Meet the radiologist connecting the dots between long-Covid and breathlessness

Fergus Gleeson has long held an interest in MRI scanning techniques that use hyperpolarised xenon – an odourless gas – to detect early-stage lung disease. Here, he discusses his interest in xenon, how the gas works in practice and his latest research findings in relation to long-Covid.

In 2020, Fergus Gleeson, professor of radiology at Oxford University and consultant radiologist at Oxford University Hospitals NHS Foundation Trust, turned his attention to a small study of post-Covid patients. They were experiencing breathlessness several months after being discharged from hospital, despite CT scans that appeared to show their lungs were normal.

The findings from this small study prompted Professor Gleeson to widen the research to investigate possible lung damage in non-hospitalised, post-Covid patients who continue to experience breathlessness many months after infection.

He is the principal investigator of the EXPLAIN study, one of 19 projects to receive nearly £40m from the National Institute for Health Research to improve understanding of long-Covid, from diagnosis and treatment through to rehabilitation and recovery.

Why did you decide to use hyperpolarised xenon MRI scans on long-Covid patients?

I’ve worked in the xenon field since 2007/08 to identify patients with obstructive lung disease and interstitial lung disease, as have other researchers, including Professor Jim Wild, who is the head of imaging and NIHR research professor of magnetic resonance at the University of Sheffield. [Indeed, Wild pioneered the method, development and applications of hyperpolarised xenon MRI used in the EXPLAIN study.]

Xenon is unique in its ability to measure gas transfer in the lungs. The MRI scanner is programmed to detect signal from polarised xenon. The oxygen in the normal air we breathe isn’t used because it does not give enough MRI signal. Xenon behaves just like oxygen, so radiologists can use it to observe how it moves from the lungs into the blood stream and highlight any areas where it is not flowing well between the airways, gas exchange membranes and capillaries in the lungs.

How does the scan work in practice and what are the advantages?

The patient lies in an MRI scanner on a magnet with a vest like coil around their chest and breathes in one litre of inert gas xenon through a plastic straw. It is possible to watch the physiology of a patient’s lungs in real time and see where the xenon might be held up, how fast it moves, whether it gets to the alveoli and from this assess how well the exchange of oxygen and carbon dioxide happens in the blood. The degree of gas exchange is colour coded with areas of more damaged lungs being darker or a different colour to areas with normal exchange.

The scan times may be very short, for example a single sequence may only require the patient to breathe in and hold their breath for 14-20 seconds. There’s no radiation exposure so it can be repeated over time to see whether the changes to the lungs improve. If the research proves to be clinically useful, the equipment could be set up in multiple regional centres in a relatively short space of time. All that is needed is a cylinder of xenon and the polariser – which is about the size of a large chest of drawers. The MRI scanner would also need to be modified to detect the signal from the xenon gas.

How many xenon MRI locations are there in the UK and overseas?

Ours is located in the radiology department at the Churchill Hospital in Oxford. There’s one in Sheffield University’s imaging department, one is being installed at University College Hospital London and one at Manchester University. There’s also a couple in Denmark, two in Germany, several in the United States and at least one in Canada.

You first began studying hospitalised Covid-19 patients who were still experiencing breathlessness three months after the infection. Can you tell us more about that?

Some people were complaining of persistent breathlessness and fatigue for many months after the Covid-19 infection, so we conducted a small study on patients aged between 19 and 69. None of them required intensive care or ventilation, and standard CT scans showed no significant lung damage. The hyperpolarised xenon MRI scans revealed signs of lung damage for a number of the patients who were reporting breathlessness.

We then broadened the study out to include non-hospitalised individuals who had tested positive for Covid-19 across a range of age groups. Now, there are many different arms of the study and we’re working with three other hospital sites: Sheffield, Manchester and Cardiff. Hundreds of thousands of people in the UK continue to experience symptoms months after having Covid-19, with breathlessness one of the most commonly reported symptoms.

This broader research is the EXPLAIN study, for which you’re the principal investigator. What are the aims of this research and how is it being conducted?

We hope to identify what’s causing patients with long-Covid breathlessness and essentially give them answers as to how long they might have these abnormalities and whether they’ll get better.

We’re using hyperpolarised xenon MRI scans to investigate possible lung damage in long-Covid patients who have not been hospitalised with Covid-19 but who continue to experience breathlessness. The full study will recruit around 400 participants following on from our two initial pilot studies. The EXPLAIN study will include:

• 200 patients diagnosed with long-Covid with breathlessness who have been seen in long-Covid clinics and who have normal CT scans
• 50 people who’ve been in hospital with Covid-19 and discharged more than three months previously who have normal or nearly normal CT scans
• 50 patients seen in long-Covid clinics but do not have breathlessness
• 50 people in an age-and-gender-matched control group who do not have long-Covid symptoms and who have not been hospitalised with Covid-19.

What did the initial results show in the pilot studies?

We detected significantly impaired gas transfer from the lungs to the bloodstream in long-Covid patients when other tests were normal. These patients had never been in hospital, did not have an acute severe illness when they had their Covid-19 infection, and some had experienced symptoms for a year after contracting it. The important questions that now need answering are how many patients with long-Covid will have abnormal scans, what the significance of the abnormality we’ve detected is, what the cause of the abnormality is and what its longer-term consequences will be. Once we understand the mechanisms driving these symptoms, we will be better placed to develop more effective treatments.

What are your main priorities and next steps for this long-Covid research?

We need to complete recruitment and analyse the data, so we have some way to go before fully understanding the nature of the lung impairment that follows Covid-19 infection. However, the clinical-academic collaboration in EXPLAIN and other studies funded by NIHR are fundamental steps towards understanding the biological basis of long-Covid. This, in turn, will help us to develop more effective therapies.