Pharmacogenomics and Pediatric Asthmatic Medications

Round 1

Reviewer 1 Report

In this review, the authors discussed the impact of genetic variability and response to asthma medications in the pediatric population.
I have read this review with great interest and I think it can make a contribution to the research sector.
The topic of the study is interesting since there are few similar recent works in the literature.
It might be useful to add a paragraph to deepen the discussion on biological drugs, some of which have recently been indicated also in the pediatric population.
It could also be useful to add similar articles to the bibliography that deal with the same topic (i.e .: 10.2500/aap.2019.40.4254; 10.1080/14656566.2017.1317747).
The work is well organized and adequately accompanied by images and explanatory graphics.
The article is well written and has no obvious problems in the language.
Overall, the study is well done and I think the article can be accepted for publication after completing the minor revisions reported.

Author Response

We thank the reviewer for his/her thoroughness and vital suggestions.

The reviewer wrote:

It might be useful to add a paragraph to deepen the discussion on biological drugs, some of which have recently been indicated also in the pediatric population.

This is a fantastic suggestion and we have included the following text at the appropriate points within the manuscript:

"Pharmacogenomics testing on these CYP enzymes has the potential to provide guidance on future regimens. Children with the CYP3A4 *1/*1 or *1/*3 variation may be advised to use a non-beclomethasone medication, such as budesonide, as their initial ICS. Similarly, those with the CYP3A4*22 variation may be advised to start therapy with fluticasone."

"These results may favor genetic testing to identify SLCO2B1, rs12422149 GG variants, which presumably should see the greatest effect from monteluakast treatment among LTM medications. Those without the SLCO2B1, rs12422149 GG variants may see better efficacy on a different LTM."

"GINA guidelines also recommend adding on biologics such as omalizumab (Xolair) or dupilumab (Dupixent) [80]. These biologics are indicated in children ages 6 and older with severe symptoms, despite optimizing therapy with high dose ICS-LABA-oral corticosteroids.

Pharmacogenetic testing in asthmatic adults has shown cost effectiveness and increased quality of life when adding a LTM to patients identified to exhibit reduced ICS response [80]. Current guidelines recommend increasing ICS-LABA dosing to reduce exacerbations, or alternatively using a LTM as a controller therapy. Identifying children who may be genetically predisposed to ICS unresponsiveness may incline providers to initiate alternative LTM therapy earlier in the patient’s course of treatment. There are no studies to date on the effectiveness of pharmacogenomic testing for asthmatic biologics. However, future trials on the stepwise therapy model may be questioned as some children may be better suited for biologics rather than LTMs. Potential testing on certain genetic markers, such as drug transporter or CYP450 enzymes, can additionally guide clinicians when choosing initial medications among drug classes. Future studies should be conducted to evaluate the effectiveness of pharmacogenomic testing in children. Although preemptive pharmacogenomic testing for asthma is not currently recommended, due to the lack of evidence and accuracy, the hope for universal testing at an early age has the potential to eliminate prolonged medication trial and error."

We feel that this will also provide practitioners some additional guidance and background.

The reviewer also wrote:

It could also be useful to add similar articles to the bibliography that deal with the same topic (i.e .: 10.2500/aap.2019.40.4254; 10.1080/14656566.2017.1317747).

Both of these manuscripts are very nice articles and we agree with the reviewer and have included both. 

Should the reviewer have any further concerns we will be more than happy to address them.

Reviewer 2 Report

This review contribute with a structure for current knowledge. Still the data known have been of limited importance for clinical practices. 

It covers Beta 2 agonists, Stereoids and Leukotrien modifiers. 

I do miss more interpretation and comments regarding when this data might be usefult, that is when there is a need to know. 

I am hesitant regarding Beta 2 agonists but think the authors might want to focus more on  Stereoids and Leukotrien modifiers.

I would also be interesting with a more expanded discussion regarding in what situations the doctor might need to consider genetics in the treatmen of childhood asthma

Author Response

We thank the reviewer for his/her thoroughness and vital suggestions.

The reviewer wrote:

I do miss more interpretation and comments regarding when this data might be useful that is when there is a need to know.

And

I would also be interesting with a more expanded discussion regarding in what situations the doctor might need to consider genetics in the treatment of childhood asthma.

These are a fantastic suggestions and we have included the following text at the appropriate points within the manuscript:

"Pharmacogenomics testing on these CYP enzymes has the potential to provide guidance on future regimens. Children with the CYP3A4 *1/*1 or *1/*3 variation may be advised to use a non-beclomethasone medication, such as budesonide, as their initial ICS. Similarly, those with the CYP3A4*22 variation may be advised to start therapy with fluticasone."

"These results may favor genetic testing to identify SLCO2B1, rs12422149 GG variants, which presumably should see the greatest effect from monteluakast treatment among LTM medications. Those without the SLCO2B1, rs12422149 GG variants may see better efficacy on a different LTM."

We feel that this will also provide practitioners some additional guidance and background.

The reviewer also wrote:

I am hesitant regarding Beta 2 agonists but think the authors might want to focus more on Stereoids and Leukotrien modifiers.

This is a very viable suggestion and we have included the following text which also discusses guidelines related to biologics:

"GINA guidelines also recommend adding on biologics such as omalizumab (Xolair) or dupilumab (Dupixent) [80]. These biologics are indicated in children ages 6 and older with severe symptoms, despite optimizing therapy with high dose ICS-LABA-oral corticosteroids.

Pharmacogenetic testing in asthmatic adults has shown cost effectiveness and increased quality of life when adding a LTM to patients identified to exhibit reduced ICS response [80]. Current guidelines recommend increasing ICS-LABA dosing to reduce exacerbations, or alternatively using a LTM as a controller therapy. Identifying children who may be genetically predisposed to ICS unresponsiveness may incline providers to initiate alternative LTM therapy earlier in the patient’s course of treatment. There are no studies to date on the effectiveness of pharmacogenomic testing for asthmatic biologics. However, future trials on the stepwise therapy model may be questioned as some children may be better suited for biologics rather than LTMs. Potential testing on certain genetic markers, such as drug transporter or CYP450 enzymes, can additionally guide clinicians when choosing initial medications among drug classes. Future studies should be conducted to evaluate the effectiveness of pharmacogenomic testing in children. Although preemptive pharmacogenomic testing for asthma is not currently recommended, due to the lack of evidence and accuracy, the hope for universal testing at an early age has the potential to eliminate prolonged medication trial and error."

Should the reviewer have any further concerns we will be more than happy to address them.