Chest
Volume 161, Issue 5, May 2022, Pages 1239-1249
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COPD: Original Research
Identification of Sputum Biomarkers Predictive of Pulmonary Exacerbations in COPD

https://doi.org/10.1016/j.chest.2021.10.049Get rights and content

Background

Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets.

Research Question

Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations?

Study Design and Methods

We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations.

Results

Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations.

Interpretation

Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations.

Section snippets

Patients

Patients represented a subset of participants in the previously described SPIROMICS cohort8 that included groups of healthy nonsmoking patients and patients with at least a 20-pack-year smoking history. Smokers included those with preserved spirometry as well as those with COPD grouped using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (GOLD stages 1-3).9 Target sample size of 980 patients was chosen to include all patients whose sputum mucin concentrations were

Results

We analyzed cell-free sputum supernatants from 980 patients (Table 1), including samples from 77 healthy nonsmokers, 341 ever smokers with preserved spirometry, and 562 patients with COPD (178 with GOLD stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease). From the biomarker panel, we found that six metabolites were altered significantly in patients with COPD relative to healthy nonsmokers at a false discovery rate of 0.10: the mucin marker sialic acid, the

Discussion

We identified sputum biomarkers that were elevated in the airways of patients with COPD and showed significant relationships to established measures of COPD disease severity, including airway neutrophilic inflammation, GOLD status, bronchitis, and pulmonary exacerbations. The identities of these and related metabolites implicate several physiologic pathways in COPD pathogenesis, including mucus hydration, adenosine metabolism, and methionine salvage. These pathways can serve as both biomarkers

Interpretation

We identified several physiologic pathways altered in the airways of patients with COPD and associated with markers of disease severity, with the strongest relationships to metabolite biomarkers of mucus hydration and adenosine metabolism. These findings confirm previously demonstrated associations in COPD and identify new pathways. Although further validation is required, measurement of these sputum metabolites could provide a straightforward means to assess disease severity, to identify those

Acknowledgments

Author contributions: C. R. E. is responsible for the content of this manuscript. C. R. E. obtained funding, performed the analyses, wrote the manuscript, and is the guarantor of the manuscript. W. K. O., M. K., W. H. A., A. C., and R. C. B. assisted with data analysis and edited the manuscript. C. M. D., A. T. H., R. G. B., R. P. B., J. M. W., E. C. O., A. P. C., Y. T., V. K., L. M. P., C. B. C., M. K. H., Y. J. H., W. W. L., and J. L. C. contributed to SPIROMICS and edited the manuscript.

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    FUNDING/SUPPORT: This work was supported by SPIROMICS, which was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health [Grants HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, U01 HL137880, and U24 HL141762]. C. R. E. was supported by the National Institutes of Health [Grants R01-HL136961-01S1 and P30-ES10126]. R. C. B. was supported by the National Institutes of Health [Grants UH3-HL123645, P01-HL108808, P30-DK065988, P01-HL110873, P50-HL107168, and R01-HL136961].

    Collaborators from the Subpopulations and Intermediate Outcome Measures in COPD Study are listed in the Acknowledgments.

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