Clinical, radiological and pathological findings in patients with persistent lung disease following SARS-CoV-2 infection

Abstract

Several patients experience pulmonary sequelae after Sars-Cov-2 infection, ranging from self-limited abnormalities to major lung diseases. Morphological analysis of lung tissue may help in understanding pathogenic mechanisms and provide consistent personalised management. Aim of the study was to ascertain morphologic and immuno-molecular features of lung tissue. Transbronchial lung cryobiopsy was carried out in patients with persistent symptoms and computed tomography suggestive of residual lung disease after recovery from Sars-CoV-2 infection. 164 patients were referred for suspected pulmonary sequelae after COVID-19; 10 patients with parenchymal lung disease extent >5% underwent lung biopsy. Histological pattern was not homogeneous, as three different case clusters could be evidenced, which were mirrored in clinical and radiological features: cluster one (“chronic fibrosing”) characterised by post-infection progression of pre-existing interstitial pneumonias; cluster two (“acute/subacute injury”) characterised by different types and grades of lung injury, ranging from organising pneumonia and fibrosing NSIP to diffuse alveolar damage; cluster three (“vascular changes”) characterised by diffuse vascular increase, dilatation and distortion (capillaries and venules) within otherwise normal parenchyma. Clusters two and three were characterised by immunophenotypical changes similar to those observed in early/mild covid-19 pneumonias (abnormal expression of STAT3 in hyperplastic pneumocytes and PD-L1, IDO and STAT3 in endothelial cells). This is the first study correlating histological/immunohistochemical patterns with clinical and radiological pictures of patients with post-COVID lung disease. Different phenotypes with potential different underlying pathogenic mechanisms have been identified.

Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia

“…A variety of relevant changes were observed, ranging from minimal abnormalities to fibrosing interstitial disease. An intriguing finding in PACS cases of this series was the occurrence of morphological and immunophenotypical changes in the pulmonary vascular bed, similar to those observed in acute early/mild cCOVID-19 pneumonias (vascular enlargement and abnormal endothelial expression of IDO1, PD-L1 and STAT3) [ 35 , 36 ]. The persistence of these peculiar findings after virus clearance (as demonstrated by molecular analysis in lung tissue, BAL, and nasal swab in all PACS cases) strongly suggests that this phenotype occurs independently from active infection, and it is likely involved in the pathogenesis of both COVID-19 and post-COVID-19 sequelae.…”

“…The pathogenic links relating vascular abnormalities occurring in COVID-19 and PACS are currently unknown. To address these issues, we recently used lung histology and immunohistochemistry to investigate a series of transbronchial lung cryobiopsies from patients with persistent symptoms and computed tomography suggestive of residual lung disease after recovery from Sars-CoV-2 infection [ 35 ]. A variety of relevant changes were observed, ranging from minimal abnormalities to fibrosing interstitial disease.…”

“…The endothelial expression of IDO1 in other tissues is absent in normal conditions, but when up-regulated by IFNg the resulting vascular deprivation of Trp may provide antibacterial activity [ 160 ]. In our experience, the endothelial IDO1 expression in a normal lung is weak and/or restricted to scattered blood vessels [ 35 , 36 ]. A significantly different IDO1 expression pattern is observed in COVID-19 early/mild pneumonia and PACS patients, where most parenchymal blood vessels, both capillaries and venules, consistently show endothelial immunostaining ( Figure 1 ) [ 35 , 36 ].…”

“…In our experience, the endothelial IDO1 expression in a normal lung is weak and/or restricted to scattered blood vessels [ 35 , 36 ]. A significantly different IDO1 expression pattern is observed in COVID-19 early/mild pneumonia and PACS patients, where most parenchymal blood vessels, both capillaries and venules, consistently show endothelial immunostaining ( Figure 1 ) [ 35 , 36 ]. According to available data, IDO1 and IDO2 have overlapping but distinct functions and expression patterns.…”

Follow-Up CT Patterns of Residual Lung Abnormalities in Severe COVID-19 Pneumonia Survivors: A Multicenter Retrospective Study

“…These studies mostly defined the presence of fibrotic changes based on individual CT findings such as reticulations, bands, and bronchiectasis. However, it has recently been argued that those fibrotic-like changes, in the setting of recovery from an acute lung injury, may have a completely different significance than in the setting of chronic lung diseases [ 22 , 26 ]. Bands probably represent limited organizing pneumonia, GGO that reduces in extension or attenuation may reflect inflammation and immature fibrosis remodeling, and bronchial distortion and traction bronchiectasis may not be irreversible (as previously described in SARS pneumonia follow-up CT scans) [ 20 , 21 , 22 , 27 ].…”