Background In patients with post-acute COVID-19-syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other, or to symptoms and exercise limitation. The pathophysiological drivers of PACS in ever- and never-hospitalized patients are not well-understood. Purpose To determine the relationship of persistent symptoms and exercise limitation with 129 Xe MRI and CT pulmonary vascular measurements in individuals with PACS. Materials and Methods In this prospective study, patients with PACS aged 18-80 years with a positive PCR COVID test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing-capacity-of-the-lung- for-carbon-monoxide (DL co ), 129 Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 underwent spirometry, DL co , and 129 Xe MRI. The 129 Xe MRI red-blood-cell (RBC) to alveolar-barrier signal ratio, RBC area-under-the-curve (AUC), CT volume-of-pulmonary-vessels with cross-sectional-area <5mm 2 (BV5), and total-blood-volume (TBV) were quantified. St. George's Respiratory Questionnaire (SGRQ), International Physical Activity Questionnaire (IPAQ) and modified Borg Dyspnea Scale (mBDS) measured quality-of-life, exercise limitation and dyspnea. Differences between groups were compared using Welch's T-tests or Welch's ANOVA. Relationships were evaluated using Pearson (r) and Spearman (ρ) correlations. Results Forty participants were evaluated including six controls (mean age, 35±15 years[standard deviation], 3 women) and 34 participants with PACS (mean age, 53±13 years[SD], 18 women), of which 22 were never-hospitalized. The 129 Xe MRI RBC:barrier ratio was lower in ever- hospitalized participants (P=.04) compared to controls. BV5 correlated with RBC AUC (ρ=.44,P=.03). The 129 Xe MRI RBC:barrier ratio was related to DL co (r=.57,P=.002) and FEV 1 (ρ=.35,P=.03); RBC AUC was related to dyspnea (ρ=-.35,P=.04) and IPAQ score (ρ=.45,P=.02). Conclusion 129 Xe MRI measurements were lower in ever- hospitalized participants with post- acute COVID-19-syndrome, 34±25 weeks post-infection compared to controls. 129 Xe MRI measures were associated with CT pulmonary vascular density, DL co , exercise capacity, and dyspnea. ClinicalTrials.gov : NCT04584671 See also the editorial by Wild and Collier .

BackgroundPatients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS).MethodsConsenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George’s Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only.ResultsSeventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03).Conclusion129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores.Trial registration numberNCT05014516.

Background In people with post-acute COVID-19 syndrome (PACS) and normal pulmonary function, 129 Xe MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3-months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality-of-life, and 129 Xe MRI ventilation defect percent (VDP) in people with PACS evaluated 3- and 15-months post-infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. They were evaluated 3-months and 15-months post-infection for: 129 Xe MRI VDP, diffusing capacity of the lung for carbon monoxide (DL CO ), spirometry, oscillometry, six-minute walk distance (6MWD), and St. George's Respiratory Questionnaire (SGRQ). Differences between time-points were evaluated using paired t-tests. Multivariable models were generated to explain exercise capacity and quality-of-life improvements. Odds ratios (OR) were used to evaluate potential treatment influences. Results Fifty-three participants (mean age, 55 years ±18[SD]; 26 male; 27 female) attended both 3- and 15-month visits and were included in analysis. 129 Xe MRI VDP (5.4%, 4.2%; P =.003), forced expiratory volume in 1-second (85% pred , 90% pred ; P =.001), DL CO (89% pred , 99% pred ; P =.002) and SGRQ (35, 25; P <.001) improved between the 3- and 15-month visit. VDP measured at 3- months post-COVID predicted the change in 6MWD (β=-.643, P=.001) while treatment with respiratory medication at 3-months predicted improved 15-month quality-of-life score (OR=4.0; 95%CI:1.2,13.8, P =.03). Conclusion Pulmonary function, gas-exchange, exercise capacity, quality-of-life, and 129 Xe MRI ventilation defect percent (VDP) improved in participants with post-acute COVID-19 syndrome evaluated at 15-months as compared to 3-months post-infection. VDP measured at 3-months post-infection correlated with improved exercise capacity, whilst treatment with respiratory medication was associated with improved quality-of-life score at 15-months post-infection. Clinical Trial Registration: www.clinicaltrials.gov NCT05014516 See also the editorial by Vogel-Claussen in this issue.

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129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=−0.7; 95%CI=−0.2 to –1.2, p=0.019), St George’s Respiratory Questionnaire-score (SGRQ Δ=−6; 95% CI=−1 to –11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCOcorrelated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCOand SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.govNCT04584671.