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Background Dengue is the most widespread mosquito-borne viral disease of public health concern. In some patients, endothelial cell and platelet dysfunction lead to life-threatening hemorrhagic dengue fever or dengue shock syndrome. Prognostication of disease severity is urgently required to improve patient management. The pathogenesis of severe dengue has not been fully elucidated, and the role of host proteins associated with viral particles has received little exploration. Methods The proteomes of virion-enriched fractions purified from plasma pools of patients with dengue fever or severe dengue were compared. Virions were purified by ultracentrifugation combined with a water-insoluble polyelectrolyte-based technique. Following in-gel hydrolysis, peptides were analyzed by nano-liquid chromatography coupled to ion trap mass spectrometry and identified using data libraries. Results Both dengue fever and severe dengue viral-enriched fractions contained identifiable viral envelope proteins and host cellular proteins. Canonical pathway analysis revealed the identified host proteins are mainly involved in the coagulation cascade, complement pathway or acute phase response signaling pathway. Some host proteins were over- or under-represented in plasma from patients with severe dengue compared to patients with dengue fever. ELISAs were used to validate differential expression of a selection of identified host proteins in individual plasma samples of patients with dengue fever compared to patients with severe dengue. Among 22 host proteins tested, two could differentiate between dengue fever and severe dengue in two independent cohorts (olfactomedin-4: area under the curve (AUC), 0.958; and platelet factor-4: AUC, 0.836). Conclusion A novel technique of virion-enrichment from plasma has allowed to identify two host proteins that have prognostic value for classifying patients with acute dengue who are more likely to develop a severe dengue. The impact of these host proteins on pathogenicity and disease outcome are discussed.

Dengue, an acute febrile disease caused by dengue virus (DENV) infection, is endemic to Indonesia. During early 2020, an outbreak of severe dengue occurred in Maumere, East Nusa Tenggara province, a region with low dengue endemicity with limited data on the characteristics of the circulating DENV. By 18 March 2020, 1396 cases were reported with 14 fatalities. Investigation was conducted to understand the cause and characteristics of the outbreak. Sera were collected from 133 patients with dengue-like symptoms through random sampling at TC Hillers Hospital, Maumere during outbreak between February and June 2020. Dengue was confirmed using NS1 and/or RT-PCR detection. Serological status was determined using IgG/IgM ELISA and plaque reduction neutralization test (PRNT). DENV serotyping and genome sequencing were performed to identify the DENV serotype and genotype. We recruited suspected dengue patients attending the hospital during the outbreak. Dengue was confirmed in 72.2% (96/133), while 18.8% (25/133) were diagnosed as probable dengue. Children under 18 years old accounted for 85.1% (103/121) of dengue cases. Severe dengue accounted for 94.2% (81/86) of cases. Secondary infections made up 92.6% (112/121) of cases. Serotyping detected 87.3% (62/71) as DENV-3, 7.0% (5/71) as DENV-4, 2.8% (2/71) as DENV-1, and 2.8% (2/71) as DENV-2. Phylogenetic analysis revealed close evolutionary relationship of Maumere DENV to viruses from other Indonesian regions, especially Bali and Kupang. PRNT on DENV-3 secondary infections patients detected the presence of DENV-2 and DENV-4 neutralizing antibodies. The severe dengue outbreak in Maumere is caused by DENV-3 introduced from nearby islands. The high proportion of secondary infections likely contributes to the severity of the disease. The high percentage of anti-dengue neutralizing antibodies for multiple serotypes and the high proportion of anti-dengue IgG in young children suggests a history of dengue transmission with a high infection rate in the area.

Dengue hemorrhagic fever and dengue shock syndrome (DSS) are major causes of childhood morbidity and mortality in many tropical countries. Increased intravascular permeability leading to shock is the cardinal feature of DSS. Fluid resuscitation to counteract massive plasma leakage is the mainstay of treatment. A double-blind, randomized trial comparing four intravenous-fluid regimens for acute resuscitation of 50 children with DSS was conducted. Colloids (dextran 50 or the protein digest gelafundin 35,000) restored cardiac index and blood pressure and normalized hematocrit more rapidly than crystalloids (Ringer's lactate or 0.9%-weight/volume saline). Dextran 70 provided the most rapid normalization of the hematocrit and restoration of the cardiac index, without adverse effects, and may be the preferred solution for acute resuscitation in DSS. Further large-scale double-blind trials are required to provide an evidence-based approach to the management of DSS.

Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.

Dengue is an important tropical disease with considerable global impact. Despite this, there remains an urgent need for reliable biomarkers to predict disease severity, as well as effective antiviral drugs and targeted treatments. In this study, we conducted a comprehensive profiling of 41 plasma mediators in patients with asymptomatic dengue (AD) and symptomatic dengue (SD), which includes mild dengue fever (DF) and severe dengue hemorrhagic fever (DHF). Our findings revealed that the levels of nearly all measured mediators were consistently lower in AD compared to SD patients, suggesting a potential protective cytokine response signature. Time-course cytokine analysis in SD shown significantly elevated levels of pro-inflammatory cytokines and chemokines associated with inflammation and viral clearance upon the acute phase, while various growth factors were elevated during the convalescence. Notably, we identified elevated IL-15 levels in DHF patients three days before fever subsidence, highlighting its potential as an early prognostic biomarker for severe disease outcomes. Furthermore, prolonged high levels of IL-8 and IP-10 in DHF during the critical period may contribute to dengue immunopathogenesis. This study advances the understanding of cytokine dynamics in the natural course of human dengue infection, providing valuable insights for the development of targeted treatments and prognostic biomarkers.

Dengue induces a spectrum of severity in humans from the milder dengue fever to severe disease, or dengue hemorrhagic fever (DHF). Chymase is a candidate biomarker that may aid dengue prognosis. This prospective study aimed to identify whether warning signs of severe dengue, including hypovolemia and fluid accumulation, were associated with elevated chymase. Serum chymase levels were quantified prospectively and longitudinally in hospitalized pediatric dengue patients in Sri Lanka. Warning signs were determined based on daily clinical assessments, laboratory tests and ultrasound findings. Chymase was significantly elevated during the acute phase of disease in DHF or Severe dengue, defined by either the 1997 or 2009 WHO diagnosis guidelines, and persisted longer in the most severe patients. Chymase levels were higher in patients with narrow pulse pressure and clinical warning signs such as severe leakage, fluid accumulation, pleural effusion, gall-bladder wall thickening and rapid haematocrit rise concurrent with thrombocytopenia. No association between chymase and liver enlargement was observed. This study confirms that serum chymase levels are associated with DHF/Severe dengue disease in hospitalized pediatric patients. Chymase levels correlate with warning signs of vascular dysfunction highlighting the possible functional role of chymase in vascular leakage during dengue.

Predictive markers represent a solution for the proactive management of severe dengue. Despite the low mortality rate resulting from severe cases, dengue requires constant examination and round-the-clock nursing care due to the unpredictable progression of complications, posing a burden on clinical triage and material resources. Accordingly, identifying markers that allow for predicting disease prognosis from the initial diagnosis is needed. Given the improved pathogenesis understanding, myriad candidates have been proposed to be associated with severe dengue progression. Thus, we aim to review the relationship between the available biomarkers and severe dengue. We performed a systematic review and meta-analysis to compare the differences in host data collected within 72 hours of fever onset amongst the different disease severity levels. We searched nine bibliographic databases without restrictive criteria of language and publication date. We assessed risk of bias and graded robustness of evidence using NHLBI quality assessments and GRADE, respectively. This study protocol is registered in PROSPERO (CRD42018104495). Of 4000 records found, 40 studies for qualitative synthesis, 19 for meta-analysis. We identified 108 host and viral markers collected within 72 hours of fever onset from 6160 laboratory-confirmed dengue cases, including hematopoietic parameters, biochemical substances, clinical symptoms, immune mediators, viral particles, and host genes. Overall, inconsistent case classifications explained substantial heterogeneity, and meta-analyses lacked statistical power. Still, moderate-certainty evidence indicated significantly lower platelet counts (SMD -0.65, 95% CI -0.97 to -0.32) and higher AST levels (SMD 0.87, 95% CI 0.36 to 1.38) in severe cases when compared to non-severe dengue during this time window. The findings suggest that alterations of platelet count and AST level-in the first 72 hours of fever onset-are independent markers predicting the development of severe dengue.

The involvement of the immune system in the protection and pathology of natural dengue virus (DENV) has been extensively studied. However, despite studies that have referred to activation of neutrophils in DENV infections, the exact roles of neutrophils remain elusive. Here, we explored the phenotypic and functional responses of neutrophils in a cohort of adult dengue patients. Results indicated that during an acute DENV infection, neutrophils up-regulate CD66b expression, and produce a more robust respiratory response as compared with that in convalescent or healthy individuals; this confirmed neutrophil activation during DENV infection. Spontaneous decondensation of nuclei, an early event of neutrophil extracellular trap (NET) formation, was also markedly increased in cells isolated from DENV-infected patients during the acute phase of the infection. incubation of NETs with DENV-2 virus significantly decreased DENV infectivity. Interestingly, increased levels of NET components were found in the serum of patients with more severe disease form-dengue hemorrhagic fever (DHF), but not uncomplicated dengue fever, during the acute phase of the infection. Levels of pro-inflammatory cytokines IL-8 and TNFα were also increased in DHF patients as compared with those in healthy and DF subjects. This suggested that NETs may play dual roles during DENV infection. The increased ability for NET formation during acute DENV infection appeared to be independent of PAD4-mediated histone H3 hyper-citrullination. Our study suggests that neutrophils are involved in immunological responses to DENV infection.

Background Liver involvement in acute dengue infection is frequently observed and sometimes leads to acute liver failure, with fatal outcomes. Many factors are thought to contribute to liver dysfunction, including hypoxic injury due to decreased perfusion, direct damage by the virus and immune mediated injury. In this study, we sought to identify the pattern in the change in liver enzymes throughout the illness and its association with the degree of viraemia, onset and extent of plasma leakage and inflammatory mediators. Methods Serial daily blood samples were obtained from 55 adult patients with acute dengue from the time of admission to discharge and the liver function tests, viral loads and cytokines were assessed. The onset and extent of fluid leakage was measured by daily ultrasound examinations and all clinical and laboratory features were serially recorded. Results Aspartate transaminase (AST), alanine transaminase (ALT) and gamma glutamyl transferase (GGT) levels were elevated in patients with dengue infection throughout the illness. The highest AST levels were seen on day 6 of illness and both AST and GGT levels were significantly higher in patients with severe dengue (SD), when compared to those with non-severe dengue (NSD) on day 5 and 6 of illness. Three patients with SD had AST and ALT values of >1000/IU in the absence of any fluid leakage or a rise in the haematocrit (≥20 %). The peak of the AST levels and the lowest serum albumin levels were seen 24 h before the maximum fluid leakage and 24 h after the peak in viraemia. Both serum IL-10 and IL-17 levels were elevated during early illness and were significantly higher in those with SD when compared to NSD. Conclusion Dengue associated liver injury appears to peak around day 6 and 7. Therefore, liver function tests done at earlier dates might not reflect the extent of liver involvement in acute infection. Since severe liver involvement can occur in the absence of fluid leakage, after the peak viraemia, and since it is associated with high IL-17 and IL-10 levels, possible immune mechanisms leading to hepatic damage should be investigated.

Annually, around half a million people with severe dengue require hospitalization, all over the globe, with around 12,500 (2.5%) succumbing to the illness. In this prospective observational study, we recruited 74 patients with dengue infection, 28 had severe dengue and 46 had dengue with warning signs. sIL-2R levels were significantly raised in the severe dengue group, compared to the warning signs group. Using an ROC curve (receive operator characteristic), at a cutoff of 5.379 ng/ml, it predicted the severe dengue classification with a p -value of < 0.001. As a marker for predicting hemophagocytic lymphohistiocytosis (HLH), the ROC curve revealed a cutoff of ≥ 5.379 ng/ml for sIL-2R levels with the AUROC being 0.83, suggesting a strong diagnostic performance( p -value < 0.001). sIL-2R levels can be used for predicting severe dengue classification with moderate sensitivity and specificity. Secondary HLH is an under-reported entity in dengue infection and early surveillance with the help of sIL-2R may be helpful in-patient care management.