Reduced ex vivo TNFα synthesis upon whole blood stimulation with endotoxin predicts post-stroke fatigue

Abstract

Objective: Fatigue is a common, debilitating syndrome after stroke. Peripheral inflammation plays a role in the pathogenesis of fatigue of different origin, but its contribution to post-stroke fatigue (PSF) remains unclear. We aimed to determine if there is any association between ex vivo synthesized and circulating cytokines, and risk of PSF.

Methods: We included 174 patients with ischemic stroke. We stimulated in vitro blood taken on day 3 after stroke with endotoxin. We measured ex vivo released (TNFα, IP-10, IL-1β, IL-6, IL-8, IL-10, IL-12p70) and plasma (TNFα, IL-6, sIL-6R, IL-1Ra) cytokines. We assessed fatigue at month 3 using Fatigue Severity Scale (FSS). We used logistic regression to assess the relationship between cytokines and fatigue scores.

Results: Compared with patients with lower fatigue at month 3 (FSS < 36), patients with higher fatigue (FSS ≥ 36) had lower endotoxin-stimulated TNFα release after 24 h (median: 429 vs 581 pg/mL, P = 0.05). Plasma TNFα tended to be higher in patients who developed fatigue (median: 0.8 vs 0.6 pg/mL, P = 0.06). Other cytokines did not differ between groups. After adjusting for pre-stroke fatigue and depressive symptoms, TNFα release <559.7 pg/mL after 24 h was associated with an increased risk of PSF (OR: 2.61, 95%CI: 1.22-5.57, P = 0.01). Plasma TNFα >0.76 pg/mL was associated with higher risk of PSF in univariable (OR: 2.41, 95%CI: 1.13-5.15, P = 0.02), but not multivariable analysis (OR: 2.41, 95%CI: 0.96-6.00, P = 0.06).

Conclusion: Reduced ex vivo TNFα synthesis upon whole blood stimulation with endotoxin in the acute phase of stroke predicted PSF.

Keywords: Cytokines; Endotoxin; Fatigue; Stroke.