The COVID-19 pandemic has been ongoing for almost two years. Over this period, Radiology and other peer-reviewed journals have distributed information regarding the nature of the pandemic with unprecedented speed. Based upon the extensively documented clinical and imaging manifestations of acute COVID-19 infection, expert thoracic imagers have developed imaging categories that classify patterns according to the likelihood that they represent COVID-19 infection(1).
Acute COVID-19 has a somewhat unique appearance amongst viral infections on CT. It manifests as ground-glass opacities and/or consolidation often with a strong peripheral distribution. Also, there are CT findings suggesting that organizing pneumonia is a common pattern of injury. Organizing pneumonia is associated with a wide variety of different infections, however, it appears particularly common with COVID-19(2). However, the long-term pulmonary manifestations of COVID-19 pneumonia (part of so-called “long-COVID”) remain lacking in the literature.
It is important to understand our current knowledge of viral infections and their typical manifestations within the lungs. The long-term sequela of viral pneumonia, in general, vary depending upon two factors: 1) direct injury caused by the viral organisms, and 2) the host’s immune reaction to those organisms. These result in a variety of different patterns of injury, each of which is associated with specific permanent long-term sequela. The histologic manifestations of acute pulmonary viral infections can be divided broadly into two primary patterns: 1) bronchiolitis and inflammation adjacent to airways, and 2) diffuse alveolar damage. On imaging, bronchiolitis and airway inflammation manifest as bronchial wall thickening, centrilobular nodules, and tree-in-bud opacities; whereas diffuse alveolar damage manifests as bilateral ground-glass opacity and/or consolidation.
The long-term effects of these two patterns are also characteristic. Inflammation within and around the airways may induce concentric fibrosis around the bronchioles resulting in airway narrowing or obliteration. This is termed constrictive (or obliterative) bronchiolitis. Development of constrictive bronchiolitis may result in persistent dyspnea after resolution of the acute infection with an associated obstructive defect on pulmonary function tests. Typical CT findings of constrictive bronchiolitis include mosaic attenuation and air trapping, sometimes associated with bronchiectasis. The long-term manifestations of diffuse alveolar damage (DAD), on the other hand, are quite different. Histologically, fibrosis develops 1-2 weeks after the development of acute symptoms. On imaging, this is associated with the development of reticulation and traction bronchiectasis. Over time, usually months, this fibrosis may improve, although residual fibrosis is common(3). This residual fibrosis is often located in the anterior subpleural lung and may be associated with restrictive physiology on pulmonary function testing.
Organizing pneumonia (OP) is particularly common with COVID-19. The clinical and imaging features of OP have been studied (4) mainly in the setting of cryptogenic (idiopathic) disease. Organizing pneumonia is usually a highly steroid-responsive disease with opacities that quickly improve or resolve with treatment, although residual fibrosis may occur. This residual fibrosis often has a pattern that resembles nonspecific interstitial pneumonia with basilar predominant reticulation, traction bronchiectasis, and subpleural sparing(5). It is also important to note that OP and DAD may co-exist with overlapping imaging findings.
Understanding the different patterns of injury associated with viral infections and their long-term sequela is important in putting the long-term effects of COVID-19 infection in context. Han et al(6). were among the first to describe the persistent CT findings of COVID-19 six months after the onset of acute symptoms. In their study, over one-third of patients showed evidence of fibrotic changes.
In this issue of Radiology, Cho and Villacreses and colleagues (7) address these long-term pulmonary manifestations in a prospective study of 100 patients with persistent (>30 days) pulmonary symptoms after an acute COVID-19 infection. One hundred and six healthy controls were also evaluated. The particular emphasis of this investigation was on the presence of air trapping on expiratory CT. The severity of disease among studied patients varied and included outpatients, hospitalized patients, and those requiring admission to the intensive care unit (ICU). Cho and Villacreses et al. discovered that air trapping was present in 58% of patients with post-COVID-19 and had its highest prevalence in the group of patients hospitalized for their infection (73%). Using quantitative analysis, air trapping affected a mean of 25-35% of the lungs in patients with post-COVID-19 depending on the clinical severity of disease compared to 7% in controls (p<.001). The authors did not identify obstructive airways disease on spirometry in any of the groups. This lack of obstruction on spirometry in patients with air trapping is not surprising. In a cohort of soldiers deployed to Iraq and Afghanistan with biopsy-proven constrictive bronchiolitis(8), the majority did not have obstruction on pulmonary function tests. Restriction was present on spirometry in the patients with COVID-19 in the study by Cho and Villacreses et al., specifically in the inpatient and ICU groups. Ground-glass opacity, traction bronchiectasis, and other signs of fibrosis were most frequent in patients admitted to the ICU (94%, 69%, 81% of patients, respectively compared with 36%, 8%, and 3% of outpatients, respectively).
In summary, the study by Cho and Villacreses et al. demonstrates that air trapping on CT is common in patients with persistent symptoms after COVID-19 infection. When considering the long-term pulmonary effects of COVID-19 infection, this is an important finding and may correspond to the development of post-viral constrictive bronchiolitis, an entity seen with other viral infections and in particular, adenovirus infection. Interestingly, the CT findings of acute COVID-19 are not highly airway-centric. Centrilobular nodules and tree-in-bud opacities, reflecting airway-centric inflammation, are not a typical finding of acute COVID-19 infection. Regardless, these results indicate a long-term impact on bronchiolar obstruction. In the study by Cho and Villacreses et al, the presence of ground glass opacity and/or fibrosis on CT were most common in the patients admitted to the ICU and likely correspond to post-OP and/or post-DAD fibrosis.
It is important to note that not all pulmonary fibrosis, including that of the airway and of the parenchyma, is permanent. Collagen may be absorbed for months after the acute insult, thus it is not entirely clear if the abnormalities seen in the current study will be permanent. The median time from COVID-19 diagnosis to the clinic visit for persistent post-COVID-19 symptoms was only 75 days. However, 8 of 9 patients (out of 100 patients total) with imaging more than 200 days from the acute infection had persistent air trapping. Regardless of the imaging findings, the most important question is whether the airway obstruction and/or fibrosis result in clinical symptoms. This paper suggests that airways obstruction and post-OP/DAD fibrosis contribute to persistent symptoms after COVID-19 infection with the contribution of airways disease higher in the outpatients, and the contribution of OP/DAD greater in the patients admitted to ICU. 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.
Source: Brett M. Elicker. What Are the Long-term Pulmonary Sequelae of COVID-19 Infection? Radiology. Published Online: Mar 15 2022. https://pubs.rsna.org/doi/10.1148/radiol.220449 (Full text)