Long COVID is the term being universally applied to people infected with the SARS-Cov-2 virus who have recovered from the initial viral infection yet continue to experience symptoms more than three months after their initial illness. These patients can suffer from continued shortness of breath, neurological symptoms, fatigue, rapid heart rate, gastrointestinal distress or numbness and tingling.
At the University of Oxford, Fergus Gleeson, FRCP, FRCR, Professor of Radiology and a thoracic radiologist, is involved in a Long COVID clinic to evaluate patients suffering from persistent respiratory symptoms post SARS-Cov-2 infection. As elsewhere in the world, he had experience with CT scanning in patients acutely ill with COVID-19 pneumonia and had been using CT in patients post-discharge. He has set up a post-discharge CT and hyperpolarized xenon-129 (129Xe) MR study in conjunction with Jim Wild, PhD, Professor of Magnetic Resonance Physics and a NIHR Research Professor in Pulmonary Imaging at the University of Sheffield, aiming to scan these patients three months post-discharge to allow time for the typical inflammatory disease that occurs in many hospitalized patients a chance to recover.
Professor Gleeson and Professor Wild already had experience imaging with hyperpolarized 129Xe MR. Xenon is an MR-sensitive gas that dissolves in the alveoli in the lungs and goes into the capillaries. Hyperpolarized xenon MR is being studied as a possible method for measuring and quantifying interstitial changes in fibrotic lung disease and provides insight on ventilation perfusion (VQ) mismatching.
However, what happened next was a bit surprising.
"Some of the patients with Long COVID had normal or nearly normal CT scans," Professor Gleeson explains. "These are all patients who felt short of breath but had normal or nearly normal lung function tests, meaning there was no imaging explanation for it."
"All the patients that were short of breath with normal or near normal CTs had abnormal xenon MR exams," Professor Gleeson explains. "We have conducted follow-up imaging on some of these patients, and as yet, based on their xenon MR scans some of them do not appear to be improving as fast as one might have anticipated. The underlying etiology of the disease appears to cause more than fibrotic scarring. It probably relates to the capillary microthrombosis that patients infected with SARS-CoV-2 get, which then causes inflammation of the adjacent endothelium that then causes thrombosis. So it might be the inflammation and thrombosis that is the reason they are not getting better."
The Optima™ MR450w 1.5T System at Sheffield had previously been configured to perform hyperpolarized 129Xe imaging. According to Professor Wild, the GE HDx systems at both Oxford and Nottingham were all optimized for hyperpolarized 129Xe, including a broadband RF amplifier∗ so the MR is tuned to a frequency that can detect the hyperpolarized 129Xe. The Sheffield group has worked closely with Fraser Robb, PhD, Manager of RF Coils, GE Healthcare MR, to optimize RF coils for lung MR including AIR™ Coil technology. This collaboration has also involved building a dedicated 1H receiver array∗ that improves SNR to capture both function and structure in the same breath acquisition and in developing pulse sequences for 129Xe MR∗ with Rolf Schulte, PhD, Senior MR Scientist, GE Healthcare, Munich.
Figure 1.
Patient with lung disease post COVID-19 infection. (A-C) Hydrogen (1H) ZTE provides "CT-like” images of the lung while the (D) 129Xe ventilation scan provides quantitative data on lung function, including (E) ventilation binning, (F) DWI – LmD, (G) dissolved RBC/TP, and (H-J) 1H DCE.
"Xenon is soluble, so we can monitor and image the gas exchange process in the lungs from the alveoli across the tissue and into the blood vessels," Professor Wild says. "As we’ve already shown in interstitial lung disease, MR is very sensitive to gas exchange diffusion and perfusion limitations. Similar mechanisms are occurring in acute and Long COVID patients who are unable to get enough oxygen into their blood."
With hyperpolarized 129Xe MR, Professor Gleeson adds, "there is no radiation, it doesn’t take any length of time to do and it produces quantitative measurements that are easily reproducible. So we can follow up patients and we have a quantitative value to see how well their lungs are working and whether they are getting better."
The study
In late 2020, a UK consortium led by Gisli Jenkins, BM, PhD, FRCP, NIHR Research Professor and Margaret Turner Warwick Chair of Thoracic Medicine at Imperial College London, received a UKRI grant to assess interstitial lung disease post-COVID infection. Professor Wild is coordinating an MR sub-study whereby sites at the Universities of Sheffield, Oxford and Nottingham (with Professor Ian Hall) will perform a multi-center research trial using xenon MR imaging on COVID patients – the first study of its kind in Europe. The hyperpolarized 129Xe MR imaging is giving them an idea of what is happening functionally in their lungs. As importantly, the imaging technique identifies impaired gas transfer and perfusion defects caused by the SARS-CoV-2 virus that cannot be readily detected with other imaging methods.
The protocol set up by Professor Wild and his team in Sheffield will be used on all sites to examine ventilation, perfusion and the xenon transfer as it crosses the alveolar epithelium from the alveoli into the bloodstream.
We will be able to examine if there is a problem with the alveolar gas transfer, whether it’s a vascular problem or a combination of them, says Professor Gleeson. "This capability is unique to MR and unique to xenon."Professor Fergus Gleeson
The quantitative data acquired by the xenon MR scans will be compared to normal, age-related volunteers. Each center’s MR system and sequence is generating the same information, Professor Gleeson adds, so the data can be compared across the three universities. This will allow comparisons on disease severity as well as to monitor the impact of treatment, such as steroids or antithrombotic therapy.
Reflecting on what they’ve already learned from the Long COVID patients, Professor Wild sees a comparison to what has been found in other studies of patients with interstitial lung disease, such as idiopathic pulmonary fibrosis.
"We can see the reduced signal from the red blood cells in the lungs from the xenon. The elevated signal for the tissue in the lungs tells us that these patients have some type of interstitial diffusion limitation and also some perfusion deficit, possibly resulting from the microcapillary and microthrombi that people report," Professor Wild explains.
"What we are seeing and actually measuring quantitatively is that the gas exchange limitation is diminished and the lungs aren’t oxygenating as well as they should be," he continues.
This early signal from the physiology, or the lung function, that we see with xenon MR manifests before the more structural changes that typically occur with interstitial lung disease.Professor Jim Wild
Long-term implications of COVID-19
The data being generated by this research study may also provide insight into another concern regarding Long COVID. Both Professor Gleeson and Professor Wild believe there may be a large disease burden from post-COVID lung disease. It is estimated that approximately 10% of people who had COVID-19 experience prolonged symptoms.
Professor Gleeson explains that there are two important Long COVID patient cohorts: older, hospitalized patients and younger, non-hospitalized patients, with the later potentially being able to better tolerate the initial symptoms and illness caused by SARS-CoV-2. If the non-hospitalized COVID-19 patients’ xenon MR scans show similar abnormalities to the hospitalized COVID-19 patients as an explanation for their shortness of breath, there may be important implications for healthcare systems and patient management.
"Both sets of patients may have similar symptoms, but the duration and effects upon the younger cohort who may have children and are likely still working may be significantly different for individuals and for society. We don’t yet know, although it appears this might be the case. And that will shift the goalposts."
Beyond helping clinicians understand the impact of Long COVID and post-COVID infection on a patient, Professor Gleeson sees another key aspect of this study.
"Hyperpolarized xenon MR is uniquely placed to provide information about the lungs and their function that cannot be performed or reported on by other imaging techniques or even lung function tests. So not only is it that the xenon MR images are abnormal when the lung function tests, including diffusing capacity or DLCO, are normal, but the patients are symptomatic. So, although those of us in the field have known that xenon produces additional information, for the first time, we now have an opportunity to prove it."
Figure 2.
Patient with lung disease post COVID-19 infection. Hyperpolarized 129Xe MR imaging provides (A) insight on ventilation perfusion (VQ) mismatching and (B) quantification of the uptake of xenon from the lungs and into the blood.
Reference
∗Technology in development that represents ongoing research and development efforts. These technologies are not products and may never become products. Not for sale. Not cleared or approved by the US FDA or any other global regulator for commercial availability.
