The Confluence of Chronic Rhinosinusitis and Obstructive Sleep Apnea: A Narrative Review of Pathophysiology, Epidemiology, and Therapeutic Interventions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting narrative review exploring the links between Chronic Rhinosinusitis (CRS) and Obstructive Sleep Apnea (OSA), frequently coexisting comorbidities in clinical practice, exploring the epidemiology, pathophysiology and the surgical and medical therapeutic interventions linking the two disorders.

Although across the manuscript relevant outcome data and evidence are generally presented appropriately, some improvements are needed before acceptance

Major Comments:

1. For a “comprehensive review” (title) and aiming to “provide a definitive reference” (line 54) the literature search strategy is missing and should be presented in detail (including search terms and inclusion criteria).
2. The justification of importance for readership is alluded but not explicitly justified.
3. The aims are generally formulated but not concretely with clear questions.
4. The referencing of key statements is sometimes inconsistent (see Specific comments)

Specific comments:

1. Title & abstract line 24: “Comprehensive Review…” – consider rephrasing as “Narrative Review”
2. Key words: “sleep apnea, obstructive;” consider rephrasing as “obstructive sleep apnea”.
3. Lines 70-71 - “…OSA-induced systemic inflammation may predispose the nasal mucosa to chronic infection.[5]” consider rephrasing as “…predispose the nasal mucosa to chronic inflammation” as CRS is nowadays considered a persitent inflammatory disease (line 44).
4. Lines 76-79 – “In this group, the severity … a potent predictor for the presence of OSA [1].” Note that reference 1 reports data from “a cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES)” and not the WTC responder cohort (line 75). Please clarify the meaning of “In this group…”.
5. Lines 86 – “…risk scores on the STOP-Bang questionnaire [1].” please briefly explain the meaning of this questionnaire.
6. Lines 107 – “AHI” although the acronym is defined in the abstract, I suggest to define it here, as the 1^st time it is used in the manuscript main text.
7. Lines 112-115 – Please give the appropriate original reference for the stated “Two-Hit" hypothesis” addressed in this section 3.2
8. Lines 119-120 – “These cytokines are not confined to the serum; they are detectable in the nasal lavage of OSA patients, correlating with disease severity [10].” Please check if it is the appropriate reference as it cites a RCT (ref. 10) measuring cytokines pre and pos CPAP heated humidification, apparently not reporting correlations with OSA severity.
9. Lines 129-130 – “This systemic oxidative stress …perpetuating the cycle of chronic sinusitis [6].” Please check/clarify if it is the appropriate reference as it (ref. 6) reports data on Sleep Quality of CRS&OSA, not oxidative stress biomarkers.
10. Line 187 – ref.26 appears in the manuscript before ref.25 (line 209); please check and correct.
11. Line 198 – “The PSQI” define the acronym, as it appears for the 1^st time in the manuscript.
12. Lines 222-223 – “This suggests that Dupilumab may improve sleep via central mechanisms or systemic cytokine modulation…” The scientific reasoning behind this key statement/ hypothesis needs appropriate references: is there any evidence that IL-4/IL-13 have central effects on sleep regulation and that targeting its receptor modulates these putative actions and/or other systemic sleep-regulating cytokines? Please clarify with original references, as it also relevant and relates to the final statements in section 7.3 of therapeutic and decision making (lines 316-318).
13. Lines 226-227 – “These agents (anti-IL-5 / anti-IgE) reduce the eosinophilic burden that contributes to mucosal thickening and systemic inflammation.” I suggest to delete “systemic” and rephrase as that “contributes to mucosal thickening and inflammation” (unless original references are provided for a clinical meaningful systemic effect of theses biologicals in CRS).
14. Lines 246-251 – “Currently, there is some consensus that the AHI should not be the sole metric … for both surgery and medical treatment [40].” Please clarify providing original references supporting CRS (surgical or medical) treatment effects on the referred outcomes (OD and t90).
15. Table 1 – regarding the columns “Impact on AIH” and “CIPAP Impact” several different terms are used for possible missing evidence – “not primary outcome”, “unknown”, “N/A”. Please clarify with the suggestion to use the same wording (e.g., unknow or no available evidence).
16. Line 310 – “”. The NOSE scale acronym is not defined before nor the statement previously addressed or discussed within the main manuscript text. Please review/ clarify.
17. Reference section – the citations need a complete revision according to the standard recommendations of the journal. Several have missing authors, repeated year of publication (ref 38) or missing information (ref 45). Carefully review and correct.

 

 

 

Author Response

Dear Reviewer,

We have reviewed your comments point by point and made the proposed changes.

Please refer to the following point-by-point responses. The revised manuscript is with track changes, where you can review each change and the comments in the margins.

Regarding the references, they are now all in MDPI publisher format and properly ordered. In the original article, for some reason, the order of the references was incorrect.

Thank you very much for your time, and I hope you enjoy the article.

----------------------------------------------

Reviewers #1 Comments and Suggestions for Authors
This is an interesting narrative review exploring the links between Chronic Rhinosinusitis (CRS) and Obstructive Sleep Apnea (OSA), frequently coexisting comorbidities in clinical practice, exploring the epidemiology, pathophysiology and the surgical and medical therapeutic interventions linking the two disorders.
Although across the manuscript relevant outcome data and evidence are generally presented appropriately, some improvements are needed before acceptance

Major Comments:
1. For a “comprehensive review” (title) and aiming to “provide a definitive reference” (line 54) the literature search strategy is missing and should be presented in detail (including search terms and inclusion criteria). We kept the article name and added the search strategy in a new section of the same article.
2. The justification of importance for readership is alluded but not explicitly justified. We believe that the importance of the pathology itself alludes to this issue, and is clearly explained in the manuscript.
3. The aims are generally formulated but not concretely with clear questions. As this is a review, we believe the article's objectives are based on the search itself. We do not intend to conduct a search based on a specific clinical question, but rather to describe the findings in the literature related to these important and often overlapping topics.
4. The referencing of key statements is sometimes inconsistent (see Specific comments). We answer that in the specific comments.

Specific comments:
1. Title & abstract line 24: “Comprehensive Review…” – consider rephrasing as “Narrative
Review”. Answered in the main comments, point 1.
2. Key words: “sleep apnea, obstructive;” consider rephrasing as “obstructive sleep apnea”.
corrected
3. Lines 70-71 - “…OSA-induced systemic inflammation may predispose the nasal mucosa to
chronic infection.[5]” consider rephrasing as “…predispose the nasal mucosa to chronic inflammation” as CRS is nowadays considered a persitent inflammatory disease (line 44). corrected
4. Lines 76-79 – “In this group, the severity … a potent predictor for the presence of OSA [1].” Note that reference 1 reports data from “a cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNHANES)” and not the WTC responder cohort (line 75). Please clarify the meaning of “In this group…”. corrected
5. Lines 86 – “…risk scores on the STOP-Bang questionnaire [1].” please briefly explain the meaning of this questionnaire. corrected
6. Lines 107 – “AHI” although the acronym is defined in the abstract, I suggest to define it here, as the 1st time it is used in the manuscript main text. corrected
7. Lines 112-115 – Please give the appropriate original reference for the stated “Two-Hit" hypothesis” addressed in this section 3.2 corrected
8. Lines 119-120 – “These cytokines are not confined to the serum; they are detectable in the nasal lavage of OSA patients, correlating with disease severity [10].” Please check if it is the appropriate reference as it cites a RCT (ref. 10) measuring cytokines pre and pos CPAP heated humidification, apparently not reporting correlations with OSA severity. Corrected, new reference added.
9. Lines 129-130 – “This systemic oxidative stress …perpetuating the cycle of chronic sinusitis [6].” Please check/clarify if it is the appropriate reference as it (ref. 6) reports data on Sleep Quality of CRS&OSA, not oxidative stress biomarkers. Corrected, new reference added.
10. Line 187 – ref.26 appears in the manuscript before ref.25 (line 209); please check and correct. Corrected.

11. Line 198 – “The PSQI” define the acronym, as it appears for the 1st time in the manuscript. Corrected.
12. Lines 222-223 – “This suggests that Dupilumab may improve sleep via central mechanisms or systemic cytokine modulation…” The scientific reasoning behind this key statement/ hypothesis needs appropriate references: is there any evidence that IL-4/IL-13 have central effects on sleep regulation and that targeting its receptor modulates these putative actions and/or other systemic sleep-regulating cytokines? Please clarify with original references, as it also relevant and relates to the final statements in section 7.3 of therapeutic and decision making (lines 316-318). Corrected.
13. Lines 226-227 – “These agents (anti-IL-5 / anti-IgE) reduce the eosinophilic burden that contributes to mucosal thickening and systemic inflammation.” I suggest to delete “systemic” and rephrase as that “contributes to mucosal thickening and inflammation” (unless original references are provided for a clinical meaningful systemic effect of theses biologicals in CRS). Corrected.
14. Lines 246-251 – “Currently, there is some consensus that the AHI should not be the sole metric … for both surgery and medical treatment [40].” Please clarify providing original references supporting CRS (surgical or medical) treatment effects on the referred outcomes (OD and t90). Corrected.
15. Table 1 – regarding the columns “Impact on AIH” and “CPAP Impact” several different terms are used for possible missing evidence – “not primary outcome”, “unknown”, “N/A”. Please clarify with the suggestion to use the same wording (e.g., unknow or no available evidence). Corrected.
16. Line 310 – “”. The NOSE scale acronym is not defined before nor the statement previously addressed or discussed within the main manuscript text. Please review/ clarify. Corrected.
17. Reference section – the citations need a complete revision according to the standard recommendations of the journal. Several have missing authors, repeated year of publication (ref 38) or missing information (ref 45). Carefully review and correct. The references may have shifted from their original position; we have corrected them.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a timely and comprehensive narrative overview of the interaction between chronic rhinosinusitis and obstructive sleep apnea within a “United Airway” framework. The topic is clinically relevant, the literature coverage is broad, and the manuscript is generally well written and logically structured. The authors successfully integrate epidemiological, mechanistic, and therapeutic perspectives, making the review potentially valuable for both rhinology and sleep medicine audiences.

However, in its current form, the manuscript requires revision. Key limitations include insufficient methodological transparency, occasional overinterpretation of associative data, imbalance in the discussion of mechanistic pathways, and limited critical appraisal of the quality and strength of the underlying evidence. Addressing these issues is necessary to improve scientific rigor, balance, and clarity before the manuscript can be considered for publication.

Major Comments

• The manuscript is presented as a comprehensive review; however, the absence of a clearly defined review methodology represents a major limitation. The authors do not specify how the literature was identified, which databases were searched, the time frame covered, or the inclusion and exclusion criteria applied. Even if a formal systematic review was not intended, a brief description of the search strategy and scope is essential to enhance transparency, reproducibility, and credibility, particularly given the authoritative tone and extensive referencing throughout the manuscript.
• Throughout the manuscript, several statements imply causal or mechanistic relationships between chronic rhinosinusitis and obstructive sleep apnea that are not fully supported by the cited evidence. Many of the referenced large-scale database studies and population-based cohorts demonstrate strong associations but cannot establish causality. In multiple sections—particularly those discussing CRS as a driver of OSA pathogenesis or OSA as an aggravating factor for CRS severity—the language should be moderated to more clearly distinguish hypothesis-generating associations from proven mechanisms, with explicit acknowledgment of potential residual confounding factors such as obesity, smoking, asthma, gastroesophageal reflux, and corticosteroid exposure.
• The pathophysiological sections are detailed and informative, but they are somewhat unbalanced toward selected mechanistic hypotheses, particularly inflammatory cytokine spillover and microbiome dysbiosis. While these pathways are biologically plausible and supported by emerging data, alternative explanations—such as shared risk factors, autonomic dysregulation, sleep fragmentation independent of hypoxia, and the heterogeneity of nasal resistance measurements—receive comparatively less critical discussion. A more explicit appraisal of conflicting or null findings would improve scientific balance and prevent overinterpretation of selective evidence.
• The discussion of sinonasal microbiome alterations and biofilm-mediated inflammation is conceptually interesting but currently overstates the level of clinical evidence. Most microbiome studies cited are cross-sectional, involve small cohorts, and use heterogeneous sampling and analytic techniques. Direct evidence demonstrating that modulation of the sinonasal microbiome leads to meaningful improvements in objective sleep apnea outcomes is limited. These sections would benefit from clearer framing as exploratory and hypothesis-generating rather than as established therapeutic targets.
• While the manuscript appropriately acknowledges that endoscopic sinus surgery and isolated nasal procedures rarely result in clinically meaningful reductions in the apnea–hypopnea index, some passages may still be interpreted as implying disease-modifying effects on OSA. It is important to consistently reinforce that the primary benefits of sinonasal interventions relate to subjective sleep quality, symptom burden, and facilitation of CPAP adherence, rather than direct correction of pharyngeal collapse or normalization of objective sleep apnea severity metrics.
• Although Table 1 provides a useful overview of therapeutic strategies, it does not sufficiently convey the heterogeneity and quality of the underlying evidence. Including an indication of study design or level of evidence (e.g., randomized trials versus observational studies) would improve interpretability. Additionally, a conceptual figure illustrating the proposed “Two-Hit United Airway” model could significantly enhance clarity and educational value for the reader.

Minor Comments

1. Some sections are overly long and could be streamlined (notably Sections 3.2–3.4) without loss of content.
2. Minor typographical and formatting inconsistencies are present (e.g., spacing, punctuation, occasional repetition of concepts).
3. Please ensure consistent terminology when referring to sleep metrics (e.g., ODI vs. Hypoxic Burden).
4. Consider briefly addressing pediatric vs. adult CRS–OSA interactions or clarify that the review is adult-focused.

Author Response

Dear Reviewer,

We have reviewed your comments point by point and made the proposed changes.

Please refer to the following point-by-point responses. The revised manuscript is with track changes, where you can review each change and the comments in the margins.

Regarding the references, they are now all in MDPI publisher format and properly ordered. In the original article, for some reason, the order of the references was incorrect.

Thank you very much for your time, and I hope you enjoy the article.

---------------------------------------------------------

Reviewers #2 Comments and Suggestions for Authors
This manuscript provides a timely and comprehensive narrative overview of the interaction between chronic rhinosinusitis and obstructive sleep apnea within a “United Airway” framework. The topic is clinically relevant, the literature coverage is broad, and the manuscript is generally well written and logically structured. The authors successfully integrate epidemiological, mechanistic, and therapeutic perspectives, making the review potentially valuable for both rhinology and sleep medicine audiences.
However, in its current form, the manuscript requires revision. Key limitations include insufficient methodological transparency, occasional overinterpretation of associative data, imbalance in the discussion of mechanistic pathways, and limited critical appraisal of the quality and strength of the underlying evidence. Addressing these issues is necessary to improve scientific rigor, balance, and clarity before the manuscript can be considered for publication.

Major Comments
• The manuscript is presented as a comprehensive review; however, the absence of a clearly
defined review methodology represents a major limitation. The authors do not specify how the literature was identified, which databases were searched, the time frame covered, or the inclusion and exclusion criteria applied. Even if a formal systematic review was not intended, a brief description of the search strategy and scope is essential to enhance transparency, reproducibility, and credibility, particularly given the authoritative tone and extensive referencing throughout the manuscript. We have added the search strategy in a new section, which we hope you will like and which will allow for a better understanding of the manuscript.
• Throughout the manuscript, several statements imply causal or mechanistic relationships between chronic rhinosinusitis and obstructive sleep apnea that are not fully supported by the cited evidence. Many of the referenced large-scale database studies and population-based cohorts demonstrate strong associations but cannot establish causality. In multiple sections— particularly those discussing CRS as a driver of OSA pathogenesis or OSA as an aggravating factor for CRS severity—the language should be moderated to more clearly distinguish hypothesis-generating associations from proven mechanisms, with explicit acknowledgment of potential residual confounding factors such as obesity, smoking, asthma, gastroesophageal reflux, and corticosteroid exposure. We've toned down the language to avoid confusion. We believe this comment is resolved in the following paragraphs.

• The pathophysiological sections are detailed and informative, but they are somewhat unbalanced toward selected mechanistic hypotheses, particularly inflammatory cytokine spillover and microbiome dysbiosis. While these pathways are biologically plausible and supported by emerging data, alternative explanations—such as shared risk factors, autonomic dysregulation, sleep fragmentation independent of hypoxia, and the heterogeneity of nasal resistance measurements—receive comparatively less critical discussion. A more explicit appraisal of conflicting or null findings would improve scientific balance and prevent overinterpretation of selective evidence. Thank you for this thoughtful and rigorous critique. Your point regarding the need for a more balanced appraisal of competing mechanisms is well-taken and essential for a robust scientific discussion. However, while we agree that factors such as autonomic dysregulation and sleep fragmentation are critical, the emphasis on inflammatory cytokine spillover and microbiome dysbiosis in this section was a deliberate choice based on the specific hierarchy of systemic impact we aimed to highlight.

• The discussion of sinonasal microbiome alterations and biofilm-mediated inflammation is conceptually interesting but currently overstates the level of clinical evidence. Most microbiome studies cited are cross-sectional, involve small cohorts, and use heterogeneous sampling and analytic techniques. Direct evidence demonstrating that modulation of the sinonasal microbiome leads to meaningful improvements in objective sleep apnea outcomes is limited. These sections would benefit from clearer framing as exploratory and hypothesisgenerating rather than as established therapeutic targets. Thank you for this pertinent observation. We appreciate the caution regarding the current state of clinical evidence and the need to distinguish between hypothesis and established practice. However, we would like to offer a counter-perspective on the role of microbiome and biofilm data within this framework:
• Mechanistic Plausibility over Observational Design: While we acknowledge the crosssectional nature of current human studies, the focus on these pathways is supported by robust translational and animal models that demonstrate a direct link between microbial dysbiosis and mucosal inflammatory cascades.
• Biofilms as a Persistent Pathological Factor: We argue that biofilm-mediated inflammation represents a continuous physiological stressor rather than a transient event. Even in the absence of large-scale clinical trials, the biological stability of biofilms justifies their inclusion as a significant, albeit emerging, therapeutic target.
• The Predictive Value of Exploratory Data: We believe that the current "exploratory" data provides a more comprehensive explanation for therapeutic failures in OSA than traditional mechanical models. By highlighting these targets, we aim to bridge the gap between clinical heterogeneity and individualized treatment.

• While the manuscript appropriately acknowledges that endoscopic sinus surgery and isolated nasal procedures rarely result in clinically meaningful reductions in the apnea– hypopnea index, some passages may still be interpreted as implying disease-modifying effects on OSA. It is important to consistently reinforce that the primary benefits of sinonasal interventions relate to subjective sleep quality, symptom burden, and facilitation of CPAP adherence, rather than direct correction of pharyngeal collapse or normalization of objective sleep apnea severity metrics. Thank you for this constructive feedback. We appreciate the emphasis on maintaining clinical realism regarding the outcomes of sinonasal surgery in OSA. However, we would like to clarify our position on the potential for disease-modifying effects through a more integrated physiological lens:
• Beyond the Apnea-Hypopnea Index (AHI): While we agree that AHI reductions are often modest, we contend that focusing solely on this metric may overlook significant improvements in respiratory effort and loop gain. By reducing nasal resistance, these interventions can stabilize ventilatory control, which is a key disease-modifying mechanism in non-anatomical phenotypes of OSA.
• Mitigation of Secondary Collapse: We argue that while nasal surgery does not directly correct pharyngeal anatomy, it significantly reduces the negative inspiratory pressure required to overcome nasal resistance. This reduction can prevent the "suction" effect that exacerbates pharyngeal collapse, suggesting a structural, albeit indirect, modification of disease severity.
• Systemic Inflammatory Load: By addressing chronic sinonasal inflammation (e.g., through ESS), we hypothesize a reduction in the systemic inflammatory burden that contributes to the neural and muscular dysfunction of the upper airway, potentially offering benefits that extend beyond simple symptomatic relief.

 

• Although Table 1 provides a useful overview of therapeutic strategies, it does not sufficiently convey the heterogeneity and quality of the underlying evidence. Including an indication of study design or level of evidence (e.g., randomized trials versus observational studies) would improve interpretability. Additionally, a conceptual figure illustrating the proposed “Two-Hit United Airway” model could significantly enhance clarity and educational value for the reader. Regarding the "Two-Hit United Airway" model and the presentation of evidence, we offer the following rebuttal: While we acknowledge the variability in study designs, we believe that over-stratifying Table 1 by level of evidence might inadvertently obscure the primary goal of the table: to provide a comprehensive, physiological overview of available interventions. Our intent was to prioritize the biological rationale behind these strategies, as the "Two-Hit" hypothesis suggests that even observational data can point toward significant cumulative effects that traditional RCTs may not yet have captured.
We contend that the "Two-Hit United Airway" model is supported by a convergence of disparate data types—ranging from molecular microbiome studies to clinical surgical outcomes. While individual studies may have limitations, their collective directionality provides a strong foundation for the model. We posit that the model's value lies in its predictive power for patient phenotypes that fail standard therapy, rather than solely on the weight of randomized controlled trials.
We intentionally opted for a detailed textual description of the "Two-Hit" model to avoid oversimplifying the complex interplay between localized sinonasal triggers and systemic respiratory responses. However, we see the value in a visual representation.

 

Minor Comments
1. Some sections are overly long and could be streamlined (notably Sections 3.2–3.4) without
loss of content. We strongly agree that those sections are short and no too much extended.
2. Minor typographical and formatting inconsistencies are present (e.g., spacing, punctuation,
occasional repetition of concepts). Corrected.
3. Please ensure consistent terminology when referring to sleep metrics (e.g., ODI vs. Hypoxic
Burden). Corrected.

4. Consider briefly addressing pediatric vs. adult CRS–OSA interactions or clarify that the review is adult-focused. Corrected.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Comments and Suggestions for Authors

 

The author´s mostly addressed the reviewer´ comments and improved the manuscript.

Specific points need to be addressed:

(Note that Page numbers refer to the revised version 2)

1. abstract line 24: “comprehensive review…” change to “narrative review”
2. Line 310 – The NOSE scale acronym is now defined in the revised version of the manuscript. However, as it is not previously addressed or discussed within the main text, add an appropriate reference for this subjective score scale.
3. Please recheck page numbers/date/format of reference 25, 27, 28, 29, 34, 42, 43.

Author Response

Dear revisors:

Thank you very much for your effort. Please find the reponses point by point here:

1. abstract line 24: “comprehensive review…” change to “narrative review” Changed to "narrative"
2. Line 310 – The NOSE scale acronym is now defined in the revised version of the manuscript. However, as it is not previously addressed or discussed within the main text, add an appropriate reference for this subjective score scale. For better understanding, we have added the original reference to the NOSE scale (ref 50).
3. Please recheck page numbers/date/format of reference 25, 27, 28, 29, 34, 42, 43. We checked them all, reference 29 had an incorrect format and now it´s correct.

Reviewer 2 Report

Comments and Suggestions for Authors

I have no further comments

Author Response

Thank you very much for the review.