Long-COVID Patients Show Abnormal Lung Perfusion Despite Normal CTs

VIENNA — Some patients who had mild COVID-19 infection during the first wave of the pandemic and continued to experience postinfection symptoms for at least 12 months after infection present abnormal perfusion despite showing normal CT scans. Researchers at the European Respiratory Society (ERS) 2024 International Congress called for more research to be done in this space to understand the underlying mechanism of the abnormalities observed and to find possible treatment options for this cohort of patients.

Laura Price, MD, PhD, a consultant respiratory physician at Royal Brompton Hospital and an honorary clinical senior lecturer at Imperial College London, London, told Medscape Medical News that this cohort of patients shows symptoms that seem to correlate with a pulmonary microangiopathy phenotype.

“Our clinics in the UK and around the world are full of people with long-COVID, persisting breathlessness, and fatigue. But it has been hard for people to put the finger on why patients experience these symptoms still,” Timothy Hinks, associate professor and Wellcome Trust Career Development fellow at the Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre senior research fellow, and honorary consultant at Oxford Special Airway Service at Oxford University Hospitals, England, who was not involved in the study, told Medscape Medical News.

The Study

Researchers at Imperial College London recruited 41 patients who experienced persistent post-COVID-19 infection symptoms, such as breathlessness and fatigue, but normal CT scans after a mild COVID-19 infection that did not require hospitalization. Those with pulmonary emboli or interstitial lung disease were excluded. The cohort was predominantly female (87.8%) and nonsmokers (85%), with a mean age of 44.7 years. They were assessed over 1 year after the initial infection.

Exercise intolerance was the predominant symptom, affecting 95.1% of the group. A significant proportion (46.3%) presented with myopericarditis, while a smaller subset (n = 5) exhibited dysautonomia. Echocardiography did not reveal pulmonary hypertension. Laboratory findings showed elevated angiotensin-converting enzyme and antiphospholipid antibodies. “These patients are young, female, nonsmokers, and previously healthy. This is not what you would expect to see,” Price said.

Baseline pulmonary function tests showed preserved spirometry with forced expiratory volume in 1 second and forced vital capacity above 100% predicted. However, diffusion capacity was impaired, with a mean diffusing capacity of the lungs for carbon monoxide (DLCO) of 74.7%. The carbon monoxide transfer coefficient (KCO) and alveolar volume were also mildly reduced. Oxygen saturation was within normal limits.

These abnormalities were through advanced imaging techniques like dual-energy CT scans and ventilation-perfusion scans. These tests revealed a non-segmental and “patchy” perfusion abnormality in the upper lungs, suggesting that the problem was vascular, Price explained.

Cardiopulmonary exercise testing revealed further abnormalities in 41% of patients. Peak oxygen uptake was slightly reduced, and a significant proportion of patients showed elevated alveolar-arterial gradient and dead space ventilation during peak exercise, suggesting a ventilation-perfusion mismatch.

Over time, there was a statistically significant improvement in DLCO, from 70.4% to 74.4%, suggesting some degree of recovery in lung function. However, DLCO values did not return to normal. The KCO also improved from 71.9% to 74.4%, though this change did not reach statistical significance. Most patients (n = 26) were treated with apixaban, potentially contributing to the observed improvement in gas transfer parameters, Price said.

The researchers identified a distinct phenotype of patients with persistent post-COVID-19 infection symptoms characterized by abnormal lung perfusion and reduced gas diffusion capacity, even when CT scans appear normal. Price explains that this pulmonary microangiopathy may explain the persistent symptoms. However, questions remain about the underlying mechanisms, potential treatments, and long-term outcomes for this patient population.

Causes and Treatments Remain a Mystery

Previous studies have suggested that COVID-19 causes endothelial dysfunction, which could affect the small blood vessels in the lungs. Other viral infections, such as HIV, have also been shown to cause endothelial dysfunction. However, researchers don’t fully understand how this process plays out in patients with COVID-19.

“It is possible these patients have had inflammation insults that have damaged the pulmonary vascular endothelium, which predisposes them to either clotting at a microscopic level or ongoing inflammation,” said Hinks.

Some patients (10 out of 41) in the cohort studied by the Imperial College London’s researchers presented with Raynaud syndrome, which might suggest a physiological link, Hinks explains. “Raynaud’s is a condition of vascular control or dysregulation, and potentially, there could be a common factor contributing to both breathlessness and Raynaud’s.”

He said there is an encouraging signal that these patients improve over time, but their recovery might be more complex and lengthy than for other patients. “This cohort will gradually get better. But it raises questions and gives a point that there is a true physiological deficit in some people with long-COVID.”

Price encouraged physicians to look beyond conventional diagnostic tools when visiting a patient whose CT scan looks normal yet experiences fatigue and breathlessness. Not knowing what causes the abnormalities observed in this group of patients makes treatment extremely challenging. “We need more research to understand the treatment implications and long-term impact of these pulmonary vascular abnormalities in patients with long-COVID,” Price concluded.

Price and Hinks reported no relevant financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her words have been published in The Medical Republic, Rare Disease Advisor, The Guardian, MIT Technology Review, and others.