Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

Background Early identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of ten biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD). Methods We performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included. Results On days 1-3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults. Conclusions Our findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients. Summary of the main point Higher levels of any of VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, and CRP on illness days 1-3 increased the risk of developing severe/moderate dengue. The relationships differed between children and adults and some changed when assessed together. ### Competing Interest Statement All authors report no conflicts of interest in relation to the present work. TJ reports receiving personal fees as members of the ROCHE Advisory Board on Severe Dengue. BAW reports receiving personal fees as a member of the Data Monitoring and Adjudication Committees for the Takeda dengue vaccine trials and as a member of the ROCHE Advisory Board on Severe Dengue. RBG report receiving personal fees from the Wellcome Trust (grant number 106680/Z/14/Z). SY reports receiving personal fees as a member of the ROCHE Advisory Board on Severe Dengue, for work on Janssen Pharmaceuticals Advisory Board for Dengue Antiviral Development, and from the Wellcome Trust (grant number 106680/Z/14/Z). ### Clinical Trial N/A ### Funding Statement This work was supported by the European Union Seventh Framework Programme for research, technological development and demonstration (grant FP7-281803 IDAMS; ; publication reference number IDAMS: 53), and by the World Health Organization, UNICEF/UNDP/ World Bank/WHO Special Programme for Research and Training in Tropical Diseases, and by the Bill and Melinda Gates Foundation Trust through The Global Good Fund I, LLC at Intellectual Ventures. The funders had no role in the study design, data collection and analysis, or preparation of the manuscript. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IDAMS study and the blood sample analysis were approved by the Scientific and Ethics Committees of all study sites and by the Oxford Tropical Research Ethics Committee. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data referred to in the manuscript are available in the link below. * AIC : Akaike information criterion Ang-2 : angiopoietin-2 CRP : C-reactive protein DENV : dengue virus ELISA : enzyme-linked immunosorbent assay IL-1RA : interleukin-1 receptor antagonist IL-8 : interleukin-8 IP-10 : interferon gamma-induced protein-10 OR : odds ratio OUCRU : Oxford University Clinical Research Unit RT-PCR : reverse transcriptase polymerase chain reaction S/MD : severe and moderate dengue sCD163 : soluble cluster of differentiation 163 SDC-1 : syndecan-1 sTREM-1 : soluble triggering receptor expressed on myeloid cells-1 VCAM-1 : vascular cell adhesion molecule-1 WHO : World Health Organization