key: cord-0032189-y8og7u2f authors: Parraga, Grace; Matheson, Alexander M. title: Step on the (129)Xe Gas: The MRI Race to Uncover Drivers of Post-COVID-19 Symptoms date: 2022-05-24 journal: Radiology DOI: 10.1148/radiol.221098 sha: 300a614b66dc79c0f4c02fac41c1ec69eac807c4 doc_id: 32189 cord_uid: y8og7u2f nan This copy is for personal use only. To order printed copies, contact reprints@rsna.org Following COVID-19 infection, symptoms may persist in patients for long periods of time, which in some cases, has a tremendous impact on quality-of-life. 1 The American Centers for Disease Control and Prevention (CDC) coined the term post-COVID condition to help explain such persistent symptoms defined as "a wide range of new, returning, or ongoing health problems people can experience four or more weeks after first being infected with COVID-19." 2 The World Health Organization (WHO) also developed a consensus definition for the post-COVID-19 condition as: "usually three months from the onset of COVID-19 with symptoms that last at least two months." 3 Alternatively, post-acute sequelae of COVID-19 was also defined as symptoms in those people who survived at least the first 30 days following a COVID-19 diagnosis. 4 Finally, the National Institute for Health and Care Excellence coined the term long-COVID to describe the signs and symptoms that continue or develop from 4 to 12 weeks following the acute infectious phase of COVID-19. 5 Regardless the confusing nomenclature and emerging definitions, such symptoms in patients can vary considerably, with fatigue, dyspnea, exercise limitation, exertional dyspnea, chest pain, and brain fog, most commonly reported. 1, 6 In ever-hospitalized post-COVID-19 patients, chest CT has revealed fibrotic lung abnormalities which may be partially responsible for respiratory symptoms. 1 However, and uninformatively, symptomatic post-COVID-19 patients typically report normal pulmonary function tests 6, 7 and in some cases, normal or very mildly abnormal diffusing-capacityof-the-lung-for-carbon-monoxide. 7 Hence, and unfortunately, the pathophysiological drivers of post-acute COVID-19 symptoms are not well-understood, which makes treatment decisions difficult, if not impossible. In an effort to understand the underlying cause of post-COVID-19 symptoms and limitations, two recent pilot studies harnessed the unique strengths of hyperpolarized 129 Xe MRI to investigate two I n p r e s s small groups of participants from Wuhan 8 and Oxford UK, 9 respectively. Hyperpolarized 129 Xe MRI pulmonary measurements are driven by the unique properties of inhaled 129 Xe gas, which in the healthy human lung instantaneously fills the terminal bronchi and lung parenchyma, participates in transmembrane diffusion through the alveolar-capillary membranes and binds to red blood cells (RBC) in the pulmonary capillaries. This novel pulmonary functional imaging method provides a way to non-invasively and simultaneously capture a subvoxel snapshot in time of inhaled gas delivery, flow, diffusion and RBC binding throughout the entire lung. Both previous studies evaluated recently discharged COVID patients 8, 9 and reported abnormal 129 Xe MRI RBC to alveolar tissue barrier ratios which suggested persistently abnormal oxygen and carbon dioxide gas-exchange. These initial studies did not interrogate post-COVID-19 patients who had never been hospitalized, nor did they evaluate the relationship of 129 Xe MRI findings with symptoms including dyspnea and exercise limitation. Moreover, whether the measured gas- This important study expanded on previously published 129 Xe MRI COVID-19 work 8 by focusing on ever-and never-hospitalized participants and examining relationships between 129 Xe and clinical measurements. Importantly, the authors also observed a relationship between RBC:barrier and DLCO in both NHLC and PHC groups. Similar findings have been previously reported in patients with idiopathic pulmonary fibrosis, 10 suggesting that RBC:barrier provides a surrogate measure of gas-transfer. In addition, here the 129 Xe MRI RBC:barrier ratio and dyspnea (Dyspnea-12 and modified BORG scale) trended towards an association (P=.06 and P=.08), which speaks to a potential relationship between these symptoms and MRI measurements. Despite abnormal MRI measurements in post-COVID-19 participants, CT images were normal or only modestly abnormal. While CT has superior spatial resolution, here the 129 Xe MRI signal was I n p r e s s generated at the alveolar level and averaged over an entire voxel, effectively allowing 129 Xe MRI to probe abnormalities with subvoxel, alveolar membrane spatial resolution. Therefore, it is not surprising that 129 Xe MRI may be sensitive to functional abnormalities not observed structurally on CT. Whether the 129 Xe MRI RBC:barrier ratio is similarly impaired in the presence of fibrosis should be studied further. Limitations included the small sample size which likely resulted in an inability to measure significant relationships between the novel MRI measurements and symptoms or exercise limitation, which is a pity. In addition, future studies ought to consider larger sample sizes with a longitudinal component because it is still difficult to be certain about the pre-COVID lung health of the patients studied here. Previous 129 Xe MRI studies focused on ever-hospitalized post-COVID-19 participants which limited our understanding of the post-COVID condition to those with the most severe disease. Alarmingly, here Grist and colleagues reported that both PHC and NHLC participants had significantly lower MRI RBC:barrier ratio compared to healthy volunteers. This important finding tells us that even mild disease can result in persistent symptoms and gas-exchange differences. An exact timepoint at which COVID infection may resolved is still a matter of debate, however here data in never-hospitalized participants was acquired at least six months following infection. It is therefore unlikely that these changes were due to residual infection, and more likely they reflect temporally persistent gas-exchange abnormalities that stem from the pulmonary vasculature or alveolar membrane. Taken together, these results emphasize the power and sensitivity of pulmonary functional imaging and the fact that gas-exchange abnormalities that stem either from the alveolar membrane or pulmonary vasculature may be important pathophysiological drivers of symptoms in post-COVID- Post-acute COVID-19 syndrome A clinical case definition of post-COVID-19 condition by a Delphi consensus High-dimensional characterization of post-acute sequelae of COVID-19 COVID-19 rapid guideline: managing the long-term effects of COVID-19. National Institute for Health and Care Excellence 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis Damaged lung gas exchange function of discharged COVID-19 patients detected by hyperpolarized (129)Xe MRI Hyperpolarized (129)Xe MRI Abnormalities in Dyspneic Patients 3 Months after COVID-19 Pneumonia: Preliminary Results Dissolved (129) Xe lung MRI with four-echo 3D radial spectroscopic imaging: Quantification of regional gas transfer in idiopathic pulmonary fibrosis