Silent Airway Mucus Plugs in COPD and Clinical Implications

Abstract

Background

Airway mucus plugs are frequently identified on CT scans of patients with COPD with a smoking history without mucus-related symptoms (ie, cough, phlegm [silent mucus plugs]).

Research Question

In patients with COPD, what are the risk and protective factors associated with silent airway mucus plugs? Are silent mucus plugs associated with functional, structural, and clinical measures of disease?

Study Design and Methods

We identified mucus plugs on chest CT scans of participants with COPD from the COPDGene study. The mucus plug score was defined as the number of pulmonary segments with mucus plugs, ranging from 0 to 18, and categorized into three groups (0, 1-2, and ≥ 3). We determined risk and protective factors for silent mucus plugs and the associations of silent mucus plugs with measures of disease severity using multivariable linear and logistic regression models.

Results

Of 4,363 participants with COPD, 1,739 had no cough or phlegm. Among the 1,739 participants, 627 (36%) had airway mucus plugs identified on CT scan. Risk factors of silent mucus plugs (compared with symptomatic mucus plugs) were older age (OR, 1.02), female sex (OR, 1.40), and Black race (OR, 1.93) (all P values < .01). Among those without cough or phlegm, silent mucus plugs (vs absence of mucus plugs) were associated with worse 6-min walk distance, worse resting arterial oxygen saturation, worse FEV₁ % predicted, greater emphysema, thicker airway walls, and higher odds of severe exacerbation in the past year in adjusted models.

Interpretation

Mucus plugs are common in patients with COPD without mucus-related symptoms. Silent mucus plugs are associated with worse functional, structural, and clinical measures of disease. CT scan-identified mucus plugs can complement the evaluation of patients with COPD.

Graphical Abstract

Take-home Points.

Study Question: Are silent mucus plugs (mucus plugs identified on CT scans in people without cough or phlegm symptoms) clinically significant, and who is more likely to have silent mucus plugs?

Results: Older age, female sex, and Black race are risk factors for silent mucus plugs, and silent mucus plugs are associated with worse functional, structural, and clinical measures of COPD.

Interpretation: CT assessment of mucus plugs can complement the evaluation of patients with COPD who do not have cough and phlegm symptoms.

Mucus plugs are a manifestation of airway pathology, and up to 67% of patients with COPD have airway mucus plugs identified on chest CT scans.^1,2 The presence of mucus plugs on CT scan is associated with airflow limitation, worse quality of life, and higher all-cause mortality.1, 2, 3

Although it may be intuitive to assume that mucus plugs coincide with chronic bronchitis (also known as chronic mucus hypersecretion), chronic cough and sputum production are frequently absent in individuals with mucus plugs.^4,5 Studies have found that about 30% of people with active tobacco use and people who previously smoked who report no cough or phlegm have airway mucus plugs on CT scan.^1,2,6 However, the clinical implications of radiographically identified mucus plugs in the absence of cough and phlegm (hereafter termed silent mucus plugs) in patients with COPD have not been systematically studied.

In this study, we aimed to identify which participants are more likely to have silent mucus plugs as opposed to symptomatic mucus plugs, and to determine the clinical significance of silent mucus plugs (ie, associations with outcomes). We used the COPDGene study,⁷ a well-characterized cohort of people with active tobacco use and people who previously smoked with the full spectrum of COPD severity with CT scan-based assessment of mucus plugs. We hypothesized that there may be differences in participant characteristics between those with silent mucus plugs and those with symptomatic mucus plugs, and that certain participant characteristics (eg, age, sex, race, history of asthma) may be associated with silent mucus plugs. We also hypothesized that for participants without cough or phlegm, a higher burden of mucus plugs would be associated with clinical, functional, and structural measures of disease.

Study Design and Methods

Study Design and Population

We performed cross-sectional analyses of selected participants of the COPDGene study. The study design and protocols of the COPDGene study have been described previously and can be accessed at www.COPDGene.org (clinical trial identifier No. NCT00608764).⁷ Briefly, the COPDGene study is an observational prospective cohort study which included 45- to 80-year-old non-Hispanic White or non-Hispanic Black patients with a ≥ 10 pack-year smoking history with or without COPD. Participants were enrolled between 2008 and 2011 (phase 1) and completed questionnaires, pulmonary function tests, and chest CT imaging. The institutional review board at each participating clinical center approved the COPDGene study, and all participants gave written informed consent. All 4,363 participants who had a diagnosis of COPD at the baseline visit, defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 (mild) through 4 (very severe), and whose CT imaging quality was adequate to assess mucus plugs were included in this study (Fig 1).

Figure 1.

Inclusion flowchart. GOLD = Global Initiative for Chronic Obstructive Lung Disease.

CT Assessment

The COPDGene imaging protocols and CT assessment of mucus plugging have been described previously.^1,7 Briefly, baseline CT scans were assessed for mucus plugs by readers who had at least 2 years of experience in lung imaging and airway mucus plug assessment. Each CT scan was assessed for airway mucus plugs by a first reader. Then all CT scans positive for mucus plugs and 20% of the negative scans were independently scored by a second reader. When mucus plug scores were discrepant between the two readers, the images were assessed by a third reader. Middle-to-large airways (ie, 2- to 10-mm lumen diameter) were surveyed. A mucus plug was defined as an opacity that completely occluded the lumen of an airway. Lung parenchyma within 2 cm from the costal or diaphragmatic pleura was excluded because the airways in those regions are too small to accurately ascertain occlusive luminal plugs. A final mucus plug score for each study participant was assigned based on the number of pulmonary segments with mucus plugs according to the Netter bronchial anatomy nomenclature. The mucus plug score ranged from 0 (no mucus plugs evident on CT scan) to 18 (mucus plugs in all pulmonary segments). Participants were categorized into three groups based on their mucus plug scores: 0, 1 to 2, and ≥ 3 pulmonary segments with mucus plugs, as previously described. The grouping was based on the distribution of mucus plugs in participants with COPD,³ showing a similar percentage falling into the 1 to 2 and ≥ 3 categories. Further analysis demonstrated an association between 1 to 2 and ≥ 3 categories and all-cause mortality,³ supporting its use for the current analysis.

The quantitative assessment of airway wall thickness was performed with Thirona software. Airway wall thickness was defined as the square root of the wall area of an ideal 10-mm inner-perimeter airway.⁸ We also used parametric response modeling estimates of emphysema and functional small airways disease.^9,10 Emphysema was defined as low attenuation areas < −950 Hounsfield units (HU) on inspiration and < −856 HU on expiration, and small airway disease was defined as low attenuation areas < −856 HU on expiration but > −950 HU on inspiration.^7,10,11 Parametric response modeling measures of emphysema and functional small airway disease represent the percentage of inspiratory-expiratory matched voxels meeting criteria for those features. Higher values indicate higher burden of emphysema and functional small airways disease.¹¹ Participants were considered to have emphysema when the affected lung volume was > 5%.⁹

Clinical Assessment

Participants of the COPDGene study completed standardized questionnaires pertaining to their demographic (age, sex, race, BMI) and clinical information (smoking history, comorbidities, respiratory symptoms).^7,12 Typically, participants completed questionnaires and chest CT scans on the same day. Race was self-reported by participants.

Symptom Assessment

Symptoms were assessed using the St. George’s Respiratory Questionnaire (SGRQ)^13,14 and the American Thoracic Society Division of Lung Disease (ATS-DLD) 1978 questionnaire.¹⁵ The SGRQ questions are divided into symptom, activity, and impact components. Each component score ranges from 0 to 100, with higher scores indicating worse health-related quality of life.

History of Asthma and Congestive Heart Failure

Participants were considered to have a history of asthma if they responded yes to the following question: Have you ever had asthma? They were considered to have a history of congestive heart failure if they responded yes to the following question: Have you ever been told by a physician that you have congestive heart failure?

Episodes of Exacerbation

An exacerbation was defined as a new onset of or increase in cough, phlegm, or dyspnea. Participants were also asked whether they had severe COPD exacerbations, defined as episodes requiring hospitalizations, in the past 12 months.

Pulmonary Function Tests

Spirometry was performed before the administration of inhaled bronchodilator (albuterol 180 μg) and repeated 20 to 30 min afterward. Postbronchodilator FEV₁ % predicted and postbronchodilator FEV₁/FVC ratio were calculated. The Third National Health and Nutrition Examination Survey predicted spirometry values were used as reference values for predicted FEV₁.¹⁶ COPD was defined as postbronchodilator FEV₁/FVC ratio < 0.70. GOLD grades 1 through 4 were determined based on FEV₁ % predicted values.¹⁷ Our study included participants with COPD with GOLD grades 1 through 4 (Fig 1).

6-Min Walk Test

The 6-min walk test measured the distance participants were able to walk in 6 min (6-min walk distance [6MWD]) in meters. If participants used supplemental oxygen at baseline, they were allowed to use it during the walk test.

Arterial Oxygen Saturation

Resting arterial oxygen saturation (Spo₂) was measured with pulse oximetry while participants were at rest in a seated position. If participants used supplemental oxygen at rest, oxygen was withheld, and participants breathed room air for 10 min prior to recording Spo₂. Supplemental oxygen was restarted if Spo₂ fell below 82%.

Definitions of Silent Mucus Plug and Symptomatic Mucus Plug

We defined silent mucus plugs as the presence of mucus plugs despite absence of symptoms of chronic mucus hypersecretion (ie, cough, phlegm) using the SGRQ questions. Participants were considered to have cough or phlegm if they coughed (excluding clearing of the throat) or brought up phlegm almost every day or several days a week in the past 4 weeks (SGRQ). Conversely, we defined symptomatic mucus plugs as the presence of mucus plugs on CT imaging along with participant-reported cough and phlegm. We performed the same analysis using cough and phlegm symptoms defined by the ATS-DLD questions (e-Tables 1-3). Cough and phlegm questions in the ATS-DLD 1978 questionnaire were as follows: (1) Do you usually have a cough excluding clearing of the throat?; and (2) Do you usually bring up phlegm from your chest?

Outcomes

Outcomes of interest included the 6MWD, resting Spo₂, SGRQ scores, postbronchodilator FEV₁ % predicted, postbronchodilator FEV₁/FVC ratio, structural changes on CT scan (eg, emphysema, wall thickness, small airways disease), and participant-reported severe exacerbations requiring hospitalizations in the past 12 months. These outcomes were measured during the phase 1 visit concurrently with the CT assessment.

Statistical Analysis

We compared demographics (age, sex, race), BMI, smoking status, pack-year, comorbidities (congestive heart failure or asthma), baseline GOLD stages, and lung functional measures between participants with silent mucus plugs and those with symptomatic mucus plugs. We used two-sample t tests when comparing continuous variables between participants with silent and symptomatic mucus plugs, univariable linear regression models with the mucus plug score category (0, 1-2, and ≥ 3) as an ordinal variable when comparing continuous variables between mucus plug score categories, and χ² tests when comparing categorical variables between groups. To identify risk factors of silent mucus plugs (vs symptomatic mucus plugs), we performed a multivariable logistic analysis with demographics, BMI, smoking status, pack-year, congestive heart failure, and asthma as covariates.

We then focused on participants with silent mucus plugs, by assessing the associations of score categories (0, 1-2, and ≥ 3) and outcomes, using a priori multivariable linear and logistic regression models. For multivariable regression models, we considered the no mucus plug group as the reference group. For all multivariable models, we adjusted for age, sex, race, BMI, smoking status, pack-year, congestive heart failure, and asthma.

Statistical significance was defined as P < .05. All analyses were performed using the statistical software R (version 4.2.1).¹⁸

Results

Airway Mucus Plugs and Symptoms of Cough or Phlegm

In total, 4,363 participants were assessed for airway mucus plugs on chest CT scan and symptoms of cough and phlegm. Among these, 1,739 participants (40%) did not report cough or phlegm, with 627 (35.3%) having mucus plugs (ie, silent mucus plug). The median mucus plug scores were 2 (interquartile range, 1-4) and 2.5 (interquartile range, 1-4.67) in participants with silent (n = 627) vs symptomatic mucus plugs (n = 1,151), respectively. Notably, silent mucus plugs were also frequently found in participants with mucus plug scores ≥ 3 (Fig 2).

Figure 2.

Histograms of mucus plug scores by cough or phlegm symptoms.

Upper and middle lobes were more frequently involved in people with silent mucus plugs, whereas lower lobe involvement was more common in people with symptomatic mucus plugs (e-Table 4). These differences were more pronounced in people with mucus plug scores 1 to 2 than with scores ≥ 3.

Characteristics of Individuals With Silent vs Symptomatic Mucus Plugs

We first compared the characteristics of the 1,778 participants with mucus plugs by mucus-related symptoms status (ie, silent vs symptomatic mucus plugs) (Table 1). The baseline characteristics of individuals without mucus plugs (n = 2,585) have been described previously.³ Compared with those with symptomatic mucus plugs, those with silent mucus plugs were more likely older, female, and not currently smoking with fewer pack-years. These participants also had higher FEV₁ % predicted, higher percentage of emphysema, and lower airway wall thickness on CT scans, and lower SGRQ scores in all domains. There were no significant differences in the distribution of GOLD grades, 6MWD, resting Spo₂, postbronchodilator FEV₁ in liters, and FEV₁/FVC. Results were consistent when silent mucus plugs were defined using the ATS-DLD questions (e-Table 1).

Table 1.

Characteristics of Participants With Silent vs Symptomatic Mucus Plugs

Characteristic	Silent Mucus Plugs (n = 627)	Symptomatic Mucus Plugs (n = 1,151)	P Value
Age, y	65.7 ± 8.3	63.2 ± 8.8	< .001
Female	337 (53.7)	511 (44.4)	< .001
Race			.072
Non-Hispanic White	492 (78.5)	945 (82.1)
Non-Hispanic Black	135 (21.5)	206 (17.9)
BMI, kg/m2	26.8 ± 5.9	27.1 ± 5.8	.398
Pack-years, y	51.1 ± 27.8	54.0 ± 28.3	.038
Smoking status			< .001
Previously smoked	468 (74.6)	580 (50.4)
Active tobacco use	159 (25.4)	571 (49.6)
GOLD stage			.115
1	82 (13.1)	87 (7.6)
2	214 (34.1)	423 (36.8)
3	196 (31.3)	408 (35.4)
4	135 (21.5)	233 (20.2)
Postbronchodilator FEV1, L	1.36 ± 0.69	1.39 ± 0.67	.513
Postbronchodilator FEV1/FVC	0.48 ± 0.14	0.48 ± 0.13	.97
Postbronchodilator FEV1 % predicted	50.9 ± 22.95	48.6 ± 20.36	.034
Postbronchodilator FEF25%-75%, L/sec	0.54 ± 0.41	0.55 ± 0.38	.874
6-min walk distance, m	360 ± 121	349 ± 121	.077
Resting Spo2, %	94.7 ± 3.7	94.5 ± 3.6	.218
History of congestive heart failure, %	5	4	.476
History of asthma, %	28	33	.037
SGRQ symptom score	27.54 ± 18.65	59.06 ± 20.21	< .001
SGRQ activity score	49.8 ± 29.4	62 ± 25.2	< .001
SGRQ impact score	22.5 ± 19.6	35.7 ± 21.5	< .001
SGRQ total score	31.7 ± 20.7	47.4 ± 20.6	< .001
Had COPD exacerbation requiring hospitalization in the past 12 mo, %	12	16	.017
Presence of emphysemaa, %	62	59	.187
Quantitative emphysemab on CT scan, % lung volume	15.7 ± 15.0	13.2 ± 13.3	.001
Airway wall thickness (Pi10), mm	2.68 ± 0.59	2.88 ± 0.62	< .001
Small airways disease, % lung volume	28.6 ± 12.0	29.4 ± 12.7	.224

Values are mean ± SD, No. (%), or as otherwise indicated. FEF_25%-75% = forced expiratory flow between 25% and 75% of the forced vital capacity; GOLD = Global Initiative for Chronic Obstructive Lung Disease; Pi10 = the average airway wall thickness of a hypothetical airway with an inner perimeter of 10 mm; SGRQ = St. George’s Respiratory Questionnaire; Spo₂ = arterial oxygen saturation.

^aPresence of emphysema was defined as affected lung volume > 5% on CT scan.

^bEstimates include all participants (ie, averaged including those whose lung volume affected was < 5%).

In both male and female participants, people who previously smoked were less likely to have symptoms of cough or phlegm than people with active tobacco use (Fig 3). Female participants were more likely to have silent mucus plugs than male participants regardless of smoking status. The proportion of participants without cough or phlegm was lower in the mucus plug score ≥ 3 group than in the score 1 to 2 group in all strata (sex and smoking status). Of note, the proportion of people who previously smoked (who quit smoking by the time of the study participation) was 55.5% among male participants and 58.5% in female participants. This difference did not reach statistical significance (χ² test, P = .05).

Figure 3.

Proportion of participants without symptoms by mucus plug score category stratified by sex and smoking status. The absolute number of participants without symptoms belonging to each group is shown on top of each bar (the total number in parenthesis). For example, among 463 female patients with active tobacco use with a mucus plug score of 0, 153 had no cough or phlegm.

Risk and Protective Factors of Silent Mucus Plugs

In the multivariable model (Table 2), the risk factors of silent mucus plugs (vs symptomatic mucus plugs) were older age, female sex, and Black race, whereas current smoking status and history of asthma were protective factors (ie, associated with symptomatic mucus plugs rather than silent mucus plugs). BMI, pack-years, and history of congestive heart failure were not associated with the odds of silent mucus plugs in the multivariable model. When silent mucus plugs were defined using the ATS-DLD questions, results were consistent with the same direction of effect in all covariates; however, race did not reach statistical significance (e-Table 2).

Table 2.

Risk Factors for Silent Mucus Plugs vs Symptomatic Mucus Plugs

Covariate	OR (95% CI)	P Value
Age	1.02 (1.01-1.04)	.004
Female sex (vs male)	1.4 (1.12-1.74)	.003
Black race (vs non-Hispanic White)	1.93 (1.44-2.59)	< .001
BMI	0.99 (0.97-1.01)	.45
Active tobacco use (vs previously smoked)	0.35 (0.27-0.45)	< .001
Pack-y	0.997 (0.993-1.001)	.193
History of congestive heart failure	1.18 (0.7-1.97)	.533
History of asthma	0.69 (0.54-0.88)	.003

Values from a multivariable logistic regression model are shown.

Risk Factors of Cough and Phlegm in the Absence of Mucus Plugs

We also compared the characteristics of participants without mucus plugs (n = 2,585) between those with cough and phlegm (n = 1,112) and those without those symptoms (n = 1,473) (e-Table 5). In a multivariable model, male sex, non-Hispanic White race, higher BMI, current smoking status, more pack-years, and history of asthma were significantly associated with increased odds of having cough or phlegm symptoms (e-Table 6).

Characteristics of Participants Without Cough and Phlegm by Mucus Plug Score Category

We then focused on all participants without cough and phlegm symptoms (n = 1,739) to compare their characteristics by mucus plug score (e-Table 7). Compared with participants without mucus plugs, those with a mucus plug score ≥ 3 were more likely to be older, female, to have previously used tobacco, and have lower BMI. They tend to have severe-to-very severe COPD (GOLD grades 3 and 4). These participants also had a shorter 6MWD and lower resting Spo₂. A history of asthma was more common with higher mucus plug burden. SGRQ scores (symptom, activity, impact, and total) were higher among those with higher mucus plug burden.

Associations of Silent Mucus Plugs With Measures of Disease Severity

Among asymptomatic individuals, mucus plug score categories of 1 to 2 and ≥ 3 were associated with shorter 6MWD, lower resting Spo₂ and FEV₁, more emphysema on CT imaging, thicker airway walls, higher SGRQ scores (ie, worse quality of life), and greater odds of severe exacerbations in the past 12 months compared with those with no mucus plug in adjusted models (e-Fig 1, Table 3). The effect sizes were larger in the mucus plug score category of ≥ 3 than the score category of 1 to 2 for 6MWD, SGRQ scores, FEV₁/FVC, FEV₁ % predicted, quantitative emphysema, airway wall thickness, and small airways disease. Similarly, the odds of exacerbation in the past 12 months were greater in the ≥ 3 than the 1 to 2 category. The results were consistent when we defined silent mucus plugs using the cough and phlegm questions of the ATS-DLD questionnaire (e-Table 3).

Table 3.

Associations of Silent Mucus Plugs With Measures of Lung Function, Quality of Life, and Structural Changes on Chest Imaging in Multivariable Models

Outcome	Mucus Plug Score Category (No. of Lung Segments With Mucus Plugs)
	1-2 vs 0		≥ 3 vs 0
	Mean Difference (95% CI)	P Value	Mean Difference (95% CI)	P Value
Linear regression models
6-min walk distance, m	−35.88 (−50.17 to −21.58)	< .001	−61.48 (−78.61 to −44.35)	< .001
Resting Spo2, %	−0.88 (−1.25 to −0.51)	< .001	−0.68 (−1.13 to −0.23)	.003
SGRQ total score	6.48 (4.22 to 8.75)	< .001	10.2 (7.46 to 12.93)	< .001
SGRQ impact score	5.48 (3.42 to 7.53)	< .001	9.01 (6.53 to 11.49)	< .001
SGRQ activity score	8.31 (4.94 to 11.69)	< .001	12.51 (8.43 to 16.58)	< .001
Postbronchodilator FEV1/FVC	−0.05 (−0.07 to −0.04)	< .001	−0.08 (−0.1 to −0.07)	< .001
Postbronchodilator FEV1 % predicted	−9.79 (−12.38 to −7.21)	< .001	−16.21 (−19.33 to −13.09)	< .001
Emphysema, % lung volume	4.16 (2.66 to 5.66)	< .001	5.34 (3.52 to 7.17)	< .001
Airway wall thickness (Pi10), mm	0.22 (0.15 to 0.28)	< .001	0.39 (0.31 to 0.47)	< .001
Small airways disease, % lung volume	4.16 (2.72 to 5.6)	< .001	6.53 (4.77 to 8.29)	< .001
Logistic regression models
Had COPD exacerbation requiring hospitalization in the past 12 mo	1.79 (1.14 to 2.76)	.0101	2.26 (1.38 to 3.62)	< .001

Multivariable models adjusted for age, sex, race, BMI, smoking status, pack-year, congestive heart failure, and asthma. Coefficients and P values are shown. Pi10 = the average airway wall thickness of a hypothetical airway with an inner perimeter of 10 mm; SGRQ = St. George’s Respiratory Questionnaire; Spo₂ = arterial oxygen saturation.

Discussion

Studies have shown associations between mucus plugs identified on CT scans and impaired lung function, worse quality of life, and higher all-cause mortality in patients with COPD.1, 2, 3 In this study, we analyzed data from more than 4,300 people who previously smoked and people with active tobacco use with COPD whose baseline CT scans were assessed for mucus plugs, focusing on participants without cough and phlegm symptoms. We found that older age, female sex, and Black race were risk factors of silent mucus plugs, whereas a history of asthma and active tobacco use were associated with reduced odds of silent mucus plugging. We also showed that silent mucus plugs were prevalent even in participants with a higher burden of mucus plugs and were associated with significant functional, structural, and clinical impairments. Participants with silent mucus plugs had lower exercise capacity, lower resting Spo₂, lower FEV₁, lower FEV₁/FVC, worse health-related quality of life, greater emphysema, and thicker airway walls and higher odds of having had severe exacerbations in the past 12 months than those without mucus plugs.

Chronic cough and phlegm are defining features of chronic bronchitis and are thought to be symptomatic manifestations of mucus dysfunction.^17,19 In recent years, advances in lung imaging have allowed for more detailed characterization of this airway pathology in COPD. In this study, we used volumetric CT scans to assess mucus plugs in middle-to-large sized airways and found that a large proportion of individuals with airway mucus plugs on CT scan do not have accompanying symptoms of cough and phlegm. The prevalence of silent mucus plugs observed in our study is in line with data from the Subpopulations and Intermediate Outcome Measures in COPD (SPIROMICS) cohort,² and in a prior study of patients with asthma.²⁰ More importantly, in participants with COPD without cough or phlegm, a higher burden of mucus plugs in the lungs was associated with functional and structural impairment. The associations between silent mucus plugs and function and structural impairments held after adjusting for age, sex, race, BMI, smoking status, pack-years, and history of congestive heart failure and asthma. The associations between a higher burden of mucus plugs and airflow limitation, lower exercise capacity, and greater CT measures of emphysema and airway wall thickness are consistent with prior studies using COPDGene and SPIROMICS data.^1,2 The present and prior studies further support the use of lung CT scan to characterize people with COPD, as suggested in guidelines.^17,21 Also, the findings suggest mucus plugs may be a potential therapeutic target or can serve as additional selection criteria for clinical trials; however, more studies are needed to further delineate these possibilities. Of note, using mucus plugs as a treatment target is under investigation in patients with asthma.²²

It is unclear why certain individuals with airway mucus plugs present with cough and phlegm and some do not. Notably, even among those with extensive mucus plugs (more than three lung segments with mucus plugs), nearly 30% reported no cough or phlegm. We identified several risk factors associated with silent mucus plugs, which were older age, female sex, and Black race. The sensitivity of peripheral cough receptors, which may be influenced by age, could play a role in silent mucus plugs (ie, an older person might be less sensitive to the same amount of mucus than a younger individual and cough less as a result).^5,23,24 The reasons for sex differences are unclear but could be related to differences in airway physiology or mucus characteristics that lead to a decreased ability to move mucus proximally.²⁵ These possibilities could be explored in future studies (eg, airway physiology, transcriptomic and proteomic data of sputum and epithelial cells). We also found that Black race was associated with increased odds of silent mucus plugs. It is possible that social behavioral (eg, differences in reporting cough) or environmental factors (eg, differences in exposure to ambient air pollution and green areas) play a role in racial differences in silent mucus plugs. Additionally, our findings show that people with active tobacco use are less likely to have silent mucus plugs than people who previously smoked, and more likely to have symptomatic mucus plugs. It is unclear from our results whether people with active tobacco use manifest symptoms of cough and phlegm through direct irritation of airways by compounds of cigarettes regardless of the presence of mucus plugs, or whether the characteristics of mucus plugs in people with active tobacco use are different from those of people who previously smoked. Studies have shown that expression of specific genes related to smoking status (eg, MUC5AC) may contribute to the development and progression of COPD.²⁶ Further studies are needed to explore whether proteomic, transcriptomic, or genomic pathways differ in the formation of silent vs symptomatic mucus plugs in people with active tobacco use vs people who do not smoke. Finally, we found that a history of asthma was also associated with reduced odds of silent mucus plugs. This is consistent with results from the Severe Asthma Research Program (SARP), which showed a dissociation between mucus plugs on CT scan and symptoms in people with severe asthma.²⁰

Our study found that participants with silent mucus plugs tend to have more emphysema. The ability to generate a high expiratory flow is important to expectorate mucus in the airways. Emphysema causes reduction in the expiratory airflow because of loss of elastic recoil and increased airway collapsibility.²⁷ Collapsed airways decrease or block expiratory airflow, and in turn may facilitate mucus retention in the distal airways. As a result, mucus plugs may not be moved proximally enough to cause cough (because of lack of cough receptors in the distal airways), which is compounded by inability to perceive the increased phlegm production. However, we were not able to determine the validity of this hypothesis with our limited observational data.

Although the perceived disease severity levels measured by SGRQ scores (activity and impact domains) were significantly worse among those with symptomatic mucus plugs, there were no significant differences in spirometry measures, resting Spo₂, or 6MWD between individuals with silent and symptomatic mucus plugs. Our results suggest that in individuals who present with impaired spirometry measures and functionality that are disproportionately severe despite the absence of cough and phlegm symptoms, silent airway mucus plugs should be suspected.

Interestingly, the demographic characteristics of people with silent mucus plugs are the opposite of the typically known demographics of patients with chronic bronchitis (ie, male, younger age, higher BMI, greater pack-years of smoking).¹⁷ Also, there were several notable differences in structural changes between silent and symptomatic mucus plugs. Those with silent mucus plugs had a higher percentage emphysema on CT scan. The presence and extent of silent mucus plugs were associated with more small airways disease in people without cough and phlegm. Furthermore, about one-quarter of individuals without emphysema or chronic bronchitis symptoms were found to have mucus plugs on CT scan. Taken together, these findings suggest that airway mucus plugging may be a distinct phenotype of COPD that shares features of both chronic bronchitis and emphysema, rather than a radiologic manifestation of chronic bronchitis.

Our study has several limitations. First, our study is an observational study, and causal statements cannot be made. Second, we defined symptoms of cough and phlegm based on participants’ responses to the study questionnaires. There may be inconsistency between true symptoms and responses to questionnaires because of recall bias or understanding and interpretation of the questions. For example, the differences in statistical significance of results when using ATS-DLD questions may be because the interpretation of the wording of questions differs by participants. Furthermore, our data did not contain information on the generation or the size of the airway at which mucus plugs were identified. Although mucus plugs in middle- to large-sized airways may be associated with more symptoms because cough receptors might be less or even absent in small peripheral airways,^5,23,24 we could not prove or disprove this hypothesis in our study. Finally, we defined silent vs symptomatic mucus plugs solely based on cough and phlegm, but not other symptoms (eg, shortness of breath, wheezing, chest infection), because our primary question was whether mucus plugs and chronic bronchitis were separable phenotypes of COPD. The term silent mucus plugs should not be interpreted as symptom-free mucus plugs because mucus plugs can present with a broad spectrum of symptoms other than cough and phlegm.

Interpretation

Silent mucus plugs are common in people with active tobacco use and people who previously smoked with COPD. Risk factors for silent mucus plugs were older age, female sex, and Black race. Silent mucus plugs are associated with worse quality of life, lung functional measures, and structural measures. Airway mucus plugging may be a distinct phenotype of COPD and could be an imaging biomarker.

Funding/Support

This work was supported by the NHLBI [Grants U01 HL089897, U01 HL089856]. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an industry advisory committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. A. A. D. is supported by the NIH National Heart, Lung, and Blood Institute [Grants R01-HL149861, R01-HL164824].

Financial/Nonfinancial Disclosures

The authors have reported to CHEST the following: M. H. C. reported receiving grants from Bayer. A. A. D. reported receiving personal fees from Boehringer-Ingelheim and having a patent for Methods and Compositions Relating to Airway Dysfunction pending (701586-190200USPT). N. L. T. reported that she and/or her husband are general stockholders with no controlling interest in the following: Johnson & Johnson, Kimberly-Clark Corp, Microsoft Corp, Amgen Inc, Bristol Myers Squibb, Cisco Systems Inc, Medtronic, Merck & Co Inc, Procter & Gamble, Crisper Therapeutics, Nvidia, Texas Instruments, Hewlett-Packard, United Health, Abbott Labs, Eli Lilly and Co, AbbVie Inc, and LyondellBasell Industries. Ruben S. J. Estépar reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Raúl S. J. Estépar reported being a founder and equity holder of Quantitative Imaging Solutions; receiving grants from Boehringer-Ingelheim; contracts to serve as image core from Insmed and Lung Biotechnology; and personal fees from LeukoLab and Chiesi. A. C. Y. is supported by the NIH [Grants R01HL149861, R01HL164824, U01HL089897]. None declared (S. K. M., H. P. N., S. G., J. L. O., W. R. D., P. N., S. J. K., K. J., P. P. M., M. A., M. U. A., M. Z., A. N. A., R. E., S. S., E. B., W. W., J. B. R.).