Comparison of Cardiopulmonary Exercise Testing and Respiratory Function Testing in Long COVID and Myalgic Encephalomyelitis: Systematic Review and Meta-Analysis

Abstract

Introduction: Post-exertional malaise (PEM), a key symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), is characterized by worsening symptoms after minimal physical, mental, or emotional exertion. With the emergence of the COVID-19 pandemic, a significant proportion of individuals who recovered from the acute illness developed a prolonged condition, Long COVID, which shares several characteristics with ME/CFS, notably exercise intolerance and PEM. Both clinical conditions have been associated with cardiorespiratory and metabolic abnormalities, which become evident during exertion. Objective: This study aims to analyze the physiological dysfunction present in ME/CFS and long COVID, with a special focus on cardiorespiratory function test variables and cardiopulmonary exercise test (CPET) parameters, to explore a possible shared pathophysiology between the two conditions and identify objective variables for differential diagnosis with other pathologies. Methods: In July 2025, studies were identified through a search of PubMed, Science Direct and SCOPUS databases. Studies were screened independently by two blinded reviewers and were integrated if they included adults diagnosed with Long COVID or ME/CFS and that evaluated CPET, spirometry, body plethysmography, DLCO or maximum respiratory pressures. Data extraction was performed according to the PRISMA reporting guideline. Results: This systematic review included 18 studies, 7 focused on ME/CFS and 11 on Long COVID, covering 1,684 participants. Based on a meta-analysis of 8 studies that included 336 individuals with ME/CFS and 143 individuals with Long COVID, compared with 182 control individuals, the mean difference in peak VO2 was -4.98 (95% CI, -1.09 to -0.48) mL/kg/min which demonstrates reduced exercise tolerance. Respiratory function tests did not show consistent results in both conditions. The existing literature was limited by small sample sizes and CPET interpretations, resulting in high risk of bias and heterogeneity. Discussion: The older ME/CFS research focuses on disease characterization and symptom validation, while the more recent long COVID research is rapidly advancing toward evaluating treatments and patient subgroups. Respiratory function analysis has revealed that lung alterations are not a universal feature of ME/CFS, but long COVID can present persistent pulmonary sequelae. One of the most important findings linking the two diseases is PEM, a core symptom that can be objectively measured with the two-day CPET. Conclusion: Despite the similarities, the methodological heterogeneity of the studies, with different protocols and sample sizes, highlights the need for standardization in future research to obtain more robust conclusions about the underlying mechanisms and the development of more effective therapies.