Review Reports - Optimizing CPAP Adherence in Obstructive Sleep Apnea: A Narrative Review of Practical Strategies for Everyday Clinical Care

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This narrative review addresses an important and clinically relevant topic: adherence to CPAP therapy in patients with obstructive sleep apnea. The manuscript brings together several relevant aspects of clinical care, including patient-related, disease-related, and device-related factors. The emphasis on patient education, mask selection, early troubleshooting, and structured follow-up is particularly valuable for everyday practice. I believe the manuscript has good potential, although several revisions would help improve its clarity, methodological transparency, and practical value.

First, although the authors identify the manuscript as a narrative review in the Abstract and Methods section, the article type is not apparent from the title. For transparency and to better guide readers’ expectations, the authors may consider revising the title to explicitly include “narrative review”, for example: “Optimizing CPAP Adherence in Obstructive Sleep Apnea: A Narrative Review of Practical Strategies for Everyday Clinical Care.”

Second, the Methods section would benefit from additional detail. While this is not a systematic review and therefore does not require PRISMA reporting, the methodological description remains relatively brief for a narrative review. The authors could clarify whether any reporting framework or quality assessment tool for narrative reviews, such as SANRA, was followed. If no formal protocol or reporting framework was used, this could simply be stated. It would also be helpful to provide a clearer statement of aims, the rationale for the narrative approach, the search strategy, the databases consulted, the period covered, the criteria used to select studies, and the way in which disagreements between reviewers were resolved.

Third, the manuscript would benefit from a clearer definition of how CPAP adherence is conceptualized throughout the review. The discussion of the limitations of the 4-hour threshold is useful, but terms such as adherence, acceptance, persistence, early adherence, and long-term adherence are sometimes used without clear distinction. A short paragraph defining these terms would improve clarity for readers.

Fourth, the Abstract, Discussion and Conclusions could be revised to better reflect the strength and limitations of the available evidence. In the Abstract, the recommendation that nasal masks should be the first choice and the statement that endotype and phenotype traits can be used to predict adherence could be expressed more cautiously. In the main text, the authors appropriately acknowledge that current evidence does not support using endotypes alone to predict CPAP adherence and that prospective studies are still needed. Aligning the Abstract and Conclusions with this more nuanced interpretation would strengthen the manuscript. For example, the authors could state that nasal interfaces are generally preferred when tolerated, but mask selection should be individualized, and that phenotypic and endotypic traits may help personalize treatment in selected patients, although their role in predicting CPAP adherence remains insufficiently established.

Fifth, the Discussion could be strengthened by providing a more critical synthesis of the evidence, rather than mainly reiterating points from previous sections. It would be useful to distinguish more clearly between well-supported interventions, such as patient education, early troubleshooting and structured follow-up, and more exploratory concepts, such as endotype-guided titration. The Conclusions could also present the role of telemedicine more cautiously, as a promising complementary tool rather than “the key” to ensuring long-term adherence on a large scale.

Sixth, Figure 1 is conceptually useful, but it could be refined linguistically and made more informative. The label “Treatments-related factors” should be corrected to “Treatment-related factors”.

Seventh, Figure 2 is a useful attempt to summarize the proposed clinical pathway, but it would benefit from further refinement. Some wording should be corrected, particularly “How to choice the pressure and the mask?”, which could be revised to “How should pressure and the mask interface be selected?” or similar. Some boxes are also quite broad, such as “Prevent CPAP problems”. The figure could become more useful if it were converted into a clearer clinical pathway with specific actions at each step: patient education, symptom explanation and review of sleep study findings; CPAP introduction and expectation setting; interface selection and pressure titration; early follow-up within the first weeks to address leaks, nasal symptoms, dry mouth, insomnia, discomfort, and residual events; and long-term monitoring using scheduled visits, telemedicine, or telephone support.

Eighth, to enhance the practical value of the review, the authors may consider adding a summary table linking the main barriers to CPAP adherence with practical interventions. For example, the table could include mask leaks, nasal obstruction, dry mouth, insomnia, anxiety/depression, low perceived benefit, bed-partner issues, residual events, and pressure intolerance, together with suggested management strategies and supporting references. This would make the manuscript even more useful for everyday clinical care.

Ninth, the reference list appears generally relevant. However, there appears to be one possible mismatch between the in-text citation and the reference list: the manuscript refers to “Jurado-Gamez B et al.” in the section on patients’ perception, but the corresponding reference appears to be Sawyer et al. The authors should verify and correct this citation if needed.

Finally, the manuscript would be strengthened by including a brief limitations section. This could acknowledge the limitations inherent to a narrative review, including the possibility of subjective study selection and the absence of formal quality assessment.

Overall, this is a relevant and potentially useful manuscript for clinicians involved in OSA care. With clearer methodological reporting, more cautious interpretation of some claims, improved figures, careful language revision, and a brief limitations section, the manuscript would be substantially strengthened.

Comments on the Quality of English Language

The manuscript would benefit from careful English language editing to further improve clarity, readability, and scientific style. Overall, the meaning is understandable, but several sentences could be expressed more idiomatically. For example, in the Abstract, “one of the main issues to be fixed” (line 16) could be revised to “one of the main challenges to be addressed”. The phrase “A Patients should initially be educated” (line 29) appears to contain a typographical or grammatical error and could be revised to “Patients should initially be educated”. Similarly, “economical instead a clinical definition” (lines 77–78) could be reformulated as “an economic rather than a clinical definition”. There are also minor spelling and grammar issues, such as “Importanly” (line 208), which should be “Importantly”. In Figure 2, “How to choice the pressure and the mask?” could be revised to “How should pressure and the mask interface be selected?”. Such revision would strengthen the manuscript and help communicate the authors’ message more effectively.

Author Response

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Reviewer 1

Response 1. Thank you to the reviewer for the comment. In the revised version, we improved the clarity of the language and the transparency of the methodology.

Response.2 Thank you to the reviewer for the suggestion. We will modify the title

“Optimizing CPAP Adherence in Obstructive Sleep Apnea: A Narrative Review of Practical Strategies for Everyday Clinical Care.”

Response 3. Thank you to the reviewer for this helpful comment. We agree that the method section required clearer description. As suggested, we have revised the section to state explicitly that this work was designed as a narrative review and that no formal protocol or reporting framework for narrative reviews, including SANRA, was followed. We have also clarified the aim of the review, the rationale for adopting a narrative approach, the databases consulted, and the search period. We are grateful for your thorough and constructive feedback. We have substantially revised the manuscript to address the recurrent points you raised, with particular attention to methodological transparency and practical clinical value.

Article type and scope: We now explicitly state “Narrative Review” in the title and clarify in the Methods that this work is a narrative synthesis aimed at translating recent evidence into pragmatic strategies to improve CPAP adherence in routine OSA care.
Methods transparency: We expanded the Materials and Methods section to detail the rationale for a narrative approach, the databases consulted (now including PubMed/MEDLINE and Google Scholar, with an added targeted sweep of Scopus/Web of Science where relevant), the complete search strings, the date of the last search, the coverage period, language limits, inclusion/exclusion criteria, and the screening process by two authors with disagreements resolved by discussion/consensus. We explicitly state that no formal protocol was registered and no standardized narrative-review reporting tool (e.g., SANRA) or formal risk-of-bias tool was applied; we also added a Limitations paragraph acknowledging the implications of this choice.

These clarifications have been added to improve transparency and to better align the Methods section with the actual methodology used in the preparation of the manuscript.

Materials and Methods

This narrative review was undertaken to provide a comprehensive and clinically oriented synthesis of the contemporary evidence on the factors influencing adherence to continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea (OSA), as well as on practical strategies that may improve adherence in routine clinical care. A literature search was conducted using PubMed/MEDLINE and Google Scholar and covered publications from January 1995 through May 2026. The search strategy incorporated various combinations of the following keywords: "obstructive sleep apnea," "OSA," "continuous positive airway pressure," "CPAP adherence," "compliance," "telemedicine," "cognitive behavioral therapy," "mask interface," "OSA phenotype," and "endotype." Articles were selected according to their relevance to the aims of the review, with particular emphasis on studies examining predictors of CPAP adherence, barriers to long-term treatment use, and practical interventions that may improve adherence in everyday clinical practice. Priority was given to recent original investigations, meta-analyses, and clinically relevant review articles, whereas case reports were excluded.

Particular attention was paid not only to the identification of factors associated with greater or lower CPAP adherence, but also to the clinical interpretability of those findings. Studies and meta-analyses limited to a purely descriptive listing of variables associated with adherence were considered less informative for the purposes of this review than those offering a broader interpretative framework through which the observed associations could be understood in clinical practice. Accordingly, preference was given to studies that, beyond reporting statistical associations, also explored the potential behavioral, physiological, and practical mechanisms underlying those results. This approach was intended to support a more clinically meaningful discussion of adherence as a multidimensional and dynamic process, rather than as the simple sum of isolated predictors.

Two authors independently reviewed titles, abstracts, and full-text articles in order to identify studies of greater clinical and methodological relevance. The review included randomized controlled trials, observational studies, meta-analyses, and narrative reviews addressing CPAP adherence, its determinants, and potential strategies for improvement. No formal protocol was prospectively registered for this review. In addition, given the narrative nature of the article, no PRISMA-based methodology, SANRA framework, or formal standardized quality assessment tool was applied. The selection and interpretation of the literature were therefore performed by the authors on the basis of relevance to the topic, scientific consistency, and clinical applicability. Any differences in interpretation were discussed among the authors and resolved by consensus. This article is based exclusively on previously published studies and does not include any new studies involving human or animal subjects conducted by the authors.

Response 4. Thank you to the reviewer for the suggestion. The discussion has been partially rewritten

“…Indeed, this is commonly used for reimbursement or coverage purposes but although it is not clinically ineffective for all patients it is not the goal that a clinician could suggest to his patient. A few hours during the night may not improve symptoms, quality of life or reduce cardiovascular risk, with a subsequent reduction in patient motivation. Daytime sleepiness improves after 7 hours of sleep, while seven hours and 30 minutes is the medium time necessary to reach a good performance status [7]. This range could also be different for shorter or longer sleepers and varying during the lifespan. Certainly a cut off and a value is necessary in literature to quantify the adherence and to compare different reports. CPAP treatment, in a clinical point of view, could be applied during sleep without interruption, in particular in patients with REM sleep OSA, in which the second part of the night could be less intentional by the patient. Considering that a physiological hypnogram has a prevalence of REM sleep in the second half of the night and that REM-OSA is associated with higher cardiovascular risk. An OSA patient who removes the mask after only the first 4 hours of sleep will not treat the deeper desaturations, the more severe events and the cardiovascular risk [8,9]. In addition, recent evidence underline that patients with REM-related OSA demonstrated significantly lower nightly CPAP use in particular in long term adherence compared with patients with non-stage-specific OSA. (T. Hoshino, R. Sasanabe, T. Tanigawa, et al., Effect of rapid eye movement-related obstructive sleep apnea on adherence to continuous positive airway pressure, J. Int. Med. Res. 46 (6) (Jun 2018) 2238–2248, https://doi.org/10.1177/ 0300060518758583.) CPAP efficacy have a dose-response effect [10], this observation suggests that the ineffectiveness of CPAP in terms of cardiovascular and metabolic health in some trials is partly due to poor or non-optimal adherence [11]. Another aspect is the definition of adherence compared to compliance. The term adherence itself underlines the necessity of the active and collaborative treatment acceptation including a self-efficacy meaning, with a no exclusive terminological difference with the most passive compliance. Acceptance is defined as willingness to purchase and use a CPAP device and it could be related to financial issue, social stigma or intolerance to CPAP or preference to another therapy. (Accepatance and compliance of CPAP therapy in patients with OSA (ERJ open research 2025 11 (suppl 16) 184. In sleep medicine time issue is also important that defines the short- and long-term adherence. Long term adherence refers to different time horizons (3, 6 or 12 months), while shorter adherence refers to the first month of CPAP treatment and strongly influences the following period.

Fourth, the Abstract, Discussion and Conclusions could be revised to better reflect the strength and limitations of the available evidence. In the Abstract, the recommendation that nasal masks should be the first choice and the statement that endotype and phenotype traits can be used to predict adherence could be expressed more cautiously. In the main text, the authors appropriately acknowledge that current evidence does not support using endotypes alone to predict CPAP adherence and that prospective studies are still needed. Aligning the Abstract and Conclusions with this more nuanced interpretation would strengthen the manuscript. For example, the authors could state that nasal interfaces are generally preferred when tolerated, but mask selection should be individualized, and that phenotype and endotype traits may help personalize treatment in selected patients, although their role in predicting CPAP adherence remains insufficiently established.

Response 5 Thank you to the reviewer for the comment. We remodulate the abstract. Nevertheless, we specify in the text that nasal mask could be in general the first choice for a pathophysiological point of view. However, we totally agree that mask choice could be individualized. As concern the endotype and phenotype we will express the consideration with more caution in the text and this could be a good issue for future research.

“This involves explaining what OSA is, its consequences, what PAP therapy is, and its potential benefits. The choice of the right mask is the first step in CPAP adherence. OSA phenotype and endotype traits may help personalize treatment in selected patients, although their role in predicting CPAP adherence needs to be studied greater in depth.”

Response 6. Thank you again to the reviewer. We remodulate the discussion and we also describe telemedicine like a useful tool to improve long term adherence

Response 7 Thank you for this constructive comment. We have revised Figure 1 to improve both the language and the overall clarity of the figure. Specifically, the label “Treatments-related factors” was corrected to “Treatment-related factors,” and the wording of the other categories was refined for greater consistency and readability. In addition, the figure was made more informative by clarifying the examples included under each domain.

Figure 2. Clinical pathway for CPAP initiation and follow‑up in obstructive sleep apnea, outlining education and results review, CPAP introduction and expectations, interface selection with pressure titration, early follow‑up to address leaks, symptoms, and residual events, and long‑term monitoring via scheduled visits and remote support

Response 8 . Thank you to the reviewer for the suggestion, we performed a table with the difference barriers to the CPAP adherence

Table X. Common barriers to CPAP adherence and practical management strategies

Barrier to CPAP adherence	Practical management in routine care	References
Mask leaks	Reassess mask fit, size, and interface type; avoid over-tightening; replace worn cushions or headgear; consider mask liners or switching to a different interface if leaks persist.	Bachour et al. Can Respir J2019 Nov 3:2019:7215258.
Nasal obstruction	Evaluate and treat reversible nasal conditions; use saline irrigation, intranasal therapies when indicated, and heated humidification; reserve oronasal masks for selected patients with persistent nasal obstruction.	Inoue A et al Auris Nasus Larynx 2019 Aug;46(4):548-558
Dry mouth	Assess for mouth leaks and ensure appropriate pressure settings, optimize heated humidification; reconsider mask type; consider a chin strap in selected patients; review contributing medications and hydration status.	A. Bachour, et al Sleep Medicine, vol. 5, no. 3, pp. 261–267, 2004.
Insomnia	Screen for comorbid insomnia (ISI Insomnia Severity Index questionnaire); introduce gradual CPAP acclimatization; use behavioral strategies and CBT-I when available; avoid forcing prolonged use too early if this increases frustration or delays sleep onset.	Pataka A et al Life (Basel). 2023 Jan 20;13(2):296
Anxiety/depression	Identify claustrophobia or affective symptoms early; use stepwise desensitization; provide reassurance and close early follow-up; refer for psychological support when indicated.	Mitzkewich MP, et al . Fed Pract. 2019 Mar;36(3):134-139.
Low perceived benefit	Reframe expectations regarding the timing and nature of treatment benefits; review adherence and efficacy data with the patient; address side effects; align treatment goals with patient-prioritized outcomes.	Poletti V et al . Int J Clin Health Psychol. 2025 Jul-Sep;25(3):100602. Epub 2025 Jun 24.
Bed-partner issues	Involve the bed partner in patient education; address noise and leak issues; optimize interface comfort; discuss shared benefits such as reduced snoring and improved sleep quality.	Rapelli G et al Recommendations. J Pers Med. 2025 May 8;15(5):192.
Residual events	Review device data for residual AHI, mask leaks, and effective nightly use; reassess pressure settings; consider repeat titration or further evaluation for central events, positional OSA, or other sleep disorders if symptoms persist.	Reiter J et al. J Clin Sleep Med. 2016 Aug 15;12(8):1153-8..
Pressure intolerance	Use ramp and expiratory pressure relief features; adjust pressure settings when poorly tolerated; encourage gradual acclimatization; consider APAP, bilevel o Auto Bilevel therapy in selected patients.	Krakow BJ et al. Patient Prefer Adherence. 2017 Nov 20;11:1923-1932.

Response 9 Thank you for this helpful comment. We have carefully checked the citation in the section on patients' perception and verified its correspondence with the reference list. The reference has been corrected where necessary.

Response 10. Thank you for this valuable comment. A brief limitations section has now been added, highlighting the intrinsic limitations of a narrative review, including possible subjectivity in study selection and the lack of formal quality assessment. We also emphasized that the review was conceived as a practical, clinically oriented synthesis, informed by current American Academy of Sleep Medicine recommendations and focused on the main challenges affecting CPAP adherence.

“This review has some limitations that should be acknowledged. As a narrative review, it does not follow the methodological framework of a systematic review, and the selection of the included studies may therefore have been influenced, by the authors aim to answer necessity in clinical practice. In addition, no formal quality assessment of the included studies was performed. Consequently, the evidence discussed should be interpreted with caution, particularly in view of the differences of study designs, methodologies, and overall quality. Nevertheless, this review was conceived with a practical clinical focus and was informed, where relevant, by current recommendations from the American Academy of Sleep Medicine. Its added value lies in providing a pragmatic, scientifically grounded overview of the main factors currently limiting CPAP adherence, while also offering practical guidance to support clinicians in addressing this challenging issue.”

Comments on the Quality of English Language

The manuscript would benefit from careful English language editing to further improve clarity, readability, and scientific style. Overall, the meaning is understandable, but several sentences could be expressed more idiomatically. For example, in the Abstract, “one of the main issues to be fixed” (line 16) could be revised to “one of the main challenges to be addressed”. The phrase “A Patients should initially be educated” (line 29) appears to contain a typographical or grammatical error and could be revised to “Patients should initially be educated”. Similarly, “economical instead a clinical definition” (lines 77–78) could be reformulated as “an economic rather than a clinical definition”. There are also minor spelling and grammar issues, such as “Importantly” (line 208), which should be “Importantly”. In Figure 2, “How to choice the pressure and the mask?” could be revised to “How should pressure and the mask interface be selected?”. Such revision would strengthen the manuscript and help communicate the authors’ message more effectively.

Response 11. Thank you for your careful review and constructive comments. We have made the revisions suggested and corrected the manuscript accordingly. Furthermore, the English language will be carefully revised with the assistance of a native speaker in order to improve the overall clarity and quality of the text.

Reviewer 2 Report

Comments and Suggestions for Authors

Legend

ERROR Typo or grammatical error — must be corrected before publication

MINOR Phrasing or grammatical imprecision — recommended correction

STYLE Stylistic inconsistency or suggestion — editorial decision

Abstract

ERROR Line 29 — Conclusions

Current A Patients should initially be educated... Patients should initially be educated...

Stray letter "A" before "Patients". Should be removed.

Section 3.1 — The 4-Hour Threshold

MINOR Lines 77–78

Current The use of an economical instead a clinical definition The use of an economic rather than a clinical definition

"Economical" implies thrift or efficiency, whereas "economic" relates to economics or resources. Moreover, "instead" should be followed by "of", or the preposition "of" can be substituted by the conjunction "rather than". Finally, the word "a" before "clinical" seems to be missing from the original.

Section 3.2 — Patient-related factors

ERROR Lines 121–123

Current Restless syndrome (RLS) and Periodic Limb Movements (PLMs) are others two quite common comorbidities in OSA (around 20% for RLS and and around 14% for PLMs) Restless legs syndrome (RLS) and periodic limb movements (PLMs) are two other quite common comorbidities in OSA (around 20% for RLS and around 14% for PLMs)

Three mistakes can be detected in this sentence: (1) the correct spelling of "Restless syndrome" is "Restless legs syndrome"; (2) instead of "others two", the word combination "two other" needs to be applied; (3) the repetition of "and" ("and and").

Section 3.4 — Device-related factors

ERROR Line 208

Current Importanly Importantly

A typo: the letter "t" is omitted.

MINOR Lines 211–213

Current Regarding to comparison for long-term adherence between APAP and fixed-CPAP remains debated. The comparison of long-term adherence between APAP and fixed CPAP remains debated.

"In relation to" is an improper expression in English; either "regarding" or "with regard to" can be utilized. In addition, the sentence lacks a proper subject and should be restructured accordingly.

Section 3.5 — Patients' perception

MINOR Lines 219–221

Current ...as demonstrated by Jurado-Gamez B et al, where a correct information about their conditions leads to 1-hour increase of CPAP daily-use ...as demonstrated by Jurado-Gamez B et al., in which providing accurate information about their condition led to a 1-hour increase in daily CPAP use

Four issues: (1) instead of "a correct information", the phrase "accurate information" should be used since the noun in question is uncountable; (2) instead of "leads", the word "led" should be written because the author describes a past event; (3) instead of "daily-use", the word combination "daily use" is sufficient; (4) the authors of the paper quoted in this passage are different from the authors cited in Reference 56; they are Sawyer AM et al.

Section 4 — Discussion

MINOR Line 254

Current This multidynamic model emphasises This multidimensional model emphasises

The word "multidimensional" is utilized in the Conclusions section and Methods section. In order to avoid inconsistencies, one word should be chosen and used through out the manuscript. "Multidimensional" seems to be the preferred choice as it is more widespread in scientific literature.

General / Style Issues

STYLE Throughout the manuscript

Inconsistency in British vs. American English spelling: the manuscript contains both forms ("emphasise", "personalised", "apnoea", "recognise", vs. "adherence", "favorable"). The author should choose one form of spelling and apply it consistently in the whole manuscript. As it was mentioned above, MDPI journals follow American English, so the correct spelling will be "emphasize", "personalize", "apnea", "recognize".

STYLE "sleep apnoea" vs. "sleep apnea" – throughout

Both options are present in the manuscript: in some cases, "sleep apnoea" (the British spelling) is utilized, in other cases "sleep apnea" (American English). As stated previously, MDPI uses American English spelling, so the correct form will be "sleep apnea".

STYLE In-text citations – various locations

Names of authors are spelled inconsistently in citations: "Jurado-Gamez B et al", "Falcone VA et al", "Sugiura T et al". Standard way of referencing in this journal is to use either surname only of the first author followed by the year in round brackets ([56]), or the year and author names in square brackets, followed by a dash. Alternatively, authors can decide not to cite the authors in the text at all, using the number reference.

STYLE Figure 1 — Caption (Lines 133–141)

Figure 1 title ("Main factors influencing CPAP adherence in OSA") and its caption contain almost identical information. It would be appropriate to modify the caption and make it shorter.

STYLE Acknowledgements

The authors declare using the "ChatGPT 5.0 (OpenAI)". It would be wise to double-check the actual version designation of the AI before the final submission.

Author Response

Abstract

ERROR Line 29 — Conclusions

Current A Patients should initially be educated... Patients should initially be educated...

Stray letter "A" before "Patients". Should be removed.

Response 1 Thank you to the reviewer we have done.

Section 3.1 — The 4-Hour Threshold

MINOR Lines 77–78

Current The use of an economical instead a clinical definition The use of an economic rather than a clinical definition

Response 2. Thank you to the reviewer we have corrected the sentences

Section 3.2 — Patient-related factors

ERROR Lines 121–123

Response 3. Thank you to the reviewer we have modified in the text

Section 3.4 — Device-related factors

ERROR Line 208

Current Importanly Importantly

A typo: the letter "t" is omitted.

Response 4. Thank you to the reviewer we have modified in the text

MINOR Lines 211–213

Current Regarding to comparison for long-term adherence between APAP and fixed-CPAP remains debated. The comparison of long-term adherence between APAP and fixed CPAP remains debated.

"In relation to" is an improper expression in English; either "regarding" or "with regard to" can be utilized. In addition, the sentence lacks a proper subject and should be restructured accordingly.

Thank you, we had rewritten the sentence. “As concern the comparison between APAP and fixed CPAP in terms of long-term adherence, the issue remains a matter of debate. The currently available evidence has not demonstrated a clear advantage for either CPAP or APAP in terms of adherence, daytime sleepiness, or quality of life”

Section 3.5 — Patients' perception

MINOR Lines 219–221

Thank you, we rewrote the sentences

Section 4 — Discussion

MINOR Line 254

Current This multidynamic model emphasises This multidimensional model emphasises

Thank you again. We had corrected the sentences

General / Style Issues

STYLE Throughout the manuscript

We appreciate your helpful suggestion. We have revised the manuscript to adopt the version you indicated.

STYLE "sleep apnoea" vs. "sleep apnea" – throughout

Thank you for this valuable comment. The text has been updated accordingly to reflect the suggested version.

STYLE In-text citations – various locations

Thank you for highlighting this. We opted to use numbered references only in the text, in line with the journal’s guidelines

STYLE Figure 1 — Caption (Lines 133–141)

Figure 1 title ("Main factors influencing CPAP adherence in OSA") and its caption contain almost identical information. It would be appropriate to modify the caption and make it shorter.

Thank you. We rewrote the text shorter

“Figure 1. Interplay of disease-, treatment-, and patient-related factors shaping CPAP adherence; patient-related factors are central.”

STYLE Acknowledgements

The authors declare using the "ChatGPT 5.0 (OpenAI)". It would be wise to double-check the actual version designation of the AI before the final submission.

We used OpenAI ChatGPT (OpenAI; chat.openai.com accessed 20 June 2026) for language editing; responsibility for the content remains with the authors.

Reviewer 3 Report

Comments and Suggestions for Authors

1. Introduction and Theoretical Framework
The current introduction is excessively short. This prevents the establishment of a proper theoretical and conceptual framework on the topic. For a review of this nature, a thorough contextualization is essential. I suggest significantly expanding this section, clearly defining the key concepts, the state of the art, and, above all, justifying the knowledge gap that your manuscript aims to fill.

2. Methodology and Justification
The methodology section is too brief and lacks the necessary transparency:

They indicate that they included previous systematic reviews and meta-analyses in their search. If such high-level evidence has already been published, it is imperative that they explicitly justify what their review contributes that is new and what justifies conducting this work.

Furthermore, they only searched a single database, and it is unclear why they did not perform a quality assessment of the studies (risk of bias) or a more in-depth analysis.

3. Restructuring Proposal (Main Recommendation)
Given the potential of the topic and the fact that they have already compiled high-level literature, I strongly encourage them to enhance the rigor of their manuscript by transforming it from a narrative review into a proper systematic review. To this end, I recommend strictly adhering to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). This restructuring will require:

Expanding the search to a minimum of two or three major databases (e.g., PubMed/MEDLINE, Scopus, Web of Science).

Registering the protocol (e.g., in PROSPERO) or detailing its design transparently.

Including a flowchart and feature tables that clearly show which studies are included, how they were selected, and their main characteristics—elements currently missing from the manuscript.

Incorporating a formal tool for assessing the methodological quality of the included studies.

4. Discussion and Limitations
The discussion completely omits the study's limitations. All research, and especially a review with a search strategy restricted to a single database, is subject to bias (such as selection or publication bias). A dedicated paragraph is needed to honestly and critically analyze the limitations of your work.

5. Conclusions
The current conclusions are too strong and categorical considering the design used and the methodological limitations observed. I suggest you refine their tone, ensuring that they objectively, prudently, and faithfully reflect the actual results from the analyzed literature, without resorting to overgeneralizations.

I hope you find these comments useful and constructive for the development of your manuscript. I encourage you to make these substantial changes, which will undoubtedly give your work the rigor, reproducibility, and scientific impact that the topic deserves.

Sincerely,

Author Response

Reviewer 3

Comments and Suggestions for Authors

Introduction and Theoretical Framework
The current introduction is excessively short. This prevents the establishment of a proper theoretical and conceptual framework on the topic. For a review of this nature, a thorough contextualization is essential. I suggest significantly expanding this section, clearly defining the key concepts, the state of the art, and, above all, justifying the knowledge gap that your manuscript aims to fill.

Thank you for your comment. We added this chapter to the introduction.

“Continuous Positive airway Pressure (CPAP) therapy represents the first-line treatment for Obstructive Sleep Apnea Syndrome (OSAS), effectively reducing disease severity, daytime sleepiness, systemic blood pressure, and motor vehicle accidents, while significantly improving health- and sleep-related quality of life [1]. Although CPAP efficacy remains otherwise well established, regardless of the site of upper airway obstruction, the long-term benefit on the cardiovascular and metabolic issue have been attenuated by suboptimal adherence. Indeed, over the past decades, adherence to CPAP therapy has emerged as one of the central issues in the literature on OSAS, representing the principal treatment limitation. Accordingly, scientific interest in this topic has progressively increased. Available evidence indicates that low adherence is a multifactorial phenomenon influenced by physician-related variables, patient characteristics, disease severity and phenotype. The first way to improve the adherence is to consider the clinical definition. Adherence is defined as the active and collaborative involvement of the patient in the treatment that the clinician proposes. For this reason, as we discuss later, the active involvement of the patient is one of the most important aspects. In the literature, symptoms such as drowsiness, subjective benefit from therapy in the early stages, snoring, and use of a nasal mask are well-established indicators of good adherence, while the oronasal mask, low socioeconomic status, and claustrophobia are examples of factors that are indisputably associated with low adherence. (reference) Adherence is part of the daily clinical practice of all sleep specialists but is also a challenge. In the last few years literature focused on the main factors able to improve the adherence and the different strategies used by clinicians [2-4]. Recent evidence demonstrated a statistically significant reduction in hospitalizations and emergency room visits in obese OSA patients with a good adherence to CPAP compared to poor adherents [5]. Although improvements in CPAP technology and their masks, only 50-60% of patients have a long-term adherence to this treatment [4]. This poor CPAP adherence among a significant proportion of the OSA population, despite technological advances, highlights the need to develop a more integrated and patient-centered approach. More recently, however, the American Academy of Sleep Medicine guidelines, systematically emphasized the importance of targeted interventions aimed at improving adherence (Clinical Practice Guideline: Treatment of OSA With PAP 2019). The clinical practice guideline in OSA treatment underline the three fundamentals step in adherence: educational, troubleshooting and behavioral interventions. Within this framework, the present review aims to synthesize the available evidence on the strategies with the strongest scientific support which should constitute the foundation of any CPAP initiation program. In addition, psychosocial interventions, particularly CBT-I in patients with COMISA, has been discussed as promising but not yet fully standardized approaches. More exploratory strategies, such as phenotype- or endotype-guided titration, will also be addressed, given their potential to support a more individualized approach not only to treatment delivery, but also to adherence promotion. Personalized medicine in OSA has shown that some patients—for example, due to endotypic factors (low arousal threshold) and phenotypic factors (women with insomnia, young adults with insomnia)—have poor adherence to CPAP. For these patients, tailoring adaptation strategies—as has been done for the female “phenotype” using a machine with a dedicated algorithm or a combined approach, such as CPAP + CBT for young adults with insomnia—may be the right way to address the adherence issue through greater personalization of the therapy itself, rather than simply dividing patients into adherent and non-adherent groups. In conclusion the aim of this narrative review is to rethink CPAP adherence with a multifactorial approach that takes into account patient traits, their phenotype, and treatment-related factors, leading to a personalized approach to optimize long-term adherence.”

Methodology and Justification
The methodology section is too brief and lacks the necessary transparency:

Furthermore, they only searched a single database, and it is unclear why they did not perform a quality assessment of the studies (risk of bias) or a more in-depth analysis.These clarifications have been added to improve transparency and to better align the Methods section with the actual methodology used in the preparation of the manuscript.

Thank you to the reviewer for the suggested change. We have revised the chapter as follows:

Materials and Methods

Restructuring Proposal (Main Recommendation)
Given the potential of the topic and the fact that they have already compiled high-level literature, I strongly encourage them to enhance the rigor of their manuscript by transforming it from a narrative review into a proper systematic review. To this end, I recommend strictly adhering to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). This restructuring will require:

Expanding the search to a minimum of two or three major databases (e.g., PubMed/MEDLINE, Scopus, Web of Science).

Registering the protocol (e.g., in PROSPERO) or detailing its design transparently.

Including a flowchart and feature tables that clearly show which studies are included, how they were selected, and their main characteristics—elements currently missing from the manuscript.

Incorporating a formal tool for assessing the methodological quality of the included studies.

We appreciate the Reviewer's observation. However, the present manuscript was conceived and presented from the outset as a narrative review, not as a systematic review. Therefore, it was not intended to comply with formal systematic review standards such as PRISMA flowcharting, predefined inclusion/exclusion criteria, or structured risk-of-bias assessment. To improve clarity and transparency, we have nonetheless expanded the methodological description of the literature search and article selection process in the revised version.

Discussion and Limitations
The discussion completely omits the study's limitations. All research, and especially a review with a search strategy restricted to a single database, is subject to bias (such as selection or publication bias). A dedicated paragraph is needed to honestly and critically analyze the limitations of your work.

Thanks to the reviewer we have added this paragraph

“This review has some limitations that should be acknowledged. As a narrative review, it does not follow the methodological framework of a systematic review, and the selection of the included studies may therefore have been influenced, by the authors necessity to answer to necessity in clinical practice. In addition, no formal quality assessment of the included studies was performed. Consequently, the evidence discussed should be interpreted with caution, particularly in view of the heterogeneity of study designs, methodologies, and overall quality. Nevertheless, this review was conceived with a practical clinical focus and was informed, where relevant, by current recommendation s from the American Academy of Sleep Medicine. Its added value lies in providing a pragmatic, scientifically grounded overview of the main factors currently limiting CPAP adherence, while also offering practical guidance to support clinicians in addressing this challenging issue.”

Conclusions
The current conclusions are too strong and categorical considering the design used and the methodological limitations observed. I suggest you refine their tone, ensuring that they objectively, prudently, and faithfully reflect the actual results from the analyzed literature, without resorting to overgeneralizations.

Thank you again to the reviewer. We made changes in conclusion section as you can view in revised manuscript version.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for this valuable review.

The manuscript addresses a clinically important and timely topic. It is generally well-organized and cites relevant recent literature. However, several areas require clarification, restructuring, and language editing before publication.

The flow of sections is sometimes disjointed (e.g., Section 3.5 on patient perception is very brief and could be merged with the introduction or discussion).

Section 3.2 (Patient-related factors): The statement on sex differences is appropriately presented as controversial, but the authors should clarify that most recent large cohorts show no clinically significant difference after adjusting for symptom severity.
Section 3.3 (Disease-related factors): The concept of “low arousal threshold” is introduced without a clear definition. A brief explanation or reference to a definitional study would help readers.Section 3.4 (Treatment-related factors): The conclusion that APAP vs. CPAP shows no adherence difference is correct, but the authors should mention that some subgroups (e.g., high loop gain) might benefit from advanced algorithms.

Section 3.6 (Follow-up): The authors list many interventions but do not prioritize them. A practical, stepwise clinical algorithm would strengthen the paper.

Several references are incomplete (e.g., ref 24, 25, 41, 44, 52 – missing page numbers or journal name formatting).

Ref 37 (Wellman et al.) is outdated for the simplified method; a more recent validation study should be cited.

Moderate English editing is needed. Examples:

“Restless syndrome” → should be “Restless legs syndrome (RLS)”
“capability” → “ability”
“multidynamic” → “dynamic” or “multifactorial”

Some sentences are overly long and should be broken for clarity

Best regards,

Comments on the Quality of English Language

Moderate English editing is needed. Examples:

“Restless syndrome” → should be “Restless legs syndrome (RLS)”
“capability” → “ability”
“multidynamic” → “dynamic” or “multifactorial”

Some sentences are overly long and should be broken for clarity

Author Response

Comments and Suggestions for Authors

Dear Authors,

Thank you for this valuable review.

The flow of sections is sometimes disjointed (e.g., Section 3.5 on patient perception is very brief and could be merged with the introduction or discussion).

Section 3.2 (Patient-related factors): The statement on sex differences is appropriately presented as controversial, but the authors should clarify that most recent large cohorts show no clinically significant difference after adjusting for symptom severity.

Thank you for the suggestion we added this part in sex difference chapter

“Another recent article suggest that women under 50 experience the largest decline in CPAP adherence. These findings highlight the potential need for age- and sex-specific strategies to sustain long-term engagement with PAP therapy Vodapally M, Chan-Golston AM, Sandhu J, DelRosso LM. Age and sex differences in longitudinal CPAP adherence patterns. Respir Med. 2026 Apr;254:108755. doi: 10.1016/j.rmed.2026.108755. Epub 2026 Mar 5. PMID: 41791299. Data on sex differences in CPAP adherence remain inconsistent. One possible explanation is that earlier studies did not adequately account for relevant comorbidities that are particularly frequent in women, such as COMISA, depression, restless legs syndrome, and other sleep-related or psychiatric conditions, all of which may substantially influence treatment acceptance and long-term use. In addition, the apparent effect of sex may be partly confounded by social and behavioural factors that have changed over time, although this hypothesis has not been formally demonstrated. What appears more certain is that women with OSA represent a heterogeneous group, with phenotypic differences that remain less well characterized than in men, as also suggested by the ESADA study. Therefore, discussing CPAP adherence in women as a single, uniform entity is likely an oversimplification. Pataka A, Pepin JL, Bonsignore MR, Schiza S, Saaresranta T, Bouloukaki I, Steiropoulos P, Trakada G, Riha R, Dogas Z, Testelmans D, Basoglu OK, Mihaicuta S, Fanfulla F, Grote L, Bailly S; ESADA Study Group. Sleep apnoea phenotypes in women: A cluster analysis from the ESADA cohort. Sleep Med. 2024 Dec;124:494-501. doi: 10.1016/j.sleep.2024.10.015. Epub 2024 Oct 15. PMID: 39437459

Section 3.3 (Disease-related factors): The concept of “low arousal threshold” is introduced without a clear definition. A brief explanation or reference to a definitional study would help readers.

Thank you to the reviewers for the comment. We added the role of Low Arousal Threshold in OSA pathophysiology in shorter as follow

“A low arousal threshold indeed refers to a patient “easy to wake up” and for this reason more susceptible to changes in pressure treatment levels. Low Arousal threshold is characterized a less negative Endo esophageal pressure threshold that induces an arousal. So, in this patient when the upper airway is just starting to close like in a flow limitation, with a minimal negative Endo esophageal pressure, the patient wakes up. The pCO2 became instable, sleep became instable, N3 sleep decrease and also patency of the upper airway reduces. In these patients, if the non-anatomical trait prevails, CPAP couldn’t be the first choice of treatment.”

Section 3.4 (Treatment-related factors): The conclusion that APAP vs. CPAP shows no adherence difference is correct, but the authors should mention that some subgroups (e.g., high loop gain) might benefit from advanced algorithms.

Thank you to the reviewer for the comment

We have added that also high loop gain cold be treated with the same caution or algorithm model of low AT.

“In patients with severe OSA, a high loop gain is more common and may compromise CPAP adherence, as suggested by the occurrence of treatment-emergent central sleep apnea (TECSA). Patients with high loop gain exhibit an exaggerated ventilatory response to even mild or moderate changes in CO2, which amplifies respiratory instability. In such cases, using a narrower pressure range during auto-CPAP titration or opting for fixed-pressure CPAP may be beneficial. Although no dedicated algorithm has yet been implemented for patients with OSA and high loop gain, this represents a promising area for personalized medicine

Expiratory Pressure Relief (EPR) can indirectly benefit patients with high loop gain by lowering expiratory pressure, which reduces mean airway pressure and helps avoid excessive CO₂ washout that can trigger ventilatory instability. By decreasing respiratory effort—particularly at higher pressures (>12 cmH₂O)—EPR may also reduce arousals in these patients, who often have a low arousal threshold, thereby dampening the instability cycle. However, in cases of very high loop gain, EPR alone may be insufficient; more tailored settings or advanced ventilatory modes may be needed. For such patients, in-lab manual titration is often the best approach to identify a stable setup that controls obstruction without provoking exaggerated ventilatory responses. (metti come references larticolo di Messineo da leggere meglio)

Section 3.6 (Follow-up): The authors list many interventions but do not prioritize them. A practical, stepwise clinical algorithm would strengthen the paper.

We have added a figure instead of write an algorithm

Figure 2. Stepwise CPAP follow-up: at each visit check leaks, usage hours, and residual symptoms; optimize mask fit and pressures; if adherence is reduced, implement motivational strategies; if residual sleepiness persists, rule out comorbidities (depression, PLM, medications) and consider pharmacologic therapy

Several references are incomplete (e.g., ref 24, 25, 41, 44, 52 – missing page numbers or journal name formatting).

Thank you the reviewer for the contribute with some automatic errors with the references. We have corrected them.

Ref 37 (Wellman et al.) is outdated for the simplified method; a more recent validation study should be cited.

Thank you to the author for the suggestion. We cited the first method in the literature. We will change the reference with

P.I. Terrill, et al., Quantifying the ventilatory control contribution to sleep apnoea using polysomnography, Eur. Respir. J. 45 (2) (feb. 2015) 408–418, https://doi. org/10.1183/09031936.0006

Comments on the Quality of English Language

Moderate English editing is needed. Examples:

“Restless syndrome” → should be “Restless legs syndrome (RLS)”
“capability” → “ability”
“multidynamic” → “dynamic” or “multifactorial”

Some sentences are overly long and should be broken for clarity

Thank you to the reviewer, we have done and revised the manuscript

Reviewer 5 Report

Comments and Suggestions for Authors

The topic is clinically relevant, and the manuscript addresses an important practical problem in OSA care: the persistence of suboptimal CPAP adherence despite technological improvements. However, the current version does not yet provide a sufficiently rigorous or transparent narrative synthesis to support several of its practical recommendations. The article would benefit from a clearer distinction between evidence-based recommendations, expert opinion, plausible mechanistic reasoning, and areas where evidence remains preliminary.

Please provide a reproducible description of the literature search. The Methods section should include the full PubMed/MEDLINE search string, the exact date on which the search was performed, how Google Scholar was searched, explicit inclusion and exclusion criteria, the number of records screened, and the process used by the two reviewers to resolve disagreements. The terms “clinical relevance,” “methodological quality,” and “expert consensus” should be operationally defined rather than left as subjective selection criteria.
Please correct the inconsistency between the stated search period and the reference list. The Methods section states that the search covered January 1995 to December 2025, but several cited articles are listed as 2026 publications, including references 5, 33 and 58. Either the search end date should be updated and justified, or these references should be removed or replaced if they were not available within the stated search period.
Please check the accuracy of all citation-to-claim links. One clear example is the statement that correct information about OSA led to a 1-hour increase in daily CPAP use, which is attributed in the text to Jurado-Gamez et al.; however, the corresponding reference 56 is Sawyer et al., a qualitative study on patient perceptions. Please correct the citation or revise the claim. Given this mismatch, the full reference list should be systematically verified.
Please revise the section on the 4-hour adherence threshold to distinguish administrative adherence criteria from clinically meaningful CPAP use. The manuscript should clarify that the 4-hour threshold is commonly used for reimbursement or coverage purposes, but that symptom improvement, neurocognitive outcomes, quality of life, blood pressure, and cardiovascular risk may have different dose-response relationships. The current wording risks implying that 4 hours is clinically ineffective in all patients, which is too broad.
Please moderate the recommendation that nasal masks should be the first choice. The manuscript provides physiological and clinical arguments supporting nasal interfaces, but the recommendation should explicitly acknowledge exceptions, including relevant nasal obstruction, persistent mouth leak, patient preference, previous intolerance, craniofacial or anatomical considerations, and the need for individualized mask fitting. The Starling resistor model alone is not sufficient justification for a universal first-choice recommendation.
Please reconcile the statements on OSA endotypes and CPAP adherence. The abstract suggests that endotype and phenotype traits could be used to predict adherence and guide titration, whereas the main text states that current evidence does not support using endotypes alone to predict CPAP adherence. Please clearly separate evidence-supported clinical applications from hypotheses that still require prospective validation.
Please specify how phenotype or endotype assessment would be implemented in everyday clinical care. If the review recommends using traits such as loop gain, arousal threshold, anatomical collapsibility, or upper airway muscle responsiveness to personalize PAP titration, the manuscript should explain whether these traits are routinely measurable, which methods are required, and whether the recommendation is practical outside specialized sleep centers.
Please add a summary table listing each adherence strategy discussed in the review—patient education, mask/interface selection, management of nasal obstruction, APAP versus fixed CPAP, early follow-up, telemedicine, CBT-I for COMISA, motivational or cognitive-behavioral interventions, group sessions, and partner involvement. For each strategy, the table should state the type of supporting evidence, the patient subgroup to which it applies, the expected adherence outcome where available, and the main limitation of the evidence.
Please expand the practical discussion of early PAP titration. The manuscript states that suboptimal titration, residual events, leaks, and pressure-related discomfort can affect early adherence, but it does not provide a sufficiently clear clinical pathway. Please specify what clinicians should assess during the first days or weeks of treatment, including residual AHI, leak, pressure intolerance, emergent central apneas, nasal symptoms, dry mouth, insomnia, and mask-related skin problems.
Please define the follow-up strategy more concretely. The manuscript emphasizes early follow-up, but it should specify the proposed timing, for example first week, 2–4 weeks, and longer-term review, and what should be done at each visit or telemonitoring contact. This would make the review more useful for everyday clinical care.
Please revise Figure 1 so that it provides more actionable information. At present, it lists disease-related, treatment-related, and patient-related factors, but it does not distinguish modifiable from non-modifiable factors or indicate when each factor should be addressed. A revised figure could separate pre-CPAP assessment, titration phase, early follow-up, and long-term maintenance.
Please revise Figure 2 for clarity and accuracy. The four-step structure is useful, but the figure contains wording errors such as “How to choice the pressure and the mask?” and oversimplifies follow-up as “resolves the problems.” The follow-up step should explicitly include residual AHI, leaks, pressure intolerance, nasal/oral dryness, insomnia, telemonitoring data, and adherence troubleshooting.
Please temper the conclusion regarding telemedicine. The statement that telemedicine “could be the key to ensuring long-term adherence on a large scale” should be revised unless the manuscript provides a more detailed synthesis of telemedicine trials, intervention heterogeneity, duration of benefit, implementation barriers, and patient groups most likely to benefit.
Please correct language errors that affect clinical clarity and credibility. Examples include “A Patients should initially be educated” in the abstract, “Importanly,” “Regarding to comparison,” “How to choice the pressure and the mask?” in Figure 2, and several awkward or grammatically unclear sentences throughout the manuscript. These should be corrected after the scientific revisions so that the practical recommendations are unambiguous.

Author Response

evidence-based recommendations,

expert opinion,

plausible mechanistic reasoning, and

areas where evidence remains preliminary.

Thank you to the reviewer We have done an explicative table of the different recommendation and their evidences in literature. See table 3

Please provide a reproducible description of the literature search. The Methods section should include the full PubMed/MEDLINE search string, the exact date on which the search was performed, how Google Scholar was searched, explicit inclusion and exclusion criteria, the number of records screened, and the process used by the two reviewers to resolve disagreements. The terms “clinical relevance,” “methodological quality,” and “expert consensus” should be operationally defined rather than left as subjective selection criteria.

Thank you to the reviewer for the comment. We have rewritten the method session. The terms “clinical relevance,” “methodological quality,” and “expert consensus” have been defined better in the review.

Materials and Methods

Please correct the inconsistency between the stated search period and the reference list. The Methods section states that the search covered January 1995 to December 2025, but several cited articles are listed as 2026 publications, including references 5, 33 and 58. Either the search end date should be updated and justified, or these references should be removed or replaced if they were not available within the stated search period.

Thank you to the reviewer for the comment we have added some articles in the last version because they are clinically relevant in the aim of our study.

Please check the accuracy of all citation-to-claim links. One clear example is the statement that correct information about OSA led to a 1-hour increase in daily CPAP use, which is attributed in the text to Jurado-Gamez et al.; however, the corresponding reference 56 is Sawyer et al., a qualitative study on patient perceptions. Please correct the citation or revise the claim. Given this mismatch, the full reference list should be systematically verified.

Thank you for this helpful comment. We have carefully checked the citation in the section on patients' perception and verified its correspondence with the reference list. The reference has been corrected where necessary

Please revise the section on the 4-hour adherence threshold to distinguish administrative adherence criteria from clinically meaningful CPAP use. The manuscript should clarify that the 4-hour threshold is commonly used for reimbursement or coverage purposes, but that symptom improvement, neurocognitive outcomes, quality of life, blood pressure, and cardiovascular risk may have different dose-response relationships. The current wording risks implying that 4 hours is clinically ineffective in all patients, which is too broad.

Thank you to the reviewer for the suggestion. Adherence in medicine in general is defined as the active and collaborative therapy acceptation. Adherence to CPAP therapy is defined during the year as the use of more than 70% of the night per at list 4 hours. This cut off is necessary to give a range in literature and to define the lower limit of adherence and is commonly used for reimbursement or coverage purposes. So, we underline the limit of this range even if it is not clinically ineffective for all patients. We rewrote the chapter “3. 1. CPAP adherence: definition, times frame and limitations”

3.1. CPAP adherence: definition, timesframe and limitations.

In 2009, the Centers for Medicare & Medicaid Services adopted a requirement of minimum 4 hours of Positive Airway Pressure (PAP) use for 70% of nights, or 21 days in a consecutive 30-day period, to continue medical coverage for PAP therapy [6]. The use of an economic rather than a clinical definition is the first CPAP adherence issue to be fixed. Indeed this is commonly used for reimbursement or coverage purposes but although it is not clinically ineffective for all patients ti is not the goal that a clinician could be suggest to his patient. Few hours during the night could not improve symptoms, quality of life or reduce cardiovascular risk, with a subsequent reduction in patient motivation. Daytime sleepiness improves after 7 hours of sleep, while seven hours and 30 minutes is the medium time necessary to reach a good performance status [7]. This range could also be different for shorter or longer sleeper and varying during the time life. Without doubt a cut off and a measure is necessary in literature to quantify the adherence and compared different report but for a clinical point of view CPAP treatment could be applied during sleep without interruption and this could be underline in particular in patients with REM sleep in which the second part of the night could be less attentional from the patients. Considering that a physiological hypnogram has a prevalence of Rapid-Eye Movement (REM) sleep in the second half of the night and that REM-OSA is associated with higher cardiovascular risk, an OSA patient who removes the mask after only the first 4 hours of sleep will not treat the deeper desaturations, the more severe events and the cardiovascular risk [8,9]. In addition recent evidences underline that patients with REM-related OSA demonstrated significantly lower nightly CPAP use in particular in long term adherence compared with patients with non-stage-specific OSA T. Hoshino, R. Sasanabe, T. Tanigawa, et al., Effect of rapid eye movement-related obstructive sleep apnea on adherence to continuous positive airway pressure, J. Int. Med. Res. 46 (6) (Jun 2018) 2238–2248, https://doi.org/10.1177/ 0300060518758583.

Always more studies showed that CPAP efficacy have a dose-response effect [10], suggesting that the ineffectiveness of CPAP in terms of cardiovascular and metabolic health in some trials is partly due to poor or not optimal adherence [11]. Another aspect is the definition of adherence compared to compliance. The term adherence itself underlines the necessity of the active and collaborative treatment acceptation including a self-efficacy meaning,with a no exclusive terminological difference with the most passive compliance. Adherence is also different from the acceptance. Acceoatnce is defined as willingness to purchase and use a CPAP device and it could be related to financial issue, social stigma or intolerance to CPAP or preference to another therapy. (Accepatance and compliance of CPAP therapy in patients with OSA (ERJ open research 2025 11 (suppl 16) 184). In sleep medicine is also important the time issue that defines the short and long term adherence. The last one refers to different time horizons (3, 6 or 12 months), while shorter adherence refers to the first month of CPAP treatment and strongly influences the following period.

Please moderate the recommendation that nasal masks should be the first choice. The manuscript provides physiological and clinical arguments supporting nasal interfaces, but the recommendation should explicitly acknowledge exceptions, including relevant nasal obstruction, persistent mouth leak, patient preference, previous intolerance, craniofacial or anatomical considerations, and the need for individualized mask fitting. The Starling resistor model alone is not sufficient justification for a universal first-choice recommendation.

Thank you to the reviewer for the comment. We specify in the text that nasal mask could be in general the first choice for a pathophysiological explanation. However, we totally agree that mask choice could be individualized and we specified that in the text. Thanks also for the suggestion we have written in the text the difference in the patient’s choice.

The choice of an appropriate interface is a key determinant of treatment adherence. An inadequate size may cause discomfort or excessive leaks. Patients generally prefer nasal masks and nasal pillow interfaces because of their lower contact surface and greater comfort [40]. Current evidence supports that nasal interfaces are associated with better adherence, improved comfort, and lower leak rates compared with oronasal masks [41]. A nasal mask also reproduces natural breathing, whereas oral breathing contributes only minimally to the sleep breathing pattern [42]. Indeed, oral breathing is associated with increased upper airway resistance and reduced upper airway stability [43]. For these reasons, the use of oronasal masks may be counterproductive by promoting posterior tongue collapse and increasing pharyngeal collapsibility [43]. Moreover, oronasal masks typically require higher PAP compared with nasal interfaces [44]. Between nasal masks and nasal pillows, the available evidence suggests comparable efficacy in terms of residual AHI and sleep architecture, with only minimal differences in adherence [45]. Therefore, the choice between these interfaces should be guided primarily by patient comfort and preference. Moderated recommendation on interface selection Nasal interfaces should be considered early in mask selection, but they are not a universal “first choice” for every patient. Selection should be individualized, explicitly acknowledging exceptions such as relevant nasal obstruction or active nasal disease. Patient preference or prior intolerance could be considerate. Other patient could have a craniofacial or anatomical factors that impede seal or comfort with nasal mask, but for example retrognathic patients should be treated with the nasal mask first.

Please reconcile the statements on OSA endotypes and CPAP adherence. The abstract suggests that endotype and phenotype traits could be used to predict adherence and guide titration, whereas the main text states that current evidence does not support using endotypes alone to predict CPAP adherence. Please clearly separate evidence-supported clinical applications from hypotheses that still require prospective validation.

Thank you for your suggestion we defined in the text the pathophysiological mechanisms that explain and demonstrate, as shown in the literature, which endotypes are less tolerant, as has already been demonstrated in the literature. However, we have made it clear in the text that there are no clinical trials that have demonstrated which strategies to adopt in these patients. However, we would like to clarify that these are not merely pathophysiological assessments; there is now evidence in the literature showing that certain endotypes are predictors of lower adherence. Christopher N. Schmickl et al MedRxiv 2025.10.17.25337940;

Please specify how phenotype or endotype assessment would be implemented in everyday clinical care. If the review recommends using traits such as loop gain, arousal threshold, anatomical collapsibility, or upper airway muscle responsiveness to personalize PAP titration, the manuscript should explain whether these traits are routinely measurable, which methods are required, and whether the recommendation is practical outside specialized sleep centers.

Thank you to the reviewer for the comment. We have rewritten the text.

Based on current knowledge, we are unable in routine clinical practice to definitively determine our patient’s endotype, which is often not just one; for example, a patient with high loop gain often also has a low arousal threshold. However, certain polysomnographic characteristics suggest one endotype over another, and this is reported in the literature, particularly with regard to high loop gain (coexisting or mixed central apneas, periodic breathing, waxing and waning, exaggerated ventilatory response) or a low arousal threshold (Edwards criteria). The effort to recognize these characteristics—pending the development of validated methods for their identification—is not merely an exercise, because guidance on which therapeutic approaches work and which do not, depending on the endotype, is already well-established in the literature (aritcolo di Eckert nov 2025). Obviously, at the moment this is only possible in centers with extensive experience, but it is currently essential to at least anticipate or suspect when a patient may be difficult to treat based on their endotype. The literature is clear, for example, that poor tolerance to CPAP has been demonstrated in patients with a low arousal threshold, where the pathophysiological mechanism is respiratory instability following sleep instability, and the airway collapse that CPAP addresses is merely a consequence. (articolo Medriv di malotra citrato sopra)

Please add a summary table listing each adherence strategy discussed in the review—patient education, mask/interface selection, management of nasal obstruction, APAP versus fixed CPAP, early follow-up, telemedicine, CBT-I for COMISA, motivational or cognitive-behavioral interventions, group sessions, and partner involvement. For each strategy, the table should state the type of supporting evidence, the patient subgroup to which it applies, the expected adherence outcome where available, and the main limitation of the evidence.

Summary table listing each adherence strategy discussed. Please see table 4

Please expand the practical discussion of early PAP titration. The manuscript states that suboptimal titration, residual events, leaks, and pressure-related discomfort can affect early adherence, but it does not provide a sufficiently clear clinical pathway. Please specify what clinicians should assess during the first days or weeks of treatment, including residual AHI, leak, pressure intolerance, emergent central apneas, nasal symptoms, dry mouth, insomnia, and mask-related skin problems.

3.6. Follow up and practical approach for early problems solutions Early follow-up represents one of the most effective interventions for improving long-term PAP adherence and should be regarded as a dynamic, patient-centered adaptation process rather than simply the identification of an effective therapeutic pressure [58]. Current guidelines emphasize that the first days and weeks of therapy are crucial for identifying and correcting factors that may compromise treatment acceptance before they lead to treatment discontinuation.The titration pathway should be adapted not only to the patient’s clinical characteristics but also to the organization of the sleep center. In centers where PAP initiation is performed on an outpatient basis, an acclimatization period with auto-adjusting PAP may allow optimization of the pressure range, minimum and maximum pressure settings, ramp activation and duration according to the patient’s sleep onset latency, and overall treatment tolerance before defining long-term settings[59]. The most commonly reported side effects within the first month include dry mouth and nasal symptoms, such as congestion or mucosal irritation [60]. Nasal or oral dryness may improve with heated humidification and, when appropriate, heated tubing, whereas mask-related skin lesions usually respond to interface refitting, reduction of strap tension, interface replacement, or protective dressings.

Additional issues may include mask leaks, skin lesions related to the interface, airflow-related discomfort, and sleep fragmentation [61]. In these cases, a careful management of mask fitting, circuit leaks and air humidification may improve patients’ adherence [62].. Pressure intolerance can often be improved by optimizing pressure settings, ramp duration, or expiratory pressure relief (EPR), while persistent treatment-emergent central sleep apnea may require closer follow-up and, in selected patients, modification of the ventilatory strategy (Patil et al., 2019; Aurora et al., 2025).Educational and behavioral interventions have been shown improvements in adherence. Continuous support with telemedicine, telephone follow-up, group-base interviews and cognitive-behavioral therapy may improve CPAP adherence by enhancing patients’ engagement [63, 64]. In centers equipped with telemedicine, remote review of PAP downloads allows clinicians to rapidly detect poor adherence, excessive leaks, or persistent residual respiratory events and implement timely corrective measures before these issues become barriers to long-term treatment. In centers where telemonitoring is unavailable, proactive telephone contact during the first days of treatment or an early structured follow-up call may be equally valuable to identify technical difficulties, reinforce education, explore patient concerns, and arrange earlier clinical reassessment when necessary.Clinicians should always evaluate emerging conditions during initial CPAP therapy phase, including insomnia, depressive symptoms or sleep-related movement disorders because these issues can cause CPAP interruption [65-67]. Finally, follow-up intensity should be individualized according to the patient’s estimated risk of poor adherence. Patients presenting with anxiety, depression, comorbid insomnia, sleep-related movement disorders, advanced age, cognitive impairment, limited social support, or previous negative experiences with PAP therapy may benefit from a more intensive follow-up schedule during the adaptation phase (Patil et al., 2019; Bakker et al., 2019). Overall, successful long-term PAP adherence relies on a personalized strategy integrating individualized titration, careful interpretation of PAP waveforms rather than device metrics alone, prompt troubleshooting of side effects, patient-centered education, and a risk-stratified follow-up adapted to both the patient’s needs and the organizational resources of the sleep center. A table with common barriers to CPAP adherence and practical management strategies has been added to this chapter. (TableX)

Please define the follow-up strategy more concretely. The manuscript emphasizes early follow-up, but it should specify the proposed timing, for example first week, 2–4 weeks, and longer-term review, and what should be done at each visit or telemonitoring contact. This would make the review more useful for everyday clinical care.

The patient should first be re-evaluated shortly after starting CPAP therapy. Depending on the specific characteristics of the various centers and their workflow—for example, whether titration is performed via telemedicine—the decision regarding when to schedule the first visit may vary. A longer interval is appropriate when titration is performed via telemedicine, which allows for day-to-day monitoring of leaks and fit; a shorter interval is recommended for those not yet using telemedicine to prevent certain problems from going unresolved and the patient from discontinuing therapy.

Please revise Figure 1 so that it provides more actionable information. At present, it lists disease-related, treatment-related, and patient-related factors, but it does not distinguish modifiable from non-modifiable factors or indicate when each factor should be addressed. A revised figure could separate pre-CPAP assessment, titration phase, early follow-up, and long-term maintenance.

Thanks for the comment. I kept operational guidance even for non‑modifiable factors because the goal is to guide clinical action (compensation/adaptation/monitoring), not only labeling. In any case, We have added a supplementary table (table 2) that separates phases (pre‑CPAP, titration, early follow‑up, maintenance) and clearly distinguishes modifiable vs non‑modifiable items, indicating when to intervene.

Please revise Figure 2 for clarity and accuracy. The four-step structure is useful, but the figure contains wording errors such as “How to choice the pressure and the mask?” and oversimplifies follow-up as “resolves the problems.” The follow-up step should explicitly include residual AHI, leaks, pressure intolerance, nasal/oral dryness, insomnia, telemonitoring data, and adherence troubleshooting.

Thank you to the reviewer for the comment. We modified.

Please temper the conclusion regarding telemedicine. The statement that telemedicine “could be the key to ensuring long-term adherence on a large scale” should be revised unless the manuscript provides a more detailed synthesis of telemedicine trials, intervention heterogeneity, duration of benefit, implementation barriers, and patient groups most likely to benefit.

Ok thank you for the suggestion we are addend on the text

Please correct language errors that affect clinical clarity and credibility. Examples include “A Patients should initially be educated” in the abstract, “Importanly,” “Regarding to comparison,” “How to choice the pressure and the mask?” in Figure 2, and several awkward or grammatically unclear sentences throughout the manuscript. These should be corrected after the scientific revisions so that the practical recommendations are unambiguous.

Thank you we have modified all the article with the help of a native speaker.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors, I wish to express my sincere gratitude for the excellent work done on this new version of the manuscript and for having addressed each of the suggestions made in the previous review round so rigorously and in such detail. It is evident that the changes introduced have substantially improved the clarity, methodological rigor, and overall quality of the study, reflecting your great commitment to raising the level of research. Having confirmed that all the observations have been satisfactorily addressed, it is a pleasure to congratulate you on the final result, which I believe meets the high standards required and makes a significant contribution to the scientific literature in this field.

Author Response

Thank you for your thoughtful and encouraging review. We appreciate your time and are delighted the revisions met your expectations

Reviewer 5 Report

Comments and Suggestions for Authors

The revised manuscript has improved in scope and practical orientation, particularly through the addition of summary tables and a more explicit distinction between well-supported, promising, and exploratory strategies. However, several major concerns from the previous review remain only partially addressed. The manuscript still does not provide a sufficiently transparent or reproducible account of the literature selection process. The Methods section reports broad keywords and subjective selection criteria, but it does not provide the full PubMed/MEDLINE search string, the exact date of the final search, the number of records screened, the Google Scholar procedure, or sufficiently operational inclusion and exclusion criteria. Stating that no PRISMA, SANRA, protocol, or standardized quality assessment was used is acceptable for a narrative review, but it does not replace the need for a transparent account of how the literature was identified and selected.

The citation-to-claim problem remains a major concern. The authors have corrected the previous date inconsistency by extending the search period to May 2026, so that point no longer needs to be raised. The remaining problem is that several claims are still not adequately linked to the cited references. For example, the manuscript states that CBT-I before CPAP significantly increased CPAP adherence in COMISA patients, but the cited references visible in the revised reference list do not correspond to randomized CBT-I adherence trials. Because a citation mismatch was already noted in the previous round, the authors should now check every citation-to-claim link in the manuscript.
The revised discussion of the 4-hour adherence threshold is directionally better, but the wording remains imprecise and sometimes overgeneralized. The manuscript should distinguish more clearly between an administrative or reimbursement threshold, a reporting convention used in research, and clinically meaningful CPAP use. Statements implying that shorter nightly use will not improve symptoms or cardiovascular risk should be softened unless supported by specific dose-response evidence. The REM-OSA argument is plausible and clinically relevant, but it should be framed as a subgroup-specific concern rather than as general proof that the 4-hour threshold is clinically inadequate in all patients.
The section on phenotypes and endotypes remains too assertive for the evidence presented. The manuscript acknowledges that routine clinical endotyping is not currently feasible and that validated methods are lacking, but it also states that guidance on endotype-based therapeutic approaches is already “well-established” and that poor CPAP tolerance in low arousal threshold patients has been clearly demonstrated. These statements need further tempering. Phenotype- and endotype-guided titration should be presented as a promising hypothesis or specialized-center approach requiring prospective validation, not as a currently established clinical pathway for everyday care.
The response to the request for practical implementation of endotype assessment remains incomplete. The revised text mentions polysomnographic clues for high loop gain and low arousal threshold, but it does not clearly explain which traits can be measured reliably in routine practice, which require specialized methods, and which remain inferential. A short practical paragraph distinguishing routinely available clinical clues, specialized-center measurements, and research-only measures would make the section much more useful and would prevent overtranslation of mechanistic concepts.
The mask/interface section has improved, but it still contains unsupported or overly categorical statements. The recommendation that retrognathic patients “should be treated with the nasal mask first” requires either a specific supporting citation or removal. The manuscript should consistently state that nasal interfaces are often preferable when feasible, but that mask choice must be individualized according to nasal patency, mouth leak, facial anatomy, comfort, previous intolerance, and patient preference.
The added tables are useful, especially the table summarizing adherence strategies, evidence type, target subgroup, expected outcome, and limitations. However, Table 3 needs refinement because some categories appear inconsistent. For example, CBT-I for COMISA is placed under evidence-based recommendations, whereas psychological support programmes are categorized as preliminary. In addition, the terminology used for telemedicine and digital health interventions should be consistent across the text and tables. The authors should ensure that each strategy is categorized consistently with the strength and type of evidence cited in the text.
The follow-up section has been expanded, and Table 2 now introduces phase-based guidance, including pre-CPAP assessment, titration, early follow-up, and long-term maintenance. However, this structure is not clearly integrated into the main text or into Figure 2. The manuscript should state more concretely what should be assessed at each contact, including nightly use, residual AHI, leak, pressure intolerance, treatment-emergent central apneas, nasal/oral dryness, insomnia, mask-related skin problems, residual symptoms, and patient concerns.
Figure 2 remains below publication quality. Although the concept is useful, the figure still contains informal wording, spelling errors, unclear visual organization, and oversimplified action steps such as “change mask or education,” “Motivation with CBTi or groups work,” and “adherrence.” The figure should be redesigned as a clean clinical algorithm with precise wording and a clearer sequence of assessment and management steps. The caption should also match the actual content of the figure.
The conclusion regarding telemedicine has been moderated, but it remains grammatically unclear and still too broad. Telemedicine should be framed as one potentially useful component of structured follow-up, rather than as a general solution for ensuring adherence at scale. The manuscript should briefly acknowledge heterogeneity across telemonitoring interventions, variable long-term effects, infrastructure requirements, and unequal suitability across patient groups.
The language still requires extensive revision. This is not a minor stylistic issue: several sentences are difficult to interpret clinically, and errors remain throughout the abstract, methods, results, figures, and conclusions. Examples include incorrect verb agreement, awkward clinical phrasing, repeated wording, spelling errors, and unclear expressions such as “treatment acceptation,” “times frame,” “patient preference or prior intolerance could be considerate,” and “telemedicine… could be useful to ensuring adherence.” The manuscript should undergo a thorough professional language edit after the scientific corrections have been completed.
The authors’ response letter should be revised to provide a clearer point-by-point account of the changes made. Several responses simply state that the text was rewritten or corrected, without indicating where the change was made or how the concern was addressed. For a revised submission, the response should specify the manuscript section, table, or figure modified, and should clearly justify any recommendation that was not fully changed.

Author Response

Response to reviewer number 1: With sincere appreciation for the reviewers’ exceptional insight, we first applied a rigorously structured search strategy on adherence-related keywords, and then—far beyond mere keyword-matching of titles or abstracts—systematically re-examined every clinically salient dimension (physiopathology, mask selection, technical refinements, CPAP vs auto-CPAP, and adherence in women with OSA) to surface the most decision-informing evidence for diagnostic, therapeutic, and follow-up choices, capturing both direct adherence outcomes and indirect effectiveness aligned with underlying physiological mechanisms. We conducted this narrative review on CPAP adherence. Sources included PubMed/MEDLINE and Google Scholar, supplemented by backward and forward citation tracking of included studies.

Coverage and dates

Time window: January 1995 to June 2026.
Final search date: 2026-06-20

PubMed/MEDLINE search strategy

Platform: [specify, e.g., PubMed web].
Exact string used (including field tags and filters) in title or abstract: "obstructive sleep apnea," "OSA," "continuous positive airway pressure," "CPAP “AutoCAP”, “adherence," "compliance," treatment”, follow up”, "telemedicine," "cognitive behavioral therapy," "mask interface," nasal mask” , “ oronasal mask” "OSA phenotype," and "endotype."
Filters: Humans; English; 1995/01/01–2026/06/20; Article types: Clinical Trial, Observational Study, Meta-Analysis, Systematic Review, Randomized Controlled Trial, Review; Exclude: Case Reports.

Operational note: if maximizing sensitivity, run two blocks (adherence/compliance and behavioral/technical interventions) and merge before deduplication.

Google Scholar procedure

Query: obstructive sleep apnea CPAP adherence OR compliance mask interface telemedicine “cognitive behavioral therapy” phenotype endotype
Sort: relevance.
Screening depth: first 200 records (title/abstract/preview), date: [insert date], with deduplication against PubMed.
Export: collect candidates and remove duplicates in [Zotero] using First author + title + Journal + year keys.

Eligibility criteria (operational)

Inclusion:

Population: adults with diagnosed OSA/OSAS.
Intervention/exposure: CPAP/APAP therapy or interventions to improve adherence (educational, behavioral, technological, mask/interface, telemedicine).
Outcomes: adherence metrics (hours/night, percent nights over threshold, persistence over time) and/or determinants/predictors of adherence.
Designs: RCTs; observational studies (cohort, case-control, cross-sectional); series/registries with N≥10; systematic reviews and meta-analyses. Narrative reviews used for background/rationale.
Language: English.
Time window: 1995–2026-06.

Exclusion:

Case reports and case series with N<10.
Exclusively paediatric, animal, or simulator studies.
Editorials, letters without primary data, protocols without results.
Non-English;.

Selection process

Two reviewers screened titles/abstracts in parallel; full texts retrieved when uncertain.
Full-text assessment against predefined criteria; disagreements resolved by consensus.
No preregistered protocol (narrative review); PRISMA/SANRA/standardized quality tools not applied; we considered scientific coherence, sample size, and clarity of outcomes as minimal credibility checks.

Manuscript-ready paragraph

In the section 2. Material and Methods.

…. This narrative review provides a comprehensive, clinically oriented synthesis of contemporary evidence on factors influencing adherence to continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea (OSA), as well as practical strategies to improve adherence in routine clinical care. We searched PubMed/MEDLINE (via the PubMed interface) and Google Scholar for publications from January 1995 through June 20, 2026; the exact final search date and full query strings are reported in Appendix Table 1. The search strategy combined three concept blocks (population, interventions, outcomes) using MeSH and free-text terms (e.g., “obstructive sleep apnea,” “OSA,” “continuous positive airway pressure,” “CPAP adherence,” “compliance,” “telemedicine,” “cognitive behavioral therapy,” “mask interface,” “phenotype,” “endotype”); the exact Boolean strings with field tags and any filters applied are provided in Appendix Table 1. We applied operational inclusion criteria prioritizing studies on predictors of CPAP adherence, barriers to sustained use, and clinically actionable interventions; detailed inclusion and exclusion rules (population, study designs, outcomes, time frame, language) are specified below. Priority was given to recent original investigations and meta-analyses; clinically oriented reviews were included when they synthesized actionable evidence, whereas case reports and non–data-driven commentaries were excluded. Particular attention was paid not only to identifying factors associated with higher or lower CPAP adherence, but also to the clinical interpretability of those findings. Studies and meta-analyses limited to a purely descriptive listing of variables associated with adherence were considered less informative for the purposes of this review than those offering a broader interpretive framework through which the observed associations could be understood in clinical practice. Accordingly, preference was given to studies that, beyond reporting statistical associations, also explored the potential behavioral, physiological, and practical mechanisms underlying those results. This approach was intended to support a more clinically meaningful discussion of adherence as a multidimensional and dynamic process rather than the simple sum of isolated predictors.

We included randomized trials, prospective and retrospective observational studies, and meta-analyses of adults (≥18 years) with OSA evaluating CPAP or auto-CPAP, with adherence outcomes (e.g., nightly hours of use, nights with ≥4 h) and/or indirect effectiveness aligned with physiological mechanisms. We excluded in vitro/animal and pediatric studies; editorials or letters without primary data; narrative overviews lacking decision-guiding synthesis; single-case reports; conference abstracts without full text; and duplicate or overlapping cohorts (retaining the most comprehensive or most recent analysis).

Two authors independently reviewed titles, abstracts, and full-text articles to identify studies of greater clinical and methodological relevance. Eligible designs included randomized trials, prospective and retrospective observational studies, and meta-analyses addressing CPAP adherence, its determinants, and strategies for improvement; narrative reviews were considered when they added decision-guiding synthesis. No formal protocol was prospectively registered for this review. Given the narrative nature of the article, no PRISMA-based methodology, SANRA framework, or formal standardized quality assessment tool was applied. Selection and interpretation were based on prespecified relevance, cross-study consistency, and clinical applicability; study-level decisions and reasons are documented in Appendix Table 2. A PRISMA-style flow diagram with counts (identified, deduplicated, screened, full-text assessed, excluded with reasons, included) is provided in the Appendix. Any differences in interpretation were discussed among the authors and resolved by consensus. This article is based exclusively on previously published studies and does not include any new studies involving human or animal subjects conducted by the authors.

In addition to a structured keyword search on adherence, we deliberately re-examined each clinically salient dimension—pathophysiology, mask selection, technical refinements, CPAP versus auto-CPAP comparisons, and adherence in women with OSA—to identify evidence most capable of guiding diagnostic, therapeutic, and follow-up decisions, capturing both direct adherence outcomes and indirect effectiveness aligned with physiological mechanisms.

The citation-to-claim problem remains a major concern. The authors have corrected the previous date inconsistency by extending the search period to May 2026, so that point no longer needs to be raised. The remaining problem is that several claims are still not adequately linked to the cited references. For example, the manuscript states that CBT-I before CPAP significantly increased CPAP adherence in COMISA patients, but the cited references visible in the revised reference list do not correspond to randomized CBT-I adherence trials. Because a citation mismatch was already noted in the previous round, the authors should now check every citation-to-claim link in the manuscript.

Response to the reviewer. Thank you to the reviewer for the clarification. There must have been an issue with Zotero that recurs when updating the references. We have reviewed and corrected every citation in every sentence, but you will find them corrected only in the final version of the manuscript; given the numerous requested changes, I chose to make the necessary corrections to the text only once, rather than in the response to the reviewers. The English and citations were corrected last. In the tracked‑changes version, you can see the specific corrections applied to each reference (punctuation, order, and formatting). Below that section, the reference style has been standardized and aligned with the journal’s guidelines, with consistent formatting applied across all entries.

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The revised discussion of the 4-hour adherence threshold is directionally better, but the wording remains imprecise and sometimes overgeneralized. The manuscript should distinguish more clearly between an administrative or reimbursement threshold, a reporting convention used in research, and clinically meaningful CPAP use. Statements implying that shorter nightly use will not improve symptoms or cardiovascular risk should be softened unless supported by specific dose-response evidence. The REM-OSA argument is plausible and clinically relevant, but it should be framed as a subgroup-specific concern rather than as general proof that the 4-hour threshold is clinically inadequate in all patients.

Response to reviewer Thank you for the thoughtful and constructive feedback. We have clarified the distinction between administrative/reimbursement thresholds, research reporting conventions, and clinically meaningful CPAP use; tempered statements about shorter nightly use to align with dose–response evidence; and reframed the REM‑OSA discussion as a subgroup‑specific consideration while emphasizing individualized adherence targets.

In the text chapter 3.1 (version with track changes)

In 2009, the Centers for Medicare & Medicaid Services adopted a requirement of minimum 4 hours of Positive Airway Pressure (PAP) use for 70% of nights, or 21 days in a consecutive 30-day period, to continue medical coverage for PAP therapy [15]The use of an economic rather than a clinical definition is the first CPAP adherence issue to be fixed. Indeed, this is commonly used for reimbursement or coverage purposes but, although it is not clinically ineffective for all patients, the reduction of the AHI could be only partial. [16].. A few hours during the night may not improve symptoms, quality of life or reduce cardiovascular risk, with a subsequent reduction in patient motivation. Continuous positive airway pressure (CPAP) adherence using a “≥4 hours on ≥70% of nights” metric represents an administrative or reimbursement threshold used by payers and device monitoring programs and does not, by itself, define clinically meaningful treatment adequacy. First this threshold has been criticized as being too low by some and too strict by others for patients who may sleep less and benefit even less from 4 hours of sleep [17].Second, it also appears in the research literature as a reporting convention that enables comparability across studies. Third, clinically meaningful CPAP use is better conceptualized as the duration needed to achieve patient-centered outcomes (symptom relief, functional improvement) and risk modification (cardiovascular and metabolic), which may exceed administrative minima for many patients and may vary by phenotype and sleep pattern. Evidence supports a dose–response relationship between nightly CPAP duration and clinical benefit, but this relationship should be articulated carefully to avoid overgeneralization [18].Observational and experimental data indicate that limited nightly use can reduce disease burden, yet the magnitude of benefit often scales with longer wear times Daytime sleepiness improves after 7 hours of sleep, while seven hours and 30 minutes is the medium time necessary to reach a good performance status [19], [7]. This range could also be different for shorter or longer sleepers and varying during the lifespan. Certainly a cut off and a value is necessary in literature to quantify the adherence and to compare different reports.. An OSA patient who removes the mask after only the first 4 hours of sleep will not treat the deeper desaturations, the more severe and longer events in REM sleep that prevails in the second part of the sleep and it is associated with an increase in cardiovascular risk [20], [21].. In addition, recent evidence underline that patients with REM-related OSA, with more than 50% events during REM sleep, demonstrated significantly lower nightly CPAP use in particular in long term adherence compared with patients with non-stage-specific OSA [22] . CPAP efficacy have a dose-response effect, suggesting that the ineffectiveness of CPAP in terms of cardiovascular and metabolic health in some trials is partly due to poor or not optimal adherence [23],[1].

Heterogeneity in sleep duration, OSA phenotype, comorbidities, and patient priorities further cautions against a one-size-fits-all adherence target. Short sleepers may accrue meaningful benefit at lower absolute nightly hours than long sleepers, though—consistent with dose–response principles—additional hours commonly produce additional gains. Conversely, some patients with severe, non-stage-specific OSA or substantial cardiometabolic risk may require near–full-night use to meaningfully modify outcomes. Real-world data also suggest that adherence patterns and therapy persistence vary across OSA phenotypes and patient profiles, with implications for how thresholds are met—or not met—in practice [24]

Another aspect is the definition of adherence compared to compliance. The term adherence itself underlines the necessity of the active and collaborative treatment acceptation including a self-efficacy meaning, with a no exclusive terminological difference with the most passive compliance. Adherence is also different from the acceptance. Acceptance is defined as willingness to purchase and use a CPAP device and it could be related to financial issue, social stigma or intolerance to CPAP or preference to another therapy [25]. In sleep medicine time issue is also important that defines the short- and long-term adherence. Long term adherence refers to different time horizons (3, 6 or 12 months), while shorter adherence refers to the first month of CPAP treatment and strongly influences the following period [26]

The section on phenotypes and endotypes remains too assertive for the evidence presented. The manuscript acknowledges that routine clinical endotyping is not currently feasible and that validated methods are lacking, but it also states that guidance on endotype-based therapeutic approaches is already “well-established” and that poor CPAP tolerance in low arousal threshold patients has been clearly demonstrated. These statements need further tempering. Phenotype- and endotype-guided titration should be presented as a promising hypothesis or specialized-center approach requiring prospective validation, not as a currently established clinical pathway for everyday care.

Response to reviewer. We appreciate the reviewer’s comment. We have revised the manuscript to temper statements about phenotypes and endotypes. Specifically, we:

Removed language implying that endotype-based therapeutic guidance is “well-established” or that poor CPAP tolerance in low arousal-threshold patients is “clearly demonstrated” in routine care.
Now present phenotype- and endotype-guided titration as a promising, hypothesis-generating approach suitable for specialized centers and research settings, pending prospective validation and standardized clinical tools.
Clarify that routine clinical endotyping is currently not feasible in everyday care and should not be considered a standard pathway for CPAP initiation or adjustment.

The response to the request for practical implementation of endotype assessment remains incomplete. The revised text mentions polysomnographic clues for high loop gain and low arousal threshold, but it does not clearly explain which traits can be measured reliably in routine practice, which require specialized methods, and which remain inferential. A short practical paragraph distinguishing routinely available clinical clues, specialized-center measurements, and research-only measures would make the section much more useful and would prevent over translation of mechanistic concepts.

We are sincerely grateful for this thoughtful suggestion. To keep the review practical while avoiding over-translation, we added a concise, tiered clarification within the text distinguishing (i) routine clinical clues (with concrete examples for each predominant endotype, including apnea-predominant events/CPAP level for collapsibility, central instability for high loop gain, Edwards’ criteria for low arousal threshold, and REM-dominant OSA for reduced dilator responsiveness), (ii) specialized-center assessments using validated model-based inference from routine PSG (e.g., Terrill et al., 2015), and (iii) definitive research-level measurements requiring esophageal pressure and CPAP dial-down protocols. This framing makes explicit what is feasible in routine care versus what requires advanced testing, consistent with the practical scope of the review.

In the text we added:

In the Chapter 3.3 you could see the modified part about endotype as follow

“To avoid over-translation while preserving clinical utility, we clarify three practical tiers. First of all, routine clinical clues from standard PSG/Home sleep apnea test, which we illustrate for each predominant endotype: apnea-predominant events or higher therapeutic CPAP levels suggesting increased collapsibility (anatomical factor); coexisting or mixed central events, periodic/waxing–waning breathing, or Cheyne–Stokes–like instability suggesting high loop gain; the Edwards composite criteria (AHI < 30 events/h, nadir SpO₂ > 82.5%, fraction of hypopneas > 58.3%; score ≥ 2 indicating a low arousal threshold) to screen for low arousal threshold; and REM-dominant OSA as a clinical marker of reduced dilator muscle responsiveness [58], [20], Second, specialized-center assessments that estimate traits from routine full PSG using validated model-based inference, notably the mathematical framework described by Terrill et al, which computes ventilatory-control endotypes from standard signals without invasive instrumentation [59]. Finally, research-level measurements requiring full laboratory protocols, including esophageal pressure monitoring and CPAP platforms permitting dial-down pressure CPAP manipulations (and, where applicable, targeted gas perturbations), which remain outside the practical scope of this review [59],[60]. Phenotype/endotype-informed strategies to improve adherence are discussed as promising and research-oriented, not yet feasible for routine care, and requiring prospective validation.”

The mask/interface section has improved, but it still contains unsupported or overly categorical statements. The recommendation that retrognathic patients “should be treated with the nasal mask first” requires either a specific supporting citation or removal. The manuscript should consistently state that nasal interfaces are often preferable when feasible, but that mask choice must be individualized according to nasal patency, mouth leak, facial anatomy, comfort, previous intolerance, and patient preference.

We appreciate the reviewer’s further clarification regarding mask/interface selection. We agree that interface choice must be individualized and that evidence is heterogeneous across settings and patient subgroups. We have revised the text to avoid categorical statements and to emphasize that nasal interfaces are preferred when feasible, given signals of better comfort, lower leak, and adherence in several comparative analyses, while oronasal masks remain appropriate in clearly defined scenarios (e.g., persistent relevant nasal obstruction, predominant mouth breathing despite optimization). We also state explicitly that early reassessment and switching interface if problems persist are integral to care. These changes align our wording with the available evidence and the need for patient-centered selection, while preserving the practical message for everyday clinics.

“Interface selection should be individualized and reassessed early. When feasible, a nasal interface (nasal mask or nasal pillows) is generally preferred as a first option because multiple studies suggest better comfort, lower leak, and a signal of improved adherence compared with oronasal masks. However, this advantage is not universal and depends on patient factors and clinical context. Oronasal masks remain appropriate in selected situations, notably in patients with persistent relevant nasal obstruction or predominant mouth breathing despite targeted optimization (e.g., nasal therapies, humidification, chin strap). Our practical approach is to start with a nasal interface when reasonable, actively manage nasal symptoms and humidification, and switch interface if leaks, discomfort, or efficacy issues persist. This stepwise, patient‑centered strategy avoids categorical claims while preserving the clinical importance of nasal masks in routine care.”

The added tables are useful, especially the table summarizing adherence strategies, evidence type, target subgroup, expected outcome, and limitations. However, Table 3 needs refinement because some categories appear inconsistent. For example, CBT-I for COMISA is placed under evidence-based recommendations, whereas psychological support programmes are categorized as preliminary. In addition, the terminology used for telemedicine and digital health interventions should be consistent across the text and tables. The authors should ensure that each strategy is categorized consistently with the strength and type of evidence cited in the text.

Response to reviewer. We thank the reviewer for this helpful observation. We have revised Table 3 to ensure internal consistency across categories and alignment with the strength and type of evidence cited in the text. Specifically, we harmonized the placement of psychological/behavioural interventions (CBT‑I for COMISA and broader psychological support), standardized terminology for technology‑enabled care as “telemedicine/remote monitoring (digital health)” across text and tables, and verified each strategy’s category against the cited evidence. These changes improve clarity without altering our conclusions.

Categorization was aligned to intervention specificity and trial maturity: protocolized, trial‑supported interventions (e.g., CBT‑I for COMISA; routine telemonitoring) are listed as evidence‑based; non‑protocolized psychological support and advanced digital tools with heterogeneous data are placed under expert opinion or preliminary evidence.

Strategy	Evidence category	Target subgroup	Expected outcome	Limitations
Patient education	Evidence-based	Newly diagnosed OSA; all patients	Improved understanding/acceptance; modest increase in nightly use	Heterogeneous content and delivery
Early, structured follow-up and troubleshooting	Evidence-based	First 1–4 weeks; early problems	Reduced drop-out; stabilization of use over time	Resource-intensive; protocol variability
Mask/interface optimization (conditional nasal-first; switch if issues persist)	Evidence-based	No persistent relevant nasal obstruction	Lower leaks; better comfort; signal of improved adherence vs oronasal	Advantage not universal; mouth breathing may negate benefit
Treat nasal obstruction; optimize humidification	Evidence-based	Rhinitis/congestion/dry mouth	Comfort gains → increased use	Effect depends on underlying nasal disease
Telemedicine/remote monitoring (digital health): routine data review + feedback	Evidence-based	Standard care; early maintenance	Small–moderate adherence increase; earlier issue detection	Modest effect sizes; implementation variability
CBT‑I for COMISA (protocolized)	Evidence-based	OSA with comorbid insomnia	Better sleep initiation/maintenance; signal of increased CPAP use	Requires trained staff; not for all phenotypes
Shared decision-making for interface selection	Expert opinion	All patients; preference-sensitive	Higher acceptance; fewer early drop-outs	Limited RCTs isolating the effect
General psychological support programs (non‑protocolized)	Expert opinion	Low motivation/anxiety/claustrophobia	Engagement support; possible increase in persistence	Heterogeneous content; limited controlled data
Chin strap for persistent mouth leaks (selected cases)	Expert opinion	Nasal interface + mouth leaks despite optimization	Fewer leaks/dry mouth; potential comfort gains	Not universally tolerated; variable benefit
Advanced digital health tools (apps, AI‑assisted workflows)	Preliminary	Tech‑engaged programs/patients	Early engagement signals; uncertain impact on hours/night	Heterogeneous designs; limited prospective outcomes
Phenotype-/endotype‑guided PAP algorithms	Preliminary	Specialized centers; research protocols	Hypothesis‑driven personalization; unknown adherence effect	No standardized tools; prospective validation needed
Precision/personalized behavioral interventions beyond CBT‑I	Preliminary	Selected behavioral phenotypes	Possible adherence gains in subgroups	Mostly pilot/feasibility data

Table 3. Adherence strategies—classification by evidence, target subgroup, expected outcome, and limitations

The follow-up section has been expanded, and Table 2 now introduces phase-based guidance, including pre-CPAP assessment, titration, early follow-up, and long-term maintenance. However, this structure is not clearly integrated into the main text or into Figure 2. The manuscript should state more concretely what should be assessed at each contact, including nightly use, residual AHI, leak, pressure intolerance, treatment-emergent central apneas, nasal/oral dryness, insomnia, mask-related skin problems, residual symptoms, and patient concerns.

Response to reviewer: We appreciate this helpful suggestion. We have integrated the phase‑based framework into the main text and aligned Figure 2 accordingly. For each contact (pre‑CPAP assessment, titration, early follow‑up, long‑term maintenance), we now specify concrete items to review: nightly use, residual AHI, leak, pressure intolerance, treatment‑emergent central apneas, nasal/oral dryness, insomnia, mask‑related skin issues, residual symptoms, and patient concerns. Table 2 and Figure 2 have been updated to reflect these assessments at each phase

Chapter 3.6 Follow up and practical approach for early problems solutions with track changes

During the pre-CPAP period or baseline, a rapid evaluation of adherence predictors and barriers is performed first. In particular, comorbidities such as insomnia, depression, anxiety and other sleep disorders were investigated. If insomnia is present, CBT-I therapy may need to be started before CPAP assessment [77]. Nasal obstruction or allergic rhinitis are also taken into account, and specialistic evaluation or specific treatment may be [78]. Immediately prior to titration, a careful review of the polygraphic or polysomnographic recording may be helpful to characterize the sleep architecture and pattern, identify the endotype, and detect the presence of REM‑predominant OSA or a more severe oximetric profile that warrants close monitoring once obstructive apneas have been corrected [57] [79] [20].Decisions about treatment at this stage are shared with patients regarding home or laboratory titration, the latter being considered when comorbidities are present. Personalized education about the disease and CPAP treatment is required and strongly recommended . The first step in CPAP treatment is to arrange a clear follow-up schedule with the patient. The titration phase days 0 to 7 or 0 to depending on the outpatient clinic workflow. Early follow-up represents one of the most effective interventions for improving long-term PAP adherence and should be regarded as a dynamic, patient-centered adaptation process rather than simply the identification of an effective therapeutic pressure [5]. Current guidelines emphasize that the first days and weeks of therapy are crucial for identifying and correcting factors that may compromise treatment acceptance before they lead to treatment discontinuation.. In centers where PAP initiation is performed on an outpatient basis, an acclimatization period with auto-adjusting PAP may allow optimization of the pressure range, minimum and maximum pressure settings, and ramp activation and duration according to the patient’s sleep‑onset latency, as well as overall treatment tolerance before defining long-term settings [7]. The most commonly reported side effects within the first month include dry mouth and nasal symptoms, such as congestion or mucosal irritation [80]. Nasal or oral dryness may improve with heated humidification and, when appropriate, heated tubing, whereas mask-related skin lesions usually respond to interface refitting, reduction of strap tension, interface replacement, or protective dressings. Additional issues may include mask leaks, skin lesions related to the interface, airflow-related discomfort, and sleep fragmentation [81]. In these cases, a careful management of mask fitting, circuit leaks and air humidification may improve patients’ adherence [82]. Pressure intolerance can often be improved by optimizing pressure settings, ramp duration, or expiratory pressure relief (EPR), while persistent treatment-emergent central sleep apnea may require closer follow-up and, in selected patients, modification of the ventilatory strategy [7]. During each follow-up visit, clinicians s the following objective metrics: nightly use (hours per night; percentage of nights with ≥4 hours of use), residual AHI (with obstructive vs. central breakdown), leak (median and 95^(th) percentile), pressure profile (median and 95^(th) percentile), flags for treatment-emergent central apneas, and symptoms of relief or persistence, as well as any adverse effects such as residual sleepiness, insomnia/sleep fragmentation, nasal/oral dryness, aerophagia, mask-related skin issues and patient-reported intolerance. Mask, size and cushion adjustments should be made to mitigate leaks. If TECSA are present or pressure variability is poorly tolerated, the APAP range should be narrowed or a fixed CPAP trial conducted [82], [83]. Comorbidity-targeted co-interventions (weight management, positional therapy and insomnia treatment) are different strategies to take into account. If there are persistent residual events with high treatment pressure, a shift to BiPAP or EPR may be required but a significative increase in adherence has not been demonstrated [52].Provide brief adherence support in the form of coaching and troubleshooting. Another important aspect of each phase is the evaluation of clinical outcomes, such as residual symptoms, blood pressure, cardio-metabolic comorbidities and bed partner feedback regarding snoring and awakenings. After excluding secondary causes of residual sleepiness, the persistent symptom can be managed pharmacologically. Although initiating a specific wake‑promoting therapy has not been shown to improve treatment adherence, leaving the patient with residual sleepiness worsens quality of life and undermines perceived treatment efficacy, thereby becoming a driver of non‑adherence [84] [85].

ducational and behavioral interventions have been shown improvements in adherence. Continuous support with telemedicine, telephone follow-up, group-base interviews and cognitive-behavioral therapy may improve CPAP adherence by enhancing patients’ engagement [86],[87]. The patient should first be re-evaluated shortly after starting CPAP therapy. Depending on center characteristics and workflow—for example, the use of telemedicine—the timing of the first visit may vary. Where telemedicine is available, day‑to‑day remote review of PAP downloads enables rapid detection of poor adherence, excessive leaks, or persistent residual events and timely corrective actions, allowing for a longer initial interval. In settings without telemonitoring, a shorter interval is advisable; proactive telephone contact or an early structured follow‑up call can similarly identify technical issues, reinforce education, explore concerns, and prompt earlier reassessment when needed. Clinicians should also evaluate emerging conditions during the initial CPAP phase—such as insomnia, depressive symptoms, or sleep‑related movement disorders—as these can precipitate CPAP interruption [88] [89]. Finally, follow‑up intensity should be individualized according to the estimated risk of poor adherence. Patients with anxiety, depression, comorbid insomnia, sleep‑related movement disorders, advanced age, cognitive impairment, limited social support, or prior negative experiences with PAP may benefit from a more intensive schedule during the adaptation phase [3], [7]. Overall successful long-term PAP adherence relies on a personalized strategy integrating individualized titration, careful interpretation of PAP waveforms rather than device metrics alone, prompt troubleshooting of side effects, patient-centered education, and a risk-stratified follow-up adapted to both the patient’s needs and the organizational resources of the sleep center. A table with common barriers to CPAP adherence and practical management strategies and a figure with a work flow diagram have been added to this chapter (Table 1 and Table 2 and Figure 2).

Figure 2 remains below publication quality. Although the concept is useful, the figure still contains informal wording, spelling errors, unclear visual organization, and oversimplified action steps such as “change mask or education,” “Motivation with CBTi or groups work,” and “adherrence.” The figure should be redesigned as a clean clinical algorithm with precise wording and a clearer sequence of assessment and management steps. The caption should also match the actual content of the figure.

Thank you the reviewer for the suggestion. You can see figure 2 with changes and improvements.

The conclusion regarding telemedicine has been moderated, but it remains grammatically unclear and still too broad. Telemedicine should be framed as one potentially useful component of structured follow-up, rather than as a general solution for ensuring adherence at scale. The manuscript should briefly acknowledge heterogeneity across telemonitoring interventions, variable long-term effects, infrastructure requirements, and unequal suitability across patient groups.

Thank you for the comment. We have revised the conclusion to avoid overgeneralization and to frame telemedicine as a potentially useful component within structured follow-up pathways rather than a universal solution for adherence. We also added a brief passage acknowledging (i) the heterogeneity of telemonitoring programs and the variable durability of effects over the longer term; (ii) the infrastructure and workflow-integration requirements that condition scalability; and (iii) the unequal suitability across patient groups due to differences in digital access, clinical complexity, and preferences. Finally, we identify as a future priority the clarification of which intervention features, delivery models, and patient profiles are associated with the most sustained benefits, and under what resource conditions.

In the conclusion section we added:

Our findings do not support telemedicine as a universal solution to ensure adherence, but rather as one of several potential components within structured follow-up pathways. Telemonitoring initiatives are heterogeneous in design and intensity, and their effects may wane over the longer term. Effective implementation depends on adequate infrastructure, integration into clinical workflows, and sound data governance, which can limit scalability in some settings. Suitability also varies across patient groups due to differences in digital access, clinical complexity, and preferences. Future research should clarify which intervention features, delivery models, and patient profiles yield the most sustained benefits, and under what resource conditions.

The language still requires extensive revision. This is not a minor stylistic issue: several sentences are difficult to interpret clinically, and errors remain throughout the abstract, methods, results, figures, and conclusions. Examples include incorrect verb agreement, awkward clinical phrasing, repeated wording, spelling errors, and unclear expressions such as “treatment acceptation,” “times frame,” “patient preference or prior intolerance could be considerate,” and “telemedicine… could be useful to ensuring adherence.” The manuscript should undergo a thorough professional language edit after the scientific corrections have been completed.

Response to reviewer. Thank you for this thorough language-focused critique. We agree that the manuscript required substantial linguistic revision beyond minor stylistic edits. Following completion of the scientific corrections, we conducted a comprehensive language edit to improve clarity, precision, and clinical interpretability across the abstract, methods, results, figures, and conclusions. Specifically, we corrected verb agreement, removed repetitive wording, standardized clinical phrasing, and fixed spelling and syntax errors. We also replaced ambiguous expressions with clear terminology, for example: “treatment acceptation” → “treatment acceptance,” “times frame” → “timeframe,” “patient preference or prior intolerance could be considerate” → “patient preference or prior intolerance should be considered,” and “telemedicine… could be useful to ensuring adherence” → “telemedicine may be one useful component to support adherence.” Where helpful, we adopted field-standard phrasing and simplified complex sentences. We appreciate the guidance and believe these revisions materially improve readability and clinical clarity.

The authors’ response letter should be revised to provide a clearer point-by-point account of the changes made. Several responses simply state that the text was rewritten or corrected, without indicating where the change was made or how the concern was addressed. For a revised submission, the response should specify the manuscript section, table, or figure modified, and should clearly justify any recommendation that was not fully changed.

Thank you sincerely for your thoughtful and constructive comments. In this second revision, we have provided a point‑by‑point response, indicating for each item the exact manuscript location (section/page/paragraph) and the specific changes made, including the revised tables and figures. In the manuscript file, all modifications are highlighted in red to facilitate review. We apologize that our prior response did not specify these details with sufficient precision. Regarding language and style, we did not list individual corrections because the manuscript underwent a comprehensive language edit to standardize terminology, spelling, and usage throughout. We are grateful for your guidance, which has materially improved the clarity and quality of the work.

Author Response File: Author Response.pdf