Review Reports - The Role of Dual Bronchodilation and the Conscientious Use of Inhaled Corticosteroid in COPD

Round 1

Reviewer 1 Report

This mini review has been prepared based on the paper entitled "Withdrawal of inhaled corticosteroids in COPD: a European Respiratory Society guideline" by Chalmers JD et al. The current mini review will not add additional information in this area in comparison to Chalmers' original paper. Due to its word limit, it is not as straightforward as the paper by Chalmers JD et al. The review also contains several statements without citations that need to be revised.

Major comments:

1- Abstract lines 16-18: this statement "Elevated eosinophil concentrations have been positively correlated to reduced risk of future exacerbations when inhaled corticosteroids (ICS) were associated to ongoing treatment with bronchodilators." needs to be revised because the elevated eosinophil concentrations are not clear enough.

2- Lines 33-35: please apply proper citation(s) for the following statement: "Evidence suggests that eosinophil blood count can be a trustworthy marker to identify phenotypes that are more or less likely to benefit from treatment with inhaled corticosteroids."

3- I suggest using "the LABA/LAMA combination" instead of "the LABA/LAMA association" across the manuscript.

4- Lines 46-47: please apply proper citation(s) for the following statement: "These finding have been replicated in different populations and ethnic groups."

5- lines 48-50: please apply proper citation(s) for the following statements "It is known that progressive dyspnea is the principal factor for incapacity and reduced life quality in patients with COPD. During exercise, airflow obstruction and reduced pulmonary elastic retraction favours an incremental increase in residual volume, with concomitant flattening of inspiratory capacity (IC)."

6- Lines 71-73: please apply proper citation(s) for the following statement: "Patients with Eos>300 represent the subgroup with the highest probable benefit, while the clinical response of the 100-300 Eos interval continues to be variable and uncertain."

7- Lines 65-67: please apply proper citation(s) for the following statement "Elevated eosinophil concentrations have been positively correlated to reduced risk of future exacerbations when ICS were associated to ongoing treatment with bronchodilators."

8- Figure 1 needs to be revised; the picture and the figure caption.

9- Lines 71-73: please apply proper citation for the following statement: "Patients with Eos>300 represent the subgroup with the highest probable benefit, while the clinical response of the 100-300 Eos interval continues to be variable and uncertain."

10- Lines 77-82: please apply proper citation for the following statements "In patients without frequent history of exacerbation, usually defined as one or two exacerbations per year, there is a conditional recommendation to consider the suspension of ICS in favour of ongoing therapy with one or two bronchodilators. The painel also opposed the suspension of ICS in patients with Eos>300 cells/microliter, with or without a previous history of frequent exacerbations. For patients with Eos<300, there was no formal recommendation concerning the suspension of ICS for lack of conclusive evidence. If there is to be an interruption, it should be abrupt, without the need for a gradual weaning."

Minor/ Editorial comments

Lines 34-35: please add the initial (ICS) for "inhaled corticosteroids"

Line 71: EOS is applied here for the first time please add the complete word before EOS

Line 76: "European Society (ERS) guideline" should be corrected to European Respiratory Society (ERS)

Line 79: "painel" should be corrected to "panel"

Author Response

Dear Reviewer

I have attached here the revised version of our manuscript entitled "The Role of Dual Bronchodilation and the Conscientious Use of Inhaled Corticosteroid in COPD", resubmitted for your consideration for publication in Sinusitis. You will find our point-by-point responses to the editorial revisions below. All changes in the revised text have been highlighted.

Please feel free to contact us with any questions or concerns, and we eagerly await your response.

Reviewer #1: This mini review has been prepared based on the paper entitled "Withdrawal of inhaled corticosteroids in COPD: a European Respiratory Society guideline" by Chalmers JD et al. The current mini review will not add additional information in this area in comparison to Chalmers' original paper. Due to its word limit, it is not as straightforward as the paper by Chalmers JD et al. The review also contains several statements without citations that need to be revised.

1 - Abstract lines 16-18: this statement "Elevated eosinophil concentrations have been positively correlated to reduced risk of future exacerbations when inhaled corticosteroids (ICS) were associated to ongoing treatment with bronchodilators." needs to be revised because the elevated eosinophil concentrations are not clear enough.

R – We thank the reviewer for carefully reading the manuscript and for constructive comments. We have revised the text which we present below:

“Eosinophil blood count is a simple biomarker that may guide personalized treatment strategies by identifying patients with greater clinical benefits of inhaled corticosteroids (ICS) treatment”

2 - Lines 33-35: please apply proper citation(s) for the following statement: "Evidence suggests that eosinophil blood count can be a trustworthy marker to identify phenotypes that are more or less likely to benefit from treatment with inhaled corticosteroids."

R - We agree with the reviewer that a more significant number of references would add relevance to the reader. We included the following citation to support this statement:

Eltboli O, Mistry V, Barker B, Brightling CE. Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane thickening in chronic obstructive pulmonary disease. Respirology. 2015;20(4):667–670.

3- I suggest using "the LABA/LAMA combination" instead of "the LABA/LAMA association" across the manuscript.

R - Revised accordingly (lines 56 and 58).

4- Lines 46-47: please apply proper citation(s) for the following statement: "These findings have been replicated in different populations and ethnic groups."

R – We included two references as support for this statement:

Rodrigo GJ, Price D, Anzueto A, Singh D, Altman P, Bader G, et al. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2017;12:907–22.

Barrecheguren M, Monteagudo M, Miravitlles M. Population-based study of LAMA monotherapy effectiveness compared with LABA/LAMA as initial treatment for COPD in primary care. NPJ Prim Care Respir Med. 2018;28:36.

5- lines 48-50: please apply proper citation(s) for the following statements "It is known that progressive dyspnea is the principal factor for incapacity and reduced life quality in patients with COPD. During exercise, airflow obstruction and reduced pulmonary elastic retraction favors an incremental increase in residual volume, with concomitant flattening of inspiratory capacity (IC)."

R - We agree with the reviewer that a more significant number of references would add relevance to the reader. We included the following citations to support this statement:

Nici L, Donner C, Wouters E, et al. American thoracic society/European respiratory society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;173(12):1390–1413.

Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emil J, Lisboa C. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. Eur Respir J. 2000 Aug;16(2):269-75.

R - We included the following citation to support this statement:

Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2021. (https://goldcopd.org/. Accessed Mai 10, 2021)

R - We thank the reviewer for the suggestion. We have revised the text which we present below and included a proper reference:

"Elevated eosinophil concentrations have been positively associated with higher exacerbation risk in COPD patients." (Chan MC, Yeung YC, Yu ELM, Yu WC. Blood Eosinophil and Risk of Exacerbation in Chronic Obstructive Pulmonary Disease Patients: A Retrospective Cohort Analysis. Int J Chron Obstruct Pulmon Dis. 2020 Nov 10;15:2869-2877.)

8- Figure 1 needs to be revised; the picture and the figure caption.

R – Figure 1 illustrates bronchodilator treatment in COPD according to the Latin America Thoracic Association (ALAT) and Brazilian Respiratory Society (SBPT) guidelines. Although it may differ from GOLD strategy, it is a straightforward alternative way to guide treatment decisions for clinicians. Nevertheless, we agree to withdraw this figure if it does not meet editorial criteria

R - We included the following citation to support this statement:

Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2021. (https://goldcopd.org/. Accessed Mai 10, 2021)

10- Lines 77-82: please apply proper citation for the following statements "In patients without a frequent history of exacerbation, usually defined as one or two exacerbations per year, there is a conditional recommendation to consider the suspension of ICS in favor of ongoing therapy with one or two bronchodilators. The painel also opposed the suspension of ICS in patients with Eos>300 cells/microliter, with or without a previous history of frequent exacerbations. For patients with Eos<300, there was no formal recommendation concerning the suspension of ICS for lack of conclusive evidence. If there is to be an interruption, it should be abrupt, without the need for gradual weaning."

R - This paragraph is based on the European Society (ERS) guideline published in 2020. We included the following citation to support this statement:

Chalmers, James D., Irena F. Laska, Frits M.E. Franssen, Wim Janssens, Ian Pavord, David Rigau, Melissa J. McDonnell, et al. 2020. “Withdrawal of Inhaled Corticosteroids in COPD: A European Respiratory Society Guideline.” European Respiratory Journal 55 (6): 2000351. https://doi.org/10.1183/13993003.00351-2020.

Minor/ Editorial comments

Lines 34-35: please add the initial (ICS) for "inhaled corticosteroids"

R – We revised accordingly

Line 71: EOS is applied here for the first time please add the complete word before EOS

R – We revised accordingly: “Eosinophil blood (EOS) count is a simple and reasonably reproducible tool that should only be used therapeutically after taking into consideration individual exacerbating risk factors (severity, hospitalizations and previous exacerbations)”

Line 76: "European Society (ERS) guideline" should be corrected to European Respiratory Society (ERS)

R – We revised accordingly

Line 79: "painel" should be corrected to "panel"

R – We revised accordingly

Reviewer 2 Report

This mini review is interesting for physicians in the field of COPD management and suitable with GOLD and WHO recommendations. However, there are some minor issues which should be corrected by the authors:

1. The reference for WHO cited should be added in the first paragraph of introduction section.

2. The number of people suffering from COPD should be updated in the introduction section with 2022 GOLD recommendations ( not only 250 millions but more than billion ).

3. The cut-off values in the Table should be presented as standard equation : A < FEV1 < B ...for example

Author Response

Dear Reviewer

Please feel free to contact us with any questions or concerns, and we eagerly await your response.

1. The reference for WHO cited should be added in the first paragraph of introduction section.

R – We thank the reviewer for carefully reading the manuscript and for constructive comments. We included the follow citation to support this statement: Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care. 2001 Aug;46(8):798-825.

2. The number of people suffering from COPD should be updated in the introduction section with 2022 GOLD recommendations ( not only 250 millions but more than billion ).

R - We have revised the text according GOLD 2022 which we present below: "Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by pulmonary and systemic dysfunctions that affects approximately 384 million people worldwide in 2020"

3. The cut-off values in the Table should be presented as standard equation : A < FEV1 < B ...for example

R - Revised accordingly