Effects of therapeutic interventions on long COVID: a meta-analysis of randomized controlled trials.

Background: Long COVID, characterized by persistent multi-organ symptoms post-SARS-CoV-2 infection, poses a substantial global health burden. While diverse therapeutic interventions have been proposed, their comparative efficacy remains uncertain due to fragmented evidence and methodological heterogeneity in prior studies. Therefore, we conducted a meta-analysis to comprehensively explore the effectiveness of diverse therapeutic interventions in long COVID.

Methods: In this meta-analysis, we searched PubMed, Cochrane Library, Embase, Web of Science, SPORTDiscus (EBSCO), CINAHL (EBSCO), and Rehabilitation & Sports medicine source (EBSCO) from inception to July 20, 2025, for randomized controlled trials (RCTs) evaluating exercise training, respiratory muscle training, telerehabilitation, transcranial direct current stimulation (tDCS), olfactory training, palmitoylethanolamide with luteolin (PEA-LUT), and steroid sprays in adults with Long COVID. Primary outcomes included cardiopulmonary function, exercise capacity, fatigue, and olfactory recovery. Data were pooled using random-effects models, with sensitivity analyses (leave-one-out method) and Egger's test to assess robustness and publication bias. GRADE criteria evaluated evidence certainty. The study was registered with PROSPERO (CRD42024591704).

Findings: We identified a total of 51 eligible trials, comprising 4026 participants. Significant differences were observed in the following outcomes in the context of exercise training: 6MWT (MD, 83.20; 95% CI 52.04-114.37), 30sSTS (MD, 3.05; 95% CI 1.96-4.13), SF-12 Mental Component Summary (SF-12-MCS) (MD, 3.10; 95% CI 0.78-5.43), VO2 peak (% predicted) (MD, 6.00; 95% CI 0.45-11.54), VO2 peak (L/kg/min) (MD, 1.61; 95% CI 0.40-2.81), VO2 peak (L/min) (MD, 0.14; 95% CI 0.03-0.25), mMRC dyspnea scale (MD, -1.04; 95% CI -1.73 to -0.35), the Multidimensional Functional Assessment of Daily Living Scale (MBDS) (MD, -4.61; 95% CI -8.19 to -1.03), and Visual Analogue Fatigue Scale (VAFS) (MD -1.69; 95% CI -3.07 to -0.31). Furthermore, significant differences were also found in the following key outcomes: 6MWT (MD, 89.54; 95% CI 9.86-169.23), MIP (% predicted) (MD, 15.79; 95% CI 2.73-28.84), MIP (cm HO) (MD, 19.69; 95% CI 10.14-29.24), and mMRC (MD, -1.02; 95% CI -1.86 to -0.18) in respiratory muscle training; 6MWT (MD 34.14; 95% CI 2.54-65.74), 30sSTS (MD 1.41; 95% CI 0.67-2.15), and FSS (MD -1.59; 95% CI -2.64 to -0.53) in telerehabilitation; MFIS-physical (MD, -2.29; 95% CI -4.36 to -0.22) in tDCS; and TDI Score (MD, 4.66; 95% CI 2.16-7.15) in PEA-LUT.

Interpretation: Exercise training should be prioritized for improving cardiopulmonary function and exercise capacity in Long COVID, supported by high-certainty evidence. Respiratory muscle training and PEA-LUT offer targeted benefits for respiratory strength and anosmia, while tDCS may address fatigue. Telerehabilitation, as a form of supervision, also improved the effectiveness of the intervention. In contrast, steroid sprays and olfactory training lack efficacy, highlighting the need for personalized, symptom-specific approaches. These findings advocate for updated clinical guidelines integrating multimodal therapies and underscore the urgency of large-scale trials to optimize dosing and long-term outcomes.

Funding: This study was supported by the Hunan Provincial Natural Foundation of China (2021JJ30040), the National Key Research and Development Plan (2022YFC3601900, 2022YFC2505500), the National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University (2021KFJJ06), and the National Natural Science Foundation of China (No. 81672225).