Prognostic value of senescence, lymphatic proliferation, and histology in post-COVID-19 interstitial lung disease

BACKGROUND: In a subset of patients, interstitial lung disease (ILD) sequelae following COVID-19 pneumonia persist beyond 6 months after hospital discharge. However, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to evaluate the prognostic value of histopathological patterns, cellular senescence, and lymphatic proliferation in patients with post-COVID-19 ILD. METHODS: This prospective observational study of patients hospitalized at Vall d'Hebron University Hospital due to COVID-19 pneumonia and presenting respiratory symptoms, radiological alterations, and pulmonary function test impairment during the 3-month follow-up visit after discharge. Lung cryobiopsies were performed, and the histopathological findings and expression of senescence and lymphatic proliferation (P16 and D2-40) were analyzed. RESULTS: Between March 2020 and February 2021, 4332 patients were hospitalized at Vall d'Hebron University Hospital due to COVID-19 pneumonia, and 1403 were visited in the Respiratory Clinic 3 months after discharge. The first 66 patients presenting with respiratory symptoms, radiological alterations, and decreased pulmonary function tests during the post hospitalization follow-up underwent cryobiopsy for diagnostic purposes. Multivariate regression showed that Masson bodies in the 3-month cryobiopsy were related to a higher forced vital capacity at 6 months whereas higher expression of senescence and lymphatic proliferation markers, such as P-16 and D2-40, in the histological samples were related to decreased carbon monoxide transfer test values at 6 months. CONCLUSION: Cellular senescence and lymphatic proliferation in lung tissue are associated with impaired gas exchange in mid-term follow-up, suggesting their potential as prognostic markers in post-COVID-19 ILD.