The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and 1-yr follow-up

Shiqi Zhang*, Leonoor S. Boers*, Justin de Brabander, Laura B. van den Heuvel, Siebe G. Blok, Robert F.J. Kullberg, Barbara S. Smids-Dierdorp, Tamara Dekker, Hella L. Aberson, Lilian J. Meijboom, Alexander P.J. Vlaar, Leo Heunks, Esther J. Nossent, Tom van der Poll, Lieuwe D.J. Bos, Jan Willem Duitman, ArtDECO consortium and the Amsterdam UMC COVID study group

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS. This study aimed to assess the association between dynamic changes in alveolar FPR and long-term outcomes, as well as mortality in COVID-19 ARDS patients. We conducted a prospective cohort study of 154 COVID-19 ARDS patients. We collected bronchoalveolar lavage (BAL) and blood samples for measurement of 17 pulmonary fibrosis biomarkers, including NT-PCP-III. We assessed pulmonary function and chest computed tomography (CT) at 3 and 12 mo after hospital discharge. We performed joint modeling to assess the association between longitudinal changes in biomarker levels and mortality at day 90 after starting mechanical ventilation. 154 patients with 284 BAL samples were analyzed. Of all patients, 40% survived to day 90, of whom 54 completed the follow-up procedure. A longitudinal increase in NT-PCP-III was associated with increased mortality (HR 2.89, 95% CI: 2.55-3.28; P < 0.001). Forced vital capacity and diffusion for carbon monoxide were impaired at 3 mo but improved significantly at one year after hospital discharge (P = 0.03 and P = 0.004, respectively). There was no strong evidence linking alveolar FPR during hospitalization and signs of pulmonary fibrosis in pulmonary function or chest CT images during 1-yr follow-up. In COVID-19 ARDS patients, alveolar FPR during hospitalization was associated with higher mortality but not with the presence of long-term fibrotic lung sequelae within survivors.NEW & NOTEWORTHY This is the first prospective study on the longitudinal alveolar fibroproliferative response in COVID-19 ARDS and its relationship with mortality and long-term follow-up. We used the largest cohort of COVID-19 ARDS patients who had consecutive bronchoalveolar lavages and measured 17 pulmonary fibroproliferative biomarkers. We found that a higher fibroproliferative response during admission was associated with increased mortality, but not correlated with long-term fibrotic lung sequelae in survivors.

Original languageEnglish
Pages (from-to)L7-L18
JournalAmerican journal of physiology. Lung cellular and molecular physiology
Issue number1
Publication statusPublished - 1 Jan 2024

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