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 .

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation‐free gases (such as 3He and 129Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129Xe uniquely enables imaging the transfer of inhaled gas across the alveolar–capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8–15 s), cost‐effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single‐photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar–capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

Pulmonary functional magnetic resonance imaging (PfMRI) provides a way to non-invasively map and measure the spatial distribution of pulmonary ventilation, perfusion and gas-exchange abnormalities with unprecedented detail of functional processes at the level of airways, alveoli and the alveolar-capillary membrane. Current PfMRI approaches are dominated by hyperpolarized helium-3 (3He) and xenon-129 (129Xe) gases, which both provide rapid (8-15s) and well-tolerated imaging examinations in patients with severe pulmonary diseases and pediatric populations, whilst employing no ionizing radiation. While a number of review papers summarize the required image acquisition hardware and software requirements needed to enable PfMRI, here we focus on the image analysis and processing methods required for reproducible measurements using hyperpolarized gas ventilation MRI. We start with the transition in the literature from qualitative and subjective scoring systems to quantitative and objective measurements which enable precise quantification of the lung’s critical structure-function relationships. We provide an overview of quantitative biomarkers and the relevant respiratory system parameters that may be measured using PfMRI methods, outlining the history of developments in the field, current methods and then knowledge gaps and typical limitations. We focus on hyperpolarized noble gas MR image processing methods used for quantifying ventilation and gas distribution in the lungs, and discuss the utility and applications of imaging biomarkers generated through these techniques. We conclude with a summary of the current and future directions to further the development of image processing methods, and discuss the remaining challenges for potential clinical translation of these approaches and their integration into standard clinical workflows.

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