Elevated club cell protein linked to persistent fibrosis-like lung changes years after COVID-19

A multicohort biomarker study suggests circulating club cell secretory protein-16 may help flag COVID-19 survivors with fibrosis-like changes on chest imaging.

Higher circulating levels of club cell secretory protein-16 (CC16) were associated with fibrosis-like abnormalities on thoracic computed tomography (CT) for up to 3 years after hospitalization for COVID-19, according to a multicohort biomarker study published in JCI Insight.

Persistent radiographic lung abnormalities after severe COVID-19 remain a concern for clinicians running post-COVID and interstitial lung disease (ILD) follow-up clinics, but no serum biomarker has previously been validated to help identify which survivors are more likely to show fibrosis-like changes over time. This study set out to test whether a panel of circulating biomarkers, including CC16, tracked with CT-defined fibrosis-like abnormalities across a multi-year follow-up period, and to explore a possible underlying mechanism.

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Why does this matter?

A proportion of patients hospitalized with severe COVID-19 go on to show persistent reticulation, traction bronchiectasis, or honeycombing on CT, patterns that overlap with those seen in other fibrotic lung diseases.² Respiratory physicians running post-COVID or ILD clinics currently rely on serial imaging and lung function testing to track these patients, with no blood-based tool to support risk stratification or prioritize specialist review. A validated biomarker could, in principle, help direct follow-up resources toward higher-risk survivors. The authors also propose that CC16, secreted by club cells lining the small airways, may reflect small-airway epithelial remodeling relevant to fibrosis development.⁴ However, this study was observational and mechanistic in design, and did not directly test whether this remodeling process causes fibrosis-like changes.

What did the study investigate?

The discovery cohort comprised 150 adults hospitalized with severe-to-critical COVID-19 at Columbia University (New York, NY, USA), who underwent serial thoracic CT and serum sampling at hospital discharge and again at 4 months, 15 months, and 3 years. CT scans were assessed for fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing), and a CT-derived airway-to-lung ratio was calculated to test for a dose-response relationship. Investigators tested associations between candidate serum biomarkers and these radiographic findings in both cross-sectional and longitudinal analyses, then sought external validation in 2 independent cohorts of moderate-to-critical COVID-19 survivors in Canada, at the University of British Columbia (Vancouver, BC, Canada) and McGill University (Montreal, QC, Canada) (n=56 and n=37, respectively). To probe a possible mechanism, the team performed single-cell RNA sequencing (scRNA-seq) on transbronchial lung biopsies taken from survivors 3 years after hospitalization, and immunofluorescence staining on explanted lung tissue from patients with COVID-19-related lung disease.

What do the data show?

Among the biomarkers tested in the 150-participant discovery cohort, only higher CC16, encoded by the SCGB1A1 gene, was consistently associated with CT fibrosis-like abnormalities at every time point measured (discharge, 4 months, 15 months, and 3 years), in both cross-sectional and longitudinal analyses. This association was replicated in both external validation cohorts. CC16 levels also showed a linear, dose-response relationship with the CT-derived airway-to-lung ratio. In the mechanistic sub-study, scRNA-seq of lung biopsies obtained 3 years after hospitalization showed a greater proportion of epithelial cells expressing SCGB1A1, and cells co-expressing SCGB1A1 and MUC5B, in survivors with fibrosis-like changes. Immunofluorescence of explanted lung tissue localized this epithelial expansion specifically to small airways under 100 micrometers in diameter, with 3-fold more CC16/MUC5B co-expressing cells identified in respiratory bronchioles compared with larger, more proximal airways.

Why is this relevant for respiratory physicians?

The findings raise the possibility that a blood-based test could, in future, complement imaging in identifying COVID-19 survivors at higher likelihood of fibrosis-like lung changes, potentially supporting triage toward specialist ILD or post-COVID follow-up.³ The parallel mechanistic data add a biologically plausible explanation, pointing to dysregulated small-airway epithelial remodeling, but this remains a research finding rather than a clinical tool. CC16 has not been validated against clinical outcomes such as lung function decline or symptom burden, and it is not ready to inform referral or treatment decisions outside a research setting.

Limitations

This was an observational, association-based study; it cannot establish that elevated CC16 causes fibrosis-like remodeling rather than simply reflecting ongoing airway injury or repair. The discovery cohort was drawn from a single center, and both validation cohorts were modest in size (n=56 and n=37), which limits precision, particularly for subgroup comparisons that were not reported in this paper. All participants had moderate-to-critical COVID-19 requiring hospitalization, so findings may not generalize to the much larger population of patients with mild or non-hospitalized infection. The primary outcome, CT fibrosis-like abnormality, is a radiographic surrogate rather than a clinical endpoint such as lung function decline, breathlessness, or mortality. The mechanistic scRNA-seq and immunofluorescence analyses involved small numbers of biopsy and explant samples, and the explant findings come from patients with more advanced lung disease, which may not reflect the broader survivor population. Follow-up to 3 years also carries a risk of attrition bias in a longitudinal cohort of this size.

Clinical takeaway

In this multicohort biomarker study, higher circulating CC16 was consistently associated with CT fibrosis-like abnormalities for up to 3 years after COVID-19 hospitalization, with mechanistic data pointing to small-airway epithelial remodeling as a plausible contributing process. The findings are hypothesis-generating rather than practice-changing: CC16 is not a validated clinical test, and prospective studies in broader, less severely affected populations, incorporating lung function and symptom outcomes, are needed before a biomarker-based approach could inform post-COVID follow-up pathways.

References

1. Baldwin MR, Jones AE, Zhang D, et al. Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16. JCI Insight. 2026;11. doi:10.1172/jci.insight.199983
2. George PM, Barratt SL, Condliffe R, et al. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax. 2020;75(11):1009–16.
3. Salvi S, Ghorpade D, Dhoori S, et al. Role of antifibrotic drugs in the management of post-COVID-19 interstitial lung disease: a review of literature and report from an expert working group. Lung India. 2022;39:177–86.
4. Almuntashiri S, Zhu Y, Han Y, Wang X, Somanath PR, Zhang D. Club cell secreted protein CC16: potential applications in prognosis and therapy for pulmonary diseases. J Clin Med. 2020;9:4039.