Home›Allergy & Immunology› Cytokine and endothelial markers show strong associations with severe dengue cases across 47,612 patients
Cytokine and endothelial markers show strong associations with severe dengue cases across 47,612 patientsMarkers for severe dengue disease show promise in large data
medRxivPublished July 2, 2026Study authors: Asaga, P. M.; Kroeger, A. A.; Kadukkatti, V.; Arsha, L.; Airiohuodion, P.DOI ↗Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease
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Key Takeaway
Note that cytokine and endothelial markers correlate with dengue severity but require further validation before clinical use.
This meta-analysis evaluates the association of various biomarker signatures with severe dengue across a large cohort of 47,612 patients. The analysis categorized markers into pathogen-side, cytokine/chemokine, endothelial/glycocalyx, and routine clinical indicators to determine their predictive value for disease severity.
Findings indicate that cytokine and chemokine markers (IL-10, IL-6, IL-8, CXCL10/IP-10) showed larger pooled effects associated with severe disease. Endothelial and glycocalyx markers (angiopoietin-2, syndecan-1) provided the most direct mechanistic link to plasma leakage. Pathogen-side markers showed modest associations that varied by day of illness and serotype. Routine clinical markers like platelet count and lactate retained substantial discriminatory value. Prediction models demonstrated high performance with AUC values up to 0.96 in internal validation and 0.97 in discovery analyses.
The authors note several limitations, including the fact that only three prediction models were externally validated and decision-curve analysis was not reported for any model. Calibration was also only reported for two models. While these markers are promising candidates for clinical use, the authors caution that a parsimonious panel requires further prospective external validation before it can be implemented in routine practice.
How this fits prior evidence
This meta-analysis extends prior evidence regarding dengue management by identifying specific biomarkers associated with severity. It builds upon previous findings where clinical prediction models were used for arbovirus surveillance based on signs, symptoms, and comorbidities. While the current study identifies high AUC values for several markers, it emphasizes that these associations do not establish direct causation.
When someone contracts the dengue virus, doctors need to know quickly if the illness will become severe. This study looked at data from over 47,000 patients to find patterns that signal a worsening condition. The researchers found that certain markers in the blood, specifically cytokine and chemokine levels, showed strong links to more severe disease.
While viral load also showed some connection to severity, it varied depending on how long the person had been sick and which strain of the virus they caught. However, markers related to endothelial and glycocalyx health provided a very direct link to plasma leakage, which is a major concern in serious dengue cases. These findings suggest that combining these specific markers with standard clinical tests could help doctors identify high-risk patients more accurately.
It is important to note that while the data looks promising, these markers are not ready for everyday use in clinics just yet. The study notes that many of these indicators need more testing in real-world settings before they can be used as routine tools. For now, these findings help researchers prioritize which tests might eventually help doctors catch severe cases earlier.
What this means for you:
Specific blood markers like cytokines and endothelial signals show strong links to predicting severe dengue cases.
Common questions
What markers are linked to severe dengue?
The study found that cytokine and chemokine markers (such as IL-10, IL-6, IL-8, and CXCL10) showed large links to severe disease. Additionally, endothelial and glycocalyx markers like angiopoietin-2 and syndecan-1 provided a direct link to plasma leakage.
Are these tests ready for use in clinics today?
Not yet. While the results are promising for identifying risk, the study notes that these markers need more prospective external validation before they can be used as routine tools in a clinical setting to manage patients.
How accurate were the prediction models?
The prediction models showed high performance in internal tests, with scores reaching up to 0.96 and 0.97. However, only three of these models were externally validated by the researchers.
Summary Background Severe dengue reflects a temporally regulated interaction between viral burden, NS1 antigenaemia, cytokine and chemokine amplification, endothelial activation, glycocalyx injury, and organ stress. Although individual cytokines, endothelial markers, viral-burden measures, and clinical markers have been widely studied, the integrated pathogen-host evidence base remains fragmented. We synthesised evidence for cytokine, endothelial, and viral-burden signatures associated with severe dengue and assessed whether paired pathogen-host measurement provides a biologically coherent framework for severity assessment. Methods We searched MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, Global Health, WHO Global Index Medicus, and medRxiv from database inception to 30 April 2026, without language restriction, for studies reporting viral burden, NS1 antigenaemia, cytokine, chemokine, endothelial, glycocalyx, inflammatory, or routine host-response markers in laboratory-confirmed dengue with severity outcomes. Eligible designs were prognostic-factor association studies, cross-sectional biomarker studies, and multivariable prediction-model studies. Risk of bias was assessed using QUIPS for prognostic-factor studies, PROBAST for prediction-model studies, and the relevant JBI critical appraisal checklist for cross-sectional biomarker studies, with the Newcastle-Ottawa Scale used selectively for cohort or case-control designs not amenable to QUIPS. Random-effects meta-analysis pooled standardised mean differences using restricted maximum likelihood with Hartung-Knapp adjustment. The protocol was registered with PROSPERO (CRD420261396923) before final extraction and synthesis. Findings Of 4,180 records identified, 79 studies including 47,612 participants met eligibility criteria. Forty-nine studies evaluated paired pathogen-host markers, 14 evaluated viral burden or NS1 antigenaemia alone, nine evaluated host biomarkers alone, and seven reported multivariable prediction models. Pathogen-side markers showed modest pooled severity associations whose magnitude depended on day of illness, immune status, and infecting serotype. Cytokine and chemokine markers, particularly IL-10, IL-6, IL-8, and CXCL10/IP-10, showed larger pooled effects favouring severe disease, while endothelial and glycocalyx markers, including angiopoietin-2 and syndecan-1, provided the most direct mechanistic link to plasma leakage. Routine clinical markers, especially platelet count, AST, ferritin, ALT, and lactate, retained substantial discriminatory value. Prediction models reported areas under the curve of up to 0{middle dot}96 in internal validation and 0{middle dot}97 in discovery analyses, but three had been externally validated, calibration was reported in two, and decision-curve analysis in none. Interpretation Current evidence supports severe dengue as an integrated pathogen-host injury syndrome in which viral burden and NS1 antigenaemia interact with cytokine amplification, endothelial dysfunction, glycocalyx injury, and routine markers of organ stress. The strongest translational direction is not a single biomarker but a parsimonious cytokine-endothelial-pathogen panel requiring prospective external validation across age groups, serotypes, immune-status strata, and endemic regions. Existing evidence supports candidate marker prioritisation and mechanistic synthesis, but not immediate routine clinical deployment.
