Multimodal physiological determinants of persistent dyspnea nearly four years after COVID-19 hospitalization

Dyspnea is a frequent and disabling symptom following COVID-19 and may persist despite preserved pulmonary and cardiac function. The physiological mechanisms underlying persistent dyspnea at long-term follow-up remain incompletely characterized. We conducted a cross-sectional analysis nested within a prospective cohort of COVID-19 survivors evaluated 41–47 months after hospitalization. Participants with identifiable structural cardiopulmonary disease were excluded based on comprehensive pulmonary function testing and echocardiography. Dyspnea was assessed using the modified Medical Research Council (mMRC) scale and analyzed as both a binary (mMRC ≥ 2) and ordinal outcome. Inspiratory muscle weakness was defined as concomitant reductions in maximal inspiratory pressure and sniff nasal inspiratory pressure (< 70% predicted). A standardized multimodal assessment included respiratory and peripheral muscle function, ultrasonography, functional capacity testing, and fatigue evaluation. Associations were examined using hierarchical logistic and ordinal regression models. Among 270 participants, clinically relevant dyspnea (mMRC ≥ 2) was present in 34.4%. In multivariable hierarchical models, dyspnea was independently associated with inspiratory muscle weakness (OR 8.86, 95% CI 6.33–12.41), along with female sex, obesity, higher fatigue burden, respiratory muscle ultrasound abnormalities, and reduced peripheral muscle strength. Model discrimination improved stepwise across hierarchical models, reaching an AUC of 0.89 for dyspnea. Dyspnea severity showed graded associations with respiratory muscle dysfunction, peripheral muscle impairment, reduced functional capacity, and fatigue. Inspiratory muscle weakness (23.4%) was characterized by a distinct muscular profile involving diaphragmatic and parasternal intercostal abnormalities together with reduced peripheral muscle mass and strength. Hierarchical models predicting inspiratory muscle weakness also demonstrated strong discriminative performance, with AUC up to 0.92. Nearly four years after hospitalization, persistent dyspnea remains common among COVID-19 survivors without structural cardiopulmonary disease and is associated with a multidimensional physiological profile. Respiratory muscle dysfunction, integrated with peripheral muscle impairment and fatigue, represents a key correlate of long-term dyspnea.