The cytokines CXCL10 and CCL2 and the kynurenine metabolite anthranilic acid accurately predict patients at risk of developing dengue with warning signs

• Main Authors: Jusof, Felicita Fedelis, Lim, Chai K., Aziz, Fazidatul Nadhirah, Soe, Hui Jen, Raju, Chandramathi Samudi, Sekaran, Shamala Devi, Guillemin, Gilles J.
• Format: Article
• Published: Oxford University Press (OUP) 2022
• Subjects: QR355 Virology
• Online Access: http://eprints.um.edu.my/40443/; https://doi.org/10.1093/infdis/jiac273

Background The resolution or aggravation of dengue infection depends on the patient's immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity. Methods KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs DWS-], dengue with warning signs DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma IFN-gamma], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 IP-10], interleukin 18 IL-18], CCL2/monocyte chemoattractant protein-1 MCP-1], and CCL4/macrophage inflammatory protein-1beta MIP-1 beta] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry GCMS] assays. Results Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-gamma, CXCL10, CCL4, and IL-18 than those with DWS-. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%. Conclusions The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection. Stronger activation of the kynurenine pathway is discernible in patients with dengue with warning signs as CCL2, CCL4, CXCL10, IFN-gamma, and IL-18 are elevated, accompanied by increased kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid.