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Clinical Context

Nearly 30% of patients with post-acute sequelae of COVID-19 (PASC), including persons who had mild infection not requiring hospitalization, have persistent respiratory symptoms. Small airways disease with air trapping appears to be a long-lasting sequela of SARS-CoV-2 infection, according to a prospective study that compared 100 COVID-19 survivors who had persistent symptoms and 106 healthy control participants.

"Something is going on in the distal airways related to either inflammation or fibrosis that is giving us a signal of air trapping," noted senior author Alejandro P. Comellas, MD, in a press release.^[1] The study was stimulated by reports from University of Iowa clinicians noting that many patients with initial SARS-CoV-2 infection who were either hospitalized or were treated in the ambulatory setting later reported shortness of breath and other respiratory symptoms indicative of chronic lung disease.

Given the millions of COVID-19 infections worldwide, this finding may have a substantial potential impact on healthcare systems. While this initial study had limitations, emerging data continues to be a vital tool for earlier identification and initiation of appropriate treatment for active COVID-19 infections and PASC; thus, improving patient outcomes.

Study Results

Investigators classified patients (mean age, 48 years; 66 women) with PASC according to whether they were ambulatory (67%), hospitalized (17%), or required treatment in the intensive care unit (ICU) (16%). They then compared computed tomography (CT) findings of patients who had COVID-19 and persistent symptoms with those of a healthy control group.

COVID-19 severity did not affect the percentage of cases of lung with air trapping among these patients. Air trapping occurred at rates of 25.4% among ambulatory patients, 34.6% in hospitalized patients, and in 27.3% of patients requiring intensive care (P = .1). The percentage of lung affected by air trapping in ambulatory participants was sharply and significantly higher than in healthy control participants (25.4% vs 7.2%; P < .001). Also, air trapping persisted; it was still present in 8 of 9 participants who underwent imaging more than 200 days postdiagnosis.

Qualitative analysis of chest CT images showed that the most common imaging abnormality was air trapping (58%); ground-glass opacities (GGOs) were found in 51% (46/91), noted Comellas and co-authors. This suggests ongoing lung inflammation, edema, or fibrosis. These symptoms are often observed during acute COVID-19, frequently in an organizing pneumonia pattern, and have been shown to persist for months after infection in survivors of severe disease. The mean percentage of total lung classified as having regional GGO on chest CT scans was 13.2% and 28.7%, respectively, in the hospitalized and ICU groups, both very much higher than in the ambulatory group, at 3.7% (P < .001 for both). Among healthy control participants, the GGO rate on chest CT was only 0.06% (P < .001).

In addition, air trapping correlated with the ratio of residual volume to total lung capacity (r = 0.6; P < .001) but not with spirometry results. In fact, the investigators did not observe airflow obstruction by spirometry in any group, suggesting that air trapping in these patients involves only small rather than large airways and that these small airways contribute little to total airway resistance. Only when a large percentage, perhaps 75% or more, of all small airways are obstructed will spirometry pick up small airways disease, the authors observed.

Continuing Disease

The findings taken together suggest that functional small airways disease (fSAD) and air trapping are consequences of SARS-CoV-2 infection, according to Comellas.

"If a portion of patients continues to have small airways disease, then we need to think about the mechanisms behind it," he said. "It could be something related to inflammation that's reversible, or it may be something related to a scar that is irreversible, and then we need to look at ways to prevent further progression of the disease."

He added, "Studies aimed at determining the natural history of [fSAD] in patients with post-acute sequelae of COVID-19 and the biological mechanisms that underlie these findings are urgently needed to identify therapeutic and preventative interventions," Comellas, professor of internal medicine at Carver College of Medicine, University of Iowa, Iowa City, concluded.

The study limitations, the authors stated, include the fact that theirs was a single-center study that enrolled participants infected early during the COVID-19 pandemic and did not include patients with delta or omicron variants, thus limiting the generalizability of the findings.

The study was published in Radiology.^[2]

The reported findings "indicate a long-term impact on bronchiolar obstruction," stated Brett M. Elicker, MD, professor of clinical radiology, University of California, San Francisco, in an accompanying editorial.^[3]

Because collagen may be absorbed for months after an acute insult, it is not entirely clear whether the abnormalities seen in the current study will be permanent.

Elicker said further, "the presence of [GGO] and/or fibrosis on CT were most common in the patients admitted to the ICU and likely correspond to post-organizing pneumonia and/or post-diffuse alveolar damage fibrosis."

He also pointed out that organizing pneumonia is especially common among patients with COVID-19 and is usually highly steroid-responsive. The opacities improve or resolve with treatment, but sometimes residual fibrosis occurs.

"Longer-term studies assessing the clinical and imaging manifestations 1-2 years after the initial infection are needed to fully ascertain the permanent manifestations of post-COVID fibrosis," Elicker concluded.

The study was supported by grants from the National Institutes of Health. The authors and Elicker have disclosed no relevant financial relationships.

Clinical Implications

• In COVID-19 survivors, small airways disease with air trapping is a long-lasting sequela occurring independently of initial infection severity.
• Persistence of respiratory abnormalities raises concern for permanent airway remodeling and fibrosis after SARS-CoV-2 infection.
• Implications for the Healthcare Team: While identifying therapeutic and preventative interventions, clinicians should recall that air trapping is often missed with spirometry but detected with inspiratory and expiratory CT imaging and plethysmography.

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