tetano
Editor, Senior Moderator
JCI Insight
. 2026 Jul 8;11(13):e199983.
doi: 10.1172/jci.insight.199983.
Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16
Matthew R Baldwin[SUP] 1 2 [/SUP], Ansley E Jones[SUP] 1 [/SUP], David Zhang[SUP] 1 [/SUP], Chandan Gurung[SUP] 1 [/SUP], Zain Khan[SUP] 3 [/SUP], Anjali Saqi[SUP] 4 [/SUP], Xuehan Yang[SUP] 3 [/SUP], Ying Wei[SUP] 3 [/SUP], Renu Nandakumar[SUP] 2 [/SUP], Scarlett O Murphy[SUP] 1 [/SUP], Claire F McGroder[SUP] 1 [/SUP], Faisal Shaikh[SUP] 1 [/SUP], Selim Arcasoy[SUP] 1 [/SUP], Luke Benvenuto[SUP] 1 [/SUP], Harpreet Grewal[SUP] 1 [/SUP], Benjamin M Smith[SUP] 1 5 [/SUP], Eric A Hoffman[SUP] 6 [/SUP], Agnes Cy Yuen[SUP] 7 [/SUP], Parteek Johal[SUP] 7 [/SUP], Christopher Carlsten[SUP] 7 [/SUP], Christopher J Ryerson[SUP] 7 [/SUP], J Brent Richards[SUP] 8 9 [/SUP], Alyson W Wong[SUP] 7 [/SUP], Tomoko Nakanishi[SUP] 10 11 12 13 [/SUP], Aditi S Shah[SUP] 7 [/SUP], Christine Kim Garcia[SUP] 1 14 [/SUP]
Affiliations
BACKGROUNDThere are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post-COVID-19 pulmonary fibrosis.METHODSWe tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTSAmong 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATIONNot applicable.FUNDINGDepartment of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.
Keywords: Biomarkers; COVID-19; Fibrosis; Infectious disease; Pulmonology.
. 2026 Jul 8;11(13):e199983.
doi: 10.1172/jci.insight.199983.
Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16
Matthew R Baldwin[SUP] 1 2 [/SUP], Ansley E Jones[SUP] 1 [/SUP], David Zhang[SUP] 1 [/SUP], Chandan Gurung[SUP] 1 [/SUP], Zain Khan[SUP] 3 [/SUP], Anjali Saqi[SUP] 4 [/SUP], Xuehan Yang[SUP] 3 [/SUP], Ying Wei[SUP] 3 [/SUP], Renu Nandakumar[SUP] 2 [/SUP], Scarlett O Murphy[SUP] 1 [/SUP], Claire F McGroder[SUP] 1 [/SUP], Faisal Shaikh[SUP] 1 [/SUP], Selim Arcasoy[SUP] 1 [/SUP], Luke Benvenuto[SUP] 1 [/SUP], Harpreet Grewal[SUP] 1 [/SUP], Benjamin M Smith[SUP] 1 5 [/SUP], Eric A Hoffman[SUP] 6 [/SUP], Agnes Cy Yuen[SUP] 7 [/SUP], Parteek Johal[SUP] 7 [/SUP], Christopher Carlsten[SUP] 7 [/SUP], Christopher J Ryerson[SUP] 7 [/SUP], J Brent Richards[SUP] 8 9 [/SUP], Alyson W Wong[SUP] 7 [/SUP], Tomoko Nakanishi[SUP] 10 11 12 13 [/SUP], Aditi S Shah[SUP] 7 [/SUP], Christine Kim Garcia[SUP] 1 14 [/SUP]
Affiliations
- PMID: 42417165
- DOI: 10.1172/jci.insight.199983
BACKGROUNDThere are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post-COVID-19 pulmonary fibrosis.METHODSWe tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTSAmong 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATIONNot applicable.FUNDINGDepartment of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.
Keywords: Biomarkers; COVID-19; Fibrosis; Infectious disease; Pulmonology.