Long COVID (post-acute sequelae of SARS-CoV-2 infection) affects approximately 5%-30% of survivors and is characterized by persistent fatigue, dyspnea, exercise intolerance, and cognitive impairment. We evaluated the immunological effects of supervised exercise in adults with long COVID. In this pre-specified exploratory substudy of the EXER-COVID randomized 2 × 2 crossover trial, participants completed a 6-week supervised exercise program (twice weekly) or usual care before crossing over after a 3-5 day washout. Plasma cytokines (IL-1β, IL-6, IL-10, TNF-α, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, and IP-10/CXCL10) were measured by multiplex immunoassay. Immunophenotyping included 20 CD4+ and CD8+ T-cell subsets and five innate immune populations. Treatment effects were estimated using within-period change scores, with multiple testing controlled by the Benjamini-Hochberg procedure (false discovery rate < 5%). Five variables reached nominal significance before correction (two CD8+ T-cell subsets and IL-1β, IL-10, and MIP-1α), but none remained significant after adjustment. No changes were observed in innate immune populations, and no evidence of carryover was detected. Supervised exercise was not associated with significant immunological changes after correction for multiple comparisons, supporting the short-term immunological safety of moderate-intensity exercise in PESE-negative adults with long COVID (ClinicalTrials.gov: NCT04797871).
