Viral Infection, Pulmonary Fibrosis, and Long COVID

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected hundreds of millions of people worldwide, resulting in long-term complications for many. The multiorgan syndrome known as “long COVID” has emerged as an important socioeconomic issue, and long-term pulmonary complications represent an important component of long COVID (1). Chest computed tomographic (CT) imaging plays a key role in the diagnosis and monitoring of coronavirus disease (COVID-19). Several studies described the CT manifestations of sequelae of COVID-19 once patients recovered from acute infection (2–7). Han and colleagues (8) recently reported that 35 (56%) of 62 patients imaged 1 year after severe COVID-19 pneumonia had developed interstitial changes that included reticulation or traction bronchiectasis. These changes resembled those associated with fibrotic interstitial lung abnormalities (ILA), which were previously identified as incidental findings on CT scans of large-scale research cohorts (9, 10). There have been reports studying the shared genetic etiology (11, 12) and circulating biomarkers (13, 14) between idiopathic pulmonary fibrosis and COVID-19 severity. These preliminary observations raise significant questions and concerns regarding the lungs of the hundreds of millions of people worldwide who have now recovered from SARS-CoV-2 infection.

In this issue of the Journal, Stewart and colleagues (pp. 693–703) report the results from the UKILD Post-COVID (UK Interstitial Lung Disease Post-COVID) study interim analysis to estimate the prevalence of residual lung abnormalities in those hospitalized with COVID-19 (15). Stewart and colleagues rationalized that the common symptoms and genetic polymorphisms between COVID-19 and lung fibrosis suggest that SARS-CoV-2 infection can lead to progressive lung disease (15). PHOSP-COVID (Post-Hospitalization COVID) study, a prospective longitudinal cohort study of adults discharged from National Health Service hospitals across the United Kingdom after admission for confirmed or clinically diagnosed COVID-19, was used for analysis of follow-up within 240 days of discharge. The study included participants who had had hospital discharges by the conclusion of March 2021 coincident with the first wave of the pandemic. Data were accumulated until October 2021 and were limited to 240 days of discharge. Analyses included data from routine clinical follow-up (PHOSP-COVID Tier 1) and from research visits (PHOSP-COVID Tier 2). CT scans were scored for residual lung abnormalities (either reticulations or ground-glass opacities). The interim group encompassed 3,700 people. Out of these, 255 patients (6.9%) had an identifiable thoracic CT scan performed. Of these, 220 were Tier 2 participants (9.2% of 2,396), and 35 were in Tier 1 (2.7% of 1,304) (P < 0.001). Of 255 CT scans (median, 113 d of discharge; interquartile range, 69–166), 209 (82.0%) were scored with reviewer concurrence on 70% of scans (Cohen’s κ, 0.33). Persistent lung abnormalities >10% were present in 166 (79.4%) of 209 participants. Visual scoring identified ground-glass opacities in an average of 25.5 ± 15.9% of the lung, reticulation in an average of 15.1 ± 11.0%, with the sum of these residual abnormalities involving an average of 40.6 ± 20.8% of the lung. Risk factors for abnormalities were identified as the presence of an abnormal chest radiograph (Relative Risk (RR), 1.21; 95% confidence interval [CI], 1.05–1.40), percent predicted Dl_CO <80% (RR, 1.25; 95% CI, 1.00–1.56), and severe illness requiring ventilation (RR, 1.27; 95% CI, 1.07–1.55). In the other 3,491 patients, moderate to very high risk persistent lung findings were classified in 7.8%, postdischarge prevalence was estimated to be 8.5% (95% CI, 7.6–9.5%), which rose to 11.7% (95% CI, 10.3–13.1%) in a sensitivity analysis. The authors conclude that COVID-19 postdischarge lung abnormalities were likely present after ∼11% of hospitalizations. Thus, the authors suggest that healthcare providers monitor high-risk individuals for long-term functional complications.

To our knowledge, this is the first report of this nationwide multicenter study with the largest number of study subjects comparing the previous reports (15) and reconfirming the results of multiple smaller reports (2–8). The estimation of up to 11% prevalence of residual lung abnormalities in people hospitalized with COVID-19 is based on 209 CT scans among 3,700 hospitalized patients. Our own unpublished preliminary data at a U.S. academic medical center demonstrate post–COVID-19 lung abnormalities in approximately one-third of 132 patients with CT scans during the time period of alpha and delta variants, with a tendency for higher incidence of post-COVID lung abnormalities in more severe pneumonia (that involved a larger extent of the lungs on the initial CT scan) (unpublished results). Also, recently, we reported that vaccinated patients demonstrated milder COVID-19 pneumonia on CT scans at the time of diagnosis than did unvaccinated patients among 303 patients with CT scans during the period of delta and omicron variants, which suggests the possibility of decrease in the prevalence of post–COVID-19 lung abnormalities in the future with vaccination (16). Little is known about the histopathology of residual lung abnormalities after SARS-CoV-2 infection. Ravaglia and colleagues reported radiologic and pathologic findings in 10 patients with high-resolution CT and histology by transbronchial lung cryobiopsies at 32–227 days after SARS-CoV-2 infection, with results demonstrating three types of pathologies (17). One type (“chronic fibrosing”) demonstrated progression of interstitial pneumonia. The second type (“acute/subacute injury”) demonstrated different lung injuries, including organizing pneumonia, fibrosing nonspecific interstitial pneumonia, and diffuse alveolar damage. The third type (“vascular changes”) demonstrated vascular increase, dilatation, and distortion of capillaries and venules (17).

This work suggests that the COVID-19 pandemic may lead to a substantial worldwide burden of patients with CT scan findings of fibrotic ILA or nonspecific interstitial pneumonia. The immense numbers and intensity of investigation of SARS-CoV-2 infection are largely unprecedented. It is interesting to speculate that other, less well-studied viral infections may lead to similar CT lung abnormalities. It is even possible that a substantial proportion of “idiopathic” cases with these CT scan findings may be due to prior unrecognized viral (COVID-19 or other viral) pneumonia (Figure 1). Future investigation into the long-term pulmonary effects of COVID-19 and other viral lung infections will be important to gain a better understanding of the role of these organisms in chronic fibrotic or other lung disease. The SARS-CoV-2 pandemic has provided answers but also raises new questions regarding the genetics, molecular biology, inflammatory networks, pathophysiology, and possible etiology of fibrotic lung disease. There is a need for systematic, multidisciplinary, large-scale, international multicenter collaborations, in addition to ongoing individual and institutional efforts, to address these questions.

Figure 1.

Etiologies of fibrotic lung disease after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In the future, we speculate that SARS-CoV-2 and other viral infections may be identified as the etiologic cause of much fibrotic lung disease that was previously categorized as idiopathic.