Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present an interesting narrative synthesis of more than a decade of translational research investigating biological, behavioural, and lifestyle determinants of pulmonary rehabilitation responsiveness in patients with severe COPD. The attempt to integrate several factors within a precision rehabilitation framework is potentially valuable; however, several issues should be addressed to better define the scope of the manuscript, contextualize the proposed model within the broader literature, and appropriately frame the strength and generalizability of the available evidence.

Major comments:

1. Most of the evidence discussed derives from a single longitudinal translational programme, while no search strategy or methodological approach for selecting the external literature is provided. The manuscript therefore lies somewhere between a narrative review and a conceptual synthesis of the authors' own research programme.
   The authors should explicitly define the nature and scope of the article. If the manuscript is intended as a synthesis of their translational programme, this should be clearly stated throughout. Alternatively, if it is intended as a broader narrative review of precision pulmonary rehabilitation, the authors should briefly describe how the external literature was identified and more systematically incorporate independent evidence.
2. The manuscript appropriately emphasizes that conventional clinical and functional variables only partly explain heterogeneity in PR response. However, discussion of biomarker-based stratification relies predominantly on studies from the authors' own programme, despite the existence of recent literature specifically addressing biomarkers in exercise-based PR. In light of the above, the Introduction and Discussion sections should more clearly position the proposed model within the broader evidence base. Looking at recent literature on biomarkers for phenotyping, monitoring, and predicting response to PR in COPD would be particularly relevant (e.g., doi: 10.1016/j.rmed.2025.108282) might be useful to discuss the current strengths and limitations of biomarker-informed PR.
3. Transcriptomics, metabolomics, and lipidomics are repeatedly presented as important components of the proposed framework, although the manuscript later clarifies that these analyses are still ongoing. This may give the impression that multi-omics already form part of the empirical evidence supporting the model. The authors should clearly distinguish between published findings, ongoing analyses, and future research directions. This distinction could also be reflected in Table 1 or in the figures. Since metabolomics is emphasized as a future component of the framework, the Discussion could also briefly acknowledge the current evidence and methodological challenges of metabolomic profiling in COPD (e.g., doi: 10.1088/1752-7163/ae2f95).
4. Several conclusions appear stronger than what is actually supported by the mainly observational and relatively small studies summarized in the review. For example, terms such as “determinants”, “modulate”, “predict”, or “improve stratification” may imply causal or validated predictive relationships that have not yet been demonstrated. I’d recommend that the manuscript, particularly Table 1 and the Discussion be revised to distinguish association from causation and candidate biomarkers from validated predictors.
5. The studies summarized appear to derive largely from the same or partially overlapping cohort of elderly patients with severe COPD undergoing inpatient PR. Moreover, “responsiveness” is treated as a relatively homogeneous construct despite the use of different outcomes across studies. PR response is inherently multidimensional, and patients may respond differently in terms of exercise capacity, symptoms, quality of life, or functional status. The authors should therefore clarify the degree of overlap between study populations and acknowledge that convergence across studies does not necessarily represent independent replication. Table 1 could indicate the main outcome used to define response in each study. The Discussion should also explicitly state that PR responsiveness is multidimensional and outcome-dependent. Finally, the proposed model should be framed as a hypothesis-generating framework requiring validation in independent cohorts and across different rehabilitation settings before clinical implementation.

Minor comments:

1. The end of the Methodological Approach contains some repetition and could be streamlined.
2. “Manuscript in preparation” should not be given the same evidentiary weight as peer-reviewed studies and should either be clearly identified as preliminary evidence or removed from the main synthesis.
3. Terminology related to COPD severity should be standardized, particularly the use of “GOLD stage 3–4”.
4. A careful editorial revision is recommended to harmonize punctuation and citation formatting throughout the manuscript.

Author Response

see attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The article addresses an interesting and potentially important topic that may represent an important future direction in the treatment of patients with COPD. However, at present, the findings have limited clinical applicability, and further studies are needed before this approach can be considered relevant to routine clinical practice.

Overall, the manuscript is well written and clearly presented. Nevertheless, I believe that the limitations of the study should be emphasized more explicitly in the Discussion. In particular, the authors should further discuss the fact that the study population consists exclusively of older patients with COPD, which limits the generalizability of the findings to the broader COPD population. In addition, the single-center design is an important limitation, and the lack of a multicenter approach should be acknowledged more prominently. These factors should be considered when interpreting the results and assessing their potential clinical applicability.

Author Response

see attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am satisfied with the revisions made by the Authors.