Discussion
To our knowledge, this is the first multicentre study that explores ventilation heterogeneity in ever-hospitalised and never-hospitalised post-COVID-19 participants with persistent and serious symptoms necessitating clinical follow-up. In 76 participants, we observed: (1) significantly different (worse) MRI VDP in ever-COVID as compared with never-COVID, and in never-hospitalised as compared with ever-hospitalised COVID-19 participants, who also experienced significantly different (worse) DLCO and 6MWD, (2) significant relationships between CT airway and spirometry measurements and (3) significant relationships between post-exertional SpO2 with two measurements of ventilation heterogeneity, MRI VDP and LCI, and between MRI VDP and the 6MWD.
First, we observed that MRI VDP was significantly different in ever-COVID as compared with never-COVID participants and mean VDP in ever-COVID patients was consistent with previously reported values20 in asymptomatic ever-hospitalised patients, post discharge. The finding of significantly different MRI VDP in ever-hospitalised as compared with never-hospitalised participants was novel as was the coincident finding of significantly different 6MWD and post-exertional SpO2 in these participants. Previous studies have observed worse 6MWD in severe versus mild–moderate post-COVID patients,47–49 however, the classification for mild, moderate or severe infection was not based on prior hospitalisation and not all participants experienced ongoing COVID-19 symptoms. When dichotomised by VDP, 6MWD and post-exertional SpO2 were also significantly different between groups. The link between exercise limitation, post-exertional oxygen saturation and ventilation heterogeneity in PACS is novel and points to a mechanistic relationship between persistent symptoms and airway pathologies and/or occlusion/obliteration.
Underscoring these central results was the finding of significant relationships for post-6MWD SpO2 with MRI VDP and with LCI—both are measurements of ventilation heterogeneity that are thought to reflect airway inhalational (MRI) and exhalational (LCI) function. This is the first supportive evidence of a potential link between exercise intolerance following COVID-19 and objective (LCI and MRI VDP) and direct (MRI VDP) measurements of abnormal airway function. This evidence was also supported by the significant associations between CT findings including total airway count (reflecting airway narrowing or obliteration/occlusion), airway lumen area (narrowing or occlusion) and airway wall thickness with spirometry measurements of airflow obstruction. Recent studies have provided evidence of small airways disease in post-COVID-19 patients using the full-scale airway network flow model50 or CT air-trapping functional small airways disease.51 We did not acquire inspiratory–expiratory CT and thus could not quantify CT air-trapping, although the ratio of residual volume to total lung capacity (RV/TLC) was measured in 38 of our 76 participants and of these, 14 (37%) reported RV/TLC > upper limit of normal.52 In addition, the median RV/TLC value in these 38 participants was 0.41±0.17, suggesting air-trapping, and this value was greater than the evaluation group reported by Cho et al (median RV/TLC=0.30).51 Taken together, these findings support the use of airways disease treatments, including inhaled combination corticosteroid–long-acting beta agonist, in post-COVID patients with persistent symptoms.
We acknowledge a number of limitations in this convenience-sample study, including the relatively small sample size. We should note that Site 1 participants were monitored over time by a long-COVID clinic designed to follow and treat long-term symptoms, including dyspnoea, and this clinic referred participants to consider enrolling in the study. Hence, there is a potential for bias towards a greater number and intensity of unexplained symptoms for participants enrolled. In addition, for most of the never-hospitalised participants enrolled, there was no prior clinical history of respiratory disease and thus first-time chest imaging and pulmonary function test results were reported. Therefore, we had to untangle any previous clinical history from the impact of COVID-19 on symptoms. Furthermore, pulmonary function tests, as well as CT and MR imaging measurements, prior to COVID-19 infection were not available, and thus, the impact of COVID-19 on existing lung function is still not completely clear. For a relatively large number of ever-COVID participants, chest CT was either declined (n=18) or not quantitatively evaluable (n=13) which also limits the generalisability of the CT results. It is also important to acknowledge that this was a multicentre study, with participants enrolled from two relatively diverse regional healthcare systems embedded within a population of 14.7 million people served by a single universal and comprehensive healthcare insurance plan. Site 1 enrolment derived from a quaternary care academic health centre serving a mainly rural population and Site 2 enrolment derived from another quaternary care academic health centre, located about 100 km away from Site 1 with a mainly urban population, hence our findings may not be generalisable to other healthcare jurisdictions. Moreover, we also recognise that the convenience study group we evaluated included a relatively large number of people with previously diagnosed asthma (n=21) and COPD (n=6), which is a greater proportion of patients with comorbid obstructive lung disease than previous reports.2–5 19 20 We expect that the presence of previous obstructive lung disease likely has complex interactions with post-COVID pulmonary measurements including MRI VDP. Importantly, there were no significant differences for SGRQ and IPAQ scores between participants with and without a previous diagnosis of obstructive lung disease, which underscores the severity of illness in PACS. Finally, as previously reported,53 older people are at greater risk for poor COVID-19 outcomes and there is also a complex relationship between age and MRI VDP,54 so age must be considered as an important factor in our results. It should also be noted that the ever-COVID group was significantly older compared with never-COVID and hence this may have influenced VDP measurements in this group. However, MRI VDP was still greater in the ever-COVID group than predicted based on age alone.55
In conclusion, we explored a potential role for MRI and CT pulmonary pathologies to help explain persistent and life-altering symptoms including exercise limitation in post-COVID patients. While mean SGRQ score was not normal in the PACS participants studied here, spirometry, DLCO and CT measurements were normal or nearly normal. This provides some context to the growing body of evidence that shows MRI VDP provides a sensitive measurement of abnormal physiology that, in the PACS participants studied here, may contribute to exercise limitation.
In this study, participants were unable to achieve pre-COVID work and day-to-day life activities, so we asked the question, is there an airways component to PACS that can be measured using MRI VDP and does this relate to quality-of-life? Yes, this exploratory study did point to a relationship between the lung pathologies that resulted in abnormal MRI VDP (or ventilation heterogeneity) as well as exercise limitation and abnormal post-exertional SpO2. SGRQ and IPAQ scores also were highly abnormal and very similar among ever-COVID participants. The study results point to a possible airways disease explanation for the persistent symptoms experienced following COVID-19 infection, which may help improve and target treatment.