Athol U. Wells, Anand Devaraj, Sujal R. Desai Jan 26 2021https://doi.org/10.1148/radiol.2021204482
Coronavirus disease 2019 (COVID-19) has now caused more than a million deaths worldwide. These deaths are often due to severe pulmonary involvement. In fatal cases, features of diffuse alveolar damage are a frequent finding. Many survivors with severe infection have long-term residual abnormalities on their thoracic CT scans, but current studies do not extend follow-up beyond 6 months. Residual pulmonary disease is sometimes referred to as “post-COVID interstitial lung disease” (ILD).
In this issue of Radiology, Han and Fan et al (1) report on a prospective cohort of 114 patients with severe COVID-19 pneumonia undergoing CT during hospital admission and 6 months later. In 62% of participants, there were residual CT abnormalities at 6 months. This included 35% of the total cohort with “fibrotic-like” features (the presence of parenchymal bands, irregular interfaces [bronchovascular, pleural, or mediastinal], traction bronchiectasis, and/or honeycombing). The remaining participants with residual abnormalities had ground-glass opacification and interstitial thickening; 26% of patients had reduced gas transfer levels.
Initial features predictive of fibrotic-like abnormalities at 6 months were also independent predictors in multivariable analysis. These included age, markers of disease severity (tachycardia, hospital stay of 17 days or longer, total extent of disease at CT), acute respiratory distress syndrome (ARDS), and mechanical ventilation. The link between ARDS and fibrotic-like changes at 6 months was especially striking. ARDS was present in 63% of this participant subgroup but in only 8% of the remaining patients (odds ratio of 13 in multivariable analysis).
Serial CT evaluation showed an increase in features suggestive of underlying fibrosis but a decrease in the total extent of disease at CT and in ground-glass opacification and consolidation. Fibrotic-like change was present in only two patients at initial CT (ie, in only 5% of the 40 participants with this CT appearance at 6 months). The extent of fibrotic-like change was positively correlated at 6 months with the total extent of disease and the extent of ground-glass opacification.
In severe COVID-19, histologic information is mostly confined to fatal cases in which ARDS (ie, histologic features of diffuse alveolar damage) is a prominent feature. This observation is not directly relevant to residual CT findings at 6 months. It is important to stress that Han and Fan et al interpreted CT patterns without evaluating underlying histologic appearances. In general, the term fibrosis applies to irreversible disease. The authors are correct to refer to “fibrotic-like” appearances, an important caveat. Similarly, the widespread use of the term post-COVID ILD implies something more than the slow regression of abnormalities following the acute episode. It presupposes that residual abnormalities, when clinically significant, will remain so in the longer term. Thus, although the study by Han and Fan et al provides invaluable CT information at 6 months, it remains essential that major uncertainties about both the histologic and the long-term clinical significance of the CT observations are clearly understood.
What do the CT patterns mean, in reality? Do the “fibrotic-like” changes truly represent irreversible disease in a post-ARDS setting? It is important to note that in post–severe acute respiratory syndrome, CT findings considered to denote fibrosis at initial CT follow-up continue to regress in the longer term (2). In attempting to separate fibrotic and nonfibrotic appearances, one difficulty is the “gray area” in which immature fibrosis (fibroblastic change), arising because of diffuse alveolar damage, remodels with time. In the current study, two problems apply to the attempt to separate fibrotic and nonfibrotic CT abnormalities.
First, it is not entirely clear that all the abnormalities grouped as “fibrotic-like” are reliably indicative of irreversible disease in a post-ARDS setting. Bands are especially difficult to interpret. Identical appearances are seen in cryptogenic organizing pneumonia (3), and organizing pneumonia–like change is often seen during and following COVID-19, as in the current study. Honeycombing might reasonably represent genuinely irreversible disease, but is this also true of other fibrotic-like patterns? Or will these features mostly regress with time and the remodeling of immature fibrosis?
Second, the histologic and clinical significance of the “non-fibrotic” CT patterns is questionable. Han and Fan et al argue that ground-glass opacification at CT is likely to reflect inflammatory disease, although they acknowledge the nature of inflammation is not currently understood if this is the case. Despite partial regression over 6 months, it is interesting that the extent of ground-glass opacification and the total extent of disease at 6 months were the CT features correlating most strongly with the extent of fibrotic-like abnormalities at 6 months. Ground-glass opacification is sometimes indicative of fine interstitial fibrosis that is genuinely irreversible in chronic ILD (4). It is not unreasonable to hypothesize that regression of ground-glass opacification at least partially reflects remodeling of immature fibrosis.
These uncertainties are inescapable, as it is unlikely that future histologic studies will evaluate residual disease on CT scans of patients recovering from serious COVID-19. Han and Fan et al make reasonable broad separations based on past CT-histologic correlations; however, as discussed earlier, these may not be accurate in the short-term follow-up of ARDS survivors. It can be argued that Han and Fan et al lost a major opportunity to examine regional CT links between patterns. Each individual CT pattern was examined in isolation, both at 6 months and with respect to serial change. Ground-glass opacities and fibrotic-like scores were positively correlated at 6 months, but it is not clear whether fibrotic-like change colocalized regionally with areas of residual ground-glass opacities. Similarly, it is unclear whether features considered to denote fibrosis at 6 months arose in areas with intense ground-glass opacities or consolidation on the acute scan. In a nutshell, the evolution of CT patterns (whether from inflammatory to fibrotic disease or reflecting partial regression of immature fibrosis with residual disease more overtly fibrotic) was not explored.
This deficiency is important because of the argument that there are twin pathogenetic pathways in severe COVID-19. One pathway involves diffuse alveolar damage as a toxic viral effect, perhaps fueled by ventilator-induced lung injury. The other involves auto-inflammatory pathways contributing to vascular lesions and organizing pneumonia–like change. A small COVID-19 autopsy study recently documented the existence of inflammatory perivascular lesions distant from sites of epithelial injury (5). It is well recognized that viruses can trigger autoimmune disease (6), and there are case reports of COVID-19 triggering systemic lupus erythematosus, antiphospholipid syndrome, Guillain-Barré syndrome, and lupus anticoagulant positivity. However, it is not known whether the CT features, both acutely and at follow-up, represent a pathogenetic continuum or whether separating diffuse alveolar damage and/or ventilator-induced lung injury from auto-inflammatory pathways would enhance our understanding of COVID-19. In this regard, future serial CT studies examining relationships between individual patterns and their evolution have much to offer.
Future studies of patients with residual CT abnormalities at 6 months should consider several additional baseline candidate risk factors. Pulmonary vascular lesions are a major consideration in acute COVID-19 and might contribute to residual defects in gas transfer. The study by Han and Fan et al showed a link between D-dimer levels and the existence of fibrotic-like features at 6 months, but this link was not retained on multivariable analysis. Dual-energy CT might be harnessed to capture intravascular thrombosis in acute COVID-19 (7) in order to identify associations with subsequent CT findings. The impact of ventilator-induced lung injury might best be captured as the duration of high-pressure ventilation, which is linked to residual CT abnormalities 1 year after ARDS (8). Finally, a baseline variable that may be more difficult to capture is the pre-existence of limited interstitial lung abnormalities. This variable is present in screening studies in 5%–10% of older adults (9), the demographic at greatest risk of COVID-19 mortality. It is conceivable that extensive parenchymal opacification during acute COVID-19 might mask limited interstitial lung abnormalities and that COVID-19 might promote their evolution to apparent residual fibrotic changes post-COVID.
More important, future work must pursue a longer-term follow-up of patients—at or beyond a year—to determine whether residual CT abnormalities at 6 months largely regress, as in past forms of diffuse alveolar damage, or persist. In this regard, it may be important to distinguish between post-ARDS abnormalities (including ventilator-induced injury) and auto-inflammatory and/or autoimmune pathways triggered by COVID-19, perhaps giving rise to progressive fibrotic lung disease in a small minority of patients.
In summary, the study by Han and Fan et al is an important addition to the literature because it documents the existence of residual CT abnormalities at 6 months in a large proportion of patients with severe COVID-19. It is helpful for clinicians to know that this outcome is linked separately to ARDS, the use of mechanical ventilation, and extensive disease at CT during the acute episode. Yet, there are many unanswered questions that future works must explore. Areas needing further exploration include the pathogenetic significance of and relationships between individual CT patterns and their longer-term clinical significance. Only time and serial disease behavior will inform us whether the term post-COVID ILD is appropriate.Disclosures of Conflicts of Interest: A.U.W. Activities related to the present article: received an honorarium from the Fleischner Society for a lecture on post–COVID-19 CT abnormalities at a Fleischner-sponsored symposium. Activities not related to the present article: received compensation from Roche and Boehringer Ingelheim for consultancy work and lectures. Other relationships: disclosed no relevant relationships. A.D. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received compensation from Boehringer Ingelheim, GSK, Galapagos, and Galecto Biotech for consultancy work. Other relationships: disclosed no relevant relationships. S.R.D. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: co-founder and director of teleradiology company DMC Radiology Reporting (no compensation received to date); received compensation from GSK and AstraZeneca as a clinical trial committee member; received compensation from Boehringer Ingelheim for the development of hands-on ILD courses; provided consultancy services to Sensyne Health Group for artificial intelligence software development (no compensation received to date). Other relationships: disclosed no relevant relationships.
Article History
Received: Dec 2 2020
Revision requested: Dec 7 2020
Revision received: Dec 9 2020
Accepted: Dec 10 2020
Published online: Jan 26 2021
Published in print: Apr 2021