Abstract Long-COVID remains incompletely understood, particularly regarding the roles of peripheral systemic inflammation and neuroinflammation. The persistence and extent of these processes remain debated. We conducted a single-center, age- and sex-matched case–control study at Stavanger University Hospital, Norway, recruiting participants from the general population. Forty-eight long-COVID patients and 48 recovered controls were included at a median of 69 weeks post-SARS-CoV-2 infection. Exclusion criteria included autoimmune or chronic inflammatory diseases, cancer, and other conditions affecting fatigue. Plasma levels of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), triggering receptor expressed on myeloid cells 2 (TREM2), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured using ultrasensitive NULISA™ technology. CRP, TNF-α, and IL-6 were additionally assessed by a standard hospital laboratory method (CRP) and MSD S-Plex chemiluminescence immunoassay (TNF-α and IL-6 MSD). No significant differences in NfL or GFAP were observed between groups, suggesting no ongoing neuronal injury or neuroinflammation. Routine immunoassays showed no differences for inflammatory markers. In unadjusted analyses using ultrasensitive assays, long-COVID patients showed nominally elevated levels of CRP ( p = 0.04), TNF-α ( p = 0.01), IL-6 ( p = 0.02), and TREM2 ( p = 0.02). However, these differences did not survive correction for multiple comparisons (all false discovery rate-adjusted p > 0.05). The absence of neuroinflammation markers is consistent with the hypothesis that persistent long-COVID symptoms are unlikely due to ongoing neuronal injury or central nervous system inflammation. Alternatively, persisting long-COVID symptoms may reflect a chronic, extremely low-level immune activation, that contributes to fatigue, pain, and other sickness phenomena through mechanisms such as pro-inflammatory signaling in the brain, or epigenetic mechanisms underlying the sickness behavior response. These findings should be considered preliminary and warrant validation in larger, longitudinal cohorts.
Omdal et al. (Tue,) studied this question.