Is Bronchiectasis (BE) Properly Investigated in Patients with Severe Asthma? A Real-Life Report from Eight Italian Centers

Round 1

Reviewer 1 Report

Dear colleagues,

Thank you for your interesting research paper regarding real-life status of asthma and bronchiectasis co-occurrence in some centers from your country. 

Please rephrase Introduction section because title of your paper is on Severe Asthma and in this section you are presenting in several statements a "still unclear complex relation,  between asthma and bronchiectasis". Should be presented more precise the study hypothesis, in current context of available literature. 

In Materials and Methods section you are stating "92 patients, already diagnosed with non-CF and non-ASBA bronchiectasis"

This cohort of 92 patients seems to be very inhomogeneous, the few common aspects being CT-documented bronchiectasis in a patient with asthma-like disease (variable airway obstruction with positive bronchodilation test - but not all patients tested!) - please clarify inclusion and exclusion criteria. 

What does "non-ASBA" stands for (you have not inserted an explanation for acronym in first two pages...)? 

Please describe in more detail how was performed a retrospective study with inclusion at T0 and next visits at 6, respective 12 months later from enrolment?

Please clarify if monitoring schedule was preset before T0 and data that had to be collected were part of the research project?

Because you are stating : "Methods: All centers received a database fille out with clinical, diagnostic and therapeutic data of their patients at baseline (T0), after 6 (T1) and 12 months from enrolment (T2)."

If this was the case, it is really surprising that compliance with this approach was at best modest, among centers being noted some that performed 0% of a given item/test. Centers 2 and 7 seem to be more compliant with study protocol than others. 

Please clarify why all patients were on biological treatment, in spite of having only 63% blood eosinophilia tested, 81.5% IgE tested and 35.8% FeNO tests performed?

Severe Allergic Asthma (SAA) patients with or without bronchiectasis could benefit from biologicals (Crimi C, Campisi R, Nolasco S, Cacopardo G, Intravaia R, Porto M, Impellizzeri P, Pelaia C, Crimi N. Mepolizumab effectiveness in patients with severe eosinophilic asthma and co-presence of bronchiectasis: A real-world retrospective pilot study. Respir Med. 2021 Aug-Sep;185:106491. doi: 10.1016/j.rmed.2021.106491. Epub 2021 Jun 1. PMID: 34098492.

or Domingo Ribas C, Carrillo Díaz T, Blanco Aparicio M, Martínez Moragón E, Banas Conejero D, Sánchez Herrero MG; REDES Study Group. REal worlD Effectiveness and Safety of Mepolizumab in a Multicentric Spanish Cohort of Asthma Patients Stratified by Eosinophils: The REDES Study. Drugs. 2021 Oct;81(15):1763-1774. doi: 10.1007/s40265-021-01597-9. Epub 2021 Sep 29. Erratum in: Drugs. 2021 Oct 21;: PMID: 34586602; PMCID: PMC8550660.

or Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, Trevor JL, Magnan A, Ten Brinke A. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017 May;5(5):390-400. doi: 10.1016/S2213-2600(17)30125-X. Epub 2017 Apr 5. PMID: 28395936.), but there are not indisputable data that these patients have all SAA.

Not all patients are unquestionably asthma patients, if alternative diagnosis has not been excluded. Immunodeficiencies, primary ciliary dyskinesia, congenital bronchiectasis, collagen diseases and others can present similar airway disfunction.

There are few data on bronchiectasis aspect and topography in your paper. Do you have data on type and location of bronchiectasis, besides laterality?

Recent literature data are suggesting that morphology and location of bronchiectasis, in association with certain biomarkers like blood eosinophilia, could represent a valuable orientation tools for tailoring treatment :  Quaranta VN, Dragonieri S, Vulpi MR, Crimi N, Crimi C, Santus P, Menzella F, Pelaia C, Scioscia G, Caruso C, Bargagli E, Scichilone N, Carpagnano GE. High Level of Blood Eosinophils and Localization of Bronchiectasis in Patients with Severe Asthma: A Pilot Study. J Clin Med. 2023 Jan 3;12(1):380. doi: 10.3390/jcm12010380. PMID: 36615179; PMCID: PMC9821283.    

   Please delineate better Conclusion section because your statement "In summary, despite the increasing scientific interest in this topic, the present study confirms that there is no adequate diagnostic flowchart and management of bronchiectasis in patients with asthma." is not accurate.

Your results show a variable approach on a given flowchart/management plan, with extreme variability between centers.

Must be improved.

Author Response

We thank the reviewer for their constructive comments, which we hope have contributed to enhancing the clarity and presentation of our study.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors preseny an intereseting overview of an intriguing and quite under-researched topic of bronciectasis in severe asthma. The research concept is valid and the findings are mostly well presented.

However, a few issues were detected:

Background: Aim- I suggest the aim to be a bit more elaborated, in terms of type of study snd main objectives. This could also be mentioned at the very beginning of the Methods section instead.

Methods: please specify mi the type of study (if not specified in the Aims) and provide more details on the time and settings of the study.

Also, inclusion and exclusion criteria need to be elaborated into more details and the authots should discuss hoe these criteria were assessed and met.

It is.not clear how the Ethics committee approvals were obtained- was the study only approved by the Reunite hopital EC ot the Ethics committees at other centres, too.

 Please also provide more detail on the recruitment process (especially on the ethics related issues, when and hoe was informed consent obtained), the study population- a general overview of their characteristics should be stated, preferably in the form of a Table (mean age, sex, main clinical charcteristics- eg. lung function, FENO, treatment at baseline etc.). The authors don't even mention whether the study population is adults only or it includes minors, too, which means the recruitment process and ethics need to be clarified even more.

Statistical analysis- the authors are advised to elaborate how missing data were handled.

Results- how was compliance assessed?

Minor editing required.

Author Response

We thank the reviewer for their constructive comments, which we hope have contributed to enhancing the clarity and presentation of our study.

Author Response File: Author Response.pdf

Reviewer 3 Report

This is a study on phenotyping of bronchiectasis on patients with both asthma and bronchiectasis. This study included 92 patients with severe asthma and bronchiectasis and this was a multicenter study in a real-life study setting. Assessment of asthma was thorough but assessment of bronchiectasis remained partial. This is important issue and the study is extremely interesting. I expect further results from this group especially considering use of biologicals and having bronchiectasis.

Major

-The Authors write: ‘bronchial alterations are a natural consequence of pro-longed airways inflammation due to asthma. However today there is no evidence to sup-port this hypothesis. ‘ I would consider this statement again. It is well known that severe asthma is associated with bronchiectasis. It is not thoroughly studied if it is because of prolonged airways asthmatic inflammation or if it is due to recurrent infections. Asthma patients and especially severe asthma patients have both virus and bacterial infections more often than non-asthmatic individuals. Further, especially high-dose inhaled steroids or some particular inhaled steroids are considered to predispose to respiratory infections.

-I would like to remind that assessment of AAT blood level may be questioned from the patient view. It is a hereditary disease without curative treatment and thus it may be that not all the patients would wish that to be examined.

-It may be also questioned if ciliary function test is a part of routine systematic assessment of all the adult patients with severe asthma and bronchiectasis (BE) although it clearly is needed in some cases (where diseases have manifestated in childhood). It the Authors consider this test to be used in all adult patients with severe asthma and BE, then I would like this to be better rationalized here and to be given with adequate references.

Minor

-        Methods: All centers received a database fille out with clinical > Should this be ‘to fill out’ etc.?

-        Table 1: I suggest that the lay out of the Tables would be such that the text in the columns would be set in the left side and not in the middle. I found the Table a little hard to read  when the text was placed in the middle and each row was of different size.

-        Hemochromome? Is the correct word in English?

-        Total IgE > Total S-IgE

-      - Methods: All centers received a database fille out with clinical > Should this be ‘to fill out’ etc.?

-   -   Hemochromome? Is the correct word in English?

-       - Total IgE > Total S-IgE

Author Response

We thank the reviewer for their constructive comments, which we hope have contributed to enhancing the clarity and presentation of our study.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Dear colleagues thank you for the clarifications provided. They provide significant insight on your valuable work and improve in a major way present paper. Minor technical aspects and editing are advisable.

There are still minor issues regarding formatting and structure, but I am sure that corrections are easy achievable.

Example

In Abstract, Introduction section 

"...with asthma receiving more attentions" [should be without an "s"]

In Abstract, Results section

" A statistically significant heterogeneous diagnostic approach emerged across the centers under study In fact, while, as expected, all involved centers" ... Here seems to be the end of a sentence. Missing punctuation?!

"... all involved centers made an in-depth investigation of SA, only few of them made a complete investigation of bronchiectasis"

You can use synonyms in order to avoid an unacademic phrasing - like "provided", 'implemented", "used", etc.

In Introduction section

"when this liaison starts it " - can be rephrased as "this interplay has important clinical implications.." 

Material and Methods

Population section

"Database fields to be filled in are those described in tables 1 and 2" - "to be inserted"

"various centers did not possess the requisite database for data entry" - "various centers used individual, variable databases for data entry"

"Patients who could not have the required database information assembled due to inadequate archived records were excluded from the study" needs a rephrasing.

Maybe a similar structure "Patients with notable absent data (as per-protocol) in their local hospital database were excluded"

Table 1 page 6 - in Comorbidities you should delete row regarding CF 0% because you are stating in Inclusion criteria that you have included only non-CF and non-ASBA bronchiectasis patients

Same table you have to harmonize FENO in table with FeNO in abbreviations as FeNO

Same table you have to change to IgE instead of IGE

Same table - try to unify typing with Table 2 page 7 - avoid capital letters in "BLOOD EOSINOPHILIA"

Same table - "Anti-LTRE" has to be changed to Anti-LTRA" and has to be inserted in abbreviation list, below table

Abbreviations can be inserted in alphabetical order.

In Table 2 page 7 - please correct "LUNF FUNCTION TESTS" with LUNG 

Same table - please unify FENO typing with Abbreviations list and delete on-line link inserted along with "FRACTIONAL EXHALED NITRIC OXIDE (FeNO) TEST" 

Abbreviations can be inserted in alphabetical order.

Page 9  "Global initiative for Asthma" is with capital letter "Initiative"

Page 9 second-last paragraph "The main results of the present study are the following:1) In severe asthma patients the presence of bilateral bronchiectasis is common; 2) Despite this, the assessment of bronchiectasis is extremely poor or heterogeneous; 3) unlike for asthma, follow-up of bronchiectasis is extremely poor." can be rephrased "The main results of the present study are: 1) In severe asthma patients the presence of bilateral bronchiectasis is common; 2) Despite this, the assessment of bronchiectasis in a real-word scenario is heterogeneous; 3) Asthma component in these SA patients has a more diligent follow-up comparing with bronchiectasis.

Discussion section page 10

"It is not thoroughly studied if it is because of prolonged airways asthmatic inflammation or if it is due to recurrent infections." - needs rephrasing, because it is not accurate - even you are inserting reference 6 that provides insights in this research question...

Maybe you can use an approach like  "Current research provides conflicting data on severe inflammation or recurrent infections, as forerunners of bronchiectasis, in SA patients" 

Author Response

Dear reviewer, we have made the suggested changes by inserting them into the manuscript.

Author Response File: Author Response.pdf