Italian Evidence-Based Clinical Recommendations on the Appropriateness of Prescriptions and Diagnostic Tests in Pediatric Allergology: Focus on Anaphylaxis, Drug Allergy and Hymenoptera Venom Allergy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Reviewer Comments

Introduction

• Please consider adding epidemiological data to highlight the burden of anaphylaxis, drug allergy, and Hymenoptera venom allergy in the pediatric population. Quantifying disease prevalence, emergency visits, or hospitalization rates would strengthen the rationale for developing Good Clinical Practice Recommendations (GCPRs).
• Given the practical limitations highlighted around line 78, please clarify whether these GCPRs are intended for use within a specific national healthcare system (Italy). Since all experts involved are from Italy, this should be explicitly stated.
  If the recommendations are country-specific, this should be clearly reflected in both the Introduction and the title of the manuscript. This is particularly relevant because certain diagnostic tools (e.g., serum tryptase, BAT, CRD) may not be readily available in many countries or low-resource settings.

Methods

• Line 205: The manuscript states that six additional studies were included based on expert opinion. Please clarify whether these studies were part of the initially identified 6,819 records or whether they were added outside the original database search. Clear reporting is essential for transparency and reproducibility of the systematic review process.
• Although meta-analysis is described in detail in the Methods section, none of the PICO questions ultimately employed quantitative synthesis. I therefore suggest either:
• removing the meta-analysis section entirely, or
• explicitly stating that meta-analysis was planned but not feasible due to lack of insufficient homogeneous data.

 

Results and Evidence Interpretation

• Line 233: Please consider adding evidence that referral to an allergist is associated with higher rates of adrenaline auto-injector (AAI) prescription. Suggested reference: Khojah A. et al. Possession of Injectable Epinephrine Among Children with Parent-Reported Food Allergies in Saudi Arabia. J Clin Med. 2025;14:5274.
  This would strengthen the argument that specialist referral directly improves patient safety.
• Line 248: Consider mentioning intranasal epinephrine as an emerging alternative to auto-injectors, particularly in patients or settings where injection is a barrier.
  Suggested reference: Ebisawa M. et al. Epinephrine Nasal Spray Improves Allergic Symptoms in Patients Undergoing Oral Food Challenge. J Allergy Clin Immunol Pract. 2025;13:2787–2794.
• Line 283: Please add Hereditary α-tryptasemia (HαT) as an important cause of elevated baseline tryptase and is a known genetic risk factor for severe anaphylaxis.
  Suggested references:
• Greiner G. et al. Blood. 2021;137:238–247.
• Lyons JJ. et al. J Allergy Clin Immunol. 2021;147:622–632.
• Line 290: The recommendation does not fully reflect the evidence presented. I suggest adding a clarifying statement indicating that serum tryptase is particularly valuable in cases where the diagnosis of anaphylaxis is uncertain or atypical.
  This is important because many patients with clinically clear anaphylaxis—especially children—may not have elevated tryptase levels.
  If the wording cannot be adjusted, consideration should be given to downgrading the strength of recommendation and/or quality of evidence.

PICO 3 – Food Allergy Diagnostics

• Line 295: The recommendation that skin prick testing (SPT) is a “first-line” diagnostic tool is not fully supported by the PICO question as currently formulated. The PICO does not compare SPT with serum-specific IgE (sIgE), and there is insufficient evidence presented to conclude superiority of one over the other.
• In clinical practice, SPT and sIgE are complementary and equivalent first-line tools, each with advantages and limitations. sIgE testing is particularly valuable when:
• skin testing is unavailable,
• standardized extracts do not exist,
• or longitudinal monitoring is needed as children outgrow food allergies.
• I strongly recommend either:

1. revising the PICO question to explicitly include sIgE testing, or
2. avoiding the term “first-line” altogether.

• Additionally, sIgE testing may reasonably be initiated by pediatricians while awaiting specialist evaluation, allowing for interim dietary guidance when access to allergists is delayed.

Discussion

• Several statements in the Discussion section are not adequately referenced. Please ensure that all major claims—particularly regarding diagnostic accuracy, cost-effectiveness, and clinical impact—are supported by appropriate citations.

 

Conclusion

• The Conclusion section should be more concise and focused on the key take-home messages.

 

Minor Comments

• Please ensure consistent terminology throughout the manuscript by using either “allergist” or “allergologist”, but not both.
• Where evidence quality is low or moderate, recommendations should be clearly framed as consensus-based, rather than evidence-driven.

Author Response

We thank very much the reviewer for the helpful comments that we believe have greatly improved the manuscript. Here the answers.

Introduction

• Please consider adding epidemiological data to highlight the burden of anaphylaxis, drug allergy, and Hymenoptera venom allergy in the pediatric population. Quantifying disease prevalence, emergency visits, or hospitalization rates would strengthen the rationale for developing Good Clinical Practice Recommendations (GCPRs).

Thank you for the comment. We added in the introduction data on prevalence of anaphylaxis and related diseases.

• Given the practical limitations highlighted around line 78, please clarify whether these GCPRs are intended for use within a specific national healthcare system (Italy). Since all experts involved are from Italy, this should be explicitly stated.
  If the recommendations are country-specific, this should be clearly reflected in both the Introduction and the title of the manuscript. This is particularly relevant because certain diagnostic tools (e.g., serum tryptase, BAT, CRD) may not be readily available in many countries or low-resource settings.

Many thanks for the helpful comment. We did clarify this point in the introduction and we changed the title..

Methods

• Line 205: The manuscript states that six additional studies were included based on expert opinion. Please clarify whether these studies were part of the initially identified 6,819 records or whether they were added outside the original database search. Clear reporting is essential for transparency and reproducibility of the systematic review process.

Thanks, we clarified.

• Although meta-analysis is described in detail in the Methods section, none of the PICO questions ultimately employed quantitative synthesis. I therefore suggest either:
• removing the meta-analysis section entirely, or
• explicitly stating that meta-analysis was planned but not feasible due to lack of insufficient homogeneous data.

Thank you very much for the comment, we modified as suggested.

Results and Evidence Interpretation

• Line 233: Please consider adding evidence that referral to an allergist is associated with higher rates of adrenaline auto-injector (AAI) prescription. Suggested reference: Khojah A. et al. Possession of Injectable Epinephrine Among Children with Parent-Reported Food Allergies in Saudi Arabia. J Clin Med. 2025;14:5274.
  This would strengthen the argument that specialist referral directly improves patient safety.

Many thanks for the suggestion. We added the sentence and the reference,

• Line 248: Consider mentioning intranasal epinephrine as an emerging alternative to auto-injectors, particularly in patients or settings where injection is a barrier.
  Suggested reference: Ebisawa M. et al. Epinephrine Nasal Spray Improves Allergic Symptoms in Patients Undergoing Oral Food Challenge. J Allergy Clin Immunol Pract. 2025;13:2787–2794.

Thanks for the suggestion, we added a paragraph on nasal epinephrine.

• Line 283: Please add Hereditary α-tryptasemia (HαT) as an important cause of elevated baseline tryptase and is a known genetic risk factor for severe anaphylaxis.
  Suggested references:
• Greiner G. et al. Blood. 2021;137:238–247.
• Lyons JJ. et al. J Allergy Clin Immunol. 2021;147:622–632.

We thank the reviewer for the suggestion. We added this condition to the chapter.

• Line 290: The recommendation does not fully reflect the evidence presented. I suggest adding a clarifying statement indicating that serum tryptase is particularly valuable in cases where the diagnosis of anaphylaxis is uncertain or atypical.
  This is important because many patients with clinically clear anaphylaxis—especially children—may not have elevated tryptase levels.
  If the wording cannot be adjusted, consideration should be given to downgrading the strength of recommendation and/or quality of evidence.

Many thanks, we adjusted the recommendation.

PICO 3 – Food Allergy Diagnostics

• Line 295: The recommendation that skin prick testing (SPT) is a “first-line” diagnostic tool is not fully supported by the PICO question as currently formulated. The PICO does not compare SPT with serum-specific IgE (sIgE), and there is insufficient evidence presented to conclude superiority of one over the other.
• In clinical practice, SPT and sIgE are complementary and equivalent first-line tools, each with advantages and limitations. sIgE testing is particularly valuable when:
• skin testing is unavailable,
• standardized extracts do not exist,
• or longitudinal monitoring is needed as children outgrow food allergies.
• I strongly recommend either:

1. revising the PICO question to explicitly include sIgE testing, or
2. avoiding the term “first-line” altogether.

• Additionally, sIgE testing may reasonably be initiated by pediatricians while awaiting specialist evaluation, allowing for interim dietary guidance when access to allergists is delayed.

Many thanks for the comments, we added the helpful cpmmments and modified the recommendation from “first line” to “first step”.

Discussion

• Several statements in the Discussion section are not adequately referenced. Please ensure that all major claims—particularly regarding diagnostic accuracy, cost-effectiveness, and clinical impact—are supported by appropriate citations.

Thank you for the udìseful comments, we added the main references to the discussion section.

Conclusion

• The Conclusion section should be more concise and focused on the key take-home messages.

The conclusions are now shorter.

Minor Comments

• Please ensure consistent terminology throughout the manuscript by using either “allergist” or “allergologist”, but not both.

We corrected accordingly.

• Where evidence quality is low or moderate, recommendations should be clearly framed as consensus-based, rather than evidence-driven.

Agree, we modified accordingly.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors

Enclosed you will find my comments and suggestions.

Comments for author File: Comments.pdf

Author Response

We thank the reviewer for the helpful comments that we believe have greatly improved the manuscript. Here the answers.

We changed the title and we corrected the words that have been reported.

In addition, we have added a paragraph on nasal epinephrine on page 9 line 257 that states as follows: "However, various concerns identified by parents may prevent or delay the utilization of AIA, including reluctance to carry the device, apprehension regarding needles, and insufficient training. (Prince BT, Mikhail I, Stukus DR. Underuse of epinephrine for the treatment of anaphylaxis: missed opportunities. J Asthma Allergy. 2018 Jun 20;11:143-151. doi: 10.2147/JAA.S159400. PMID: 29950873; PMCID: PMC6016581.). Recently, epinephrine nasal spray (neffy) was approved as the first needle-free epinephrine option for the treatment of anaphylaxis for adults and children >15 kg (Ellis AK, Casale TB, Kaliner M, Oppenheimer J, Spergel JK, Fleischer DM, et al. Development of neffy, an epinephrine nasal spray, for severe allergic reactions. Pharmaceutics 2024;16:1-16. Ebisawa M, Takahashi K, Takahashi K, Yanagida N, Sato S, Lieberman J, Pistiner M, Spergel JM, Lowenthal R, Tanimoto S. Epinephrine Nasal Spray Improves Allergic Symptoms in Patients Undergoing Oral Food Challenge, Phase 3 Trial. J Allergy Clin Immunol Pract. 2025 Oct;13(10):2787-2794. doi: 10.1016/j.jaip.2025.06.038. Epub 2025 Jul 8. PMID: 40639499). The diffusion of this device in the community of patients may have a positive impact on the management of anaphylaxis, particularly in paediatric age, overcoming the barrier of needle-phobia and promoting early administration".

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for addressing my comment