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Early identification of dengue patients at risk of adverse outcomes is important to prevent hospital overcrowding in low- to middle- income countries during epidemics. We performed a systematic review to identify which biomarkers measured in first 96 h of fever could predict dengue haemorrhagic fever (DHF, World Health Organization 1997 clinical classification) or severe dengue (SD, WHO 2009, clinical classification). PubMed, Scopus, CINAHL, Web of Science, and EMBASE databases were searched for prospective cohort and nested case–control studies published from 1997 to Feb 27, 2022. The protocol for the study was registered in PROSPERO (ID: CRD42021230053). After screening 6747 publications, and analysing 37 eligible studies reporting on 5925 patients, elevated C-reactive protein, aspartate aminotransferase, interleukin-8 and decreased albumin levels were strongly associated with dengue haemorrhagic fever (by meta-analyses of multiple studies, p < 0.05), while elevated vascular cell adhesion protein 1, syndecan-1, aspartate aminotransferase and C-reactive protein levels were strongly associated with severe dengue (by meta-analyses of multiple studies, p < 0.05). Further 44 and 28 biomarkers were associated with the risk of DHF and SD respectively, but only in a single study. The meta-analyses suggest the importance of early acute inflammation with hepatic involvement in determining the subsequent course of illness in dengue. [ABSTRACT FROM AUTHOR]

Background: At least a third of dengue patients develop plasma leakage with increased risk of life-threatening complications. Predicting plasma leakage using laboratory parameters obtained in early infection as means of triaging patients for hospital admission is important for resource-limited settings. Methods: A Sri Lankan cohort including 4,768 instances of clinical data from N = 877 patients (60.3% patients with confirmed dengue infection) recorded in the first 96 hours of fever was considered. After excluding incomplete instances, the dataset was randomly split into a development and a test set with 374 (70%) and 172 (30%) patients, respectively. From the development set, five most informative features were selected using the minimum description length (MDL) algorithm. Random forest and light gradient boosting machine (LightGBM) were used to develop a classification model using the development set based on nested cross validation. An ensemble of the learners via average stacking was used as the final model to predict plasma leakage. Results: Lymphocyte count, haemoglobin, haematocrit, age, and aspartate aminotransferase were the most informative features to predict plasma leakage. The final model achieved the area under the receiver operating characteristics curve, AUC = 0.80 with positive predictive value, PPV = 76.9%, negative predictive value, NPV = 72.5%, specificity = 87.9%, and sensitivity = 54.8% on the test set. Conclusion: The early predictors of plasma leakage identified in this study are similar to those identified in several prior studies that used non-machine learning based methods. However, our observations strengthen the evidence base for these predictors by showing their relevance even when individual data points, missing data and non-linear associations were considered. Testing the model on different populations using these low-cost observations would identify further strengths and limitations of the presented model. Author summary: Current machine learning approaches are mostly designed for decision support systems that used for predicting severity of dengue and forecasting of dengue cases. The few studies to predict plasma leakage rely on traditional statistical approach with a priori predictors. To our knowledge, no study used machine learning to predict plasma leakage in suspected dengue patients. This is the first study to develop a machine learning model to identify predictors that detect plasma leakage in the early stages of dengue infection. In addition, this study placed focus on a limited resource setting enabling decision support systems to be utilised in the low- to middle-income country of Sri Lanka. The study identified five accessible predictors as inputs to the model to aid the decision making for hospital admission for suspected cases of dengue. Lastly, the multi-metric assessments, model fairness and Shapley additive explanations push the agenda for model transparency and interpretability. Our machine learning approach demonstrated reasonable performance and has the potential to identify patients who are likely to develop plasma leakage for close monitoring to prevent severe consequences. [ABSTRACT FROM AUTHOR]

Given the structural similarity between Zika and dengue viruses, prior infection from one virus is hypothesized to modulate the severity of a subsequent infection from the other virus. A previous paediatric cohort study observed that a prior Zika infection may increase the risk of a subsequent symptomatic or severe dengue infection. The Colombo Dengue study is a prospective hospital-based cohort study in Sri Lanka that recruits symptomatic adult dengue patients within the first three days of fever. Anti-Dengue Envelope and anti-Zika NS1 IgG antibodies were tested by ELISA (Euroimmun, Lubeck, Germany) in all recruited patients. Associations between pre-morbid seroprevalence for either or both infections and adverse clinical outcomes of the current dengue infection were explored. A total of 507 dengue infected patients were assessed of whom 342 (68%) and 132 (26%) patients had anti-dengue IgG and anti-Zika IgG respectively. People with combined prior dengue and zika exposure as well as prior dengue exposure alone, were at increased risk of plasma leakage, compensated and uncompensated shock, and severe dengue (p < 0·05), compared to people without prior exposure to either infection. The effect of prior Zika exposure alone could not be established due to the small the number of primary dengue infections with prior Zika exposure. [ABSTRACT FROM AUTHOR]

Plasma leakage is a precursor to life-threatening complications of dengue, but this group is poorly defined and not often reported in literature. Patients with Dengue haemorrhagic fever (DHF) as defined in the 1997 World Health Organization classification are often reported, and they all have plasma leakage, but some patients with plasma leakage do not meet the definition of DHF. The study aims to estimate the frequency of plasma leakage and DHF (as a surrogate of plasma leakage) in dengue and its variations based on virus serotype, geography, patient gender and pre-existing immunity to dengue. PUBMED, Scopus, EMBASE, CINAHL and Web of Science were searched for prospective observational studies reporting on plasma leakage or DHF. Quality of data was assessed using the NIH quality assessment tool for cohort studies. Forty-three studies that recruited 15,794 confirmed dengue patients were eligible. Cumulative frequency of plasma leakage was 36.8% (15 studies, 1642/4462, 95% CI 35.4-38.2%), but surprisingly the estimated cumulative frequency of DHF was higher (45.7%, 32 studies, 4758/10417, 95% CI 44.7-46.6%), indicating that current medical literature over-reports DHF or under-reports plasma leakage. Therefore, a reliable estimate for the proportion of dengue patients developing plasma leakage cannot be derived from existing medical literature even after applying rigorous inclusion criteria to select homogenous studies. Plasma leakage is an important marker of "at-risk" dengue patients and standardizing its definition, diagnosis and reporting should be a priority in research and global policy. [ABSTRACT FROM AUTHOR]

Objectives: To compare the traditional haematocrit‐based criteria (>20% rise above baseline) with ultrasonography for diagnosing plasma leakage in dengue fever and to identify clinical indicators for triaging patients in resource‐limited settings when the demand for ultrasonography is high. Methods: The Colombo Dengue Study is a prospective observational cohort study recruiting dengue patients in the first three days of dengue fever, before plasma leakage. Serial haematocrit assessments and ultrasonography were performed in patients recruited from October 2017 to February 2020. Clinical signs/symptoms and laboratory investigation results independently associated with ultrasound detected plasma leakage were identified with a derivation cohort and confirmed in a validation cohort. Results: 129 of 426 patients had ultrasonography‐confirmed plasma leakage while 146 had a haematocrit rise >20%. Those positive on ultrasonography were also likely to fulfil the haematocrit‐based criteria (OR: 4.42, 95% CI: 2.85–6.86), but the two groups did not overlap fully. In the derivation cohort (n = 317), platelet count <97 000/µl, AST/ALT > 51 IU/l and having abdominal pain in the first three days of fever were independent predictors of ultrasound‐detected plasma leakage. In the validation cohort (n = 109), the combination of low platelet count and high aminotransferase level had better predictive capacity in terms of sensitivity and specificity. Conclusion: Dengue patients should be monitored with both serial haematocrit and ultrasonography whenever possible and plasma leakage should be diagnosed by either one of these criteria. If accessibility to scans is limited, platelet count, serum transaminase levels and presence of abdominal pain are useful to triage patients. [ABSTRACT FROM AUTHOR]

In 2017, a dengue epidemic of unexpected magnitude occurred in Sri Lanka. A total of 186,101 suspected cases and 440 dengue-related deaths occurred. We conducted a comprehensive analysis of this epidemic by comparing national surveillance data for 2017 with data from the preceding 5 years. In all Sri Lanka districts, dengue incidence in 2017 increased significantly over incidence during the previous 5 years. Older schoolchildren and young adults were more clinically symptomatic than those at extremes of age. Limited virologic surveillance showed the dominant circulating variant was dengue virus type 2 cosmopolitan genotype in the most affected district. One quarter of total annual cases were reported 5 weeks after the southwest monsoon started. Changes in vector abundance were not predictive of the increased incidence. Direct government expenditures on dengue control activities in 2017 were US $12.7 million. The lessons learned from this outbreak are useful for other tropical nations facing increasing dengue incidence. [ABSTRACT FROM AUTHOR]

The global incidence of dengue has increased sevenfold between 1990 and 2013. Despite a low case fatality rate (<1%), during epidemics, due to the large number of people affected, overall mortality rates can be significant. The risk of clinically significant bleeding in dengue is unpredictable and often contributes to an adverse outcome. This systematic review focuses on the evidence for prophylactic and therapeutic interventions for bleeding in dengue infection. PubMed, CINAHL, Cochrane Library, Embase and Google Scholar were searched for randomized, quasi-randomized and non-randomized, prospective or retrospective studies that had a control group alongside an intervention aimed at stopping or preventing bleeding in dengue infection. Eleven studies that included 1904 patients in 12 study arms were eligible. These assessed the role of platelet transfusion [two randomized controlled trials (RCTs) and three non-randomized studies], plasma transfusion (one RCT), recombinant activated factor VII (one RCT), anti-D globulin (two RCTs), immunoglobulin (one RCT) and interleukin 11 (one RCT) as prevention or treatment for bleeding. Due to significant heterogeneity in study design and outcome reporting, a meta-analysis was not performed. Currently there is no evidence that any of the above interventions would have a beneficial effect in preventing or treating clinically significant bleeding in dengue. [ABSTRACT FROM AUTHOR]

Dengue infection causes significant morbidity and mortality in over 100 countries worldwide, and its incidence is on the rise. The pathophysiological basis for the development of severe dengue, characterized by plasma leakage and the "shock syndrome" are poorly understood. No specific treatment or vaccine is available, and careful monitoring and judicious administration of fluids forms the mainstay of management at present. It is postulated that vascular endothelial dysfunction, induced by cytokine and chemical mediators, is an important mechanism of plasma leakage. Although corticosteroids are potent modulators of the immune system, their role in pharmacological doses in modulating the purported immunological effects that take place in severe dengue has been a subject of controversy. The key evidence related to the role of corticosteroids for various manifestations of dengue are reviewed here. In summary, there is currently no high quality evidence supporting the beneficial effects of corticosteroids for treatment of shock, prevention of serious complications, or increasing platelet counts. Non-randomized trials of corticosteroids given as rescue medication for severe shock have shown possible benefit. Nonetheless, the evidence base is small, and good quality trials are lacking. We reiterate the need for well designed and adequately powered randomized controlled trials of corticosteroids for the treatment of dengue shock. [ABSTRACT FROM AUTHOR]

Background: A major challenge in dengue management in resource limited settings is the confirmation of diagnosis. Clinical features of dengue often overlap with other infections and molecular diagnostic tools are not readily accessible to clinicians at hospitals. In addition, the prediction of plasma leakage in dengue is also difficult. Hematocrit level and ultrasound scans (combined with clinical parameters) are helpful to detect plasma leakage once it has happened, not before.Methods: Colombo Dengue Study (CDS) is a prospective cohort study of clinically suspected adult dengue patients recruited from the National hospital of Sri Lanka (within the first 3 days of fever) that aimed to a) identify clinical and basic laboratory test parameters to differentiate dengue from non-dengue fever, b) evaluate the comparative efficacy of loop-mediated isothermal amplification (LAMP) for dengue diagnosis (vs. NS1 antigen test and RT-qPCR) and c) identify early associations that are predictive of plasma leakage or severe dengue. The basic laboratory tests considered here included hematological parameters, serum biochemistry and inflammatory markers.Results: Only 70% of clinically suspected patients were confirmed as having dengue by either the NS1 antigen test or RT-qPCR. On a Bayesian latent class model which assumes no "gold standard", LAMP performed equally or better than RT-qPCR and NS1 antigen test respectively. When confirmed dengue patients were compared with others, the earlier group had significantly lower lymphocyte counts and higher aspartate aminotransferase levels (AST) within the first 3 days of fever. Confirmed dengue patients with plasma leakage had a lower mean age and a higher median baseline AST level compared to those without plasma leakage (p < 0.05).Conclusion: Clinical suspicion overestimates the true number of dengue patients. RT-LAMP is a potentially useful low-cost diagnostic tool for dengue diagnosis. Confirmed dengue patients had significantly higher AST levels and lower lymphocyte counts in early disease compared to others. In confirmed dengue patients, younger age and a higher AST level in early infection were associated with subsequent plasma leakage. [ABSTRACT FROM AUTHOR]