Patients with RPRA exhibit fibrotic abnormalities on CT imaging that improve with time.

Long COVID occurs in approximately a third of COVID-19 survivors, with the CDC estimating one in 13 adults in the United States have long COVID symptoms such as brain fog, shortness of breath and chest pain. In a new study published in Nature Immunology, pulmonologists at the Northwestern Medicine Comprehensive COVID-19 Center (CCC) noticed that many patients referred to the CCC for long COVID symptoms had persistently abnormal CT scans of their lungs.

Some patients would recover, while others would remain with scar tissue. They called this respiratory post-acute sequelae of COVID-19 (PASC) with radiographic abnormalities (RPRA).

In collaboration with Brigham and Women’s Hospital, The Ohio State University and Duke University, Northwestern Medicine scientists combined state-of-the-art gene expression technology and CT scan analysis to determine which cells and molecules were responsible for radiographic abnormalities in long COVID patients, which could help inform future treatment options.

“Our understanding of long COVID is still in its early stages and there are no FDA-approved or even widely agreed-upon treatments for long COVID,” said Marc Sala, MD, associate professor of Medicine in the Division of Pulmonary and Critical Care, co-director of the Northwestern Medicine Comprehensive COVID-19 Center and a pulmonary and critical care specialist with the Northwestern Medicine Canning Thoracic Institute.

“The underlying cells and molecules that contribute to radiographic abnormalities in long COVID patients are now better established, and equally important, it appears to be the same biological processes responsible for other types of lung injury that result in pulmonary fibrosis. This common denominator explanation may help not only in developing treatments for long COVID as it continues to evolve in the future, but also contributes to our understanding of pulmonary fibrosis due to other conditions.”

The team evaluated 35 patients who had long COVID at the CCC between November 2020 and May 2022. These patients had respiratory symptoms such as cough and shortness of breath, but also had abnormal lung tissue on their CT scans. The investigators focused on this group to better understand what was causing some cases of radiographic abnormalities to worsen or improve.

Among the patients tested

• Median age was 62 (range from 32 to 83)
• 43% were female
• 66% were white, 17% were Black and 20% were Hispanic
• All patients had respiratory symptoms on presentation with shortness of breath being the most common symptom (97%) followed by cough (69%)
• Nine patients had never been hospitalized; and of the 26 who had been hospitalized, 17 were admitted to the intensive care unit
• Two patients ultimately required lung transplantation after their COVID diagnosis
• 43% of patients required oxygen therapy, including the two patients who required lung transplantation

The scientists compared patients within this cohort whose lungs improved on subsequent imaging to patients who did not improve. In additional analyses, data were compared between RPRA and previous studies involving patients who required lung transplantation after COVID, healthy control specimens, and samples from patients who had idiopathic pulmonary fibrosis.

Key findings include:

• CT scans done an average of 145 days after COVID infection were analyzed and showed 39% pulmonary fibrosis and 22% inflammatory changes in the 35 patients tested.
• Samples from lung fluid on a subset of these patients an average of 5.3 months but up to 1.5 years (after COVID infection) showed high levels of pro-inflammatory molecules leading to ongoing immune cell migration into their lungs.
• There was a persistent migration of white blood cells (including neutrophils and monocytes) into the lungs of people with radiographic abnormalities that was correlated with the severity of CT scan changes. In particular, monocyte-derived alveolar macrophages (MoAM) have been found in both mice and humans to be involved in the progression to pulmonary fibrosis.
• The MoAMs did not appear to switch to a “repair mode.” Patients with radiographic abnormalities that improved, worsened or remained the same all had similar-appearing MoAMs. This was supported by comparing their molecular characteristics to samples from patients who had end-stage pulmonary fibrosis from COVID and idiopathic pulmonary fibrosis.

“What surprised us the most was the ongoing influx of pro-inflammatory and pro-fibrotic immune cells from blood into lungs even one year after the COVID infection. Historically, we assume infection-related lung inflammation resolves by this point. The highly overlapping biological processes involving radiographic abnormalities and other non-COVID conditions that lead to fibrosis is an important finding,” Sala said.

Next steps

According to investigators, understanding the underlying drivers for protracted lung inflammation in radiographic abnormalities is an important step in addressing long COVID, which can involve nearly any organ system. Steroids were given to many patients in this cohort, but it remains to be determined whether this strategy is helpful in some patients more than others. The study serves as a step forward in understanding pulmonary fibrosis in general to aid investigations in the discovery of better medical treatments.

“The more invisible manifestations of long COVID, such as brain fog, shortness of breath, rapid heart rate and fatigue, may well involve similar prolonged inflammation and this study is an important step forward in supporting this idea,” Sala said.

“The study also supports a broader point that understanding COVID and its ongoing impacts can serve to inform our understanding of other chronic respiratory illnesses that lead to pulmonary fibrosis.”