue fever is increasing. However, as this case illustrates, there is a diagnostic conundrum in determining whether certain features are in keeping with dengue encephalopathy or dengue encephalitis. Further consensus is required.

Liver Impairment and Elevated Aminotransferase Levels Predict Severe Dengue in Vietnamese Children.

BACKGROUND: The degree of liver impairment in children with dengue infection varies from mild to severe injury. Aminotransferase levels may be useful in predicting severe dengue. This study aimed to evaluate the degree of liver impairment and determine whether elevated aminotransferases could be used to discriminate between non-severe and severe dengue in Vietnamese children. METHODS: This was a prospective cohort study of pediatric patients with confirmed dengue infection who were admitted to Can Tho Children's Hospital, Vietnam. The receiver operating characteristic (ROC) curve was used to discriminate the power of Aspartate transaminase (AST) or Alanine transaminase (ALT) to predict severe dengue. RESULTS: Two hundred and thirty confirmed dengue patients were enrolled, including 70% (161) patients with non-severe dengue and 30% (69) with severe dengue. This study indicates that 73.9% of patients had abnormal AST (＞40 U/L), and 34.8% of patients had abnormal ALT (＞40 U/L). The incidence of dengue patients with hepatitis (AST or ALT ≥ 4×ULN) and severe hepatitis (AST or ALT ≥ 10×ULN) were 18.7% and 17.0%, respectively. At a cut-off point of 120 U/L, AST's AUROC, sensitivity, and specificity were 0.93 (95% CI: 0.90-0.96), 82.5%, and 87.3%, respectively. At a cut-off point of 80 U/L, ALT's AUROC, sensitivity, and specificity were 0.89 (95% CI: 0.84-0,93), 87.5%, and 85.2%, respectively, for predicting severe dengue. CONCLUSION: Elevated aminotransferase levels were associated with severe dengue, and AST/ALT were good markers for predicting severe dengue in Vietnamese children.

Comparison of clinical and laboratory parameters of primary vs secondary dengue fever in travellers.

BACKGROUND: Dengue fever (DF), caused by the dengue virus (DENV), is the most common arboviral disease in travellers worldwide. It is hypothesized that compared with primary DF, secondary DF may result in antibody-dependent enhancement of the immune response, resulting in more severe disease. We aimed to compare clinical and laboratory parameters in travellers with primary and secondary DF to determine whether secondary DF is associated with markers of severe disease. METHODS: We conducted a retrospective cohort study, which included all patients diagnosed with DF at the Central Virology Laboratory of the Israeli Ministry of Health during 2008-19. Clinical, laboratory and virological data were extracted from laboratory and patient records. A diagnosis of DENV infection was based on a positive nonstructural protein 1 (NS1) test, polymerase chain reaction or serology testing for immunoglobulin M (IgM) and immunoglobulin G (IgG). Primary and secondary infections were classified based on travel history, NS1 result and IgM/IgG ratio. Severe DF was defined according to WHO classification. RESULTS: We identified 245 DF cases: 210 (86%) primary and 35 (14%) secondary. Whilst fever duration was significantly longer in secondary compared with primary infections (6.4 vs 5.3 days, P = 0.027), mean Aspartate aminotransferase levels were significantly higher in primary compared with secondary cases (146 vs 65 U/L, P < 0.001), and no other clinical or laboratory parameter differed significantly between the groups. Of note, only four patients had severe DF, all had primary infections and none died. CONCLUSIONS: In a cohort of returning travellers with DF, secondary infection, compared with primary infection, was not associated with a consistent trend towards greater severity of the clinical and laboratory markers examined in this study.

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.