Persistent Dyspnea in COVID-19 Survivors without Structural Cardiopulmonary Disease: Multidimensional Phenotyping at 4 Years

RATIONALE: Persistent dyspnea despite normal cardiopulmonary structure is a frequent but poorly understood long-term sequela of COVID-19. Scant data exist on the multidimensional clinical profiles that underlie dyspnea in this setting. OBJECTIVES: We aimed to characterize multidimensional phenotypes associated with persistent dyspnea several years after COVID-19 hospitalization. METHODS: Post-hospitalization COVID-19 survivors without structural cardiopulmonary disease underwent assessment 41-47 months after acute infection, including respiratory muscle strength, diaphragm and parasternal intercostal ultrasound, exercise capacity, peripheral muscle evaluation, and patient-reported outcomes. Predefined univariate analyses examined associations with persistent dyspnea (mMRC ≥ 2) and inspiratory muscle weakness (MIP and SNIP < 70% predicted). Unsupervised hierarchical clustering followed by k-means analysis identified multidimensional clinical-functional phenotypes. RESULTS: Of 316 screened individuals, 270 were included; 34.4% reported persistent dyspnea and 23.3% demonstrated inspiratory muscle weakness. Persistent dyspnea and inspiratory muscle weakness were associated with distinct patterns of impairment across diaphragmatic ultrasound indices, peripheral muscle strength, fatigue, and functional capacity. Multidimensional clustering identified three phenotypes: (1) a dyspnea-fatigue phenotype, predominantly affecting women with obesity, characterized by severe dyspnea, fatigue, and reduced six-minute walk distance; (2) a preserved phenotype, with near-normal function and minimal symptoms; and (3) a dyspnea-inspiratory muscle weakness phenotype, characterized by impaired inspiratory strength, altered diaphragm ultrasound indices, dyspnea with minimal fatigue, and reduced functional capacity. CONCLUSIONS: Persistent dyspnea several years after COVID-19 hospitalization reflects heterogeneous multidimensional phenotypic profiles rather than a uniform post-COVID condition. Multidimensional phenotyping may refine clinical characterization and inform targeted rehabilitation and long-term management strategies for post-hospitalization COVID-19 survivors.