1. Total airway mucin concentration was significantly elevated in current or former smokers with chronic bronchitis compared to non-smoker controls, and correlated with disease severity.
2. Concentrations of mucin subtypes MUC5AC and MUC5B were elevated relative to non-smoker controls, with a significantly higher MUC5AC-to-MUC5B ratio in smokers with mild-to-moderate COPD.
Evidence Rating Level: 2 (Good)
Study Rundown: Chronic bronchitis is a disease process hypothesized to occur secondary to mucus accumulation and poor mucus clearance in the airways. Mucin produced in the airways may be correlated with severity of chronic bronchitis, and a correlation is found may be a target for therapeutic research. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) is a large, multicenter study designed to further the understanding of COPD, determine biomarkers for future therapy and clinical trials, and divide COPD into homogeneous subgroups. In this study, the authors examined the utility of measuring total mucin concentration and the concentrations of MUC5B and MUC5AC mucin constituents as specific biomarkers for the chronic bronchitis phenotype. The results demonstrated a significant association between total mucin concentration and a questionnaire-diagnosis of chronic bronchitis. Receiver-operating-characteristic (ROC) curve analyses reported good sensitivity and specificity for total mucin concentration as a biomarker for chronic bronchitis. Additionally, the chronic bronchitis phenotype was associated with a specific ratio of the MUC5B and MUC5AC mucin constituents. These findings support total mucin concentration as a possible biomarker for the diagnosis and management of chronic bronchitis.
This was a multicenter, observational, cross-sectional study that aids prospective studies of biomarker, phenotypic, and clinical data in COPD. The data helps guide future therapy potentially aimed at reducing mucin production, provides clinical endpoints for future trials, and informs the pathogenesis of chronic bronchitis. The main limitation was the observational study design.
In-Depth [cross-sectional study]: SPIROMICS enrolled 2981 individuals with COPD in four groups: non-smoker controls, smokers without airflow obstruction, smokers with mild-moderate airflow obstruction, and smokers with severe airway obstruction. Current and former smokers had a greater than 20 pack-year history. Chronic bronchitis was diagnosed by questionnaire, either via the classical definition or the St. George’s Respiratory Questionnaire [SGRQ]). Emphysema was diagnosed based on computed tomography findings. Total mucin concentration was measured with chromatography after hypertonic saline sputum induction in 917 patients. The concentrations of MUC5B and MUC5AC were measured with mass spectroscopy in a subgroup of 148 patients. Total mucin concentration and questionnaire data were also analyzed in an independent cohort of 94 patients.
The mean total mucin concentration was significantly higher in all current or former smokers with reported phlegm production than non-smokers (3166±402 vs. 1515±152 mcg/mL). Sensitivity analyses also correlated total mucin concentration with COPD severity. All findings remained significant after adjustment for smoking status, asthma status, and frequency of respiratory exacerbations. Total mucin concentrations were higher in patients who experienced exacerbations (2 or more exacerbations/year, 4194±878 mcg/mL; 0-2 exacerbations/year, 2848±171 mcg/mL; 0 exacerbations, 2458±113 mcg/mL). Both MUC5B and MUC5AC were elevated in smokers versus non-smokers (296±65 vs 108±20 for MUC5B; 108±31 vs 10±4 for MUC5AC), and MUC5AC concentrations were disproportionately elevated in smokers with mild-to-moderate COPD (ratio of MUC5AC to MUC5B of 0.5±0.1 vs. 0.1±0.04 in non-smokers). Finally, the area under the ROC curve (AUC) for total mucin concentration versus a diagnosis of chronic bronchitis was 0.72 (95% confidence interval [CI], 0.65 to 0.79) in the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) in the independent cohort.
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