This report offers an early glimpse into the longer-term pathologic aftermath of severe COVID-19 managed with prolonged mechanical ventilation and ECMO, summarized in Table 1. To our knowledge, case 3 of this series represents only the second detailed description of the pulmonary pathology in a patient undergoing lung transplantation for prolonged COVID-19–related hospitalization and the longest follow-up of successful lung transplantation in this setting (the patient is alive on day 202; day 79 after transplantation). The main pathologic finding is that diffuse interstitial fibrosis with early microscopic honeycomb change can develop within this time frame. Persistence of DAD beyond 8 weeks with massive unilateral lung necrosis and extensive colonization by Candida is also hitherto unreported in COVID-19.
Potential limitations to this study include the possibility of preexisting pulmonary fibrosis or predisposing conditions (ie, lung-toxic chemotherapy in case 1) that may have predated COVID-19–related hospitalization but contributed to the fibrosis seen on resection. For case 1, chest CT on admission showed typical imaging features of COVID-19 pneumonia with no findings to suggest underlying fibrotic interstitial lung disease (Supplemental Image 1A; all supplemental materials can be found at American Journal of Clinical Pathology online). For case 2, initial portable chest radiograph showed airspace opacities in both lungs, worse in the periphery and lung bases (Supplemental Image 1B), with a subsequent radiograph obtained post-ECMO placement demonstrating worsening bilateral extensive airspace opacities with air-bronchograms, most likely related to diffuse alveolar damage (Supplemental Image 1C). Unfortunately, preadmission imaging was not available to document normal lungs, and no chest CT was performed at the time of admission, precluding a confident assertion that all findings on chest x-ray were from COVID-19 pneumonia and not preexisting background fibrosis. Case 3 unfortunately had DAD on admission.
Supplemental Image 1.
Late complications of COVID-19. A, Case 1, Coronal multiplanar reformatted CT of the patient at the time of admission demonstrated bilateral, multifocal peripheral consolidative opacities, typical CT imaging features of COVID-19. B, Case 2, Portable chest radiograph showed airspace opacities in both lungs, worse in the periphery and lung bases. C, Case 2, Portable chest radiograph obtained post ECMO placement demonstrated bilateral extensive airspace opacities with air-bronchogram, most likely related to diffuse alveolar damage.
All three patients underwent prolonged ECMO runs. Although DAD can occur in patients with COVID-19 who have never been ventilated, it is possible that ventilator-associated injury occurs in COVID-19–damaged lung despite lung-protective strategies facilitated by ECMO support. This is especially probable in nonparalyzed, spontaneously breathing patients who are asynchronous with the ventilator (so-called patient self-inflicted lung injury) and can manifest as spontaneous pneumothorax. With regard to the possibility of the observed fibrosis being a sequela of the ECMO itself, there are little data available to examine this issue due to inherent confounding in clinical situations. The issue is more one of association than of causality. The pulmonary insult that caused ARDS requiring ECMO, followed by the lungs' subsequent healing, is what most likely caused the fibrosis, not the ECMO itself. Lindén et al observed that for treatment of severe ARDS, the protracted parenchymal CT imaging abnormalities seen in conventional ventilator-treated ARDS were not present in patients treated with ECMO. The authors go on to suggest that ECMO therapy itself may in fact protect the pulmonary parenchyma from so-called ventilator-associated damage. It should be noted, however, that histologic evidence of thrombosis and evidence of organizing DAD have been reported in patients with prolonged ECMO therapy; having acknowledged this, current protocols aim to mitigate this risk to the greatest extent possible. That being the case, the largest series on the subject was consistently definitive in the authors' ability to classify the patterns of fibrosis seen in patients who received prolonged ECMO therapy as most likely being organizing DAD in nature.
In the current series, the patterns of fibrosis seen in cases 2 and 3 largely defied definitive classification. The diffuse and homogeneous interstitial changes were more reminiscent of a fibrotic NSIP pattern and not convincingly organizing DAD. While focal microscopic honeycomb change was seen, the patchwork pattern of fibrosis seen in cases of usual interstitial pneumonia was not observed. The composition of the airspace macrophages observed in case 3 was also unique in that there appeared to be evidence of prior alveolar hemorrhage in the form of hemosiderin-laden macrophages. We could not find evidence of vasculitis or capillaritis. At the same time, there appeared to be postobstructive changes given the presence of foamy-appearing macrophages, although there was little evidence of an organizing pneumonia. Postobstructive changes are commonly seen in the setting of organizing pneumonia, which has been inconsistently reported in patients with COVID-19 infections. Certain severe viral pneumonias, such as cytomegalovirus, are known to cause a necrotizing bronchiolitis that conceptually could result in some pulmonary hemorrhage without evidence of vascular inflammation. No such necrotizing pneumonia was observed in any of the patients reported herein.
Currently, there is no definitive histologic evidence to suggest that the symptoms experienced by what the lay literature has labeled COVID-19 "long haulers" are due to the development of subclinical pulmonary fibrosis.[38,39] However, the histologic findings in this report confirm that the development of interstitial fibrosis in the lungs is a real possibility in patients who survive their initial acute COVID-19 infections.
The mechanisms by which COVID-19 infection results in pulmonary fibrosis remain to be elucidated, although curiously, the mechanisms may be independent of the virus's ability to induce acute lung injury.[40,41] As a family, coronaviruses have been demonstrated to induce, within infected cells, a significant degree of endoplasmic reticulum stress, which has been linked to the development of pulmonary fibrosis, independent of acute lung injury. Endoplasmic reticulum stress has long been known to be a consequence of cellular redox imbalances. Replication of coronaviruses has been demonstrated to be dependent on the precise redox status of infected cells. It remains to be determined if the redox state of an individual cell or organ will play a significant role in mitigating the effects of COVID-19 infection.
Regardless, based on the findings presented herein, it appears that the development of varying degrees of pulmonary fibrosis can be a sequela of COVID-19 infection and will be an important avenue for future clinical research. Based on the pathologic appearance, it is plausible that the fibrosis may represent the residuum of prior organizing DAD. Although the pathogenesis of these findings is likely complex and multifactorial, our pathologic findings support observations from the radiology literature that diffuse interstitial fibrosis can occur later in the course of severe COVID-19 treated with aggressive life-supporting therapies.
Am J Clin Pathol. 2021;155(4):506-514. © 2021 American Society for Clinical Pathology