Breathlessness in Long COVID: Exploring the Relationship between Symptoms, Lung Function Tests, and Functional Imaging Using Hyperpolarised Xenon MRI

Background: Breathlessness is a common symptom in Long COVID (LC). Using hyperpolarised xenon MRI (129Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods: In this prospective, multicentre cohort study, we compared 129Xe-MRI, lung function, exercise capacity, and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129Xe-MRI metrics: red-blood cell to membrane ratio (RBC:M) and red-blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Findings: Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to imaging (median 632 days; p<0·001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower FEV₁, FVC, TLCO, and KCO z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low TLCO (14/109) showed reduced 129Xe-MRI metrics and higher breathlessness scores. Interpretation: Most LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, approximately 13% of breathless individuals demonstrated minor reductions in TLCO and 129Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.