Elevated CC16 Linked to Persistent Lung Fibrosis After Severe COVID-19

Adults hospitalized with severe or critical COVID-19 who go on to develop fibrosis-like lung damage have consistently higher levels of a circulating airway protein called club cell secretory protein-16 (CC16) for up to 3 years after discharge, according to a study published in JCI Insight.¹

Researchers from Columbia University, with validation cohorts from the University of British Columbia (UBC) and McGill University, tested 18 candidate biomarkers. In their finding, the CC16 secretory protein-16 (CC16; encoded by the SCGB1A1 gene) was the only biomarker with consistent, significant associations with fibrotic abnormalities on chest CT across all 3 cohorts.

The finding lands as health systems continue to grapple with the downstream costs of long COVID. Pulmonary fibrosis of any cause is already a high-cost condition for payers. Prior evidence from a real-world claims analysis of commercially insured and Medicare Advantage populations found that patients with idiopathic pulmonary fibrosis (IPF) had an adjusted all-cause cost ratio of 3.4 compared with matched comparators and were 2.1 times more likely to be hospitalized for any cause.² CT-confirmed fibrotic patterns showed up in more than half of severe COVID-19 survivors in this study. The low-cost blood test was capable of flagging which patients were trending toward that trajectory, potentially advising care management teams of a much earlier signal than imaging alone, thus alerting clinicians well before patients’ symptoms or a formal diagnosis prompts a specialist referral.

Study Design and Patient Population

The Columbia discovery cohort enrolled 150 adults hospitalized with severe or critical COVID-19 between March and May 2020. Sampling was weighted so that roughly half required invasive mechanical ventilation. Participants returned for chest CT and blood draws at hospital discharge, 4 months, 15 months, and 3 years. The findings were externally validated in a 56-patient UBC cohort followed to 3 months and a 37-patient nested case-control cohort from McGill.¹

Biomarkers were measured in duplicate using Luminex multiplex bead-based assays across cytokine, cardiovascular, angiogenesis, and fibrosis panels. Researchers used generalized additive models and covariate-balanced propensity scores to adjust for age, sex, race/ethnicity, body mass index (BMI), smoking history, corticosteroid and interleukin-6 receptor inhibitor use, and ventilator days.

The 3 cohorts were demographically distinct. The Columbia cohort was 56% male with a mean age of 56 years, 67% Hispanic, 37% White, and 23% Black. The mean BMI was 33, and 46% of patients required mechanical ventilation during a median 18-day hospital stay.

The UBC cohort (mean age, 61 years; 59% male) and McGill cohort (mean age, 65 years; 41% male) were predominantly White or Asian and had markedly less severe acute illness, with mechanical ventilation rates of 21% and 5.4%, respectively, and shorter median hospital stays of 8.5 and 7 days.

Asthma was more common in the Columbia cohort (20%) than in the UBC cohort (3.6%) or the McGill cohort (5.4%), while chronic obstructive pulmonary disease affected 4.7%, 3.6%, and 2.7%, respectively.

CC16 Levels Track With Fibrosis Risk Across 3 Cohorts

Fibrosis-like abnormalities—reticulations, traction bronchiectasis, or honeycombing—were present in 57% to 64% of the Columbia and UBC cohorts and in 43% of the McGill case-control cohort.

In the Columbia cohort, the adjusted odds of fibrosis-like abnormalities per natural log-fold increase in CC16 ranged from 5.0 (95% CI, 1.6-20.7) to 16.0 (95% CI, 4.1-111) across 9 cross-sectional and longitudinal analyses, and adjusted odds ratios increased 2- to 7-fold across CC16 tertiles (all P for trend <.02).

The UBC cohort showed a significant association at 3 months (adjusted OR, 2.92; 95% CI, 1.07-9.07). The McGill cohort trended in the same direction (adjusted OR, 2.36; 95% CI, 0.93-7.03) despite its smaller sample.

CC16 also rose linearly with a larger airway-to-lung ratio measured on 15-month CT. The dose-response pattern, the authors said, supports a mechanistic link rather than a coincidental association, and higher CC16 correlated with lower diffusion capacity for carbon monoxide at 4 months and 3 years in the Columbia cohort.

Small-Airway Cells Show the Molecular Fingerprint of Fibrosis

To explain where the excess CC16 originated, the researchers sequenced single cells from transbronchial lung biopsies taken 3 to 4 years post COVID-19. They then ran immunofluorescence staining on 7 explanted lungs from transplant recipients compared against 11 nondiseased control lung samples.

Both analyses pointed to the small airways: COVID-19 survivors with fibrosis had expanded populations of SCGB1A1-expressing epithelial cells. The explant tissue showed more than a 3-fold increase in cells co-expressing CC16 and the mucin protein, encoding MUC5B, in airways under 100 μm in diameter, concentrated in areas of peribronchial metaplasia.

Mean CC16 levels in the Columbia cohort at 4 and 15 months (44,800 and 52,800 pg/mL, respectively) exceeded those previously reported in a cohort of patients with IPF (31,200 pg/mL), narrowing to a similar range by 3 years. None of the COVID-19 cases carried the MUC5B promoter risk allele linked to IPF, suggesting the mucin overexpression was acquired rather than inherited.

“CC16 is a postacute circulating biomarker of COVID-19–related epithelial injury,” the study authors concluded, noting that its persistent elevation reflects deranged proliferation of airway progenitor cells rather than transient inflammation.

Limitations and What This Means for Managed Care

The authors acknowledged that their cohorts were modest in size, ranging from 37 to 150 participants, and differed in demographics, comorbidities, and mechanical ventilation rates, limiting statistical power to detect associations in the smallest validation group.

They also noted that oversampling of mechanical ventilation survivors in the discovery cohort may have inflated the observed effect sizes relative to a broader COVID-19 survivor population. Additionally, several other epithelial biomarkers linked to IPF, including MMP-7 and KL-6, were not tested.

Before CC16 testing could inform coverage or care management decisions, larger, population-based cohorts would need to confirm its prognostic value across vaccination status and viral variants not captured in this wild-type- and Delta-era cohort.

For payers already absorbing the cost of fibrotic lung disease, a validated early biomarker could eventually help target pulmonary follow-up and specialty referrals to the survivors most likely to need them.

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(13):e199983. doi:10.1172/jci.insight.199983

2. Yang J, Fee R, Steffens A, Le L, Bui BH, Borah BJ. Real-world health care resource utilization and economic burden among patients with idiopathic pulmonary fibrosis in commercially insured and Medicare Advantage populations in the United States. JHEOR. 2026;13(1):200-209. doi:10.36469/001c.161503