Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS.

Post-infectious syndromes including post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute-onset neuropsychiatric syndrome (PANS)/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) share overlapping clinical phenotypes characterized by fatigue, cognitive dysfunction, sleep disturbance, and neuropsychiatric symptoms. Increasing evidence suggests that immune dysregulation-including persistent inflammation, autoantibody production, and cellular immune dysfunction-may underlie these conditions. This narrative review synthesizes peer-reviewed literature describing immune abnormalities across these syndromes and evaluates the rationale for immunomodulatory therapies, including intravenous immunoglobulin (IVIG), rituximab, and therapeutic plasma exchange (TPE). Evidence supporting immune-targeted treatment strategies is strongest in subsets of patients with identifiable immunologic abnormalities. Notably, the phase III RituxME trial in ME/CFS and a phase II trial of TPE in post-COVID condition both failed to demonstrate efficacy in unselected populations, reinforcing the importance of biomarker-guided patient stratification. TPE functions by removing circulating immune complexes, autoantibodies, and inflammatory mediators, and observational data suggest benefit in patients with demonstrable autoantibody burden. Further controlled studies incorporating immunologic phenotyping and early intervention are needed to define the therapeutic role of immune-directed interventions across these conditions.