Figure 1. Associations between Total Mucin Concentrations and Phlegm Production and Disease Severity in Chronic Obstructive Pulmonary Disease (COPD).

Panel A shows a model representing the progression from normal lung to cigarette smoke–induced chronic bronchitis. In healthy persons, the balance of active ion absorption (Na⁺) versus secretion (Cl⁻), passive osmotically entrained water transport, and mucin secretion generates a mucus layer with secreted mucin concentrations that are lower than the tethered mucin and other glycoconjugate concentrations in the periciliary layer (PCL). The result is a well-hydrated PCL and efficient mucociliary clearance (MCC). In persons with cigarette smoke–induced chronic bronchitis, an imbalance of ion transport coupled with mucin hypersecretion increases the mucin concentration in the mucus layer, producing osmotic compression of the PCL, adhesion of hyperconcentrated mucus to airway surfaces, and cessation of MCC. The adherent mucus may be expelled as phlegm or sputum by cough. Mucus that cannot be expelled by cough continues to accumulate, concentrates, and ultimately becomes the basis for airflow obstruction and the nidus for intermittent infection or exacerbation. CFTR denotes cystic fibrosis transmembrane regulator, and ENaC epithelial sodium channel. Panel B shows total mucin concentration in controls who had never smoked and who reported no phlegm (59 participants; 10 of 69 participants did not answer the questionnaire), current or former smokers who reported no phlegm (397 participants), and current or former smokers who reported bringing up phlegm (434 participants). Panel C shows total mucin concentrations and spirometrically defined disease severity in controls who had never smoked (69 participants) and in current or former smokers with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage of 0 (indicating an increased risk of disease; 303 participants), 1 (indicating mild COPD; 165 participants), 2 (indicating moderate COPD; 293 participants), or 3 (indicating severe COPD; 85 participants). Panel D shows total mucin concentration and the prospective annualized exacerbation rate from enrollment until the end of the study (defined as the number of days until follow-up or death). Rates were classified as zero exacerbations per year (596 participants), more than zero but fewer than two exacerbations per year (262 participants), and two or more exacerbations per year (36 participants). In Panels B through D, the P values shown but not connected by a bracket are for the comparison between the designated group and the first group shown. Other significant differences between groups are shown with a bracket. The horizontal line in the boxes represents the median, the cross represents the mean, and the bottom and top of the boxes represent the 25th and 75th percentiles, respectively. I bars represent the upper adjacent value (75th percentile plus 1.5 times the interquartile range) and the lower adjacent value (25th percentile minus 1.5 times the interquartile range), and the dots outliers. Bar plots of the data in Panels B through D are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. All P values were adjusted for multiple comparisons with the use of the Tukey–Kramer method.