Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID

Abstract

Background: Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), is a debilitating condition characterized by persistent fatigue and multisystemic symptoms, such as cognitive impairment, musculoskeletal pain, and post-exertional malaise. Recently, parallels have been drawn between ME/CFS and Long COVID, a post-viral syndrome following infection with SARS-CoV-2, which shares many clinical features with CFS. Both conditions involve chronic immune activation, raising questions about their immunopathological overlap. Objectives: This study aimed to compare immune biomarkers between patients with ME/CFS or Long COVID and healthy controls to explore shared immune dysfunction. Methods: We analyzed lymphocyte subsets, cytokine profiles, psychological status and their correlations in 190 participants, 65 with CFS, 54 with Long COVID, and 70 healthy controls. Results: When compared to healthy subjects, results in both conditions were marked by lower levels of lymphocytes (CFS-2.472 × 10⁹/L, p = 0.006, LC-2.051 × 10⁹/L, p = 0.009), CD8⁺ T cells (CFS-0.394 × 10⁹/L, p = 0.001, LC-0.404 × 10⁹/L, p = 0.001), and NK cells (CFS-0.205 × 10⁹/L, p = 0.001, LC-0.180 × 10⁹/L, p = 0.001), and higher levels of proinflammatory cytokines such as IL-6 (CFS-3.35 pg/mL, p = 0.050 LC-4.04 pg/mL, p = 0.001), TNF (CFS-2.64 pg/mL, p = 0.023, LC-2.50 pg/mL, p = 0.025), IL-4 (CFS-3.72 pg/mL, p = 0.041, LC-3.45 pg/mL, p = 0.048), and IL-10 (CFS-2.29 pg/mL, p = 0.039, LC-2.25 pg/mL, p = 0.018). Conclusions: Notably, there were no significant differences between CFS and Long COVID patients in the tested biomarkers. These results demonstrate that ME/CFS and Long COVID display comparable immune and inflammatory profiles, with no significant biomarker differences observed between the two groups.

Keywords: COVID-19; chronic fatigue; chronic fatigue syndrome; long COVID.

Figure 1

Results from age-adjusted ANCOVA test, showing distribution of lymphocytes, NK and CD8⁺ T cells in the three studied groups as individual points (circles). Exact p values are provided. Results are presented as median values and interquartile ranges (coloured lines).

Figure 2

Results from age-adjusted ANCOVA test, showing serum levels of IFN-γ, TNF, IL-4, IL-2, IL-10, and IL-6 in the three studied groups as individual points (circles). Exact p values are provided where statistical significance was established. Results are presented as median values and interquartile ranges (coloured lines).

Figure 3

Results from age-adjusted ANCOVA test, showing z-score ratios of Th1 ctokine profile, Th1/Th2 + Treg ratio, proinflamatory/antiinflammatory profile, and IRC/CIRS ratio in the three studied groups as individual points (circles). Exact p values are provided where statistical significance was established. Results are presented as median values and interquartile ranges (coloured lines).