Asthma and Fixed Airways Obstruction: Real Life Aspects

Round 1

Reviewer 1 Report

The article is deal with comparison of asthma patients with fixed airways obstruction and without it. The topic discussed is very important for the treatment and prevention of severe asthma.

I would like to make a few comments:

1.       line 11:

“We found new aspects of fixed airways obstruction in severe asthma.”

Specify which aspects were found, if this was a later diagnosis, then this should be written.

2.       lines 16 and 23:

Give the explanation of FAO and ACT when you use for the first time:

…fixed airways obstruction (FAO)…        asthma control test (ACT)…..

3.       In the Introduction give, please, the description of  proposed mechanisms for remodeling and fixed airways obstruction and cite some articles, for example:

1)      Rutting S, Thamrin C, Cross TJ, King GG and Tonga KO (2022) Fixed Airflow Obstruction in Asthma: A Problem of the Whole Lung Not of Just the Airways. Front. Physiol. 13:898208. doi: 10.3389/fphys.2022.898208

2)      Bakakos A, Vogli S, Dimakou K, Hillas G. Asthma with Fixed Airflow Obstruction: From Fixed to Personalized Approach. Journal of Personalized Medicine. 2022; 12(3):333. https://doi.org/10.3390/jpm12030333

3)      M. Gaga. Fixed obstruction in severe asthma: not just a matter of time. European Respiratory Journal 2004 24: 8-10; DOI: 10.1183/09031936.04.00051804

4)      Morgan, R.K. (2013). Physiology of Fixed Airway Obstruction. In: Ernst, A., Herth, F. (eds) Principles and Practice of Interventional Pulmonology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4292-9_7

4.       item 2.1

Add please, that all patients gave voluntary consent to participate in the study and to process personal data.

5.       line132:

Delete the title as far as there is no another one:

5.2.  Figures and Tables

6.       Move table 1 to the end of section 2.2 and on line 93 give a link to it.

7.       In the footnotes of all figures, give an explanation of all abbreviations.

8.       line 213:

Change, please, the word “biases” on the word “limitations”.

9.       Can you give practical recommendations to doctors, what indicators should be taken into account in order to make a diagnosis on time? If not, then the need for further investigation and search for markers for early diagnosis should be indicated and some articles should be discussed, for example:

1) Runnstrom M, Pitner H, Xu J, Lee FEH, Kuruvilla M. Utilizing Predictive Inflammatory Markers for Guiding the Use of Biologicals in Severe Asthma. J Inflamm Res. 2022;15:241-249

https://doi.org/10.2147/JIR.S269297

2)van de Kant KD, Klaassen EM, Jöbsis Q, Nijhuis AJ, van Schayck OC, Dompeling E. Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study. BMC Public Health. 2009 Jun 29;9:210. doi: 10.1186/1471-2458-9-210

3) Utility of biomarkers in the diagnosis and monitoring of asthmatic children. ParaskeviXepapadaki et all. https://doi.org/10.1016/j.waojou.2022.100727

4) Biomolecular markers in assessment and treatment of asthma

FARNAZ FATEMI. doi: 10.1111/resp.12284

Author Response

The article is deal with comparison of asthma patients with fixed airways obstruction and without it. The topic discussed is very important for the treatment and prevention of severe asthma.

I would like to make a few comments:

1. line 11:

“We found new aspects of fixed airways obstruction in severe asthma.”

Specify which aspects were found, if this was a later diagnosis, then this should be written.

2. lines 16 and 23:

Give the explanation of FAO and ACT when you use for the first time:

…fixed airways obstruction (FAO)…        asthma control test (ACT)…..

3. In the Introduction give, please, the description of  proposed mechanisms for remodeling and fixed airways obstruction and cite some articles, for example:

1)      Rutting S, Thamrin C, Cross TJ, King GG and Tonga KO (2022) Fixed Airflow Obstruction in Asthma: A Problem of the Whole Lung Not of Just the Airways. Front. Physiol. 13:898208. doi: 10.3389/fphys.2022.898208

2)      Bakakos A, Vogli S, Dimakou K, Hillas G. Asthma with Fixed Airflow Obstruction: From Fixed to Personalized Approach. Journal of Personalized Medicine. 2022; 12(3):333. https://doi.org/10.3390/jpm12030333

3)      M. Gaga. Fixed obstruction in severe asthma: not just a matter of time. European Respiratory Journal 2004 24: 8-10; DOI: 10.1183/09031936.04.00051804

4)      Morgan, R.K. (2013). Physiology of Fixed Airway Obstruction. In: Ernst, A., Herth, F. (eds) Principles and Practice of Interventional Pulmonology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4292-9_7

4. item 2.1

Add please, that all patients gave voluntary consent to participate in the study and to process personal data.

5. line132:

Delete the title as far as there is no another one:

5.2.  Figures and Tables

6. Move table 1 to the end of section 2.2 and on line 93 give a link to it.
7. In the footnotes of all figures, give an explanation of all abbreviations.
8. line 213:

Change, please, the word “biases” on the word “limitations”.

9. Can you give practical recommendations to doctors, what indicators should be taken into account in order to make a diagnosis on time? If not, then the need for further investigation and search for markers for early diagnosis should be indicated and some articles should be discussed, for example:

1) Runnstrom M, Pitner H, Xu J, Lee FEH, Kuruvilla M. Utilizing Predictive Inflammatory Markers for Guiding the Use of Biologicals in Severe Asthma. J Inflamm Res. 2022;15:241-249

https://doi.org/10.2147/JIR.S269297

2)van de Kant KD, Klaassen EM, Jöbsis Q, Nijhuis AJ, van Schayck OC, Dompeling E. Early diagnosis of asthma in young children by using non-invasive biomarkers of airway inflammation and early lung function measurements: study protocol of a case-control study. BMC Public Health. 2009 Jun 29;9:210. doi: 10.1186/1471-2458-9-210

3) Utility of biomarkers in the diagnosis and monitoring of asthmatic children. ParaskeviXepapadaki et all. https://doi.org/10.1016/j.waojou.2022.100727

4) Biomolecular markers in assessment and treatment of asthma

FARNAZ FATEMI. doi: 10.1111/resp.12284

 

R- Dear Reviewer, many thanks for your very constructive comments which significantly helped us to improve the quality of our paper. We have addressed all your comments. Please have a look at the revised version (highlighted parts=modifications).  

Reviewer 2 Report

The authors evaluate asthmatic patients with and without PAO. The work has gaps:

- Redo the abstract without the sections.

- The first time an abbreviation appears, put what it means.

- As an exclusion criterion, the non-signature of the consent would be missing.

- What period is T1?

- Line 77, observational is repeated.

- Values with decimals put point or comma. Line 108 vs line 116.

- Section 3.2 is superfluous, it is not necessary to put one of figures and tables.

- In the table put the lung function, the n of each group although it is stated in the methods.

- Review bibliography.

Author Response

The authors evaluate asthmatic patients with and without PAO. The work has gaps:

- Redo the abstract without the sections.

- The first time an abbreviation appears, put what it means.

- As an exclusion criterion, the non-signature of the consent would be missing.

- What period is T1?

- Line 77, observational is repeated.

- Values with decimals put point or comma. Line 108 vs line 116.

- Section 3.2 is superfluous, it is not necessary to put one of figures and tables.

- In the table put the lung function, the n of each group although it is stated in the methods.

- Review bibliography.

 

R- Dear Reviewer, many thanks for your very constructive comments which significantly helped us to improve the quality of our paper. We have addressed all your comments. Please have a look at the revised version (highlighted parts=modifications).  

Reviewer 3 Report

To the Editor,

In their concise study, Buonamicio E and Carpagnano GE et al. compared several clinical parameters in asthma patients with fixed airway obstruction (FAO) to those without FAO. Both groups turned out to be very similar clinically, including a similar change in asthma symptom control and ventilatory parameters during a prospective 1 year observation. This study adds to the long discussion on how airway remodeling in asthma (reflected by FAO) affects the course of the disease and whether it is associated with a certain clinical pattern. An important result also shows that ~70% of FAO patients did not have severe asthma and the disease was well controlled. The potential delay in the diagnosis of asthma in FAO group is noticed, but is not further explored. However, the conclusions are not strong due to the low number of participants (n=20 in each group) and the lack of a clear study design. Below, I list my suggestions to Authors for consideration.  

Major   

1.     The study design is not clear. There is no detailed information in the study design on any change in patient treatment after T0 or any other intervention. It seems like the Authors enrolled patients at T0 (‘real life’) and then during 1 year they optimized treatment using the step-up approach, etc. (‘better asthma therapy’ appears only in the discussion, line 184). This is supported by data showing, for example, an increase in the number of patients staged GINA 3-5 (from 67% at T0 to 100% at T1). Similarly, 17 patients (43%) showed an improvement in ACT and 10 patients (25%) had considerable 15% increase in FEV1 at T1. Figure 3 shows that there was actually an increase in median FEV1% at T1 compared to T0 in more than half of the patients. The Authors use term ‘variation’ here but it is actually a difference (pp. change or % change of volume, please clarify). This study design also explains the idea of MCID assessment at T1. With this approach, the T1 endpoint is also very important for clinically characterizing patients and comparing groups (second table required). For example, analysis of treatment (steroid use in FAO+ and FAO-) and best achieved level of asthma control in the two groups should be based on data from T1.

2.     The issue of FEV1 decline. Unfortunately, with such an approach as described above, it would be very difficult to trace the dynamics of FEV1 decline and how it is related to FAO. The appropriate design should include a roll-in entry period (~3 moths before T0) for the evaluation and adjustment of asthma control and the treatment, and only then the long-term observation. However, this is just my comment, but not a requirement for changing the study design. I would not expect a considerable increase in FEV1% of the predicted after one year of regular observation (without intervention). However, in general, there is a natural decline in FEV1 volume of approximately 30 ml/y related to aging. Unfortunately, detailed T0-T1 spirometry data (most importantly, actual volumes in mL) are not provided, so it is not possible to exactly determine the change in mL of FEV1 over 1 year of observation. This is very important because the FAO diagnosis assumes per se (median age is similar) that there had to be a greater decrease in FEV1 in these patients. I understand that this was not the main objective of this project, but the issue in a faster decline of lung function in some asthma patients is the first thing that comes to my mind when reading the FAO study. Some way to approach this could be just to show correlation plots (age vs FEV1) for the two cohorts, is there any difference in the slopes of regression lines?

Minor

3.     Are these ‘first visit’ patients? The groups are rather small but equal (n=20), as if the patients were somehow selected (supervised approach, potential matching for some factors, age, sex?) from a larger cohort, how was it done? Or were these just 20 consecutive patients who attended the clinic and met the inclusion criteria (unsupervised approach).

4.     I understand that according to current guidelines, as stated in the Methods Section (line 68), COPD was excluded, I assume that patients could not be assigned as asthma-COPD overlap (ACOS), either. Because there are hints in the discussion that few FAO+ patients were (or could have been?) previously diagnosed with COPD, please clearly discuss in the methods the potential ACOS in this group. Please check the COPD issue throughout the discussion to avoid confusion.     

5.     Considering that delay in asthma diagnosis (start of treatment) could be an important factor in FAO, please provide and discuss data on: the age of asthma diagnosis, the age of first airway symptoms, the duration of the period between first symptoms and asthma diagnosis, the duration of asthma, the frequency of patients with early-onset (childhood) asthma. Please add the definition of ‘late diagnosed asthma’ (line 130, Fig. 5) in the Methods section.

6.     It seems so, but did all patients who had FAO in T0 remained FAO at T1?

7.     Please provide detailed lung function data, preferably as a separate table(s).

8.     Please explain the abbreviations when first used (GERD, OSAS etc.). Also, the footnotes to the table should explain the abbreviations. The term ‘tobacco smoke exposure’ or ‘burden’ should be introduced in the discussion, instead of P/Y which is not a commonly used abbreviation.

9.     For convenience, T0-T1 changes of the parameters should be provided as a separate column added to characteristics Tables.

10.  Please, add individual data points and exact P-values to the graphs.

11.  Please, check text for some edit errors, e.g., chronic steroid assumption? (Table 1), not mentioning the peculiar ending of the discussion.

Author Response

In their concise study, Buonamicio E and Carpagnano GE et al. compared several clinical parameters in asthma patients with fixed airway obstruction (FAO) to those without FAO. Both groups turned out to be very similar clinically, including a similar change in asthma symptom control and ventilatory parameters during a prospective 1 year observation. This study adds to the long discussion on how airway remodeling in asthma (reflected by FAO) affects the course of the disease and whether it is associated with a certain clinical pattern. An important result also shows that ~70% of FAO patients did not have severe asthma and the disease was well controlled. The potential delay in the diagnosis of asthma in FAO group is noticed, but is not further explored. However, the conclusions are not strong due to the low number of participants (n=20 in each group) and the lack of a clear study design. Below, I list my suggestions to Authors for consideration.  

Major   

-The study design is not clear. There is no detailed information in the study design on any change in patient treatment after T0 or any other intervention. It seems like the Authors enrolled patients at T0 (‘real life’) and then during 1 year they optimized treatment using the step-up approach, etc. (‘better asthma therapy’ appears only in the discussion, line 184). This is supported by data showing, for example, an increase in the number of patients staged GINA 3-5 (from 67% at T0 to 100% at T1). Similarly, 17 patients (43%) showed an improvement in ACT and 10 patients (25%) had considerable 15% increase in FEV1 at T1. Figure 3 shows that there was actually an increase in median FEV1% at T1 compared to T0 in more than half of the patients. The Authors use term ‘variation’ here but it is actually a difference (pp. change or % change of volume, please clarify). This study design also explains the idea of MCID assessment at T1. With this approach, the T1 endpoint is also very important for clinically characterizing patients and comparing groups (second table required). For example, analysis of treatment (steroid use in FAO+ and FAO-) and best achieved level of asthma control in the two groups should be based on data from T1. 

 

R-Thank you for the comment. We modified the methods section highlighting the adopted approach, based on the application of GINA guidelines to our patients, adapting anti-asthma therapies according to patient’s reported symptoms through the ACT and exacerbations number. Moreover, we clarified in the paper what we considered the “ACT variation”, that is the percentage of change of volume. We spliced the table 1 in 2 tables, and we inserted the comparison between T1 ACT of the two groups.

• The issue of FEV1 decline. Unfortunately, with such an approach as described above, it would be very difficult to trace the dynamics of FEV1 decline and how it is related to FAO. The appropriate design should include a roll-in entry period (~3 moths before T0) for the evaluation and adjustment of asthma control and the treatment, and only then the long-term observation. However, this is just my comment, but not a requirement for changing the study design. I would not expect a considerable increase in FEV1% of the predicted after one year of regular observation (without intervention). However, in general, there is a natural decline in FEV1 volume of approximately 30 ml/y related to aging. Unfortunately, detailed T0-T1 spirometry data (most importantly, actual volumes in mL) are not provided, so it is not possible to exactly determine the change in mL of FEV1 over 1 year of observation. This is very important because the FAO diagnosis assumes per se (median age is similar) that there had to be a greater decrease in FEV1 in these patients. I understand that this was not the main objective of this project, but the issue in a faster decline of lung function in some asthma patients is the first thing that comes to my mind when reading the FAO study. Some way to approach this could be just to show correlation plots (age vs FEV1) for the two cohorts, is there any difference in the slopes of regression lines?

 

R- Thank you for your kind suggestion, we performed correlations between age vs FEV1 absolute values and vs FEV1 in percentage of theorical values, and we obtained that, as expected, older age is correlated to lower absolute FEV1 in both FAO+ and FAO- groups, while FEV1% doesn’t show this clear correlation in both groups and also FEV1 variation from T0 to T1 didn’t show any clear correlation to age in both groups. We provide you the graphics and a table with actual data but probably they would not add a significant value to the paper. Therefore, we have not included them in the manuscript. If you believe that some of the below graphs should be inserted in the paper let us know and we will add them accordingly. (Please see attached file)

 

Minor

• Are these ‘first visit’ patients? The groups are rather small but equal (n=20), as if the patients were somehow selected (supervised approach, potential matching for some factors, age, sex?) from a larger cohort, how was it done? Or were these just 20 consecutive patients who attended the clinic and met the inclusion criteria (unsupervised approach). 

 

R- Thank you for the comment, there were few first visit patients (7 in the FAO+ group, 9 in the FAO- group), but some of them were already on anti-asthma drugs prescribed by GP. Our patients were selected with an unsupervised approach, that took 3 years in order to find a proper number of asthmatic patients with FAO that met the inclusion and exclusion criteria. We modified the paper highlighting the adopted approach.

 -      I understand that according to current guidelines, as stated in the Methods Section (line 68), COPD was excluded, I assume that patients could not be assigned as asthma-COPD overlap (ACOS), either. Because there are hints in the discussion that few FAO+ patients were (or could have been?) previously diagnosed with COPD, please clearly discuss in the methods the potential ACOS in this group. Please check the COPD issue throughout the discussion to avoid confusion.

 

R- Thank you for your interesting reflection, we highlightened that a more probable diagnosis of COPD or asthma/COPD overlap was an exclusion criterion. Unfortunately we couldn’t check among all our patients if some of them had a previous erroneous COPD diagnosis (for example, COPD diagnosis in patient without exposure to noxious agents, COPD diagnosis without limitation to expiratory airflow). However, in our everyday clinical practice this is a very common error, and we have highlighted it in the discussion section.

• Considering that delay in asthma diagnosis (start of treatment) could be an important factor in FAO, please provide and discuss data on: the age of asthma diagnosis, the age of first airway symptoms, the duration of the period between first symptoms and asthma diagnosis, the duration of asthma, the frequency of patients with early-onset (childhood) asthma. Please add the definition of ‘late diagnosed asthma’ (line 130, Fig. 5) in the Methods section. 

 

R- Thank you for your comment, we provided the requested data in table 1; definition of late diagnosed asthma is actually present in methods section, 2.2 sub-section.

• It seems so, but did all patients who had FAO in T0 remained FAO at T1?

 

R-  Thank you for your question, FAO+ was defined as patients showing values of post-bronchodilator Forced Expiratory Volume in the 1^st second/Vital Capacity (FEV1/VC) < limit of the 5th percentile (LLN) and FEV1% < 90% despite adequate control therapy, stable throughout the one-year follow-up, as stated in the materials and methods section, so all FAO patients had to remain FAO throughout all the year in order to be included in the proper group.

-     Please provide detailed lung function data, preferably as a separate table(s).

 

R-Thank you for the suggestion, we added T0, T1 and T1-T0 difference of FVC in table 2.

-  Please explain the abbreviations when first used (GERD, OSAS etc.). Also, the footnotes to the table should explain the abbreviations. The term ‘tobacco smoke exposure’ or ‘burden’ should be introduced in the discussion, instead of P/Y which is not a commonly used abbreviation. 

R- Done it. Thank you

 

-For convenience, T0-T1 changes of the parameters should be provided as a separate column added to characteristics Tables.

R- Thank you for your observation. We created Table 2 with T0 and T1 parameters and T1-T0 changes in order to accomplish to point 7 and point 9 requests.

-  Please, add individual data points and exact P-values to the graphs.

R-  Thank you for the suggestion, we provided the requested data and values in the footnotes of the figures.

 

-Please, check text for some edit errors, e.g., chronic steroid assumption? (Table 1), not mentioning the peculiar ending of the discussion.

R- Thank you for the suggestion, we checked all the text and corrected all the mistakes we found.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Please check  all the text and citing references in aprpopriate way.

For example, line 147: 

the letter p is  omitted (p<0,05,)

Author Response

Please check  all the text and citing references in aprpopriate way.

For example, line 147: 

the letter p is  omitted (p<0,05,)

 

R- We thank reviewer 1 for noticing the above errors. We apologize for that and we have promptly corrected all the mistakes. 

Reviewer 2 Report

Thanks to the authors for taking my comments into account. Just two things:

-Line 145-149. Are not the FAO+ those who have a delay in the diagnosis of asthma?

- Line 257-265: the bibliography is listed 3 times.

Author Response

Thanks to the authors for taking my comments into account. Just two things:

-Line 145-149. Are not the FAO+ those who have a delay in the diagnosis of asthma?

 

R- Yes. We apologize for the typing mistake. WE have changed from FAO- to FAO+ 

• Line 257-265: the bibliography is listed 3 times.

R- Thanks for noticing the mistake. We have corrected it. 

Reviewer 3 Report

The study design is now clearly described in the methods section. The tables are updated with T1 data and T0-T1 changes (especially lung function). The Authors also emphasize the delay in asthma diagnosis as important clinical factor associated with FAO. I appreciate provided FEV1-age correlation data (not included in the final version of the manuscript). Interestingly, it shows similar decline in FEV1L in FAO+ and FAO-, yet with considerable slope intercept in FEV1%. This suggest that FAO+ patients seem to have already initially (during early years of diagnosis) impaired lung function or lung structure, or they showed initial faster rate of decline in lung function. To some point it is actually in line with presented clinical data. Due to unique design of the study and rather small cohort, I agree with the Authors that these data should not be included in the main article.

Author Response

The study design is now clearly described in the methods section. The tables are updated with T1 data and T0-T1 changes (especially lung function). The Authors also emphasize the delay in asthma diagnosis as important clinical factor associated with FAO. I appreciate provided FEV1-age correlation data (not included in the final version of the manuscript). Interestingly, it shows similar decline in FEV1L in FAO+ and FAO-, yet with considerable slope intercept in FEV1%. This suggest that FAO+ patients seem to have already initially (during early years of diagnosis) impaired lung function or lung structure, or they showed initial faster rate of decline in lung function. To some point it is actually in line with presented clinical data. Due to unique design of the study and rather small cohort, I agree with the Authors that these data should not be included in the main article.

 

R- Many thanks for your suggestions which helped us to improve the quality of our manuscript. We will not include those data, then.