Longitudinal profiling of plasma cytokines in melioidosis and their association with mortality: a prospective cohort study.
Kaewarpai T., Ekchariyawat P., Phunpang R., Wright SW., Dulsuk A., Moonmueangsan B., Morakot C., Thiansukhon E., Day NPJ., Lertmemongkolchai G., West TE., Chantratita N.
OBJECTIVES:To characterize plasma cytokine responses in melioidosis and analyse their association with mortality. METHODS:A prospective longitudinal study was conducted in two hospitals in Northeast Thailand to enroll 161 melioidosis patients, 13 uninfected healthy controls, and 11 uninfected diabetic controls. Blood was obtained from all individuals at enrollment (day 0) and at days 5, 12, and 28 from surviving melioidosis patients. IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-23, and TNF-α were assayed in plasma. The association of each cytokine and its dynamics with 28-day mortality was determined. RESULTS:Of melioidosis patients, 131/161 (81%) were bacteraemic, and 68/161 (42%) died. On enrollment median levels of IFN-γ, IL-6, IL-8, IL-10, IL-23, and TNF-α were higher in melioidosis patients compared with uninfected healthy controls and all but IFN-γ were positively associated with 28-day mortality. IL-8 provided the best discrimination of mortality (AUROCC 0.78, 95% CI 0.71-0.85). Over time, non-survivors had increasing IL-6, IL-8, and IL-17A levels, in contrast to survivors. In joint modeling, temporal trajectories of IFN-γ, IL-6, IL-8, IL-10, and TNF-α predicted survival. CONCLUSIONS:In a severely ill cohort of melioidosis patients, specific pro- and anti-inflammatory and Th17 cytokines were associated with survival from melioidosis, at enrollment and over time. Persistent inflammation preceded death. These findings support further evaluation of these mediators as prognostic biomarkers and to guide targeted immunotherapeutic development for severe melioidosis.