To the Editor:
Recent studies have revealed that increased airway mucin concentrations in chronic obstructive pulmonary disease (COPD) slow mucociliary clearance and produce mucus adhesion with mucus plug formation (1). Furthermore, data from SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) demonstrated an association between induced sputum (IS) mucin concentrations and measures of airflow obstruction, e.g., FEV1 and FEV1/FVC (2). Peripheral airways are the earliest and dominant sites of airflow obstruction in COPD, and Hogg and colleagues demonstrated that intraluminal mucus plugs contribute a major component to peripheral airway obstruction (3). For development of targeted therapies, it is important to understand whether there are associations between mucus concentrations and peripheral airway obstruction in COPD.
We hypothesized that sputum mucin concentrations would reflect small airway mucus concentrations and hence the likelihood of small airway mucus plaques/plug-mediated obstruction. This hypothesis was based on mucus transport measurements reporting peripheral-to-central mucus transport (4) and on analyses of sputum that identified mucus plugs, which, based on their small size, may be of peripheral airway origin. Accordingly, we tested for associations between sputum mucin concentrations and characteristics with complementary spirometric and computed tomography (CT) measures of peripheral airway obstruction in the SPIROMICS cohort.
A complete description of the demographics of the SPIROMICS cohorts and methods can be found in previous publications (2, 5). For studies of mucus/peripheral airway associations, 884 subjects from whom IS was collected through SPIROMICS were analyzed. For IS analyses, total mucin concentrations were measured by gel-filtration chromatography/refractometry (6). Technicians who were blinded to the spirometric/CT outcomes scored sputum samples based on plug density and watery versus mucoid properties. These technicians were also blinded as to airway structure and function measurements. Forced expiratory flow, midexpiratory phase (FEF25–75%) spirometry measurements and CT measures of peripheral airway obstruction, including measures of residual volume/total lung volume (RV/TLV) and parametric response mapping–functional small airway disease (PRM-FSAD), were obtained according to SPIROMICS protocols (5, 7). Associations were studied with ANOVA and Tukey-Kramer tests using the mucin concentration variable divided into quartiles (2). In addition, airway dimensions, stratified by airway anatomic level (8), were related to IS total mucin concentrations and mucoid characteristics.
Analyses of mucin and peripheral airway spirometric parameters revealed that FEF25–75% was inversely related to total mucin concentrations and mucus plug density (Figures 1A and 1B). Analyses of correlation between mucus properties and CT measures of peripheral airway function revealed that both increased total mucin values and mucoid sputum were also associated with increased RV/TLV (Figures 1C and 1D) and PRM-FSAD (Figures 1E and 1F) values.
Significant associations between total sputum mucin concentrations and airway wall dimensions were also observed (Table 1). Higher mucin concentrations were associated with greater relative airway wall thickness, as defined by the percent wall area relative to the total airway area. This association was evident at the more peripheral subsegmental and sub-subsegmental levels, but not in the more centrally located airways. Partitioning the measure of percent wall area into absolute wall and lumen areas revealed that higher mucin concentrations were associated with thinner walls and even narrower lumens, resulting in a higher mucin–greater percent wall area association. A 1-SD-unit higher mucin concentration was associated with a 0.34-mm2-smaller subsegmental airway lumenal area (3.6% narrower). Similar associations with subsegmental and sub-subsegmental airway dimensions were observed for mucoid versus watery mucus consistency (not shown).
|Mean (SD)||Mean Difference in Airway Dimension (β) per SD Increment of Mucin Concentration|
|β||P Value||β||P Value|
|Percent wall area|
|Lobar airways||50.3 (5.4)||0.0||0.790||0.0||0.879|
|Wall area, mm2|
|Lobar airways||69.2 (27.8)||−0.4.||0.419||−0.3||0.434|
|Lumen area, mm2|
|Lobar airways||72.4 (43)||−0.1||0.900||0.1||0.895|
SPIROMICS sputum total mucin concentrations, mucus consistency, and plug density were associated with spirometric and CT measures of peripheral airway disease. A strong association was noted in the relationship between mucin concentration and a spirometrically determined measure of peripheral airflow, i.e., FEF25–75%. Associations with total mucin concentrations and consistency were also observed with CT measures of RV/TLV and PRM-FSAD.
Of particular relevance to the relationships between airway mucins and regional airway obstruction, analyses of mucin concentrations and airway wall dimensions revealed that the relationships were strongest in the more peripheral CT-resolved airways. Although we speculate that mucus hyperconcentration produces mucus stasis and narrowed lumens, longitudinal studies will be required to test the converse notion, i.e., that narrowed lumens produce mucus hyperconcentration/stasis. Nevertheless, because reductions in airway area produce squared reductions in airflow, the 1-SD-unit higher mucin concentration/0.34-mm2-smaller airway subsegmental airway lumenal airway relationship suggests that the magnitude of mucus obstruction is pathophysiologically relevant.
Data from theoretical, in vitro, and animal model studies have established strong relationships among mucin concentrations, mucus transport rates, and, in the event of hyperconcentrated mucus, plaque/plug formation within airway lumens (1). More recently, measures of mucus adhesive interactions with airway surfaces as a function of mucus concentration have been reported, and again revealed strong mucus concentration–airways adhesion relationships (9). Analyses have been conducted that juxtapose mucus adhesive forces with the shear forces generated by peripheral airways (low flow) versus central airways (high airflow). These studies confirmed the notion that it is difficult to clear mucus adhered to small airway surfaces by cough as compared with the relative ease of disadhering and expectorating mucus from central airways (9). Thus, it appears likely that mucin concentrations in the ranges measured in these studies, coupled with minimal peripheral airway cough clearance, will produce mucus accumulation and plug formation in peripheral COPD airways.
Notably, our measurements of mucin concentrations were obtained from IS, which likely represents material expectorated from central airways. Despite mucociliary clearance studies showing peripheral-to-central mucus transport (4), we cannot unambiguously assume that the mucins/mucus plugs collected by sputum induction reflect peripheral airway materials. Mitigating this concern is the likelihood that the increased mucin concentrations measured in IS reflects a global airway disease process that produces mucus hyperconcentration both centrally and peripherally. However, direct bronchoscopic measurements of peripheral airway mucus concentrations will be required to establish the relationship between large and small airway mucus concentrations.
Quantifying and elucidating the pathogenesis of peripheral airway disease in COPD is a key requirement for future therapeutics development and patient care. Sputum mucin concentrations may prove to be a useful biomarker in smoking subjects at risk for COPD (2) and, in view of the reported relationship between small airway mucus obstruction and early death, in COPD subjects with later disease at risk of premature death (10).
SPIROMICS Investigative Group members: Prescott G. Woodruff, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco Medical Center, San Francisco, California; MeiLan K. Han, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; Eric A. Hoffman, Department of Radiology, Division of Physiologic Imaging, University of Iowa Hospitals and Clinics, Iowa City, Iowa; Fernando Martinez, Department of Medicine, Weill Cornell Medical College, New York, New York; Jeffrey L. Curtis, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, and Medical Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan; Robert Paine III, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Utah, and Veterans Affairs Medical Center, Salt Lake City, Utah; Christopher B. Cooper, Department of Medicine and Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and Eugene R. Bleecker, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
|1.||Anderson WH, Coakley RD, Button B, Henderson AG, Zeman KL, Alexis NE, et al. The relationship of mucus concentration (hydration) to mucus osmotic pressure and transport in chronic bronchitis. Am J Respir Crit Care Med 2015;192:182–190.|
|2.||Kesimer M, Ford AA, Ceppe A, Radicioni G, Cao R, Davis CW, et al. Airway mucin concentration as a marker of chronic bronchitis. N Engl J Med 2017;377:911–922.|
|3.||Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.|
|4.||Iravani J, As van A. Mucus transport in the tracheobronchial tree of normal and bronchitic rats. J Pathol 1972;106:81–93.|
|5.||Couper D, LaVange LM, Han M, Barr RG, Bleecker E, Hoffman EA, et al.; SPIROMICS Research Group. Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax 2014;69:491–494.|
|6.||Henderson AG, Ehre C, Button B, Abdullah LH, Cai LH, Leigh MW, et al. Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 2014;124:3047–3060.|
|7.||Sieren JP, Newell JD Jr, Barr RG, Bleecker ER, Burnette N, Carretta EE, et al.; SPIROMICS Research Group. SPIROMICS protocol for multicenter quantitative computed tomography to phenotype the lungs. Am J Respir Crit Care Med 2016;194:794–806.|
|8.||Smith BM, Hoffman EA, Rabinowitz D, Bleecker E, Christenson S, Couper D, et al.; The Multi-Ethnic Study of Atherosclerosis (MESA) COPD STUDY and the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Comparison of spatially matched airways reveals thinner airway walls in COPD. Thorax 2014;69:987–996.|
|9.||Button B, Goodell HP, Atieh E, Chen YC, Williams R, Shenoy S, et al. Roles of mucus adhesion and cohesion in cough clearance. Proc Natl Acad Sci U S A (In press)|
|10.||Hogg JC, Chu FS, Tan WC, Sin DD, Patel SA, Pare PD, et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med 2007;176:454–459.|
Supported primarily by NHLBI grant R01HL110906 (M.K.) under the NHLBI Ancillary Studies in Clinical Trials program and by NIH grant R01HL130506 (B.M.S.). This study used sputum samples and data collected through SPIROMICS, which was supported by NHLBI contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C. These contracts were supplemented by contributions made through the Foundation for the National Institutes of Health from AstraZeneca, Bellerophon Therapeutics, Boehringer Ingelheim Pharmaceuticals, Chiesi Farmaceutici, Forest Research Institute, GlaxoSmithKline, Grifols Therapeutics, Ikaria, Novartis Pharmaceuticals, Nycomed, Regeneron Pharmaceuticals, Sanofi, and Takeda Pharmaceutical Company.
Originally Published in Press as DOI: 10.1164/rccm.201806-1016LE on August 21, 2018