Mucus Plugging as a Treatable Trait Across the Asthma–COPD Spectrum: The Role of Type 2 Cytokine Blockade and Quantitative Imaging

Response to Reviewer 1 Comments

Summary

“This narrative review addresses an important topic, highlighting mucus plugging as a potentially treatable trait that may be responsive to biologic therapy. The manuscript is well organized and offers a meaningful original contribution. Figures are very informative and well-designed.  At the same time, the review could be strengthened by a more comprehensive discussion of the literature, as some relevant studies may not be fully reflected.”

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted file. We believe that these revisions have substantially improved the manuscript. We are grateful to the Reviewer for the thoughtful and constructive feedback, which has allowed us to provide a more complete and clinically informative discussion of the rapidly evolving evidence on biologic-mediated mucus plug reduction.

On behalf of all co-authors,

Pier-Valerio Mari, MD

Corresponding Author

Point-by-point response to Comments and Suggestions for Authors

Comments 1

Findings to be discussed: In a post hoc analysis almost half of patients treated with dupilumab shifted from a high to a low mucus plug score category, and the greatest improvement in lung function was seen among those with the highest baseline mucus plug scores. Dupilumab was associated with reductions in mucus plug scores together with a marked improvement in pre-bronchodilator FEV₁. (Porsbjerg et al. AJRCCM 2025). An important limitation of dupilumab’s effect on mucus plugging: although scores improve, many patients still have persistent plugs after 24 weeks. This point should be further highlighted (Fahy,  AJRCCM 2025).

Response 1: We have added a new paragraph in Section 4.1 (Dupilumab) that discusses the post hoc analysis of the VESTIGE trial by Porsbjerg et al. (Am J Respir Crit Care Med 2026;212:241–252). We now report that approximately half of dupilumab-treated patients shifted from a high to a low mucus plug score category, with the greatest improvement in pre-bronchodilator FEV₁ observed among those with the highest baseline scores (LSMD +16.77 percentage points; p < 0.0001). We have also highlighted the important limitation raised by Fahy in his accompanying editorial (Am J Respir Crit Care Med 2026;212:202–204), namely that approximately one-third of dupilumab-treated patients remained in the high mucus plug score category after 24 weeks, and that most treated patients still had detectable plugs. This observation reinforces the need for a comprehensive treatment approach combining anti-inflammatory biologics with muco-active strategies.

The effect of mepolizumab on mucus plugging in a prospective study of patients with severe eosinophilic asthma (Campisi et al., JACI In Practice, 2025) and those by Götschke et al. JACI In Practice, 2025 might strengthen the authors argumentation.

Response 2: We agree that these studies provide important supporting evidence. We have expanded Section 4.3 (Anti-IL-5/IL-5Rα Agents) to include the prospective observational study by Campisi et al. (J Allergy Clin Immunol Pract 2026;14(1)), which demonstrated that 12 months of mepolizumab therapy significantly reduced the median mucus plug score from 4 to 1 (p < 0.0001) in 47 patients with severe eosinophilic asthma, with reductions correlating with improvements in biomarkers and lung function. We have also cited the retrospective analysis by Götschke et al. (J Allergy Clin Immunol Pract 2025;13:1110–1122), which showed that baseline mucus plug score independently predicted FEV₁ improvement (β = 0.72; p = 0.01) and Asthma Control Test score improvement (β = 0.24; p = 0.001) after 4 months of biologic therapy, irrespective of the specific agent used. These findings strengthen the argument that mucus plugging represents both a treatment-responsive feature and a predictive biomarker across biologic classes.

The authors correctly state that objective measurement of mucus plugging is important for the validation of treatment effects and that AI could help in this field. However, citations should be added (e.g the Van der Veer et al. study, Thorax 2025), which showed that AI-based automated mucus plug quantification confirmed associations with all-cause mortality.

Response 3: Thank you for this pertinent suggestion. We have added in Section 7.3(b) (AI-driven mucus plug detection) the study by van der Veer et al. (Thorax 2025;80:105–108), which applied an AI-based automated quantification platform (LungQ) to 9,399 participants from the COPDGene study. The automated mucus plug scores were significantly associated with all-cause mortality in COPD GOLD 1–4 (HR 1.18 and 1.27 for 1–2 and ≥3 obstructed segments, respectively), closely mirroring results from visual counting. This study represents a pivotal step toward scalable, standardized mucus plug assessment in clinical trials and routine practice.

I think a table showing the effect of each biologic agent, study design, number of participants and main results on mucus plugging and clinical outcomes could help the redaers better understand the use of these agents.

Response 4: We agree that a summary table would greatly enhance the readability and clinical utility of the review. We have added a new Table (Table X) at the end of Section 4, which summarizes the available evidence on biologic-mediated mucus plug reduction across agents and study designs. The table includes study name, biologic agent, mechanism of action, study design, sample size, follow-up duration, baseline and post-treatment mucus plug scores, and key clinical outcomes. Six studies are included: CASCADE (tezepelumab), VESTIGE and its post hoc analysis (dupilumab), the retrospective study by Hara et al. (mepolizumab), the prospective study by Campisi et al. (mepolizumab), and the multi-biologic analysis by Götschke et al.

Response to Reviewer 2 Comments

Point-by-point response to Comments and Suggestions for Authors

Comment 1

The topic is clinically relevant and well chosen.

The methodology section would benefit from a bit more detail, especially to better understand how the literature was selected.

Some parts of the manuscript, particularly those dealing with molecular mechanisms, are quite dense. The level of detail is clearly strong, but at times it makes it harder to see the clinical relevance. It would help to make the link with everyday clinical practice a bit more explicit.

A few interpretations, especially in the COPD context and in indirect comparisons between treatments, feel somewhat speculative and could probably be phrased more cautiously.

The clinical application of mucus plugging still feels a little abstract. A simple clinical pathway or even a short summary table might make this easier to follow in practice.

It would also be useful to add a few comments on the practical limitations of imaging, such as availability, cost, and variability in interpretation.

Some sections are a bit long.

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted file.

Comment 1 – Methodology. More detail on literature selection.

Response: Inclusion/exclusion criteria and the screening process have been added to the Methods paragraph (Abstract).

Comment 2 – Dense molecular sections. Make clinical relevance more explicit.

Response: We have added brief clinical “bridge sentences” at the end of Sections 2.1, 2.2, and 2.3, linking each molecular mechanism to its therapeutic implication in everyday practice.

Comment 3 – Speculative interpretations in COPD. Phrase more cautiously.

Response: We acknowledge the Reviewer’s concern. After careful re-reading, we believe that the language used in Section 5 already appropriately conveys the speculative nature of the discussed hypotheses through qualifiers such as “may,” “at least in part,” “it is tempting to speculate,” and “this hypothesis warrants prospective testing.” We have, however, added an explicit caveat noting that indirect comparisons between the BOREAS/NOTUS and MATINEE programs carry inherent limitations that preclude definitive conclusions.

Comment 4 – Clinical pathway or summary table. Make clinical application easier to follow.

Response: Section 6 already presents a three-step clinical framework (Identify → Characterize → Target) that, in our view, provides a clear and actionable pathway. We have revised the prose to make the stepwise structure more prominent and easier to follow. We chose not to add a dedicated figure, as we felt it would largely duplicate the textual content without adding substantial new information; however, we remain open to the Editor’s guidance on this point.

Comment 5 – Practical imaging limitations. Availability, cost, variability.

Response: A new paragraph has been added to Section 7.1 addressing limited HRCT availability in resource-constrained settings, cumulative radiation exposure, cost, and inter-reader variability in visual scoring.

Comment 6 – Section length. Some sections are too long.

Response: Sections have been condensed. The manuscript has been reviewed throughout for conciseness.

We are grateful for the Reviewer’s careful reading and constructive feedback.

Response to Reviewer 3 Comments

Summary

“The authors present a comprehensive narrative review summarizing the current understanding of mucus plugs in asthma and COPD, including the underlying pathobiological mechanisms, histopathological features, imaging assessment methods, therapeutic evidence with biologics, potential applicability to COPD, current limitations, and future perspectives. Mucus plugs are an increasingly important topic in both asthma and COPD, and this review provides a comprehensive overview of this important topic.”

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted file.

Point-by-point response to Comments and Suggestions for Authors

Comment 1

Figure 1 appears to summarize the content described in Section 2, specifically “2.1. The IL-4/IL-13 Axis and Goblet Cell Metaplasia.” It would improve clarity if this correspondence were explicitly stated within that subsection.

Response 1: We have added an explicit reference to Figure 1 at the end of Section 2.1, stating that the figure summarizes the pathways described in that subsection.

Comment 2

Figure 2 also seems to summarize “2.2. Eosinophil-Derived Products and Mucus Gel Stiffening.” Referring to this figure explicitly within the subsection would enhance readability.

Response 2: An explicit reference to Figure 2 has been added at the end of Section 2.2.

Comment 3

Figure 3 appears to summarize findings described in Section 4 (“Biologic Therapies and Mucus Plug Reduction”), including RCT data for dupilumab and tezepelumab, as well as observational data for mepolizumab. Clarifying this relationship within the relevant section would improve the structure and comprehensibility of the manuscript.

Response 3: A reference to Figure 3 has been added at the end of Section 4.3, clarifying that the figure summarizes the RCT and observational evidence for biologic-mediated mucus plug reduction across agents.

Comment 4

·         In Section 5, “Expanding the Paradigm to Eosinophilic Copd,” “COPD” should be capitalized.

Response 4 Done

·         In Section 7.1 (“Limitations of the Current Evidence”), the authors state: “Several limitations of the current evidence base can be noted. First, RCT data on mucus plug outcomes are limited to three trials in asthma, all with relatively small sample sizes (N = 82–109) and short follow-up periods (24–28 weeks).” It would be helpful to provide appropriate references for these three trials.

Response 5: References to the CASCADE trial (Nordenmark et al. 2023), the VESTIGE trial (Castro et al. 2025), and the RCT by Svenningsen et al. (2023) have been added to the relevant sentence in Section 7.1.