Graded Oral Challenge Safe, Effective for Pediatric Macrolide Allergy

Carly Sillcox, BSc

Credit: LinkedIn

Direct graded oral challenges (GOC) for macrolide allergies are an efficacious and safe strategy for pediatric patients who report having skin-limited symptoms which are non-severe during macrolide treatment, according to recent findings, though additional data on adult GOCs may be necessary to confirm such findings for children.¹

Carly Sillcox, BSc, led the team of investigators authoring this analysis. Sillcox works for the division of pediatric allergy and clinical immunology at McGill University Health Centre in Montréal.

The research team noted that given the lack of standardized skin tests for the diagnosis of macrolide allergy, and given the use of challenge tests as the only recommended confirmation method, an evaluation of direct GOCs safety was essential.²

“We assessed use of direct GOCs for confirming suspected macrolide allergies in children by evaluating clinical characteristics, management, and risk factors associated with true macrolide allergy,” Sillcox and colleagues wrote.¹

Research and Design

The investigators noted that as much as 30% of all oral antibiotic prescriptions are macrolides, adding that they are commonly implemented as alternatives to β-lactams for individuals with allergies. However, macrolides have led to experiences of allergic reactions in some and many children who report such reactions are not assessed by specialists.

This may result in lifelong avoidance of macrolides among such children. Hence, the investigators of the ‘β-Lactam and Other Antibiotics in Children: Tests, Assessment, and Management’ study carried out their analysis.

Sillcox et al., over a period from November 2012 - November 2023, collected their data and focused their attention on subjects aged 18 or younger with suspected macrolide allergy. They enrolled their participants from allergy clinics found in both the Montreal Children’s Hospital in Québec and the Janeway Children’s Health and Rehabilitation Centre located in Newfoundland and Labrador.

There was a 2-step, non-blinded GOC to the suspected macrolide allergen in their analysis. A 10% dose of the macrolide began the process, and this was later followed by a 90% dose following the 20-minute mark.

For 1 hour, subjects were observed and those who were found not to have any symptoms were deemed by the research team as tolerant. Participants who were noted as having developed symptoms were classified as ‘immediate reactors’ and treated accordingly.

Instructions were given to families to report any non-immediate symptoms within a week following the challenge. The team retrospectively collected information related to the suspected allergic reactions, referred to as index macrolide reactions.

Some of these data included the demographics of subjects, clinical details, and how the reactions were handled, with the investigators implementing a standardized questionnaire. GOC outcomes were later gathered prospectively. The team used a multivariate logistic regression analysis to determine factors linked to positive GOC reactions and had a significance level set at P < .05.

Major Findings

There were 112 total participants who were shown to have macrolide allergies, with 58.9% being male and 41.1% being female. These individuals were noted as having a median (IQR) age of 5.5 years (3.0-9.3) years.

The investigators reported that the implicated macrolides were clarithromycin among 72.3% of subjects and azithromycin among 27.7%. They noted that 90.2% of the 112 direct GOCs tolerated the challenge, though 8.0% were shown to have an immediate reaction and 1.8% reported a non-immediate reaction.

Outside of a single subject who experienced anaphylaxis and was given intramuscular epinephrine and diphenhydramine treatment 5 minutes following the initial dose of clarithromycin, all other positive GOC findings involved skin-limited rashes and a lack of mucosa involvement or blisters.

The research team also found that among children older than 12 years of age, positive GOC results were shown to be more likely (adjusted odds ratio [AOR], 1.43 (95% CI, 1.26-1.61). This was also the case for participants with other antibiotic allergies (AOR, 1.22; 95% CI, 1.02-1.46).

The team concluded that reactions were not as likely among subjects reporting a known food allergy comorbidity (AOR 0.84; 95% CI 0.73-0.97). During the investigators’ follow-up interactions with subjects in January 2024, it was noted that 17.4% of those with negative GOC results used their culprit macrolide since their GOC and did not report adverse reactions.

“A study limitation is recall bias due to our method of documenting index reaction characteristics, but time between index macrolide reaction and patient recruitment during GOC was under a year, which likely limits implications of recall bias,” they concluded.

References

1. ^{Sillcox C, Gabrielli S, O’Keefe A, et al. Evaluating Pediatric Macrolide Allergy Using Direct Graded Oral Challenges. JAMA Pediatr. Published online October 07, 2024. doi:10.1001/jamapediatrics.2024.3685.}
2. ^{Khan DA, Banerji A, Blumenthal KG, et al; Chief Editor(s); Workgroup Contributors; Joint Task Force on Practice Parameters Reviewers. Drug allergy: a 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333-1393. doi:10.1016/j.jaci.2022.08.028.}