Authors: Mario Cazzola, Paola Rogliani, Josuel Ora, Luigino Calzetta, Maria Gabriella Matera
Categories: Review Article
Source: Drugs
Authors: Mario Cazzola, Paola Rogliani, Josuel Ora, Luigino Calzetta, Maria Gabriella Matera
Chronic airway diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis, are increasingly recognized as heterogeneous disorders characterized by overlapping pathophysiological mechanisms. Among these, abnormalities in mucus production, composition, and clearance have been identified as clinically significant contributors to symptoms, airflow limitation, exacerbations, and disease progression. Within the “treatable traits” framework, mucus-related abnormalities represent a distinct, modifiable phenotype that supports personalized management strategies. This narrative review explores mucus as a treatable trait across chronic airways diseases, integrating mechanistic insights with clinical assessment, biomarkers, and current and emerging therapeutic approaches. We discuss the role of mucus in disease phenotyping, its impact on morbidity, and the potential of targeted interventions to improve outcomes. Recognizing mucus as a treatable trait aligns with the principles of precision medicine and offers a pathway toward individualized therapy beyond traditional diagnostic labels.
Abnormal mucus production, composition, and clearance represent a distinct and measurable treatable trait across chronic airways diseases such as asthma, chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. Recognizing mucus as a modifiable trait shifts focus from disease labels to targeted management.Mucus burden can be objectively assessed through clinical symptoms (chronic productive cough), imaging (CT mucus plug quantification), and biomarkers (mucin profiles, sputum characteristics), allowing clinicians to identify patients in whom mucus is a dominant trait driving morbidity.Although mucus hypersecretion satisfies the defining criteria of a treatable trait across airway diseases, durable clinical benefit depends on accurate trait identification and alignment of therapy with the dominant pathophysiological mechanism sustaining mucus accumulation.
Chronic airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis (CF), represent a substantial global health burden. They are characterized by high morbidity, frequent exacerbations, and significant healthcare expenditures [1–4]. Conventionally, management of these conditions has relied on diagnostic labels. However, there is growing recognition of the heterogeneity both within and across these diseases.
The treatable traits paradigm proposes a precision medicine framework in which distinct, measurable, and clinically relevant features of disease are identified and targeted for intervention [5, 6]. Among these traits, excessive mucus production and impaired clearance have emerged as central contributors to disease progression. Mucus hypersecretion, combined with altered rheological properties and impaired mucociliary clearance (MCC), can lead to airway obstruction, mucus plug formation, infection, inflammation, and worsened clinical outcomes [7, 8].
Mucus plugs, dense accumulations of thickened mucus that can occlude airways, represent a clinically significant but often under-recognized consequence of impaired mucus dynamics (Fig. 1) [9]. Recent imaging studies indicate that mucus plugs are common, occurring in 25–67% of patients with COPD [10] and 58% of patients with asthma [11]. They are often persistent, remaining in the same bronchopulmonary segments for years [10, 11], and independently predict disease progression, exacerbations, and mortality across chronic airway diseases [10–12].Fig. 1Mucus pathobiology and plugging in chronic airway diseases
Despite its clinical importance, mucus is frequently overlooked as a distinct, treatable target in chronic airway management. This narrative review synthesizes current knowledge on mucus as a treatable trait, focusing on pathophysiology, clinical assessment, biomarkers, and therapeutic strategies across major chronic airway diseases.
This article is designed as a narrative review aimed at critically evaluating mucus as a treatable trait in chronic airway diseases. A comprehensive literature search was conducted using major biomedical databases, including PubMed, ScienceDirect, Google Scholar, Mendeley, Scopus, Web of Science, and the Cochrane Library, covering publications up to December 2025. The search strategy combined controlled vocabulary terms and free-text keywords related to the disease and interventions of interest, including but not limited “mucus,” “asthma,” “COPD,” “bronchiectasis,” “cystic fibrosis,” and “treatable tract.”
Translational studies, Phase I–IV clinical trials, meta-analyses, and high-quality real-world evidence, regulatory documents, and pertinent consensus guidelines were reviewed to contextualize clinical findings and inform expert interpretation. The reference lists of selected articles were manually reviewed to identify additional relevant publications.
Because this review is narrative in nature, formal systematic review criteria were not used to select studies, and no quantitative synthesis was performed. Instead, evidence was integrated using a critical and interpretive approach that focused on identifying mucus as a treatable feature in chronic airway diseases and its current and future treatments. The final selection of studies reflects the authors' expert judgment regarding the scientific quality, novelty, and relevance of the collected information.
In healthy airways, mucus is a viscoelastic gel composed predominantly of water (97–98%), with the remainder comprising high-molecular–weight glycoproteins, mainly the gel-forming mucins MUC5B and MUC5AC, along with salts, lipids, and cellular debris [9, 13]. MUC5B predominates in the distal airways, particularly within the superficial epithelium and submucosal glands, whereas MUC5AC is enriched in the proximal cartilaginous airways [9, 14]. These mucins are heavily glycosylated, with carbohydrates comprising 70–80% of their mass, conferring water-binding capacity and viscoelasticity to the gel [9, 15].
The mucus layer protects the epithelium by trapping inhaled pathogens and particulates. Coordinated ciliary beating (approximately 12–15 Hz at room temperature, or 8–16 Hz at body temperature) propels mucus proximally at ~ 1 mm/min, helping to maintain airway sterility [9, 13]. Mucus viscosity is tightly regulated by epithelial ion transport, balancing sodium absorption, and chloride secretion to optimize clearance. Disruption of this balance, as occurs in muco-obstructive diseases, results in hyper-concentrated mucus, impaired clearance, and increased susceptibility to infection and inflammation [9, 13].
Airway hypersecretion arises from goblet cell hyperplasia and submucosal gland hypertrophy, commonly driven by chronic inflammation, infection, or environmental insults such as cigarette smoke [13]. Cigarette smoke induces goblet cell metaplasia and hyperplasia through epithelial-immune cell interactions, notably upregulating interleukin (IL)-13 receptor α1 via aryl hydrocarbon receptor activation. This sensitizes epithelial cells to IL-13, thereby amplifying mucus production [16].
Cytokines distinctly regulate mucin gene expression. In asthma, IL-13 promotes goblet cell hyperplasia and MUC5AC expression via the IL-4 receptor α (IL-4Rα)/signal transducer and activator of transcription 6/SAM-pointed domain-containing E26 transformation-specific transcription factor pathway while suppressing forkhead box A2, a negative regulator of MUC5AC transcription [17]. During neutrophilic inflammation, IL-17 stimulates MUC5B and MUC5AC expression through an IL-6–dependent autocrine/paracrine loop and extracellular signal-regulated kinase signaling [18]. In COPD, tumor necrosis factor-alpha and cigarette smoke activate the epidermal growth factor receptor pathway, further enhancing MUC5AC expression and driving goblet cell metaplasia [19, 20].
In chronic airway diseases, airway mucus becomes hyper-concentrated, with elevated solids comprising mucins (notably MUC5AC and MUC5B), extracellular DNA from neutrophil extracellular traps, and filamentous actin. These compositional changes generate a highly viscoelastic gel that resists ciliary clearance, promoting mucus stasis, airway obstruction, increased susceptibility to infection and inflammation [9, 14, 21, 22]. The enhanced viscosity and elasticity result from the combined contributions of mucins, which provide gel structure, and DNA/actin, which increase polymer entanglement and elastic modulus [13].
The biophysical alterations of mucus directly impair MCC, a central mechanism of airway obstruction in chronic airway disease. Accumulation of adherent mucus plaques and plugs compresses the periciliary layer, slows or abolishes mucociliary transport, and creates a nidus for bacterial colonization and infection [9, 23]. This pathophysiology is consistent across multiple chronic airway diseases, but the relative contributions of mucins and inflammatory cell-derived components differ between diseases [8, 9, 13].
Mucus abnormalities are central to the pathophysiology of asthma, COPD, bronchiectasis, and CF, with distinct molecular and biophysical features in each disease (Fig. 2).Fig. 2Mucus abnormalities central to the pathophysiology of asthma, COPD, bronchiectasis, and cystic fibrosis. The figure schematically illustrates mucus pathobiology and airway plugging across major chronic airway diseases, namely asthma, COPD, bronchiectasis, and cystic fibrosis, highlighting disease-specific epithelial alterations, inflammatory processes, and mechanisms leading to mucus hypersecretion and obstruction. *COPD * chronic obstructive pulmonary disease
In asthma, multidetector CT imaging demonstrates that mucus plugs are common, especially in severe disease, and are associated with reduced forced expiratory volume in one second (FEV1) and increased risk of exacerbations [24, 25].
Type 2 (T2) inflammation, driven by IL-4, IL-5, and IL-13, induces goblet cell hyperplasia and excessive MUC5AC production [17, 26]. Eosinophil peroxidase, released by activated eosinophils, catalyzes the formation of oxidants that crosslink cysteine thiol groups in mucins, stiffening mucus gels and promoting plug formation [8]. Charcot-Leyden crystals and extracellular DNA further increase viscosity and promote plugging [21, 22].
Airway remodeling, including goblet cell hyperplasia and smooth muscle hypertrophy, is closely linked to persistent mucus plugging [27]. Patients with a high mucus plug burden typically exhibit elevated markers of T2 inflammation, including sputum eosinophilia and increased fractional exhaled nitric oxide (FeNO), reflecting upregulation of IL-4/IL-13–dependent pathways [28].
In COPD, particularly the chronic bronchitis phenotype, goblet cell hyperplasia and submucosal gland hypertrophy result in hyper-concentrated mucus enriched in MUC5AC and MUC5B, impairing MCC and predisposing to airway blockage [2, 7, 9, 29].
Neutrophilic inflammation further increases mucus viscosity via extracellular DNA and proteases, exacerbating clearance defects and increasing susceptibility to infection [2, 7]. Chronic mucus hypersecretion in COPD is associated with increased exacerbation frequency, accelerated decline in lung function, and higher mortality [7, 30].
Bronchiectasis is characterized by impaired MCC, airway remodeling, and purulent, neutrophil-rich secretions [31]. Neutrophil elastase and other proteases drive tissue damage and correlate with disease severity and exacerbation frequency [32].
Hyper-concentrated mucus, rich in MUC5B, MUC5AC, and proinflammatory mediators such as IL-1β, impairs ciliary function and promotes mucus plugging [33]. Clinically, sputum purulence serves as a marker of disease activity and is associated with higher exacerbation rates, increased hospitalizations, and greater mortality compared with mucoid sputum [33]. This self-perpetuating cycle of infection, inflammation, and mucus retention drives progressive airway injury and remodeling [31].
In CF, defective cystic fibrosis transmembrane conductance regulator (CFTR)-mediated ion transport depletes airway-surface liquid and produces hyper-concentrated mucus (from ~ 2% solids in healthy individuals to ~ 10% in CF) with increased viscoelasticity and cohesive forces, impairing MCC and promoting airway plugging [34, 35].
Chronic neutrophilic inflammation generates oxidants that increase disulfide crosslinking of MUC5B and MUC5AC, further stiffening mucus [36, 37]. Hyper-concentrated mucus accumulates both at the epithelial surface and within submucosal glands, sustaining persistent airway plugging [34, 36].
Recent nanoscale viscometry studies reveal intrinsic, presecretory mucin defects in CF, with elevated nano-viscosity in mucin granules, suggesting that abnormal mucus properties may originate before secretion and contribute to disease pathogenesis [38]. This intrinsic defect, combined with post-secretory changes, impairs MCC and promotes persistent airway plugging and infection [34, 39]. Retained mucus initiates inflammation even in the absence of infection, creating a microenvironment that sustains bacterial colonization, amplifies mucus production, and drives progressive structural lung damage, including bronchiectasis, ultimately underpinning chronic lung disease and respiratory failure in CF [34].
Effective clinical assessment of mucus in chronic airway diseases requires a multimodal approach that integrates patient-reported symptoms, imaging findings, pulmonary function testing, and molecular biomarkers. Each modality provides complementary information. Table 1 integrates recommendations from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report and recent literature, emphasizing the multimodal approach to mucus assessment in chronic airway diseases.
Table 1Clinical assessment of mucus in chronic airway diseasesSectionKey pointsSymptom evaluationChronic productive cough, sputum volume, and purulence indicate mucus accumulation in COPD and bronchiectasis [2, 40]GOLD notes purulent sputum may indicate inflammation or bacterial exacerbation [2]Patient-reported outcomes (LCQ and CQLQ) are recommended by ACCP to assess chronic cough impact [41]LCQ correlates with SGRQ, reflecting overall respiratory health [42]ImagingHRCT visualizes mucus plugging, bronchial wall thickening, airway dilatation in asthma and COPD [11, 43]CT-detected mucus plugs are common in COPD, frequently persistent over years, and often asymptomatic (“silent plugs”) [10]Mucus plug burden is quantified by segment-based scoring (0–18) and correlates with clinical outcomes [10]Higher mucus plug scores independently predict reduced FEV1, increased exacerbations, and mortality in COPD and asthma [8, 10, 43–45]GOLD recognizes plug scoring as a promising research tool [2]Pulmonary function testsSpirometry detects airflow limitation but is insensitive to early or peripheral mucus obstruction and correlates poorly with mucus plug burden [11, 48]FEF25-75, MMEF, IOS, FOT are more sensitive for small airway involvement [45–47]The R5–R20 difference is a validated marker of small airway resistance and outperforms spirometry in early disease [49, 50]Body plethysmography (RV, RV/TLC) identifies gas trapping due to mucus-related airway closure [48, 52]BiomarkersSputum analysis for MUC5AC, MUC5B, DNA, and inflammatory cells characterizes mucus composition and airway inflammation [7]MUC5AC is associated with T2/eosinophilic inflammation; MUC5B correlates with airway sensitivity and preserved lung function [53–55]Elevated DNA and neutrophil elastase reflect neutrophilic inflammation and impaired mucociliary clearance [56]EBC is under investigation as a non-invasive biomarker, though with limited reproducibility [24]Molecular phenotyping using sputum biomarkers distinguishes T2/eosinophilic from neutrophilic endotypes [56]References in square bracketsCOPD
chronic obstructive pulmonary disease, CQLQ cough-specific quality-of-life questionnaire, EBC exhaled breath condensate, FOT forced oscillation technique, FEF25-75 forced expiratory flow at 25%–75% of forced vital capacity, FEV1 forced expiratory volume in one second, HRCT high-resolution computed tomography, IOS impulse oscillometry, LCQ Leicester Cough Questionnaire, MMEF maximal mid-expiratory flow, RV residual volume, R5-R20 difference between resistance at 5 Hz and 20 Hz, SGRQ St George's Respiratory Questionnaire, TLC total lung capacity, T2 Type 2
Chronic productive cough, sputum volume, and purulence are well-established clinical indicators of mucus accumulation in chronic lung diseases such as COPD and bronchiectasis. The GOLD report notes that purulent sputum may indicate increased airway inflammation or bacterial exacerbation, albeit with limited specificity [2]. Sputum volume is particularly relevant in bronchiectasis, where daily production may exceed 30 mL, often presenting as mucoid or mucopurulent [40].
Patient-reported outcomes are essential for measuring the subjective impact of mucus burden. The American College of Chest Physicians (ACCP) recommends the use of validated health-related quality-of-life questionnaires, specifically the Leicester Cough Questionnaire (LCQ) and the Cough-Specific Quality-of-Life Questionnaire, as reliable and responsive tools for assessing chronic cough in adults and adolescents [41]. The LCQ is valid, reliable, and responsive in COPD and chronic productive cough, and correlates closely with the St George's Respiratory Questionnaire, a widely used measure of overall respiratory health and symptom burden [42].
High-resolution computed tomography (HRCT) enables direct visualization of mucus plugs, bronchial wall thickening, and airway dilatation in patients with asthma and COPD [11, 43]. Mucus plugs are quantified by scoring the number of affected bronchopulmonary segments (ranging from 0 to 18), providing an objective measure of mucus burden that correlates with clinical outcomes [10].
Computed tomography-identified mucus plugs are common in COPD patients, occurring in 25–67% of cases, and frequently persist, with 67% remaining after 1 year and 73% after 5 years [10]. Mucus plugs are often asymptomatic. Up to 36% of patients with COPD who have mucus plugs detected on CT scans do not report coughing or phlegm. Although they are asymptomatic and referred to as “silent”, these mucus plugs are associated with worse functional, structural, and clinical disease measures, including reduced FEV1, worse exercise capacity, greater emphysema, thicker airway walls, and a higher likelihood of severe exacerbation [44]. This underscores that relying solely on patient-reported mucus symptoms can lead to a significant underestimation of the clinical burden of mucus plugging.
Elevated mucus plug scores independently predict worse lung function, a higher risk of exacerbations, reduced exercise capacity, and increased mortality in COPD [10, 43, 45]. Each incremental increase in mucus plug score is associated with an increased risk of moderate-to-severe exacerbations, even after adjusting for confounding factors [43, 45]. A landmark study of 4363 COPD patients, followed for a median of 9.5 years, found that the presence of mucus plugs in 1–2 versus 0 and ≥ 3 versus 0 lung segments was associated with adjusted hazard ratios for all-cause mortality of 1.15 and 1.24, respectively [10]. Bronchial wall thickening and airway dilatation on HRCT are also associated with airflow limitation and are often found in the same areas as mucus plugs [46].
In asthma, higher mucus plug scores are associated with lower FEV1 and increased airway eosinophilia, supporting a mechanistic link between mucus obstruction and chronic airflow limitation [8]. Longitudinal studies demonstrate that mucus plugs persist in the same bronchopulmonary segments for years, and that changes in mucus plug scores correspond with changes in lung function over time [11], supporting a causal role for mucus plugs in airflow obstruction [8]. Therefore, mucus plug scores can be used as a therapeutic target for biologics that affect T2 inflammation [47].
Although systematic mucus plug scoring is not yet common practice, GOLD recognizes its potential as a research tool due to its strong correlation with clinical outcomes [2].
Lung function tests used to detect mucus-related airway obstruction include spirometry, which identifies airflow limitation through reduced FEV1 and FEV1/forced vital capacity (FVC) ratio. However, while FEV1 is the primary endpoint in most clinical trials of mucus-targeted therapies, it is insensitive to early or small airway mucus obstruction [48] and correlates poorly with mucus plug burden on imaging [11]. Spirometry may remain normal despite significant mucus plugging, particularly in peripheral airways, limiting its utility as a stand-alone measure of mucus-related disease activity. Increased airway resistance and gas trapping are more sensitive indicators of small airway involvement, which may be due to mucus-related obstruction. Mid-range flow parameters such as forced expiratory flow at 25%–75% of FVC or maximal mid-expiratory flow can reflect small airway involvement but are limited by high variability and poor reproducibility and generally do not add to clinical decision-making beyond FEV1, FVC, and FEV1/FVC [48, 49].
Impulse oscillometry (IOS) and the forced oscillation technique provide sensitive, effort-independent assessments of small airway dysfunction associated with mucus accumulation. Research has shown that the difference between resistance at 5 Hz and 20 Hz (R5-R20) is a validated marker of small airway resistance. This difference outperforms spirometry in detecting mild or early mucus-related obstruction [49, 50]. Other IOS parameters, such as R5 and AX, are also particularly sensitive to small airway disease. They correlate better with symptoms and conventional lung function parameters than spirometry, especially in early-stage disease [51]. Body plethysmography complements these methods by quantifying airway resistance and lung volumes. Elevated residual volume (RV) or an elevated RV/total lung capacity ratio indicates gas trapping due to mucus-related airway closure and is one of the earliest manifestations of small airway disease [48, 52].
Analysis of sputum for MUC5AC and MUC5B mucin concentrations, DNA, and inflammatory cells is a mechanistically relevant approach for characterizing mucus composition and airway inflammation in chronic airway diseases. Elevated sputum levels of both MUC5AC and MUC5B are consistently observed in the sputum of patients with asthma, COPD, and chronic bronchitis [7], with MUC5AC showing a stronger association with T2/eosinophilic inflammation and airway hyperresponsiveness (AHR) and MUC5B showing a stronger association with airway sensitivity and relatively preserved lung function [53–55]. Increased levels of DNA and neutrophil elastase in sputum reflect neutrophilic inflammation and impaired MCC, particularly in COPD, bronchiectasis, and CF [56].
Although these biomarkers correlate with disease severity and chronic bronchitis diagnosis [7], their use as validated clinical trial endpoints is limited due to a lack of standardization and reproducibility. Sputum collection and processing methods vary widely, affecting biomarker concentrations and comparability across studies [57]. Although mass spectrometry-based mucin quantification offers high precision and sensitivity [58], its use is currently restricted to centers with specialized capabilities. Ongoing efforts focus on standardizing protocols and establishing clinically meaningful thresholds to enable broader clinical and research utility.
Exhaled breath condensate is being explored as a non-invasive marker of mucus-associated inflammation. However, its clinical applicability is hampered by challenges related to reproducibility and standardization [24].
Molecular phenotyping using sputum biomarkers can differentiate T2/eosinophilic and neutrophilic endotypes, providing mechanistic insight into the mechanisms of mucus pathology. T2/eosinophilic inflammation is characterized by higher MUC5B levels and lower DNA content, whereas neutrophilic inflammation is marked by elevated DNA levels, higher dry weight, and altered rheology [56].
Effective management of mucus in chronic airway diseases requires a multimodal approach that includes pharmacological therapies, non-pharmacological interventions, and lifestyle modifications (Table 2). The primary goals are to reduce mucus viscosity, enhance airway hydration, and improve MCC. However, it is important to distinguish between therapeutic interventions that are predominantly directed towards the management of mucus, such as mucolytic agents, and those that are primarily aimed at addressing other physiological mechanisms, including bronchodilators and anti-inflammatory agents, where the impact of mucus is a secondary consequence. Table 2Pharmacological strategies targeting mucus properties and mucociliary clearance across chronic airway diseasesIntervention categorySpecific agentMechanism of actionEvidence by diseaseKey clinical effectsGuideline position/clinical implicationsReferencesMucolytics (thiol-based)N-acetylcysteine (NAC), Carbocisteine, ErdosteineCleavage of mucin disulfide bonds → ↓ mucus viscosity and elasticity; antioxidant and anti-inflammatory effects (agent-specific)COPD: Modest but significant reduction in exacerbations; greatest benefit in frequent exacerbators and chronic bronchitis phenotype. Erdosteine superior to NAC and carbocisteine and effective irrespective of ICS useBronchiectasis: Inconsistent and low-quality evidence; large RCTs show no significant exacerbation reductionAsthma: No RCT evidence; not recommendedCF: No meaningful clinical benefit↓ Exacerbation frequency and hospitalizations (COPD, particularly in non-ICS users); no mortality benefit; QoL improvements below MCID; no consistent benefit in bronchiectasis, asthma, or CFATS/ERS and GOLD recommend selective use in COPD (especially high-dose NAC and non-ICS users); not recommended as monotherapy in bronchiectasis, asthma, or CF[2, 59–69, 73–75]Bronchodilatorsβ-agonists↑ Airway caliber and ↑ ciliary beat frequency → indirect enhancement of MCC; effect is dose-dependent and modest in diseased airwaysAsthma, Chronic bronchitis, COPD: Acute improvements in MCC demonstrated; reduced efficacy vs healthy controlsImproved mucus transport primarily via enhanced airflow and cough efficiency rather than altered mucus rheologyUsed primarily for bronchodilation; mucus effects considered secondary and adjunctive[76, 77, 81, 82]LAMAsInhibit acetylcholine-mediated bronchoconstriction; suppress goblet cell and submucosal gland activity → ↓ mucus hypersecretionCOPD: Reduced sputum volume, mucin content, and cough symptoms; improved nasal MCC timeImproved sputum characteristics and cough; secondary mucus-modifying effectsGOLD recognizes benefit on sputum and cough as secondary outcomes[2, 78–80]Anti-inflammatory therapyInhaled corticosteroidsDownregulate MUC5AC/MUC5B expression; ↓ goblet cell hyperplasia; suppression of IL-13–driven mucus production; modulation of ion transportAsthma and COPD (stable): Reduced mucus production and improved MCCCOPD exacerbations (viral): Potential paradoxical ↑ mucus due to impaired antiviral immunityReduced mucus burden in stable disease; context-dependent adverse effects during viral exacerbationsCore therapy in asthma and selected COPD phenotypes; mucus effects are indirect and phenotype-dependent[22, 83–87]Biologics (anti–IL-4Rα, anti–IL-13, anti–IL-5Rα)Inhibition of T2 cytokine signaling → ↓ mucin gene expression, ↓ goblet cell activity, ↓ mucus plug formation and burdenSevere Imaging studies show reduced mucus plug scores and airway mucus volume; dupilumab reduces mucus plugs and improves lung function; benralizumab and mepolizumab reduce eosinophil-driven mucus accumulationSignificant reduction in mucus plug burden on imaging; improve lung function and asthma control; link eosinophil-driven and IL-4/IL-13–mediated inflammation to mucus accumulationIndicated for severe T2-high asthma; represent disease-modifying rather than symptomatic mucus therapy[88–93]MacrolidesAnti-inflammatory (↓ IL-8, TNF-α), anti-neutrophilic, antioxidant effects → ↓ mucin expression and goblet cell hyperplasiaBronchiectasis and COPD**:** Robust evidence for reduced exacerbations and sputum volume↓ Exacerbation frequency; improved QoL; slowed lung function declineRecommended in selected patients with frequent exacerbations after risk–benefit assessment[33, 94, 95]CFTR ModulatorsElexacaftor/tezacaftor/ivacaftorRestoration of CFTR-mediated ion transport → ↑ airway surface liquid hydration; normalization of mucus viscoelasticityCF with ≥1 F508del High-quality evidence for rapid and sustained MCC improvementRapid, sustained improvements in MCC, lung function, exacerbations, and mucus plugging; superior to symptomatic therapiesGold standard therapy in eligible CF patients[34, 96–99]Hydrators/Osmotic AgentsHypertonic saline (3–7%) nebulizedMannitol inhaled dry powderOsmotic water flux into airway lumen → improved mucus hydration and clearanceCF: Strong evidence for improved MCC, lung function, and fewer exacerbationsBronchiectasis: Variable and modest benefitsImproved MCC; limited effect on exacerbation frequency in bronchiectasisStandard adjunct in CF; selectively used in bronchiectasis[34, 66, 100, 101]ATS American Thoracic Society, CF cystic fibrosis, CFTR cystic fibrosis transmembrane conductance regulator, COPD chronic obstructive pulmonary disease, ERS European Respiratory Society, GOLD Global Initiative for Chronic Obstructive Lung Disease, ICS inhaled corticosteroids, IL interleukin, IL-4Rα IL-4 receptor alpha, IL-5Rα IL-5 receptor alpha, LAMAs long-acting muscarinic antagonists, MCC mucociliary clearance, QOL quality of life, RCT randomized controlled trial, T2 type 2
A 2019 Cochrane meta-analysis found a small but statistically significant increase in the likelihood of remaining free from exacerbations with mucolytics, although with high heterogeneity and diminishing effect sizes in more recent studies [59]. Improvements in quality of life did not reach the minimal clinically important difference, and there was no clear effect on mortality.
Thiol-based mucolytic agents, N-acetylcysteine (NAC), carbocisteine, and erdosteine, which act by breaking disulfide bonds in mucins, thereby lowering mucus viscosity and enhancing expectoration, modestly reduce exacerbation rates and hospitalizations in COPD, with the greatest benefit observed in patients with frequent exacerbations and a chronic bronchitis phenotype. Comparative effectiveness varies by agent. Erdosteine demonstrates superior efficacy, significantly reducing the risk of at least one exacerbation and hospitalization, and shortening exacerbation duration [60]. Notably, the effect of erdosteine is independent of concurrent inhaled corticosteroid (ICS) use [61], while NAC and carbocisteine show benefit primarily in patients not receiving ICS or in populations with low ICS use [62, 63].
The American Thoracic Society and the European Respiratory Society (ERS) recommend considering mucolytics as an additional therapy for COPD, especially in patients with frequent exacerbations and chronic bronchitis, with high-dose therapy (e.g., NAC 600 mg twice daily) appearing more effective than low-dose therapy [64]. GOLD also supports their use for selected COPD patients, particularly those not receiving ICSs, but notes heterogeneity in studied populations and dosing regimens [2]. Recent large trials, including a 2024 study of high-dose NAC 1200 mg/day in mild-to-moderate COPD, found no significant reduction in exacerbation rates, underscoring the need for careful patient selection and realistic expectations regarding treatment benefits [65].
In bronchiectasis, the evidence for carbocisteine and NAC remains inconsistent and of limited quality. A recent large randomized controlled trial (RCT) found that carbocisteine showed no significant reduction in exacerbations over 52 weeks compared to standard care [66]. Similarly, hypertonic saline showed no significant benefit in this trial. While some smaller studies suggest potential benefits [67], and a recent registry analysis suggested higher-dose NAC (1200 mg/day) may be more effective than lower doses [68], current high-quality evidence does not support routine use of oral mucolytics as a stand-alone therapy in bronchiectasis. The 2025 ERS guidelines emphasize that muco-active treatments are best delivered as part of a comprehensive airway clearance regimen and regular physical exercise [69]. This integrated approach recognizes that muco-active agents may facilitate sputum mobilization but require concurrent mechanical clearance techniques to achieve clinical benefit.
While preclinical and translational studies indicate that disrupting mucin disulfide bonds can relieve mucus plugging and AHR in animal models and ex vivo human tissue [70, 71], no RCTs have demonstrated the clinical efficacy of mucolytics in asthma patients. Studies of chronic bronchitis and COPD specifically excluded asthma patients, and these agents are not recommended for routine use in asthma management due to the absence of clinical evidence [59]. However, emerging therapies targeting mucus properties and secretion, including novel mucolytics and biologics targeting T2 inflammation, show promise in reducing mucus in severe asthmatics [72].
In CF, clinical trials and systematic reviews demonstrate that oral or nebulized thiol derivatives, including NAC and carbocisteine, do not confer significant improvements in lung function, exacerbation rates, or quality of life compared to placebo [73, 74]. While high-dose oral NAC may modulate inflammation and improve glutathione levels in CF, these effects have not translated into clinically meaningful benefits in lung function or exacerbations [73]. In the USA, dornase alfa remains the only FDA-approved mucolytic for CF, but it is contraindicated in non-CF bronchiectasis due to evidence of harm, including increased risk of exacerbations and decline in lung function [75].
Bronchodilators primarily improve mucus clearance through enhanced airway patency and ciliary function rather than directly altering mucus biophysical properties. The administration of β-adrenoceptor agonists, such as salbutamol and formoterol, has been demonstrated to increase ciliary beat frequency and can acutely enhance MCC in asthma, chronic bronchitis, and COPD, albeit modestly and less effectively in diseased airways compared with healthy controls [76, 77]. This effect is dose-dependent, requiring higher doses for mucociliary stimulation than for bronchodilation [76].
Long-acting muscarinic antagonists (LAMAs), such as tiotropium and aclidinium, reduce acetylcholine-mediated bronchoconstriction and suppress mucus hypersecretion by inhibiting goblet cell and submucosal gland activity [78, 79]. This decreases sputum volume and improves cough symptoms in patients with moderate to severe COPD. Clinical studies have shown that tiotropium can decrease sputum character scores, reduce mucin content, and improve nasal MCC time [78, 80]. GOLD notes that LAMAs may improve sputum production and cough, reflecting secondary mucus-modifying effects [2].
Overall, bronchodilators primarily enhance mucus transport by restoring airway caliber and ciliary function rather than directly altering mucus viscosity or elasticity [81]. The relationship between bronchodilator response and improved tracheobronchial clearance in chronic bronchitis appears to be mediated through enhanced airway patency and improved cough effectiveness, rather than changes in mucus rheology [82].
Anti-inflammatory therapy reduces mucus production and secretion in airway diseases indirectly by suppressing the inflammatory pathways that drive mucin gene expression, rather than acting as a direct mucolytic agent [83]. These indirect mucus-modifying effects are complementary to, rather than redundant with, those of direct mucolytics, although the incremental benefit of adding mucolytics to optimized anti-inflammatory therapy remains unclear [64]. Importantly, the effectiveness of anti-inflammatory therapy on mucus clearance varies according to disease phenotype and the specific inflammatory milieu [22].
In asthma and COPD, ICSs such as fluticasone, budesonide, and beclomethasone have been shown to downregulate the expression of secreted mucins, particularly MUC5AC and MUC5B, and reduce the number of mucus-producing goblet cells in the bronchial epithelium [84, 85]. These effects are mediated both directly, through inhibiting mucin gene transcription, and indirectly, via suppression of pro-inflammatory cytokines such as IL-13 that stimulate mucus production [85]. In addition, corticosteroids modulate ion transport pathways and support MCC, further contributing to reduced mucus retention [86]. However ICSs may paradoxically increase mucus production by impairing antiviral immunity and promoting mucin expression, particularly in the context of suppressed interferon responses [87]. This adverse effect appears most relevant during acute viral infections, but it does not negate the overall anti-mucus benefits in stable disease.
Biological therapies that inhibit T2 inflammation, such as anti–IL-4Rα and anti–IL-13 agents, have been shown to reduce mucus production in patients with severe asthma by interrupting cytokine-driven pathways [88]. Inhibition of specific downstream signaling molecules, such as MAPK13, also attenuates IL-13–induced mucus production in airway epithelial cells [89]. Beyond reducing epithelial mucus secretion, emerging clinical data indicate that these therapies can decrease mucus plug burden in vivo. This highlights a mechanistic benefit that extends beyond simple modification of mucus properties. For example, functional respiratory imaging and CT studies of patients treated with dupilumab have demonstrated reductions in airway mucus volume and plug scores, which correlate with improvements in lung function and asthma control [90, 91]. Similarly, benralizumab, an anti–IL-5Rα therapy that depletes eosinophils, has been associated with the resolution of mucus plugs on imaging, linking eosinophil-driven inflammation with mucus accumulation and airway obstruction [92, 93]. Collectively, these findings underscore the fact that biologics targeting upstream inflammatory pathways can mitigate the fundamental drivers of mucus hypersecretion and plugging, rather than merely altering mucus rheology.
Low-dose macrolide antibiotics exert both anti-inflammatory and antimicrobial properties that reduce mucus production and exacerbation frequency in patients with bronchiectasis and COPD through multiple mechanisms. Macrolides such as azithromycin and erythromycin suppress airway inflammation by downregulating proinflammatory cytokines (e.g., IL-8 and TNF-α), inhibiting neutrophil recruitment, and reducing oxidative stress. Together, these actions decrease mucin gene expression and goblet cell hyperplasia, resulting in reduced mucus production [94]. Clinical trials and meta-analyses have shown that long-term macrolide therapy significantly reduces exacerbation rates and sputum volume in bronchiectasis and COPD, with concomitant improvements in quality of life and attenuation of lung function decline [33, 95].
The CFTR modulators are the gold standard for improving MCC in CF, as they directly target the underlying defect in CFTR-mediated ion transport, thereby restoring airway surface liquid hydration and normalizing mucus properties [96]. The most effective currently approved regimen, elexacaftor/tezacaftor/ivacaftor (ETI), is indicated for patients carrying at least one F508del mutation and results in rapid and sustained improvements in MCC, lung function, and a reduction in mucus plugging [97].
Elexacaftor/tezacaftor/ivacaftor exerts its therapeutic effect through the combination of two correctors (elexacaftor, and tezacaftor), which enhance CFTR protein folding and trafficking to the cell surface, and a potentiator (ivacaftor), which increases channel gating activity. Together, these agents restore CFTR function to approximately 40%–50% of normal levels in eligible patients [98, 99]. This mechanism is fundamentally superior to symptomatic therapies, as it reverses the pathophysiology processes of airway dehydration and increased mucus viscosity, ultimately leading to improved airway clearance and clinical outcomes [34].
Both hypertonic saline and mannitol enhance airway hydration and MCC, particularly in CF and bronchiectasis. In CF patients, inhaled hypertonic saline, typically a 3%–7% solution administered by nebulizer once or twice daily, is an established adjunct therapy that improves MCC and lung function, and reduces pulmonary exacerbations [34]. Mannitol, delivered as an inhaled dry powder (400 mg twice daily), is also approved for use in adults with CF and has been shown to improve lung function over six months, although direct comparisons with other mucolytic therapies have not demonstrated clear superiority [100].
In bronchiectasis, both agents function as osmotic hydrators that facilitate mucus clearance. Hypertonic saline is widely used in clinical practice, although evidence supporting its efficacy in non-CF bronchiectasis is less robust, with studies reporting variable and often modest benefits [66]. Moderate-quality evidence suggests that inhaled mannitol prolongs the time to first exacerbation and improves health-related quality of life in patients with bronchiectasis; however, its overall effects on exacerbation frequency and lung function appear limited [101].
Physiotherapy, oscillatory devices, and active cycle breathing techniques help clear mucus from the airways of patients with chronic conditions such as bronchiectasis and CF. The ERS endorses these airway clearance techniques (ACTs) for patients with bronchiectasis who have a chronic productive cough or difficulty expectorating sputum [102]. The ACCP also recognizes oscillatory devices, such as the flutter and high-frequency chest wall oscillation, as effective at enhancing mucus clearance; however, long-term outcome data are limited [103].
RCTs and systematic reviews demonstrate that ACTs, including physiotherapy, oscillatory devices, and active cycle of breathing techniques, can increase sputum expectoration, improve symptoms, and enhance health-related quality of life [31, 104–106]. However, differences between specific techniques are generally small, and the quality of the evidence is variable. These interventions are considered safe and can be tailored to patient preference and clinical context. Cochrane reviews for populations with CF and bronchiectasis support the use of these interventions for short-term improvements in mucus clearance and symptom control, but they also highlight the need for further research on long-term outcomes.
Hydration, particularly with nebulized hypertonic saline (typically 6% or 7%), improves mucus rheology and clearance in patients with bronchiectasis and other chronic airway diseases. It enhances airway surface hydration and reduces mucus viscosity, thereby facilitating clearance [9, 31]. To minimize the risk of bronchospasm, patients should receive a bronchodilator before administration of nebulized hypertonic saline
Although the direct effect of exercise on mucus rheology remains unclear, regular physical activity and pulmonary rehabilitation can indirectly enhance airway clearance by improving ventilatory mechanics and cough efficacy [107]. Pulmonary rehabilitation is strongly recommended for patients with bronchiectasis who have impaired exercise capacity.
Smoking cessation reverses goblet cell hyperplasia, improves mucociliary function, and decreases mucus viscosity. Benefits are seen within a year of quitting. Mechanistic studies show that smoking induces airway dehydration, increases mucus viscosity, and impairs MCC; these changes are partially reversible after quitting, as evidenced by cellular and transcriptomic analyses and recommendations from GOLD [2].
Several next-generation mucolytic agents are currently under investigation for the management of chronic airway diseases.
Fexlamose, a thiol-saccharide compound that disrupts mucin disulfide crosslinks, has demonstrated superior mucolytic activity compared with NAC and dornase alfa in preclinical and ex vivo studies [108]. In CF sputum, fexlamose induced a larger decrease in elastic modulus (G'), achieved a 50% reduction in G′ more rapidly, and caused mucolysis of a larger proportion of sputum samples within 15 minutes compared to NAC and dornase alfa. In animal models, it reduced mucus plugging, airway inflammation, and mortality. Inhaled fexlamose is well-tolerated by healthy human subjects [109]. A clinical trial is currently investigating inhaled fexlamose in patients with moderate to severe COPD (ClinicalTrials.gov ID NCT06731959).
A small-molecule mucin-reducing agent, P3001, has shown greater efficacy than NAC and dornase alfa in reducing the viscoelastic properties of CF sputum ex vivo and in animal models, supporting its continued clinical development [110]. However, clinical evidence in humans is currently limited or unpublished.
Thiolated polyglycerol sulfate (dPGS-SH), a dendritic polymer bearing multiple thiol groups, has exhibited potent mucolytic effects in CF sputum. It outperformed NAC in reducing mucin multimerization and viscoelasticity while demonstrating favorable stability and low cytotoxicity in preclinical studies [111]. The compound is designed to chemically reduce abnormal disulfide crosslinks in mucins and is based on a polysulfate scaffold with reported anti-inflammatory properties [111].
Icenticaftor, a CFTR potentiator, demonstrated clinically meaningful improvements in lung function (mean FEV1 increase of 6.5%) and sweat chloride levels in CF patients with Class III and IV CFTR mutations, but showed no significant efficacy in patients homozygous for F508del mutation [112]. In a Phase IIb trial in COPD patients with chronic bronchitis, icenticaftor (300 mg twice daily) exhibited a dose-response relationship at 24 weeks for trough FEV1, cough and sputum scores, rescue medication use, and serum fibrinogen reduction, although the primary endpoint at 12 weeks was not met [113]. The drug was well-tolerated across all studies.
OligoG CF-5/20, a low molecular weight alginate oligosaccharide, specifically rich in guluronate residues (approximately 12–15), is derived from seaweed [114]. Its primary mechanism involves direct modulation of mucus structure and function via calcium chelation, resulting in detachment and normalization of abnormally adherent mucus in chronic airway diseases such as CF and COPD. OligoG binds to respiratory mucins, altering their surface charge and increasing the porosity of the mucin network, thereby reducing mucus viscosity, and enhancing clearance [115]. Human studies showed that OligoG is safe for inhalation in CF patients, effectively deposits in the lungs, and modifies the viscoelasticity of CF sputum [115]. The mechanism of action of OligoG, involving calcium chelation and mucin network modulation, differentiates it from conventional mucolytics such as NAC and dornase alfa [114, 115]. Additionally, OligoG enhances antibiotic diffusion through mucin-rich environments and possesses biofilm-disrupting properties [116]. According to clinical pipeline summaries, OligoG development for CF appears discontinued or inactive at this time, with no ongoing recruitment or active Phase II/III programs currently listed.
Bronchoscopic interventions to reduce goblet cell hyperplasia, including liquid nitrogen metered cryospray, bronchial rheoplasty, and targeted lung denervation, are under evaluation [117].
Significant barriers limit the clinical implementation of CT-based mucus scoring despite its strong prognostic value. Visual quantification is time-consuming and subject to interobserver variability. It requires specialized training and multiple readers to ensure reliability [10]. Additionally, radiation exposure from repeated CT scans raises concerns for longitudinal monitoring, particularly in younger patients [45]. The lack of standardized protocols across centers hinders comparability and clinical adoption [118]. Furthermore, questions remain about the clinical significance of asymptomatic imaging findings and the appropriate treatment thresholds for intervention [119].
Automated quantification using artificial intelligence (AI) addresses some limitations of visual CT by providing rapid, reproducible, and objective measurements. Artificial intelligence algorithms can automatically quantify the volume of mucus plugs and other airway abnormalities across entire lung fields with near-perfect reproducibility [120]. A recent validation study in 9399 current and former smokers demonstrated that AI-quantified mucus plugs showed similar associations with all-cause mortality as visual scoring, with hazard ratios of 1.18 for 1–2 mucus-obstructed bronchial segments and 1.27 for ≥ 3 obstructed segments in patients with COPD [121]. These findings corroborate previous research on visual mucus plug counting and demonstrate the clinical validity of automated methods. However, the widespread adoption of AI-based tools remains limited by several factors. These tools require specialized software, technical expertise, and validation across diverse scanner types and protocols [2, 120]. Cost, infrastructure requirements, and the need for prospective validation in clinical decision-making currently limit implementation [118]. The GOLD 2026 report acknowledges that systematic CT-based mucus scoring is not yet standard practice [2]. The report highlights automated and AI-driven methods as promising tools for broader clinical adoption but emphasizes that further validation and standardization are required before these methods can be used routinely in patient management [2].
Mucus hypersecretion fulfills established criteria of a treatable trait [5, 6]: it is identifiable through clinical phenotyping and imaging, measurable using validated tools, clinically relevant (predicting exacerbations, lung function decline, and mortality), and modifiable through targeted interventions (Fig. 3). Precision medicine in this context refers to matching therapeutic mechanisms to disease pathophysiology, for example, CFTR modulator therapy in CF, anti–IL-13 biologics in T2-high asthma, and airway clearance techniques in primary ciliary dyskinesia [96, 122, 123].Fig. 3Conceptual framework illustrating mucus hypersecretion as a treatable trait across airway diseases. The figure summarizes the rationale for targeting mucus, its objective identification beyond symptoms (imaging, inflammatory and functional markers), and disease-specific stratification in COPD, asthma, bronchiectasis, and CF. It highlights the implementation of mechanism-matched interventions, such as CFTR modulators and biologics, distinguishing disease-modifying strategies from supportive mucus-directed therapies, and their differential clinical impact on exacerbations, lung function, and outcomes. CF cystic fibrosis, CFTR cystic fibrosis transmembrane conductance regulator, COPD chronic obstructive pulmonary disease, CT computed tomography, FeNO fractional exhaled nitric oxide, IL interleukin
Mucus plugs directly obstruct the airways, promote infection, perpetuate inflammation, and drive remodeling [10, 43, 45]. Notably, many patients with CT-detected mucus plugs are asymptomatic yet have worse outcomes, underscoring the importance of mucus as a distinct, mechanism-based therapeutic target rather than merely a symptomatic one [10].
One defining feature of mucus as a treatable trait is its imperfect correlation with symptoms. This necessitates an objective approach to identification and stratification. Structural, inflammatory, and functional markers across airway diseases provide complementary information regarding mucus burden and its clinical relevance.
In COPD, CT-detected mucus plugging identifies patients at increased risk of exacerbations, lung function decline, and mortality, including a substantial subgroup without chronic cough or sputum production [10]. This dissociation highlights the limitations of symptom-based assessments and emphasizes the importance of imaging-informed phenotyping.
In asthma, mucus plugging is associated with T2-high inflammatory traits, including eosinophilia and elevated FeNO levels [28]. Higher baseline mucus plug scores correlate with larger improvements in FEV1 and asthma control after biologic treatment, suggesting that baseline mucus burden predicts response to biologic therapy [47]. These findings suggest that mucus acts as a modifiable expression of inflammatory endotypes rather than an independent therapeutic target.
In bronchiectasis, identification of the mucus trait primarily relies on clinical assessment of sputum burden and difficulty clearing it, with imaging serving a supportive role [33]. Here, mucus interacts dynamically with infection and impaired clearance, reinforcing the need for integrated trait management [31].
In CF, identification of the mucus trait is embedded within genotype-driven diagnosis, with mucus burden serving as a key marker of treatment response rather than selection [4].
Table 3 provides a comprehensive framework linking mucus phenotypes to their underlying inflammatory patterns, preferred assessment tools, and evidence-based therapeutic options across chronic airway diseases. This synthesis facilitates clinical decision-making by matching interventions to the dominant mechanisms sustaining mucus accumulation in individual patients. Importantly, mucus phenotypes may overlap across traditional disease labels, and endotype-based stratification, rather than diagnosis alone, may improve therapeutic targeting and outcomes. Table 3Mucus phenotypes in chronic airway key features, assessment strategies, and targeted therapiesMucus phenotypeKey characteristicsAssociated diseasesPreferred assessment toolsTherapeutic optionsEosinophilic/T2High MUC5AC, eosinophil aggregates, Charcot-Leyden crystals, high viscosity, elasticAsthma (T2-high), ABPA, CRSwNP, some COPD, eosinophilic bronchitis, plastic bronchitisSputum eosinophil count, FeNO, CT plug scoring, rheology (high G', G''), blood eosinophilsICSs, anti–IL-5/IL-4Rα/IgE biologics, airway clearance, DNase in selected casesNeutrophilicHigh MUC5B, neutrophil elastase, extracellular DNA, high dry weight, viscous, purulentCOPD (chronic bronchitis), bronchiectasis, CF, some asthmaSputum neutrophil count, NE, IL-8, sputum DNA, CT plug scoring, rheology (high Tan(δ)), microbiome analysisMacrolides, mucolytics, airway clearance, hypertonic saline, treat infection, anti-inflammatory agentsHyper-concentratedIncreased solids (mucins, DNA, actin), dehydration, impaired MCC, adherent plugsCF, bronchiectasis, severe asthma, COPDSputum dry weight, solids %, mucin quantification, CT plug scoring, MCC measurementCFTR modulators (CF), osmotic agents (hypertonic saline, mannitol), airway clearance, hydration, mucolyticsMixedBoth eosinophilic and neutrophilic markers, variable mucin profile, intermediate rheologyAsthma, COPD, bronchiectasis, CFSputum differential cell count, multiplex cytokine panel, combined rheology, CT plug scoringCombination ICS/biologics + macrolides/mucolytics, airway clearance, tailored to dominant patternABPA allergic bronchopulmonary aspergillosis, CF cystic fibrosis, CFTR cystic fibrosis transmembrane conductance regulator, CRSwNP chronic rhinosinusitis with nasal polyps, CT computed tomography, DNase deoxyribonuclease, FeNO fractional exhaled nitric oxide, G′ storage modulus (elastic component of mucus rheology), G″ loss modulus (viscous component of mucus rheology), ICSs inhaled corticosteroids, IgE: immunoglobulin E, IL interleukin, IL-4Rα interleukin-4 receptor alpha, MCC mucociliary clearance, NE neutrophil elastase, Tan(δ) loss tangent (ratio of viscous to elastic modulus in rheology), T2 Type 2
Within the treatable traits framework, mucus hypersecretion is a pulmonary trait that overlaps with the inflammatory, infectious, and behavioral domains. Effective implementation requires matching interventions to the dominant mechanisms that sustain mucus accumulation rather than uniformly applying mucus-directed therapies.
Approaches that match the interventions to the dominant mechanisms sustaining mucus accumulation have been demonstrated to yield the most substantial and durable clinical benefit. Examples include CFTR modulators in CF [96] and biologics in T2-high asthma [123]. In contrast, mucolytics and airway clearance techniques act as supportive therapies, facilitating the removal of secretions and controlling symptoms without altering the disease's trajectory.
Implementation is limited by methodological and practical barriers, such as the absence of standardized mucus quantification, the limited feasibility of repeated CT imaging, and the resource requirements of specialist-led airway clearance programs. Although systematic mucus plug scoring on CT remains an area of intense research, it is not routinely performed in clinical practice due to its tedious nature [2, 10]. Consequently, mucus phenotyping is not yet systematically incorporated into routine clinical pathways.
However, emerging automated imaging and digital phenotyping tools offer opportunities to operationalize mucus as a treatable trait by enabling reproducible assessment and longitudinal monitoring [2, 124]. Integrating these tools into multidisciplinary care models could enable the dynamic adjustment of therapy as trait expression evolves.
When considered a treatable trait, mucus hypersecretion has variable, yet clinically significant, effects on different airway diseases, depending on whether interventions target the underlying causes or the consequences of mucus accumulation.
For COPD and bronchiectasis, interventions that target mucus primarily reduce exacerbation frequency and sputum-related symptoms [2, 66]. These interventions have minimal or inconsistent effects on lung function and health-related quality of life. The effect size for exacerbation reduction with mucolytics is small (approximately 0.04–0.25 fewer exacerbations per patient-year), and more recent studies demonstrate fewer benefits than earlier trials [59]. A recent RCT demonstrated that neither hypertonic saline nor carbocisteine significantly reduced exacerbations in bronchiectasis, suggesting limited clinical benefit despite proposed physiological effects [66]. These results highlight the supportive role of mucus-directed strategies in facilitating clearance without reversing the underlying disease process.
In asthma, the reduction of mucus burden primarily occurs through the control of T2 inflammation. Biologic therapies have been shown to reduce mucus plugging, which correlates with improvements in airflow limitation [47, 91]. In this context, mucus behaves as a clinically relevant downstream expression of an inflammatory trait.
In CF, mucus fulfills the criteria of a mechanism-linked treatable trait, as restoration of CFTR-mediated ion transport leads to sustained improvements in MCC, lung function, exacerbation rates, and survival [96, 97]. This is the clearest example of disease modification through trait-targeted therapy.
Addressing critical gaps is essential to establishing mucus as a treatable trait. Priorities (1) identifying patient subgroups likely to benefit through prospective phenotyping; (2) conducting adequately powered trials with hard clinical endpoints including disease progression, hospitalization, and mortality rather than surrogate markers alone; (3) standardizing mucus assessment and defining clinically meaningful thresholds; and (4) determining the added value of mucus-targeted therapies within optimized, disease-specific regimens. Whether sustained mucus modification alters disease natural history requires long-term evaluation.
Defining clinical, physiological, and molecular criteria for patient stratification is key to precision phenotyping. Patients must be clustered by inflammatory and mucociliary endotypes rather than disease labels, with neutrophilic and T2-high patterns showing distinct mucus properties, rheology, and microbiome profiles across COPD, asthma, bronchiectasis, and CF [56, 125]. Integrating multi-omics, including microbiome, proteome, metabolome, and inflammatory profiling, enables subtype stratification and biomarker identification [126]. Advanced imaging, including multidetector CT and hyperpolarized gas MRI, quantifies mucus obstruction and ventilation defects but requires harmonization [127]. Automated AI-based mucus plug quantification improves reproducibility compared to visual scoring and offers potential for routine clinical implementation and longitudinal monitoring [128]. Machine learning applied to clinical, imaging, and biomarker data may predict treatment response and disease trajectories, pending validation in different cohorts [121].
Validation of mucus biomarkers and harmonized measurement protocols are needed across respiratory diseases [24, 56, 124]. Key markers include sputum mucins (MUC5AC, MUC5B), rheological properties, inflammatory mediators, and extracellular DNA, all correlating with disease severity, but require harmonization of collection and measurement protocols [53]. Standardization of imaging and sampling techniques is essential for clinical and research applications [124, 129].
The successful integration of emerging mucus-targeted therapies into clinical practice requires operationalizing mucus hypersecretion as a treatable trait. Research should define trait identification criteria, clinically relevant intervention thresholds, and optimal combination with therapies addressing coexisting traits. For next-generation mucolytics and biologics, key questions include patient selection, comparative efficacy versus disease-label prescribing, and integration into multidimensional trait frameworks. Comparative studies of mechanism-matched (e.g., CFTR modulators, anti–IL-13 biologics) versus symptomatic mucus clearance strategies are essential to define the role of each approach within the treatable traits paradigm and to establish whether combined trait-targeted strategies yield additive or synergistic benefits.
For bronchoscopic interventions targeting goblet cell hyperplasia, critical research gaps include durability of effect, optimal patient selection based on mucus trait severity, and integration with pharmacologic strategies within a multi-trait management framework.
Integration of mucus phenotyping into electronic health records and clinical decision-making is a future goal. Stratification by inflammatory and mucociliary endotypes, rather than traditional disease labels, may enable personalized therapy and better prediction of outcomes [56]. Incorporating standardized mucus metrics and phenotypes into electronic health records will facilitate longitudinal tracking and decision support. Digital phenotyping tools embedded within clinical decision-support systems could enable the routine application of mucus phenotypes to personalize therapy and track outcomes over time. The development of point-of-care sputum assessment technologies and portable rheological measurement devices may enable real-time mucus phenotyping in clinical settings.
Mucus hypersecretion meets the criteria of a treatable trait in chronic airway diseases. It can be objectively identified and quantified using validated clinical, imaging, and biomarker-based tools, is strongly associated with exacerbations, lung function decline, and mortality, and is amenable to targeted intervention. Its clinical relevance is reinforced by the weak correlation with symptoms and frequent coexistence with other pulmonary and extrapulmonary traits, supporting objective, mechanism-based identification.
Effective implementation requires alignment of therapy with the dominant biological drivers of mucus accumulation. Mechanism-directed treatments, such as CFTR modulators in CF and anti–IL-13 biologics in T2-high asthma, provide durable benefit by targeting upstream pathways, whereas mucolytics and airway clearance strategies primarily address downstream effects. Trait-based approaches incorporating mucus phenotyping have been shown to improve disease control, reduce exacerbations, and enhance quality of life.
Despite barriers related to standardization, imaging feasibility, and resource demands, emerging automated imaging and digital phenotyping tools offer practical pathways for longitudinal assessment. Recognizing mucus hypersecretion as a treatable trait represents a key step toward precision medicine, enabling individualized targeting of modifiable pathophysiological mechanisms beyond disease labels.