Journal article
Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16
JCI insight, Vol.11(13), e199983
07/08/2026
DOI: 10.1172/jci.insight.199983
PMID: 42417165
Abstract
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.
Details
- Title: Subtitle
- Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16
- Creators
- Matthew R Baldwin - Columbia UniversityAnsley E Jones - Columbia UniversityDavid Zhang - Columbia UniversityChandan Gurung - Columbia UniversityZain Khan - Columbia UniversityAnjali Saqi - Columbia UniversityXuehan Yang - Columbia UniversityYing Wei - Columbia UniversityRenu Nandakumar - Columbia University Irving Medical CenterScarlett O Murphy - Columbia UniversityClaire F McGroder - Columbia UniversityFaisal Shaikh - Columbia UniversitySelim Arcasoy - Columbia UniversityLuke Benvenuto - Columbia UniversityHarpreet Grewal - Columbia UniversityBenjamin M Smith - Columbia UniversityEric A Hoffman - University of IowaAgnes Cy Yuen - University of British ColumbiaParteek Johal - University of British ColumbiaChristopher Carlsten - University of British ColumbiaChristopher J Ryerson - University of British ColumbiaJ Brent Richards - University of British ColumbiaAlyson W Wong - University of British ColumbiaTomoko Nakanishi - University of British ColumbiaAditi S Shah - University of British ColumbiaChristine Kim Garcia - Columbia University
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.11(13), e199983
- DOI
- 10.1172/jci.insight.199983
- PMID
- 42417165
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- US Department of Defense: W81XWH2110217, W81XWH2110216 NIH: UL1TR001873, R01HL103676, S10OD032447 Japan Society for the Promotion of Science for Young Scientists: 22KJ1190, 22J30004 JSPS KAKENHI: 23H02917
This work is the result of NIH funding, in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central.center dot US Department of Defense (W81XWH2110217 to MRB and W81XWH2110216 to CKG) .center dot NIH (UL1TR001873 to MRB, R01HL103676 and S10OD032447 to CKG) .center dot Japan Society for the Promotion of Science for Young Scientists (22KJ1190 and 22J30004 to TN) .center dot Grant-in-Aid for Scientific Research (JSPS KAKENHI grant number 23H02917 to TN) .
- Language
- English
- Date published
- 07/08/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9985180969602771
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