Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation

Post‐acute sequelae of SARS ‐ CoV ‐2 ( PASC or “long COVID ”) and chronic fatigue syndrome/myalgic encephalitis ( CFS / ME ) share symptoms such as exertional dyspnea. We used exercise oxygen pathway analysis, comprising six parameters of oxygen transport and utilization, to identify limiting mechanisms in both conditions. Invasive cardiopulmonary exercise testing was performed on 15 PASC patients, 11 CFS / ME patients, and 11 controls. We evaluated the contributions of alveolar ventilation (V̇a), lung diffusion capacity ( D L ), cardiac output (Q̇), skeletal muscle diffusion capacity ( D M ), hemoglobin (Hb), and mitochondrial oxidative phosphorylation (V max ) to peak oxygen consumption (V̇O 2peak ). To simulate targeted interventions, each variable was sequentially normalized to assess its impact on V̇O 2peak . V̇O 2peak was significantly reduced in both PASC and CFS / ME compared to controls. Skeletal muscle O 2 diffusion ( D M ) was the most impaired parameter in both patient groups ( p = 0.01). Correcting D M alone improved V̇O 2 by 66% in PASC ( p = 0.008) and 34.7% in CFS / ME ( p = 0.06), suggesting a dominant role for peripheral O 2 extraction in exercise limitation. Impaired skeletal muscle oxygen diffusion ( D M ) is a shared mechanism of exercise intolerance in PASC and CFS / ME and may represent a therapeutic target. However, our findings are limited by small sample size.