Longitudinal profiling of plasma cytokines in melioidosis and their association with mortality: a prospective cohort study

T Kaewarpai,P Ekchariyawat,R Phunpang,S.W Wright,A Dulsuk,B Moonmueangsan,C Morakot,E Thiansukhon,N.P.J Day,G Lertmemongkolchai,T.E West,N Chantratita

doi:10.1016/j.cmi.2019.10.032

Abstract

ObjectivesTo characterize plasma cytokine responses in melioidosis and analyse their association with mortality. MethodsA prospective longitudinal study was conducted in two hospitals in Northeast Thailand to enrol 161 individuals with melioidosis, plus 13 uninfected healthy individuals and 11 uninfected individuals with diabetes to act as controls. Blood was obtained from all individuals at enrolment (day 0), and at days 5, 12 and 28 from surviving melioidosis patients. Interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-23, and tumour necrosis factor-α (TNF-α) were assayed in plasma. The association of each cytokine and its dynamics with 28-day mortality was determined. ResultsOf the individuals with melioidosis, 131/161 (81%) were bacteraemic, and 68/161 (42%) died. On enrolment, median levels of IFN-γ, IL-6, IL-8, IL-10, IL-23 and TNF-α were higher in individuals with melioidosis compared with uninfected healthy individuals and all but IFN-γ were positively associated with 28-day mortality. Interleukin-8 provided the best discrimination of mortality (area under the receiver operating characteristic curve 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 modelling, temporal trajectories of IFN-γ, IL-6, IL-8, IL-10 and TNF-α predicted survival. ConclusionsIn a severely ill cohort of individuals with melioidosis, specific pro- and anti-inflammatory and T helper type 17 cytokines were associated with survival from melioidosis, at enrolment 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.

Highlights

Median levels of IFN-g, IL-6, IL-8, IL-10, IL-23 and tumour necrosis factor-a (TNF-a) were higher in individuals with melioidosis compared with uninfected healthy individuals and all but IFN-g were positively associated with 28-day mortality
Interleukin-8 provided the best discrimination of mortality
Burkholderia pseudomallei is a facultative intracellular bacterium, a characteristic that contributes to its pathogenesis and persistence in the host, and that may modulate the cytokine response to infection

Summary

Introduction

Patients may present with a wide range of clinical manifestations including pneumonia, bacteraemia, abscesses and sepsis, frequently leading to multi-organ failure and eventually death. We analysed the ex vivo human blood response of healthy individuals in northeast Thailand and observed that B. pseudomallei and the bacterial ligands lipopolysaccharide and flagellin induce significant inflammatory cytokine release [5e7]. We found that the blood cytokine responses to B. pseudomallei differ between individuals, and by age, sex and host genetics [5,8e11]. These data suggest that there is likely to be substantial variation in blood cytokine profiles in patients with melioidosis, and raise the possibility that these profiles may be useful in elucidating the pathogenesis of infection and serving as predictive biomarkers.

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