Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?

Round 1

Reviewer 1 Report

This is a thorough review of the literature relevant to sex-related differences in asthma. I have the following comments:

1.      There were no details of the methods used to identify relevant papers for the review. Even with a narrative review, rather than a formal systematic review, it is important to include details of how the literature searches were conducted and which inclusion/exclusion criteria were applied (e.g. papers published within a specific time period, English language papers only or all languages included)

2.      Section 3 on endotypes and phenotypes of asthma could be much shorter, as it is not the main topic of the paper. The information in this section tends to be presented as though the details of the different phenotypes are well-characterised and fully understood. However, more research is needed to adequately define different asthma phenotypes and describe their characteristics. For example, lines 91-96: this section is misleading as not all early onset asthma is atopic. Recent studies have identified a high proportion of children and adolescents with non-eosinophilic asthma e.g. Pembrey et al. Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic. International Journal of Epidemiology, 2022; dyac173, https://doi.org/10.1093/ije/dyac173

3.      The first part of section 5.1 is too detailed about sex hormones in general and not in the context of asthma. The later sections which discuss the action of estrogens, progesterone and testosterone and their receptors in the lung are relevant.

4.      The Conclusions paragraph is very similar to the abstract – but this is not necessarily an issue.

5.      The manuscript requires some editing for language, e.g. table 3 ‘perspective treatments’ should be ‘prospective treatments’?

6.      Line 29: consider revising the term ‘well-developed countries’ – the term ‘high income country’ (and low income country, middle income country) is more often used now. Note that the prevalence of asthma has increased in many low- and middle-income countries recently.

Please note: As an epidemiologist, I cannot comment on the accuracy of the summaries of the immunological mechanisms and interaction with sex hormones etc. but these details are generally well explained and most of the references are recent.

Author Response

Thank you for your comments and suggestions for improving our manuscript. Below you can find answers to your comments:

 

This is a thorough review of the literature relevant to sex-related differences in asthma. I have the following comments:

1. There were no details of the methods used to identify relevant papers for the review. Even with a narrative review, rather than a formal systematic review, it is important to include details of how the literature searches were conducted and which inclusion/exclusion criteria were applied (e.g. papers published within a specific time period, English language papers only or all languages included).

Response of the Authors: Our review article was prepared using information from the articles published in English and provided on PubMed. According to the Reviewer´s suggestion, this information was also added into the Abstract and into the Introduction.

2. Section 3 on endotypes and phenotypes of asthma could be much shorter, as it is not the main topic of the paper. The information in this section tends to be presented as though the details of the different phenotypes are well-characterised and fully understood. However, more research is needed to adequately define different asthma phenotypes and describe their characteristics.

Response of the Authors: Section 3 was shortened. Based on the opinion of the Reviewer („However, more research is needed to adequately define different asthma phenotypes and describe their characteristics.“), the sentence was added at the beginning of chapter 3 that different asthma endotypes and phenotypes are not fully understood and additional research is needed to adequately define different asthma endotypes and phenotypes and describe their characteristics.

For example, lines 91-96: this section is misleading as not all early onset asthma is atopic. Recent studies have identified a high proportion of children and adolescents with non-eosinophilic asthma e.g. Pembrey et al. Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic. International Journal of Epidemiology, 2022; dyac173, https://doi.org/10.1093/ije/dyac173

Response of the Authors: We would like to thank the Reviewer for this information. The text (lines 91-96) was changed accordingly and the information together with the given reference was added into the paragraph related to non-eosinophilic asthma.

3. The first part of section 5.1 is too detailed about sex hormones in general and not in the context of asthma. The later sections which discuss the action of estrogens, progesterone and testosterone and their receptors in the lung are relevant.

Response of the Authors: Section 5.1 was shortened.

4. The Conclusions paragraph is very similar to the abstract – but this is not necessarily an issue.

Response of the Authors: The paragraph Conclusions was rephrased.

5. The manuscript requires some editing for language, e.g. table 3 ‘perspective treatments’ should be ‘prospective treatments’?

Response of the Authors: In Table 3, the term „prospective treatments“ was used instead of „perspective treatments“.

6. Line 29: consider revising the term ‘well-developed countries’ – the term ‘high income country’ (and low income country, middle income country) is more often used now. Note that the prevalence of asthma has increased in many low- and middle-income countries recently.

Response of the Authors: The term „high income countries“ was used instead of „well-developed countries“.

 

Reviewer 2 Report

The submitted manuscript is focused on the most important issues concerning differences between sex in bronchial asthma. In general, some reviews in this field have been already provided.

However, the manuscript is well-written and organized. It is comprehensive and easy for readers to follow. It is worth developing the case of clinical studies or studies in general, mainly with male subjects (L. 53-59). Could the Authors provide, e.g. in table 3, the column for gender to provide data, which subjects, males or females were included in the studies. Then, the table could highlight the title of the review.

I have only minor comments:

Table 2. Please check Grx1 should be in the center of the column.

Table 3 should be divided into columns, e.g. classified drugs, examples of drugs used, and references.

 

Author Response

Thank you for your comments and suggestions for improving our manuscript. Below you can find answers to your comments:

The submitted manuscript is focused on the most important issues concerning differences between sex in bronchial asthma. In general, some reviews in this field have been already provided.

However, the manuscript is well-written and organized. It is comprehensive and easy for readers to follow. It is worth developing the case of clinical studies or studies in general, mainly with male subjects (L. 53-59). Could the Authors provide, e.g. in table 3, the column for gender to provide data, which subjects, males or females were included in the studies. Then, the table could highlight the title of the review.

Response of the Authors: We would like to thank the Reviewer for this suggestion. We tried to find appropriate data to fill the column for gender in Table 3. Unfortunately, we found that we are not able to provide the reliable data because of large inhomogenity of the source clinical studies and missing differentiation of individual subtypes of asthma in relation to the tested therapies (that fits to Table 3). However, we agree with the Reviewer that this topic needs to be corroborated. In our future paper, we plan to provide complex data from both animal and clinical studies to demonstrate gender bias in the research of asthma and to compare the situation several decades ago with a current situation which is apparently improving.

I have only minor comments:

Table 2. Please check Grx1 should be in the center of the column.

Response of the Authors: Abbreviation Grx1 was moved into the center of the column.

Table 3 should be divided into columns, e.g. classified drugs, examples of drugs used, and references.

Response of the Authors: Composition of Table 3 was changed according to suggestions of the Reviewer.

Reviewer 3 Report

 it is suggested to add the comparative table showing Sex-based differences

 

Author Response

Thank you for your comments and suggestions for improving our manuscript. Below you can find answers to your comments:

It is suggested to add the comparative table showing Sex-based differences.

Response of the Authors: Comparative table showing sex-based differences was added according to suggestions of the Reviewer (provided as Table 4).

Reviewer 4 Report

In the conclusions, I would ask you to please improve them according to the similarities and findings found in the review articles of your work.

Author Response

Thank you for your comments and suggestions for improving our manuscript. Below you can find answers to your comments:

 In the conclusions, I would ask you to please improve them according to the similarities and findings found in the review articles of your work.

Response of the Authors: The paragraph Conclusions was rephrased.