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

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.

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.

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).

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