Purpose of Review: To review current evidence on biologic therapies targeting type 2 inflammation in patients with eosinophilic COPD and respiratory comorbidities who remain uncontrolled despite optimized triple inhaled therapy. Recent Findings: Recent phase 3 trials have shown that dupilumab provides the most consistent benefit in eosinophilic COPD, reducing exacerbations and improving lung function and quality of life. Mepolizumab has shown a more limited effect, mainly on exacerbation reduction, whereas benralizumab has not demonstrated clear clinical benefit. Blood eosinophil count remains the main biomarker for treatment selection. Summary: Biologic therapies are advancing precision medicine in COPD, with dupilumab currently showing the strongest overall evidence. Careful patient selection is essential. Broader phenotyping may further improve management, as comorbidities such as chronic rhinosinusitis may contribute to symptom burden and support a multidisciplinary approach. Future studies should clarify long-term outcomes and optimal biologic selection.

Background: Airway mucus plugging is a key but long-overlooked mechanism of persistent airflow obstruction in both asthma and chronic obstructive pulmonary disease (COPD). Type 2 (T2) cytokines, particularly interleukin (IL)-4 and IL-13, drive goblet cell metaplasia, MUC5AC overexpression, and impaired mucociliary clearance, while eosinophil-derived products increase mucus viscosity and promote plug persistence. Methods: A comprehensive narrative review was conducted by searching PubMed and ClinicalTrials.gov databases from inception to February 2026. Search terms included “mucus plugs,” “mucus plugging,” “biologics,” “dupilumab,” “tezepelumab,” “mepolizumab,” “benralizumab,” “IL-4,” “IL-13,” “MUC5AC,” “quantitative CT,” “functional respiratory imaging,” “asthma,” and “COPD.” Studies were included if they reported original data or systematic evidence on mucus plug quantification, biologic-mediated changes in mucus plug scores, or imaging modalities for mucus assessment in asthma or COPD. Editorials, case reports with fewer than three patients, and studies not available in English were excluded. Two authors (P.-V.M. and A.C.) independently screened titles and abstracts; discrepancies were resolved by consensus. Randomized controlled trials, observational studies, and preclinical studies evaluating mucus plug outcomes and T2-targeted therapies were included. Reference lists of retrieved articles were hand-searched for additional relevant publications. Results: A recent systematic review identified multiple randomized controlled trials and observational studies that showed CT-assessed mucus plug scores go down with biologic therapies targeting the T2 pathway in asthma. Observational data extend this evidence to anti-IL-5/IL-5Rα agents. The VESTIGE trial provided the first functional respiratory imaging evidence of mucus plug resolution with dupilumab. In COPD, the BOREAS/NOTUS and MATINEE trials established the efficacy of dupilumab and mepolizumab in eosinophilic phenotypes; however, differences in inclusion criteria—particularly regarding FeNO thresholds and prior exacerbation burden—may explain divergent effects on lung function endpoints. Mucus plug outcomes have not been evaluated in COPD biologic trials. Quantitative imaging modalities, including HRCT mucus plug scoring, functional respiratory imaging, and hyperpolarized gas MRI, now enable objective assessment of mucus burden. Conclusions: Mucus plugging meets the definition of a treatable trait: it can be measured with CT scoring, it matters clinically, and it responds to T2 cytokine blockade. Adding mucus plug assessment to routine clinical evaluation, together with mucolytic strategies where needed, could move treatment decisions from empirical to biology-based across the asthma–COPD spectrum. Further studies are needed to confirm that mucus plug scoring works as a biomarker of treatment response in COPD and to test whether combining biologics with mucolytics improves outcomes.

Biologic therapies for eosinophilic COPD require a blood eosinophil count (BEC) ≥300 cells/µL for eligibility. Landmark trials used a single screening measurement, yet BEC exhibits substantial within-patient variability. The study aimed to evaluate the optimal number of measurements to reliably detect the eosinophilic phenotype in COPD. We developed a decision-analytic simulation model using pooled estimates of BEC variability from independent COPD cohorts, with intraclass correlation coefficients (ICCs) pooled using Fisher's z transformation. Persistence data from five cohorts - ECLIPSE, COSYCONET, CHAIN, BODE, and a Swedish cohort - comprising a total of 3347 patients, were used to estimate the probability of detecting BEC ≥300 cells/µL at least once according to the number of serial measurements. Using the ≥300 cells/µL threshold, the pooled COPD population was classified as persistent eosinophilia, 9.2%; intermittent eosinophilia, 32.5%; and never eosinophilic, 58.3%. Among patients with intermittent eosinophilia, one measurement detected BEC ≥300 cells/µL in 43% of cases. Two measurements at 6-month intervals increased detection to 67%, three measurements over 12 months to 81%, and five measurements over 24 months to 94%. Weighted pooled ICCs declined from 0.784 at ≤3 months to 0.570 at ≥36 months, supporting greater variability over longer intervals. Intermittent eosinophilia affects approximately one-third of patients with COPD and may be missed by single-BEC screening. In this model, three measurements over 12 months achieved ≥80% detection. Integrating historical and prospective BEC values may improve biologic eligibility assessment without delaying treatment decisions.

Background: Dupilumab, a monoclonal antibody blocking IL-4Rα, has recently demonstrated efficacy in patients with type 2 (T2)-inflamed chronic obstructive pulmonary disease (COPD) in the BOREAS and NOTUS trials. Real-world experience in older patients with predominant chronic bronchitis phenotype remains limited. Methods: We report a single-centre case series of 12 consecutive patients with T2-inflamed COPD treated with dupilumab 300 mg every two weeks under a compassionate-use programme at San Carlo di Nancy Hospital, Rome (first administration: April 2025). Eligibility required ≥2 moderate or ≥1 severe exacerbation in the prior 12 months despite triple inhaled therapy and a blood eosinophil count ≥300 cells/µL. Follow-up ranged from 3 to 12 months, with 6 months pre-specified as the primary analysis timepoint; data at 9 and 12 months are reported as descriptive observations. Endpoints included paired changes in annualised exacerbation rate (AER), CAT score and item-level CAT, and FEV₁, with exploratory univariate Spearman analyses of candidate baseline predictors of response. Results: The cohort was elderly (mean age 73.6 ± 5.2 years, range 65–82), predominantly female (8/12, 67%) and characterised by a chronic bronchitis phenotype with high symptom burden (mean baseline CAT 22.8 ± 7.5; CAT item 2 [phlegm] median 3, IQR 3–4). Severe exacerbations decreased significantly (Wilcoxon p = 0.0156; mean AER 0.75 → 0.19 events/patient-year; 6/12 improved, 0/12 worsened). The mean cumulative function showed a standardised incidence ratio of 0.46 (95% CI 0.19–0.95; p = 0.033) versus the pre-dupilumab rate. Mean FEV₁ increased by +66 mL at 1 month (n = 11, paired Wilcoxon p = 0.025), +78 mL at 3 months (n = 10, p = 0.082) and +120 mL at 6 months (n = 10, p = 0.007). Total CAT decreased from 22.9 to 12.5 at 6 months (Friedman p = 0.0007), with the largest absolute reductions in item 2 (phlegm; Δ = −2.6 at 6 months, p < 0.001) and item 3 (chest tightness; Δ = −2.5 at 6 months, p = 0.002). Higher baseline CAT was associated with greater reduction in severe AER (Spearman ρ = −0.79, p = 0.002). Conclusions: In this elderly real-world cohort with phlegm-driven T2 COPD, dupilumab was associated with a significant decrease in severe exacerbations, a clinically meaningful gain in lung function and a marked improvement in mucus-related symptoms. Further studies are warranted to confirm these findings and to clarify whether the reduction in severe exacerbations translates into a measurable mortality benefit.

Background and Clinical Significance: Interstitial lung disease (ILD) is an uncommon but potentially serious complication of imatinib. Its histopathological characterization has so far relied on surgical biopsy or transbronchial forceps sampling, and no case characterized by transbronchial lung cryobiopsy (TBLC) has been reported. The single previous description of a non-specific interstitial pneumonia (NSIP) pattern with imatinib came from a surgical specimen and was cellular in type, with complete radiological resolution after withdrawal. Case Presentation: A 69-year-old never-smoker began imatinib 400 mg daily for Philadelphia chromosome-positive chronic myeloid leukemia; chest computed tomography performed immediately beforehand was normal. Approximately three months later, she developed dyspnea, dry cough and a cutaneous rash, progressing to acute respiratory failure with forced vital capacity 49% and diffusing capacity 30% of predicted. Avian exposure had ceased one month before symptom onset, and she had never received amiodarone. Although serum precipitins were unavailable, hypersensitivity pneumonitis was considered less likely given the temporal relationship but could not be definitively excluded. TBLC yielded specimens showing fibrotic thickening of the alveolar septa by hyaline collagen deposition with a focal lymphomonocytic infiltrate, corresponding to a fibrotic NSIP pattern. After drug withdrawal and administration of corticosteroids, forced vital capacity rose to 82% of predicted. Multidisciplinary discussion concluded that this was drug-induced ILD, graded probable on the Naranjo scale. Imatinib was subsequently replaced by bosutinib for insufficient molecular response, without pulmonary recurrence. Conclusions: Imatinib-associated ILD may present with an organizing-pneumonia-like radiological pattern followed by a fibrosing pattern, with cryobiopsy performed later demonstrating fibrotic NSIP. Because no tissue was obtained during the acute phase, this sequence remains a hypothesis rather than a demonstrated evolution. Cryobiopsy can be performed safely when surgical biopsy is not appropriate.

Biologic therapies are expanding treatment options for chronic obstructive pulmonary disease (COPD), but their development raises unresolved questions about patient selection and the assessment of treatment benefit. This narrative review critically discusses clinical evidence, selected emerging programmes and challenges in translating targeted therapies into practice. Mepolizumab and dupilumab have demonstrated reductions in exacerbations in eosinophil-selected populations. Trials of interleukin-33 (IL-33) or ST2 inhibition enrolled patients without a blood eosinophil threshold, and reduced exacerbations in some but not all of these trials: tozorakimab met its primary endpoint in both OBERON and TITANIA, astegolimab in ALIENTO but not in ARNASA, and itepekimab in AERIFY-1 but not in AERIFY-2. Within these programmes the point estimates were numerically larger at higher blood eosinophil counts, so the absence of an enrolment threshold broadens the populations in which efficacy has been demonstrated but does not establish that eosinophils lack predictive value. Two of the three IL-33 programmes also enriched for former smokers, replacing a biomarker criterion in part with a behavioural one. Blood eosinophil variability, discordance between circulating and airway inflammation, and the distinction between prognostic and predictive biomarkers further complicate treatment selection. Emerging strategies include inhibition of multiple inflammatory pathways, earlier biologic initiation and reassessment of background inhaled therapy. Exacerbation prevention remains a central therapeutic objective, although exacerbation rates alone cannot establish modification of the underlying disease course, and no trial has prespecified a responder definition, a reassessment interval or a stopping rule. Prospective evaluation of disease stability and complementary functional and imaging measures may provide a broader understanding of treatment effects. Future research should prioritise validated predictors of response, applicability to routine clinical populations, long-term safety and harmonised, clinically meaningful outcomes to support effective and sustainable use of biologic therapies in COPD.