Fatigue, Toll-Like Receptor 4, and Pro-Inflammatory Cytokines in Adults With Subarachnoid Hemorrhage: A 6-Month Longitudinal Study

Abstract

Background Fatigue is prevalent in subarachnoid hemorrhage (SAH) survivors. Biological mechanisms underlying fatigue post-SAH are not clear. Inflammation may contribute to the development of fatigue. This study aimed to examine the associations between inflammatory markers and fatigue during the first 6 months post-SAH. Specific biomarkers examined included both early and concurrent expression of Toll-Like Receptor 4 (TLR4) messenger RNA (mRNA) and plasma concentrations of pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)1β, and IL6. Methods We conducted a 6-month longitudinal study with a convenience sample of 43 SAH survivors. We collected blood samples on days 2, 3, and 7 and 2, 3, and 6 months post-SAH to assess biomarkers. Fatigue was assessed by the PROMIS Fatigue Scale at 2, 3, and 6 months. Linear mixed models were used to test the associations between early (days 2, 3, and 7) and concurrent (2, 3, and 6 months) TLR4 mRNA expression (TagMan gene expression assays) and TNF-α, IL1β, and IL6 plasma concentrations (multiplex assays) and concurrent fatigue. Results 28% of SAH survivors experienced fatigue during the first 6 months post-SAH. Fatigue levels in SAH survivors were higher than those of the U.S. population and consistent during the 6 months. Experience of fatigue during the 6 months post-SAH was associated with higher IL1β plasma concentrations on day 7 and IL1β, IL6, and TNF-α plasma concentrations during the 6 months post-SAH. Conclusion Inflammation appears to underlie the development of fatigue in SAH survivors.