De-labelling Penicillin Allergy in Paediatric Patients Using Oral Challenge: A Retrospective Study from Northwestern Ontario

De-labelling Penicillin Allergy in Paediatric Patients Using Oral Challenge: A Retrospective Study from Northwestern Ontario | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article De-labelling Penicillin Allergy in Paediatric Patients Using Oral Challenge: A Retrospective Study from Northwestern Ontario Taha Sadeghi, Parisa Mirzajani, Rua Suror, Raga Sirror This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8845785/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 8 You are reading this latest preprint version Abstract Purpose: To find out how many children labelled as allergic to amoxicillin are truly allergic, and to assess whether a direct oral amoxicillin challenge, without prior skin testing, is a safe and effective way to remove incorrect allergy labels in low-risk pediatric patients in Northwestern Ontario. Methods: We conducted a retrospective review of pediatric patients (6 months-15 years) referred for suspected amoxicillin allergy at two Northwestern Ontario hospitals between 2015 and 2025. Eligible patients underwent oral amoxicillin challenge. Clinical data were summarized, and group comparisons were performed using Fisher’s exact and Wilcoxon tests. Results: Of 96 patients, 93 (96.9%) tolerated the oral amoxicillin challenge, while 3 (3.1%) developed mild, delayed rashes. Notably, all three had previously reported delayed reactions (5-10 days) after their initial amoxicillin exposure, and two reproduced the same rash type following the challenge. This reproducibility suggests that the timing and nature of index reactions may help predict outcomes during oral challenge. Conclusion: The prevalence of true penicillin allergy among paediatric patients labelled as penicillin-allergic in Northwestern Ontario was 3.1%. Oral amoxicillin challenge without prior skin testing proved to be a safe and effective approach for de-labelling low-risk children. Broader implementation of this strategy could enhance antibiotic stewardship, reduce healthcare-related costs, and improve patient care. Penicillin allergy Amoxicillin Pediatrics Oral challenge Allergy delabelling Retrospective review Northwestern Ontario Delayed rash Figures Figure 1 Figure 2 Introduction Penicillin, discovered in 1929, remains one of the most widely used antibiotics for bacterial infections [1]. In pediatric care, penicillin-based antibiotics are essential for treating common conditions such as otitis media, streptococcal pharyngitis, and community-acquired pneumonia [2]. Despite their effectiveness and low cost, these antibiotics are often avoided because of self-reported allergies [3]. Globally, an estimated 92-95% of children and 82-91% of adults who report a penicillin allergy in clinical settings are not truly allergic and can safely tolerate penicillin-based antimicrobial agents [4,5]. Many reported reactions are due to non-allergic side effects, such as gastrointestinal upset, or are symptoms of an underlying illness, such as viral rashes [3,6]. This high rate of mislabeling has important clinical and public health implications, as it leads to unnecessary use of second-line or broad-spectrum antibiotics that are often less effective, more expensive, and associated with increased risks of antimicrobial resistance, Clostridioides difficile infection, adverse drug events, surgical site infections, prolonged hospital stays, and overall worse patient outcomes [7–11]. The gold standard for confirming tolerance in low-risk patients is the oral drug challenge, where a supervised therapeutic dose of amoxicillin is given [12,13]. Large pediatric cohort studies from multiple countries, including Canada, Denmark, the United States, and Israel, have consistently shown that over 90% of children with a low-risk history can be safely delabeled through a direct oral challenge without prior skin testing [14–18]. For example, a 2020 study in outpatient clinics at three Danish hospitals in the Central Denmark Region found that, among 141 patients with a suspected history of amoxicillin allergy, only 2.8% had a positive graded drug challenge [19]. Penicillin allergy evaluation is now recognized as an important part of antibiotic stewardship programs [20]. In Northwestern Ontario (NWO), a standardized oral challenge protocol has been implemented for pediatric patients with reported penicillin allergies for nearly 10 years. This study evaluates the outcomes of this protocol to estimate the true rate of penicillin allergy and contribute to the growing evidence supporting safe, direct oral challenges in low-risk children. Methods Study Design and Setting This study is a retrospective chart review conducted to evaluate the outcomes of penicillin allergy delabelling through oral amoxicillin challenge in pediatric patients. The study was conducted across two publicly funded healthcare institutions in NWO: Thunder Bay Regional Health Sciences Centre (TBRHSC) and Sioux Lookout Meno Ya Win Health Centre (SLMHC). These centers provide pediatric services to a wide catchment area, including both urban and remote communities. The work was performed in a non-tertiary care environment with a single practicing allergist and included service delivery in a rural and remote setting (Sioux Lookout) The review period spans from May 1, 2015, to June 1, 2025. All data included in this review were collected from both outpatient electronic medical record (EMR) and hospital EMR during clinical encounters which were documented during routine care. The study received institutional ethics approval, and data handling was conducted in accordance with privacy and confidentiality standards. Statistical Analysis All statistical analyses were conducted using R version 4.5.0 (R Foundation for Statistical Computing, Vienna, Austria). Demographic and clinical characteristics were summarized descriptively: continuous variables such as patient age and time since initial reaction to amoxicillin were reported as medians with interquartile ranges (IQR), and categorical variables such as sex, reaction types, and oral challenge outcomes were summarized as number (n) and percentages. Comparative analyses were performed to evaluate potential associations between clinical characteristics and oral challenge outcomes (reaction vs no reaction). The Wilcoxon rank-sum test was used to compare continuous variables between groups, and Fisher’s exact test was applied for categorical variables (e.g., sex). Due to the small number of reactions, multivariable logistic regression was not performed. A p-value of <0.05 was considered statistically significant. Participants This study included pediatric patients aged 6 months to 15 years who were referred to the allergy clinic at either TBRHSC or SLMHC with a documented history of penicillin allergy. To be eligible, patients must have undergone an oral penicillin challenge between May 1, 2015, and June 1, 2025. Exclusion criteria included: Any history of anaphylaxis or airway compromise or any other immediate symptoms suggesting IgE-mediated hypersensitivity in response to penicillin or amoxicillin Symptoms consistent with serum sickness or serum sickness-like reaction Severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis) Uncertainty or lack of sufficient history to determine risk status Patients requiring intradermal skin testing prior to oral challenge These criteria were adapted based on previously published guidelines and pediatric studies assessing penicillin allergy risk [11,17,21,22]. Oral Challenge Protocol All included patients underwent clinical risk stratification based on their reported reaction history. Patients assessed as low risk for IgE-mediated penicillin allergy were eligible for oral challenge. High-risk patients, defined by a history of anaphylaxis, serum sickness, or severe cutaneous adverse reactions were excluded as outlined in the exclusion criteria. The oral challenge followed either a graded two-step protocol or a single full-dose administration, depending on clinical judgment and patient risk assessment. The two-step protocol was performed as follows: At time zero, 10% of the total amoxicillin dose (15 mg/kg, up to a maximum of 500 mg) was administered. If no symptoms developed within 20 minutes, the remaining 90% of the dose was given. Patients were observed in clinic for 60 minutes following administration of the full dose. If no immediate or objective symptoms occurred, they were discharged with standard post-challenge instructions, which included monitoring for new symptoms such as rash or other allergic manifestations and contacting the clinic if concerns arose. As an additional precaution, a subset of 16 patients were also discharged with a 5-day course of amoxicillin to be completed at home in order to extend monitoring for possible delayed hypersensitivity reactions. These patients were selected based on clinical judgment, including cases with unclear historical timing or features potentially suggestive of delayed reactions. Caregivers were specifically advised to observe for symptoms not only during the course but also in the days following completion. This protocol has been consistently implemented at both participating centers as part of routine pediatric care for penicillin allergy delabelling. Results From May 1, 2015, to June 1, 2025, a total of 96 individuals referred for suspected amoxicillin hypersensitivity underwent eighter a single full-dose administration or a graded oral amoxicillin challenge. Overall, 124 patients were screened for eligibility. Twenty-seven were excluded due to clinical histories requiring skin testing prior to oral challenge, and one was excluded before testing after symptoms consistent with serum sickness were identified during reassessment. This resulted in 96 patients eligible for analysis ( Figure 1 ). All included participants were classified as low risk based on non-severe delayed-type reactions without features of immediate hypersensitivity. Among included patients, the median time interval between the initially reported amoxicillin reaction and the oral challenge was 1.21 years (IQR: 0.58–2.79 years). The median age of participants was 5 years (interquartile range (IQR): 2-8 years) , with 54 (57%) identified as female and 42 (43%) as male . All participants were classified as low risk based on the timing and clinical features of their reported index reaction, which allowed for direct oral challenge. The study population was comparable in terms of sociodemographic characteristics, as shown in Table 1 . Clinical characteristics related to the reported reactions and comorbidities were comparable between groups, with females comprising the majority, as illustrated in Figure 1 . Of the 96 participants, 93 (96.9%) tolerated the oral amoxicillin challenge without any signs of reaction , while 3 (3.1%) exhibited clinical symptoms consistent with a delayed reaction ( Figure 2 ). All participants who reacted were male (100% vs. 42% in the non-reaction group, p = 0.08, Fisher’s exact test) , and the median age of the reaction group was 8 years compared with 5 years (IQR: 2-8 years) in the non-reaction group ( p = 0.48, Wilcoxon rank-sum test ). The time elapsed since the initial reported reaction to amoxicillin did not significantly differ between groups ( p = 0.58, Wilcoxon rank-sum test ). Most participants (91, 94.7%) were tested at TBRHSC, while 5 (5.3%) underwent testing at SLMHC. All observed reactions occurred in patients tested at TBRHSC. Two of the three males who reacted developed delayed reactions following discharge with a 5-day course of amoxicillin. The first patient developed a mild generalized maculopapular rash on day 6 (one day after completing the course) without additional systemic symptoms. The second patient developed generalized hives on day 7 (two days after discontinuing the medication). The third patient developed a mild generalized maculopapular rash two days after the oral challenge. Notably, all three participants had initially experienced symptoms 5-10 days after their first exposure to amoxicillin, with a median onset of 7 days, compared to 3 days (IQR: 2-7) among those who did not react. Family history data were collected based on parental reports of allergies or adverse reactions in the patient’s immediate family, including parents and grandparents. Reported information was categorized into four groups: (1) No family history , indicating no reported history of penicillin allergy, other medication allergies, or atopic conditions such as asthma, eczema, or environmental allergies among first- or second-degree relatives; (2) History of atopy , including asthma, eczema, and environmental allergies; (3) History of drug allergy , referring specifically to reported allergy to penicillin or other medications; and (4) Unknown , when family history was not reported or was uncertain at the time of collection. Participants with more than one type of family history (e.g., both eczema and environmental allergy) were included in all applicable categories. Among the three participants who reacted , two (67%) had no specific reported family history , and one (33%) had a family history of drug allergy . No participants in the reaction group reported a history of atopy. In the non-reaction group, a family history of atopy was more commonly reported than a history of drug allergy. Specifically, atopy was reported in 31 participants (31.6%) , including asthma in 16 (35.5%) , eczema in 13 (28.9%) , and environmental or seasonal allergies in 16 (35.6%) . Drug allergy (penicillin or other medications) was reported in 19 participant’s family history (19.6%) , and 4 (4%) had unknown family history. Figure 1 shows the distribution of clinical characteristics from participants’ initial reported reactions to amoxicillin, which prompted referral for oral provocation testing. Among these historical reactions, hives were the most frequently reported symptom, followed by maculopapular rash, itching, swelling, and vomiting. A classification of “Not differentiated” was used when the rash type was not clearly reported by the treating specialist or recalled by parents. The figure also indicates whether the reported rash was localized or generalized. As illustrated in Figure 1, these historical symptoms were more commonly reported among females in the overall cohort. Among the three participants who reacted to amoxicillin during the oral challenge, two had previously experienced generalized hives or generalized maculopapular rash, and one had a localized rash of not differentiated type. During the oral challenge, the two with generalized rashes reproduced the same reaction type, while the participant with a localized rash developed a generalized maculopapular rash. Notably, the symptoms observed during the oral challenge in these three participants were consistent with their historical reactions, with no evidence of symptom progression or new symptom development. Table 1. Participant Demographics and Clinical Features Based on Oral Penicillin Challenge Results Variables Outcome of Graded Oral Amoxicillin Challenge Overall No reaction reaction (n=96) (n=93) (n=3) Sex Female, n (%) 54(56.2) 54(58) 0(0) Male, n (%) 42(43.9) 39(42) 3(100) Age at the test, median (IQR) 5(2-8) 5(2-8) 8(-) Time since initial reaction to amoxicillin, median days (IQR) 4(2-7) 3(2-7) 7(-) Hospital TBRHSC, n (%) 91(94.7) 88(94.6) 3(100) SLMHC, n (%) 5(5.3) 5(5.4) 0(0) Family history No family history, n (%) 44(44.8) 42(44.2) 2(67) Atopy 31(31.6) 31(32.6) 0(0) Asthma, n (%) 16(35.5) 16(35.5) 0(0) Eczema, n (%) 13((28.9) 13(28.9) 0(0) Environmental & seasonal allergies, n (%) 16(35.6) 16(35.6) 0(0) Drug allergy (penicillin or other medications), n (%) 19(19.6) 18(19) 1(33) Unknown, n (%) 4(4) 4(4.2) 0(0) Discussion Based on the current evidence regarding penicillin allergy in pediatrics population, we implemented a clinical pathway that excluded prior skin testing and achieved our primary objective, successfully delabelling at least 96% of patients with a reported penicillin allergy. Without this intervention, many of these children would likely have continued to carry an inaccurate allergy label, resulting in suboptimal antibiotic selection, unnecessary healthcare costs, and potentially avoidable morbidity [18]. There remain ongoing opportunities to further enhance penicillin allergy delabeling efforts at both TBRHSC and SLMHC. Furthermore, the oral penicillin challenge was successfully completed without immediate reactions in all children, regardless of whether their index reaction had been immediate or nonimmediate. This supports the likelihood that most rash presentations during amoxicillin therapy, whether occurring soon after dosing or several days later, are attributable to concurrent viral infections rather than true drug hypersensitivity [23,24]. Interestingly, all three patients who experienced reactions after the graded oral amoxicillin challenge in our study had a history of delayed symptom onset during their initial exposure to amoxicillin, with reactions reported between 5 to 10 days after first taking the medication. During the oral challenge, two patients developed delayed reactions 1 and 2 days after completing the 5-day course of amoxicillin prescribed at discharge, while one patient developed symptoms 2 days after the single dose oral challenge. This consistency in timing between historical and challenge-related reactions suggests a reproducible delayed hypersensitivity response, likely mediated by T-cell-driven immune mechanisms [25,26]. Prior literature supports the relevance of delayed features in predicting true allergy. For example, a study by Mill et al., reported significantly increased odds of non-immediate penicillin reactions in patients whose initial rash lasted longer than 7 days, even after adjusting for demographic and clinical factors [17]. While our study did not assess rash duration per se, the delayed onset of symptoms in both historical and challenge contexts in our patients strengthens the hypothesis that timing of symptom onset can be a useful predictor in identifying delayed-type drug hypersensitivity. These findings highlight the importance of incorporating symptom timing into the clinical assessment of reported penicillin allergies, especially when determining eligibility for graded oral amoxicillin challenge in patients categorized as low risk. Our findings indicate that the vast majority of children suspected of having amoxicillin allergy are able to tolerate the drug. A key strength of this study is its inclusion of a broad pediatric age range, allowing assessment of tolerance patterns across diverse developmental and immunologic stages. This wider scope offers a more comprehensive understanding of amoxicillin tolerance in both younger and older children, with implications for refining de-labeling strategies in varied clinical settings. While female participants represented the majority of our cohort and more frequently reported historical symptoms across nearly all rash categories, all reactions during the graded oral amoxicillin challenge occurred exclusively in male participants. This finding is notable, as it suggests a possible disconnect between historical symptom reporting and the actual likelihood of a positive challenge outcome. Possible explanations include sex-based differences in immune reactivity, behavioral or recall bias in reporting prior symptoms, or other unmeasured confounders. Interestingly, adult-focused meta-analytic data have reported the opposite pattern, with females more likely than males to have a confirmed β-lactam allergy via oral challenge with relative risk of 1.40 (1.18-1.66) at 95% confidence interval [27]. Our pediatric findings therefore diverge from adult trends, suggesting that sex-specific risk profiles in drug hypersensitivity may differ across the lifespan. Future studies with larger and more diverse pediatric cohorts are needed to determine whether this pattern persists and to evaluate whether sex should be considered a statistically significant factor in risk stratification for direct oral challenge. In addition to the clinical significance, the direct health economic benefit of assessing true amoxicillin allergy by oral challenge alone is clear. In our cohort of 96 patients, only 3 (3.1%) reacted to the oral challenge. Based on current Ontario Ministry of Health and Long-Term Care fee schedule estimates of approximately $200-$300 Canadian dollar (CAD) per penicillin skin test (inclusive of physician, nursing, and reagent costs), performing skin testing for all 96 patients prior to challenge would have cost an estimated $19,200-$28,800 CAD. By proceeding directly to oral challenge, these procedural costs were avoided. Beyond procedural savings, prior work has demonstrated that removal of an inaccurate penicillin-allergy label yields substantial downstream healthcare benefits through reduced hospital stays and improved antibiotic utilization [28]. Vyles et al. also reported total cost savings of $1368 USD and cost avoidance of $1812 USD in their follow-up cohort of 36 children, with an extrapolated annual benefit of $192,223 USD for ~6700 children seen in their pediatric emergency department. Applying this model to our 93 delabeled patients yields an estimated downstream benefit of approximately $2,667 USD (2018 values), equivalent to $4,730 CAD in 2025 after inflation adjustment and currency conversion [28]. While these represent short-term savings within a single year, the long-term financial impact is likely far greater. Early delabeling during childhood prevents decades of unnecessary use of costlier, broad-spectrum antibiotics and mitigates the cumulative risks of antimicrobial resistance, adverse drug reactions, and extended hospitalizations. Over a patient’s lifetime, accurate identification and removal of false penicillin allergy labels therefore translate into substantial healthcare savings and improved treatment outcomes. This study has several limitations. First, the retrospective design of this study introduces inherent limitations, including reliance on existing documentation, potential missing data, and possible misclassification of the original reported reactions. Second, the study was conducted at two hospitals in NWO and included only pediatric patients with low-risk reactions to amoxicillin; therefore, the findings may not be generalizable to adults. Third, although follow-up was available through chart review, it is possible that some patients may have developed symptoms concerning for penicillin allergy after delabeling or had the allergy re-entered into their medical record at outside institutions. Fourth, as with similar studies [29,30], subsequent tolerance to a full therapeutic course of amoxicillin after the oral challenge was not confirmed for all participants, and it is possible that some nonimmediate reactions could occur in the context of future treatment. Fifth, the determination of family history of allergy or atopy was based on parental report, which may be subject to recall bias; however, this is unlikely to have been differential across groups and should not have affected the observed associations. Finally, our cost analysis relied on published average estimates for procedural and downstream economic impact of penicillin skin testing and delabelling, as institution-specific cost data were not available. Conclusion This study demonstrates that an oral amoxicillin provocation challenge, without preceding skin testing, is a safe and effective method for delabelling low-risk pediatric patients with a reported penicillin allergy in a hospital setting. In our cohort, 96.9% of children tolerated the challenge, and only 3.1% exhibited delayed, non-life-threatening reactions that mirrored their historical presentations. These findings support the growing evidence that penicillin allergy in children is rare and frequently overdiagnosed, and that most rash presentations during amoxicillin therapy are likely attributable to viral infections rather than true hypersensitivity. By eliminating unnecessary penicillin allergy labels, we can promote optimal antibiotic prescribing, reduce healthcare costs, and minimize avoidable morbidity. Implementation of direct oral challenge pathways in similar healthcare settings could yield substantial clinical and economic benefits. Future studies with larger, more diverse populations and longer follow-up are warranted to confirm these findings, identify predictors of positive challenge outcomes, and refine risk stratification to further enhance the safety and efficiency of pediatric penicillin allergy delabelling. Declarations Funding This research is funded by the Northern Ontario Academic Medicine Association (NOAMA) AHSC AFP Innovation Fund award. Competing interests The authors declare that they have no competing interests. Authors' contributions Taha Sadeghi: Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. Parisa Mirzajani: Writing – review & editing, Data curation. Rua Suror: Writing – review & editing. Raga Sirror: Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Ethics approval and consent to participate This study was approved by the Thunder Bay Regional Health Sciences Centre Research Ethics Board (IRB registration #00004396). The requirement for written informed consent was waived by the ethics committee due to the retrospective nature of the study. Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are not openly available due to reasons of patient privacy and are not available for request due to similar reasoning. Data is located in controlled access data storage by the corresponding author. References Fleming A. Penicillin. BMJ 1941;2:386–386. https://doi.org/10.1136/bmj.2.4210.386. Macy E, Vyles D. Who needs penicillin allergy testing? Annals of Allergy, Asthma and Immunology 2018;121:523–9. https://doi.org/10.1016/j.anai.2018.07.041. Shaker M, McWilliams S, Greenhawt M. Update on penicillin allergy delabeling. Curr Opin Pediatr 2020;32:321–7. https://doi.org/10.1097/MOP.0000000000000879. Antoon JW, Grijalva CG, Carroll AR, Johnson J, Stassun J, Bonnet K, et al. Parental Perceptions of Penicillin Allergy Risk Stratification and Delabeling. Hosp Pediatr 2023;13:300–7. https://doi.org/10.1542/hpeds.2022-006737. Powell N, Blank M, Luintel A, Elkhalifa S, Bhogal R, Wilcock M, et al. Narrative review of recent developments and the future of penicillin allergy de-labelling by non-allergists. Npj Antimicrobials and Resistance 2024;2. https://doi.org/10.1038/s44259-024-00035-6. Bhattacharya S. THE FACTS ABOUT PENICILLIN ALLERGY: A REVIEW. J Adv Pharm Technol Res n.d.;1. Kwan N, Kang K, Carr RR, Mak R, Roberts A, Jin F, et al. True Rate of Allergy among Pediatric Inpatients with Penicillin Allergy Labels (TRIAL). Canadian Journal of Hospital Pharmacy 2024;77. https://doi.org/10.4212/cjhp.3531. Sacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: A systematic review and meta-analysis. Allergy: European Journal of Allergy and Clinical Immunology 2017;72:1288–96. https://doi.org/10.1111/all.13168. Mattingly TJ, Fulton A, Lumish RA, Williams AMC, Yoon SJ, Yuen M, et al. The Cost of Self-Reported Penicillin Allergy: A Systematic Review. Journal of Allergy and Clinical Immunology: In Practice 2018;6:1649-1654.e4. https://doi.org/10.1016/j.jaip.2017.12.033. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA - Journal of the American Medical Association 2019;321:188–99. https://doi.org/10.1001/jama.2018.19283. Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, et al. Drug allergy: A 2022 practice parameter update. Journal of Allergy and Clinical Immunology 2022;150:1333–93. https://doi.org/10.1016/j.jaci.2022.08.028. Copaescu AM, Vogrin S, James F, Chua KYL, Rose MT, De Luca J, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med 2023;183:944–52. https://doi.org/10.1001/jamainternmed.2023.2986. Iammatteo M, Alvarez Arango S, Ferastraoaru D, Akbar N, Lee AY, Cohen HW, et al. Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing. Journal of Allergy and Clinical Immunology: In Practice 2019;7:236–43. https://doi.org/10.1016/j.jaip.2018.05.008. Ibáñez MD, Rodríguez del Río P, Lasa EM, Joral A, Ruiz-Hornillos J, Muñoz C, et al. Prospective assessment of diagnostic tests for pediatric penicillin allergy: From clinical history to challenge tests. Annals of Allergy, Asthma and Immunology 2018;121:235-244.e3. https://doi.org/10.1016/j.anai.2018.05.013. Labrosse R, Paradis L, Lacombe-Barrios J, Samaan K, Graham F, Paradis J, et al. Efficacy and Safety of 5-Day Challenge for the Evaluation of Nonsevere Amoxicillin Allergy in Children. Journal of Allergy and Clinical Immunology: In Practice 2018;6:1673–80. https://doi.org/10.1016/j.jaip.2018.01.030. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. Journal of Allergy and Clinical Immunology 2014;133:790–6. https://doi.org/10.1016/j.jaci.2013.09.021. Mill C, Primeau MN, Medoff E, Lejtenyi C, O’Keefe A, Netchiporouk E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr 2016;170. https://doi.org/10.1001/jamapediatrics.2016.0033. Tucker MH, Lomas CM, Ramchandar N, Waldram JD. Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. Journal of Allergy and Clinical Immunology: In Practice 2017;5:813–5. https://doi.org/10.1016/j.jaip.2017.01.023. Krusenstjerna-Hafstrøm T, Rubak S. The use of direct oral challenge to confirm allergies to penicillin class antibiotics in Danish children. BMC Pediatr 2020;20. https://doi.org/10.1186/s12887-020-02407-z. Leis JA, Palmay L, Ho G, Raybardhan S, Gill S, Kan T, et al. Point-of-Care β-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. Clinical Infectious Diseases 2017;65:1059–65. https://doi.org/10.1093/cid/cix512. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ 2018;361:k2400. https://doi.org/10.1136/bmj.k2400. Bauer ME, MacBrayne C, Stein A, Searns J, Hicks A, Sarin T, et al. A multidisciplinary quality improvement initiative to facilitate penicillin allergy delabeling among hospitalized pediatric patients. Hosp Pediatr 2021;11:427–34. https://doi.org/10.1542/HPEDS.2020-001636. Erho T, Eikkinen H, Onica M, Hint T, Asnee T, Honmaitree C. PREVALENCE OF VARIOUS RESPIRATORY VIRUSES IN THE MIDDLE EAR DURING ACUTE OTITIS MEDIA A BSTRACT Background Vaccines against respiratory viruses. 1999. Wiertsema SP, Chidlow GR, Kirkham LAS, Corscadden KJ, Mowe EN, Vijayasekaran S, et al. High detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media. J Med Virol 2011;83:2008–17. https://doi.org/10.1002/jmv.22221. Shah PN, Romar GA, Manukyan A, Ko WC, Hsieh PC, Velasquez GA, et al. Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets. Journal of Clinical Investigation 2024;134. https://doi.org/10.1172/JCI178253. Pavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, et al. T Cell-mediated hypersensitivity reactions to drugs. Annu Rev Med 2015;66:439–54. https://doi.org/10.1146/annurev-med-050913-022745. Patel NB, Cojuc-Konigsberg G, Garcia-Guaqueta D, Shah D, Balasubramaniam D, Mahajan A, et al. Effects of Sex and Gender in Immediate β-Lactam Antibiotic Allergy: A Systematic Review and Meta-Analysis. Journal of Allergy and Clinical Immunology: In Practice 2025;13:155-166.e11. https://doi.org/10.1016/j.jaip.2024.10.031. Vyles D, Chiu A, Routes J, Castells M, Phillips EJ, Kibicho J, et al. Antibiotic Use After Removal of Penicillin Allergy Label. Pediatrics 2018;141:e20173466. https://doi.org/10.1542/peds.2017-3466. Delli Colli L, Gabrielli S, Abrams EM, O’Keefe A, Protudjer JLP, Lavine E, et al. Differentiating Between β-Lactam-Induced Serum Sickness–Like Reactions and Viral Exanthem in Children Using a Graded Oral Challenge. Journal of Allergy and Clinical Immunology: In Practice 2021;9:916–21. https://doi.org/10.1016/j.jaip.2020.08.047. Gateman DP, Rumble JE, Protudjer JLP, Kim H. Amoxicillin oral provocation challenge in a primary care clinic: a descriptive analysis. CMAJ Open 2021;9:E394–9. https://doi.org/10.9778/cmajo.20200077. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 10 Apr, 2026 Reviews received at journal 22 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 13 Feb, 2026 Reviewers invited by journal 13 Feb, 2026 Editor assigned by journal 12 Feb, 2026 Submission checks completed at journal 11 Feb, 2026 First submitted to journal 10 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8845785","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593414970,"identity":"7a0c1f0c-8f52-464b-9f5d-1f5f55e7b407","order_by":0,"name":"Taha Sadeghi","email":"","orcid":"","institution":"Thunder Bay Regional Health Research Institute (TBRHRI)","correspondingAuthor":false,"prefix":"","firstName":"Taha","middleName":"","lastName":"Sadeghi","suffix":""},{"id":593414972,"identity":"b6f3f10d-448a-49f1-a8ae-365d843c0f15","order_by":1,"name":"Parisa Mirzajani","email":"","orcid":"","institution":"NOSM University","correspondingAuthor":false,"prefix":"","firstName":"Parisa","middleName":"","lastName":"Mirzajani","suffix":""},{"id":593414975,"identity":"17c74e1b-2cbe-49a0-9f61-33975b59118f","order_by":2,"name":"Rua Suror","email":"","orcid":"","institution":"Thunder Bay Regional Health Sciences Centre","correspondingAuthor":false,"prefix":"","firstName":"Rua","middleName":"","lastName":"Suror","suffix":""},{"id":593414976,"identity":"4ca6fa71-af1c-4d5c-8f3f-cf4dd94f0a5f","order_by":3,"name":"Raga Sirror","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqElEQVRIiWNgGAWjYDACZgglxyDBQ6IWYx6IFgPiLUvsIVqLfDvvsw8f99xL3y/de4C5oOIPYS0Gh9mNZ854VpzbI3MugXnGGSJsMWBmY2bmOZCQ2yORY8DM20aMw5ohWtJ5wFr+EeP9wxAtCRAtDcQ4DKiFccaBBMOeO2cMDvMcMybCYf3HmBk+HEiQZ5/dY/iYp0aOCIchgwMkqh8Fo2AUjIJRgAsAANupLY//JHQGAAAAAElFTkSuQmCC","orcid":"","institution":"NOSM University","correspondingAuthor":true,"prefix":"","firstName":"Raga","middleName":"","lastName":"Sirror","suffix":""}],"badges":[],"createdAt":"2026-02-11 00:08:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8845785/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8845785/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103165691,"identity":"9dbcf3d3-5d1d-4879-a037-2cb9f095887b","added_by":"auto","created_at":"2026-02-22 12:34:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37695,"visible":true,"origin":"","legend":"\u003cp\u003eStratification of clinical characteristics based on participants’ historical reactions to amoxicillin, prior to undergoing graded oral amoxicillin provocation challenge.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8845785/v1/5b759fa573c01b26becb595f.png"},{"id":103505249,"identity":"d69b4b6f-58a3-4236-ab18-abe4af709d63","added_by":"auto","created_at":"2026-02-26 13:28:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":221092,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart depicting patient selection and outcomes of graded oral amoxicillin challenge.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8845785/v1/ce6c4818ac84d41153d486ff.png"},{"id":103509750,"identity":"232884f2-4508-4575-98e3-fe5fb9612401","added_by":"auto","created_at":"2026-02-26 14:00:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1107177,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8845785/v1/72d81265-2ad9-4c4b-9311-eadcfbb5e42e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"De-labelling Penicillin Allergy in Paediatric Patients Using Oral Challenge: A Retrospective Study from Northwestern Ontario","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePenicillin, discovered in 1929, remains one of the most widely used antibiotics for bacterial infections [1]. In pediatric care, penicillin-based antibiotics are essential for treating common conditions such as otitis media, streptococcal pharyngitis, and community-acquired pneumonia [2]. Despite their effectiveness and low cost, these antibiotics are often avoided because of self-reported allergies [3]. Globally, an estimated 92-95% of children and 82-91% of adults who report a penicillin allergy in clinical settings are not truly allergic and can safely tolerate penicillin-based antimicrobial agents [4,5]. Many reported reactions are due to non-allergic side effects, such as gastrointestinal upset, or are symptoms of an underlying illness, such as viral rashes [3,6]. This high rate of mislabeling has important clinical and public health implications, as it leads to unnecessary use of second-line or broad-spectrum antibiotics that are often less effective, more expensive, and associated with increased risks of antimicrobial resistance, Clostridioides difficile infection, adverse drug events, surgical site infections, prolonged hospital stays, and overall worse patient outcomes\u0026nbsp;[7\u0026ndash;11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe gold standard for confirming tolerance in low-risk patients is the oral drug challenge, where a supervised therapeutic dose of amoxicillin is given [12,13]. Large pediatric cohort studies from multiple countries, including Canada, Denmark, the United States, and Israel, have consistently shown that over 90% of children with a low-risk history can be safely delabeled through a direct oral challenge without prior skin testing [14\u0026ndash;18]. For example, a 2020 study in outpatient clinics at three Danish hospitals in the Central Denmark Region found that, among 141 patients with a suspected history of amoxicillin allergy, only 2.8% had a positive graded drug challenge [19].\u003c/p\u003e\n\u003cp\u003ePenicillin allergy evaluation is now recognized as an important part of antibiotic stewardship programs [20]. In Northwestern Ontario (NWO), a standardized oral challenge protocol has been implemented for pediatric patients with reported penicillin allergies for nearly 10 years. This study evaluates the outcomes of this protocol to estimate the true rate of penicillin allergy and contribute to the growing evidence supporting safe, direct oral challenges in low-risk children.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a retrospective chart review conducted to evaluate the outcomes of penicillin allergy delabelling through oral amoxicillin challenge in pediatric patients. The study was conducted across two publicly funded healthcare institutions in NWO: Thunder Bay Regional Health Sciences Centre (TBRHSC) and Sioux Lookout Meno Ya Win Health Centre (SLMHC). These centers provide pediatric services to a wide catchment area, including both urban and remote communities. The work was performed in a non-tertiary care environment with a single practicing allergist and included service delivery in a rural and remote setting (Sioux Lookout)\u003c/p\u003e\n\u003cp\u003eThe review period spans from May 1, 2015, to June 1, 2025. All data included in this review were collected from both outpatient electronic medical record (EMR) and hospital EMR during clinical encounters which were documented during routine care. The study received institutional ethics approval, and data handling was conducted in accordance with privacy and confidentiality standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were conducted using R version 4.5.0 (R Foundation for Statistical Computing, Vienna, Austria). Demographic and clinical characteristics were summarized descriptively: continuous variables such as patient age and time since initial reaction to amoxicillin were reported as medians with interquartile ranges (IQR), and categorical variables such as sex, reaction types, and oral challenge outcomes were summarized as number (n) and percentages.\u003c/p\u003e\n\u003cp\u003eComparative analyses were performed to evaluate potential associations between clinical characteristics and oral challenge outcomes (reaction vs no reaction). The Wilcoxon rank-sum test was used to compare continuous variables between groups, and Fisher\u0026rsquo;s exact test was applied for categorical variables (e.g., sex). Due to the small number of reactions, multivariable logistic regression was not performed. A p-value of \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included pediatric patients aged 6 months to 15 years who were referred to the allergy clinic at either TBRHSC or SLMHC with a documented history of penicillin allergy. To be eligible, patients must have undergone an oral penicillin challenge between May 1, 2015, and June 1, 2025.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e included:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAny history of anaphylaxis or airway compromise or any other immediate symptoms suggesting IgE-mediated hypersensitivity in response to penicillin or amoxicillin\u003c/li\u003e\n \u003cli\u003eSymptoms consistent with serum sickness or serum sickness-like reaction\u003c/li\u003e\n \u003cli\u003eSevere cutaneous adverse reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis)\u003c/li\u003e\n \u003cli\u003eUncertainty or lack of sufficient history to determine risk status\u003c/li\u003e\n \u003cli\u003ePatients requiring intradermal skin testing prior to oral challenge\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThese criteria were adapted based on previously published guidelines and pediatric studies assessing penicillin allergy risk [11,17,21,22].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOral Challenge Protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll included patients underwent clinical risk stratification based on their reported reaction history. Patients assessed as low risk for IgE-mediated penicillin allergy were eligible for oral challenge. High-risk patients, defined by a history of anaphylaxis, serum sickness, or severe cutaneous adverse reactions were excluded as outlined in the exclusion criteria.\u003c/p\u003e\n\u003cp\u003eThe oral challenge followed either a graded two-step protocol or a single full-dose administration, depending on clinical judgment and patient risk assessment. \u0026nbsp;The two-step protocol was performed as follows: At time zero, 10% of the total amoxicillin dose (15 mg/kg, up to a maximum of 500 mg) was administered. If no symptoms developed within 20 minutes, the remaining 90% of the dose was given. Patients were observed in clinic for 60 minutes following administration of the full dose. If no immediate or objective symptoms occurred, they were discharged with standard post-challenge instructions, which included monitoring for new symptoms such as rash or other allergic manifestations and contacting the clinic if concerns arose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs an additional precaution, a subset of 16 patients were also discharged with a 5-day course of amoxicillin to be completed at home in order to extend monitoring for possible delayed hypersensitivity reactions. These patients were selected based on clinical judgment, including cases with unclear historical timing or features potentially suggestive of delayed reactions. Caregivers were specifically advised to observe for symptoms not only during the course but also in the days following completion. This protocol has been consistently implemented at both participating centers as part of routine pediatric care for penicillin allergy delabelling.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom May 1, 2015, to June 1, 2025, a total of\u0026nbsp;\u003cstrong\u003e96 individuals\u003c/strong\u003e referred for suspected amoxicillin hypersensitivity underwent eighter a single full-dose administration or a graded oral amoxicillin challenge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall, 124 patients were screened for eligibility. Twenty-seven were excluded due to clinical histories requiring skin testing prior to oral challenge, and one was excluded before testing after symptoms consistent with serum sickness were identified during reassessment. This resulted in 96 patients eligible for analysis (\u003cstrong\u003eFigure 1\u003c/strong\u003e). All included participants were classified as low risk based on non-severe delayed-type reactions without features of immediate hypersensitivity.\u003cbr\u003e\u0026nbsp;Among included patients, the median time interval between the initially reported amoxicillin reaction and the oral challenge was 1.21 years (IQR: 0.58\u0026ndash;2.79 years).\u003c/p\u003e\n\u003cp\u003eThe median age of participants was\u0026nbsp;\u003cstrong\u003e5 years (interquartile range (IQR): 2-8 years)\u003c/strong\u003e\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003ewith\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e54 (57%) identified as female and 42 (43%) as male\u003c/strong\u003e. All participants were classified as low risk based on the timing and clinical features of their reported index reaction, which allowed for direct oral challenge.\u003c/p\u003e\n\u003cp\u003eThe study population was comparable in terms of sociodemographic characteristics, as shown in \u003cstrong\u003eTable 1\u003c/strong\u003e. Clinical characteristics related to the reported reactions and comorbidities were comparable between groups, with females comprising the majority, as illustrated in \u003cstrong\u003eFigure 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eOf the 96 participants,\u0026nbsp;\u003cstrong\u003e93 (96.9%) tolerated the oral amoxicillin challenge without any signs of reaction\u003c/strong\u003e\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003ewhile\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3 (3.1%) exhibited clinical symptoms\u003c/strong\u003e consistent with a delayed reaction (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u0026nbsp;\u003cstrong\u003eAll participants who reacted were male (100% vs. 42% in the non-reaction group, p = 0.08, Fisher\u0026rsquo;s exact test)\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e and the median age of the reaction group was\u0026nbsp;\u003cstrong\u003e8 years\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ecompared with\u0026nbsp;\u003cstrong\u003e5 years (IQR: 2-8 years)\u003c/strong\u003e in the non-reaction group (\u003cstrong\u003ep = 0.48, Wilcoxon rank-sum test\u003c/strong\u003e). The time elapsed since the initial reported reaction to amoxicillin did not significantly differ between groups (\u003cstrong\u003ep = 0.58, Wilcoxon rank-sum test\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eMost participants (91, 94.7%) were tested at TBRHSC, while 5 (5.3%) underwent testing at SLMHC. All observed reactions occurred in patients tested at TBRHSC. Two of the three males who reacted developed delayed reactions following discharge with a 5-day course of amoxicillin. The first patient developed a mild generalized maculopapular rash on day 6 (one day after completing the course) without additional systemic symptoms. The second patient developed generalized hives on day 7 (two days after discontinuing the medication). The third patient developed a mild generalized maculopapular rash two days after the oral challenge. Notably, all three participants had initially experienced symptoms 5-10 days after their first exposure to amoxicillin, with a median onset of 7 days, compared to 3 days (IQR: 2-7) among those who did not react.\u003c/p\u003e\n\u003cp\u003eFamily history data were collected based on parental reports of allergies or adverse reactions in the patient\u0026rsquo;s immediate family, including parents and grandparents. Reported information was categorized into four groups: (1)\u0026nbsp;\u003cstrong\u003eNo family history\u003c/strong\u003e, indicating no reported history of penicillin allergy, other medication allergies, or atopic conditions such as asthma, eczema, or environmental allergies among first- or second-degree relatives; (2)\u0026nbsp;\u003cstrong\u003eHistory of atopy\u003c/strong\u003e, including asthma, eczema, and environmental allergies; (3)\u0026nbsp;\u003cstrong\u003eHistory of drug allergy\u003c/strong\u003e, referring specifically to reported allergy to penicillin or other medications; and (4)\u0026nbsp;\u003cstrong\u003eUnknown\u003c/strong\u003e, when family history was not reported or was uncertain at the time of collection. Participants with more than one type of family history (e.g., both eczema and environmental allergy) were included in all applicable categories.\u003c/p\u003e\n\u003cp\u003eAmong the\u0026nbsp;\u003cstrong\u003ethree participants who reacted\u003c/strong\u003e\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003etwo (67%) had no specific reported family history\u003c/strong\u003e\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eand\u0026nbsp;\u003cstrong\u003eone (33%) had a family history of drug allergy\u003c/strong\u003e.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNo participants in the reaction group reported a history of atopy.\u003c/strong\u003e In the non-reaction group, a family history of atopy was more commonly reported than a history of drug allergy. Specifically,\u0026nbsp;\u003cstrong\u003eatopy was reported in 31 participants (31.6%)\u003c/strong\u003e, including\u0026nbsp;\u003cstrong\u003easthma in 16 (35.5%)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eeczema in 13 (28.9%)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eenvironmental or seasonal allergies in 16 (35.6%)\u003c/strong\u003e. Drug allergy (penicillin or other medications) was reported in\u0026nbsp;\u003cstrong\u003e19 participant\u0026rsquo;s family history (19.6%)\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4 (4%)\u003c/strong\u003e had unknown family history.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e shows the distribution of clinical characteristics from participants\u0026rsquo; initial reported reactions to amoxicillin, which prompted referral for oral provocation testing. Among these historical reactions, hives were the most frequently reported symptom, followed by maculopapular rash, itching, swelling, and vomiting. A classification of \u0026ldquo;Not differentiated\u0026rdquo; was used when the rash type was not clearly reported by the treating specialist or recalled by parents. The figure also indicates whether the reported rash was localized or generalized. As illustrated in Figure 1, these historical symptoms were more commonly reported among females in the overall cohort.\u003c/p\u003e\n\u003cp\u003eAmong the three participants who reacted to amoxicillin during the oral challenge, two had previously experienced generalized hives or generalized maculopapular rash, and one had a localized rash of not differentiated type. During the oral challenge, the two with generalized rashes reproduced the same reaction type, while the participant with a localized rash developed a generalized maculopapular rash. Notably, the symptoms observed during the oral challenge in these three participants were consistent with their historical reactions, with no evidence of symptom progression or new symptom development.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eParticipant Demographics and Clinical Features Based on Oral Penicillin Challenge Results\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" rowspan=\"3\" valign=\"bottom\" style=\"width: 215px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 408px;\"\u003e\n \u003cp\u003eOutcome of Graded Oral Amoxicillin Challenge\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003eNo reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003ereaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e(n=96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e(n=93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e(n=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eFemale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e54(56.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e54(58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e42(43.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e39(42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e3(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eAge at the test, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5(2-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e5(2-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e8(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eTime since initial reaction to amoxicillin, median days (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4(2-7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e3(2-7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e7(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eHospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eTBRHSC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e91(94.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e88(94.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e3(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eSLMHC, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e5(5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e5(5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eFamily history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eNo family history, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e44(44.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e42(44.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e2(67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eAtopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e31(31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e31(32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 178px;\"\u003e\n \u003cp\u003eAsthma, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e16(35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e16(35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 178px;\"\u003e\n \u003cp\u003eEczema, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e13((28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e13(28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 178px;\"\u003e\n \u003cp\u003eEnvironmental \u0026amp; seasonal allergies, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e16(35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e16(35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eDrug allergy (penicillin or other medications), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e19(19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e18(19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e1(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eUnknown, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e4(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e4(4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 153px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eBased on the current evidence regarding penicillin allergy in pediatrics population, we implemented a clinical pathway that excluded prior skin testing and achieved our primary objective, successfully delabelling at least 96% of patients with a reported penicillin allergy. Without this intervention, many of these children would likely have continued to carry an inaccurate allergy label, resulting in suboptimal antibiotic selection, unnecessary healthcare costs, and potentially avoidable morbidity [18]. There remain ongoing opportunities to further enhance penicillin allergy delabeling efforts at both TBRHSC and SLMHC. Furthermore, the oral penicillin challenge was successfully completed without immediate reactions in all children, regardless of whether their index reaction had been immediate or nonimmediate. This supports the likelihood that most rash presentations during amoxicillin therapy, whether occurring soon after dosing or several days later, are attributable to concurrent viral infections rather than true drug hypersensitivity [23,24].\u003c/p\u003e\n\u003cp\u003eInterestingly, all three patients who experienced reactions after the graded oral amoxicillin challenge in our study had a history of delayed symptom onset during their initial exposure to amoxicillin, with reactions reported between 5 to 10 days after first taking the medication. During the oral challenge, two patients developed delayed reactions 1 and 2 days after completing the 5-day course of amoxicillin prescribed at discharge, while one patient developed symptoms 2 days after the single dose\u0026nbsp;oral challenge. This consistency in timing between historical and challenge-related reactions suggests a reproducible delayed hypersensitivity response, likely mediated by T-cell-driven immune mechanisms [25,26]. Prior literature supports the relevance of delayed features in predicting true allergy. For example, a study by Mill et al., reported significantly increased odds of non-immediate penicillin reactions in patients whose initial rash lasted longer than 7 days, even after adjusting for demographic and clinical factors [17]. While our study did not assess rash duration per se, the delayed onset of symptoms in both historical and challenge contexts in our patients strengthens the hypothesis that timing of symptom onset can be a useful predictor in identifying delayed-type drug hypersensitivity. These findings highlight the importance of incorporating symptom timing into the clinical assessment of reported penicillin allergies, especially when determining eligibility for graded oral amoxicillin challenge in patients categorized as low risk.\u003c/p\u003e\n\u003cp\u003eOur findings indicate that the vast majority of children suspected of having amoxicillin allergy are able to tolerate the drug. A key strength of this study is its inclusion of a broad pediatric age range, allowing assessment of tolerance patterns across diverse developmental and immunologic stages. This wider scope offers a more comprehensive understanding of amoxicillin tolerance in both younger and older children, with implications for refining de-labeling strategies in varied clinical settings.\u003c/p\u003e\n\u003cp\u003eWhile female participants represented the majority of our cohort and more frequently reported historical symptoms across nearly all rash categories, all reactions during the graded oral amoxicillin challenge occurred exclusively in male participants. This finding is notable, as it suggests a possible disconnect between historical symptom reporting and the actual likelihood of a positive challenge outcome. Possible explanations include sex-based differences in immune reactivity, behavioral or recall bias in reporting prior symptoms, or other unmeasured confounders. Interestingly, adult-focused meta-analytic data have reported the opposite pattern, with females more likely than males to have a confirmed \u0026beta;-lactam allergy via oral challenge with relative risk of 1.40 (1.18-1.66) at 95% confidence interval [27]. Our pediatric findings therefore diverge from adult trends, suggesting that sex-specific risk profiles in drug hypersensitivity may differ across the lifespan. Future studies with larger and more diverse pediatric cohorts are needed to determine whether this pattern persists and to evaluate whether sex should be considered a statistically significant factor in risk stratification for direct oral challenge.\u003c/p\u003e\n\u003cp\u003eIn addition to the clinical significance, the direct health economic benefit of assessing true amoxicillin allergy by oral challenge alone is clear. In our cohort of 96 patients, only 3 (3.1%) reacted to the oral challenge. Based on current Ontario Ministry of Health and Long-Term Care fee schedule estimates of approximately $200-$300 Canadian dollar (CAD) per penicillin skin test (inclusive of physician, nursing, and reagent costs), performing skin testing for all 96 patients prior to challenge would have cost an estimated $19,200-$28,800 CAD. By proceeding directly to oral challenge, these procedural costs were avoided. Beyond procedural savings, prior work has demonstrated that removal of an inaccurate penicillin-allergy label yields substantial downstream healthcare benefits through reduced hospital stays and improved antibiotic utilization [28]. Vyles et al. also reported total cost savings of $1368 USD and cost avoidance of $1812 USD in their follow-up cohort of 36 children, with an extrapolated annual benefit of $192,223 USD for ~6700 children seen in their pediatric emergency department. Applying this model to our 93 delabeled patients yields an estimated downstream benefit of approximately $2,667 USD (2018 values), equivalent to $4,730 CAD in 2025 after inflation adjustment and currency conversion [28]. While these represent short-term savings within a single year, the long-term financial impact is likely far greater. Early delabeling during childhood prevents decades of unnecessary use of costlier, broad-spectrum antibiotics and mitigates the cumulative risks of antimicrobial resistance, adverse drug reactions, and extended hospitalizations. Over a patient\u0026rsquo;s lifetime, accurate identification and removal of false penicillin allergy labels therefore translate into substantial healthcare savings and improved treatment outcomes.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the retrospective design of this study introduces inherent limitations, including reliance on existing documentation, potential missing data, and possible misclassification of the original reported reactions. Second, the study was conducted at two hospitals in NWO and included only pediatric patients with low-risk reactions to amoxicillin; therefore, the findings may not be generalizable to adults. Third, although follow-up was available through chart review, it is possible that some patients may have developed symptoms concerning for penicillin allergy after delabeling or had the allergy re-entered into their medical record at outside institutions. Fourth, as with similar studies [29,30], subsequent tolerance to a full therapeutic course of amoxicillin after the oral challenge was not confirmed for all participants, and it is possible that some nonimmediate reactions could occur in the context of future treatment. Fifth, the determination of family history of allergy or atopy was based on parental report, which may be subject to recall bias; however, this is unlikely to have been differential across groups and should not have affected the observed associations. Finally, our cost analysis relied on published average estimates for procedural and downstream economic impact of penicillin skin testing and delabelling, as institution-specific cost data were not available.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates that an oral amoxicillin provocation challenge, without preceding skin testing, is a safe and effective method for delabelling low-risk pediatric patients with a reported penicillin allergy in a hospital setting. In our cohort, 96.9% of children tolerated the challenge, and only 3.1% exhibited delayed, non-life-threatening reactions that mirrored their historical presentations. These findings support the growing evidence that penicillin allergy in children is rare and frequently overdiagnosed, and that most rash presentations during amoxicillin therapy are likely attributable to viral infections rather than true hypersensitivity. By eliminating unnecessary penicillin allergy labels, we can promote optimal antibiotic prescribing, reduce healthcare costs, and minimize avoidable morbidity. Implementation of direct oral challenge pathways in similar healthcare settings could yield substantial clinical and economic benefits. Future studies with larger, more diverse populations and longer follow-up are warranted to confirm these findings, identify predictors of positive challenge outcomes, and refine risk stratification to further enhance the safety and efficiency of pediatric penicillin allergy delabelling.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research is funded by the Northern Ontario Academic Medicine Association (NOAMA) AHSC AFP Innovation Fund award.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTaha Sadeghi:\u003c/strong\u003e Writing \u0026ndash; original draft, Investigation, Formal analysis, Data curation, Conceptualization. \u003cstrong\u003eParisa Mirzajani:\u003c/strong\u003e Writing \u0026ndash; review \u0026amp; editing, Data curation. \u003cstrong\u003eRua Suror:\u003c/strong\u003e Writing \u0026ndash; review \u0026amp; editing. \u003cstrong\u003eRaga Sirror:\u003c/strong\u003e Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Thunder Bay Regional Health Sciences Centre Research Ethics Board (IRB registration #00004396). \u0026nbsp;The requirement for written informed consent was waived by the ethics committee due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not openly available due to reasons of patient privacy and are not available for request due to similar reasoning. Data is located in controlled access data storage by the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFleming A. Penicillin. BMJ 1941;2:386\u0026ndash;386. https://doi.org/10.1136/bmj.2.4210.386.\u003c/li\u003e\n \u003cli\u003eMacy E, Vyles D. Who needs penicillin allergy testing? Annals of Allergy, Asthma and Immunology 2018;121:523\u0026ndash;9. https://doi.org/10.1016/j.anai.2018.07.041.\u003c/li\u003e\n \u003cli\u003eShaker M, McWilliams S, Greenhawt M. Update on penicillin allergy delabeling. Curr Opin Pediatr 2020;32:321\u0026ndash;7. https://doi.org/10.1097/MOP.0000000000000879.\u003c/li\u003e\n \u003cli\u003eAntoon JW, Grijalva CG, Carroll AR, Johnson J, Stassun J, Bonnet K, et al. Parental Perceptions of Penicillin Allergy Risk Stratification and Delabeling. Hosp Pediatr 2023;13:300\u0026ndash;7. https://doi.org/10.1542/hpeds.2022-006737.\u003c/li\u003e\n \u003cli\u003ePowell N, Blank M, Luintel A, Elkhalifa S, Bhogal R, Wilcock M, et al. Narrative review of recent developments and the future of penicillin allergy de-labelling by non-allergists. Npj Antimicrobials and Resistance 2024;2. https://doi.org/10.1038/s44259-024-00035-6.\u003c/li\u003e\n \u003cli\u003eBhattacharya S. THE FACTS ABOUT PENICILLIN ALLERGY: A REVIEW. J Adv Pharm Technol Res n.d.;1.\u003c/li\u003e\n \u003cli\u003eKwan N, Kang K, Carr RR, Mak R, Roberts A, Jin F, et al. True Rate of Allergy among Pediatric Inpatients with Penicillin Allergy Labels (TRIAL). Canadian Journal of Hospital Pharmacy 2024;77. https://doi.org/10.4212/cjhp.3531.\u003c/li\u003e\n \u003cli\u003eSacco KA, Bates A, Brigham TJ, Imam JS, Burton MC. Clinical outcomes following inpatient penicillin allergy testing: A systematic review and meta-analysis. Allergy: European Journal of Allergy and Clinical Immunology 2017;72:1288\u0026ndash;96. https://doi.org/10.1111/all.13168.\u003c/li\u003e\n \u003cli\u003eMattingly TJ, Fulton A, Lumish RA, Williams AMC, Yoon SJ, Yuen M, et al. The Cost of Self-Reported Penicillin Allergy: A Systematic Review. Journal of Allergy and Clinical Immunology: In Practice 2018;6:1649-1654.e4. https://doi.org/10.1016/j.jaip.2017.12.033.\u003c/li\u003e\n \u003cli\u003eShenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA - Journal of the American Medical Association 2019;321:188\u0026ndash;99. https://doi.org/10.1001/jama.2018.19283.\u003c/li\u003e\n \u003cli\u003eKhan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, et al. Drug allergy: A 2022 practice parameter update. Journal of Allergy and Clinical Immunology 2022;150:1333\u0026ndash;93. https://doi.org/10.1016/j.jaci.2022.08.028.\u003c/li\u003e\n \u003cli\u003eCopaescu AM, Vogrin S, James F, Chua KYL, Rose MT, De Luca J, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med 2023;183:944\u0026ndash;52. https://doi.org/10.1001/jamainternmed.2023.2986.\u003c/li\u003e\n \u003cli\u003eIammatteo M, Alvarez Arango S, Ferastraoaru D, Akbar N, Lee AY, Cohen HW, et al. Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing. Journal of Allergy and Clinical Immunology: In Practice 2019;7:236\u0026ndash;43. https://doi.org/10.1016/j.jaip.2018.05.008.\u003c/li\u003e\n \u003cli\u003eIb\u0026aacute;\u0026ntilde;ez MD, Rodr\u0026iacute;guez del R\u0026iacute;o P, Lasa EM, Joral A, Ruiz-Hornillos J, Mu\u0026ntilde;oz C, et al. Prospective assessment of diagnostic tests for pediatric penicillin allergy: From clinical history to challenge tests. Annals of Allergy, Asthma and Immunology 2018;121:235-244.e3. https://doi.org/10.1016/j.anai.2018.05.013.\u003c/li\u003e\n \u003cli\u003eLabrosse R, Paradis L, Lacombe-Barrios J, Samaan K, Graham F, Paradis J, et al. Efficacy and Safety of 5-Day Challenge for the Evaluation of Nonsevere Amoxicillin Allergy in Children. Journal of Allergy and Clinical Immunology: In Practice 2018;6:1673\u0026ndash;80. https://doi.org/10.1016/j.jaip.2018.01.030.\u003c/li\u003e\n \u003cli\u003eMacy E, Contreras R. Health care use and serious infection prevalence associated with penicillin \u0026ldquo;allergy\u0026rdquo; in hospitalized patients: A cohort study. Journal of Allergy and Clinical Immunology 2014;133:790\u0026ndash;6. https://doi.org/10.1016/j.jaci.2013.09.021.\u003c/li\u003e\n \u003cli\u003eMill C, Primeau MN, Medoff E, Lejtenyi C, O\u0026rsquo;Keefe A, Netchiporouk E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr 2016;170. https://doi.org/10.1001/jamapediatrics.2016.0033.\u003c/li\u003e\n \u003cli\u003eTucker MH, Lomas CM, Ramchandar N, Waldram JD. Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. Journal of Allergy and Clinical Immunology: In Practice 2017;5:813\u0026ndash;5. https://doi.org/10.1016/j.jaip.2017.01.023.\u003c/li\u003e\n \u003cli\u003eKrusenstjerna-Hafstr\u0026oslash;m T, Rubak S. The use of direct oral challenge to confirm allergies to penicillin class antibiotics in Danish children. BMC Pediatr 2020;20. https://doi.org/10.1186/s12887-020-02407-z.\u003c/li\u003e\n \u003cli\u003eLeis JA, Palmay L, Ho G, Raybardhan S, Gill S, Kan T, et al. Point-of-Care \u0026beta;-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. Clinical Infectious Diseases 2017;65:1059\u0026ndash;65. https://doi.org/10.1093/cid/cix512.\u003c/li\u003e\n \u003cli\u003eBlumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ 2018;361:k2400. https://doi.org/10.1136/bmj.k2400.\u003c/li\u003e\n \u003cli\u003eBauer ME, MacBrayne C, Stein A, Searns J, Hicks A, Sarin T, et al. A multidisciplinary quality improvement initiative to facilitate penicillin allergy delabeling among hospitalized pediatric patients. Hosp Pediatr 2021;11:427\u0026ndash;34. https://doi.org/10.1542/HPEDS.2020-001636.\u003c/li\u003e\n \u003cli\u003eErho T, Eikkinen H, Onica M, Hint T, Asnee T, Honmaitree C. PREVALENCE OF VARIOUS RESPIRATORY VIRUSES IN THE MIDDLE EAR DURING ACUTE OTITIS MEDIA A BSTRACT Background Vaccines against respiratory viruses. 1999.\u003c/li\u003e\n \u003cli\u003eWiertsema SP, Chidlow GR, Kirkham LAS, Corscadden KJ, Mowe EN, Vijayasekaran S, et al. High detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media. J Med Virol 2011;83:2008\u0026ndash;17. https://doi.org/10.1002/jmv.22221.\u003c/li\u003e\n \u003cli\u003eShah PN, Romar GA, Manukyan A, Ko WC, Hsieh PC, Velasquez GA, et al. Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets. Journal of Clinical Investigation 2024;134. https://doi.org/10.1172/JCI178253.\u003c/li\u003e\n \u003cli\u003ePavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, et al. T Cell-mediated hypersensitivity reactions to drugs. Annu Rev Med 2015;66:439\u0026ndash;54. https://doi.org/10.1146/annurev-med-050913-022745.\u003c/li\u003e\n \u003cli\u003ePatel NB, Cojuc-Konigsberg G, Garcia-Guaqueta D, Shah D, Balasubramaniam D, Mahajan A, et al. Effects of Sex and Gender in Immediate \u0026beta;-Lactam Antibiotic Allergy: A Systematic Review and Meta-Analysis. Journal of Allergy and Clinical Immunology: In Practice 2025;13:155-166.e11. https://doi.org/10.1016/j.jaip.2024.10.031.\u003c/li\u003e\n \u003cli\u003eVyles D, Chiu A, Routes J, Castells M, Phillips EJ, Kibicho J, et al. Antibiotic Use After Removal of Penicillin Allergy Label. Pediatrics 2018;141:e20173466. https://doi.org/10.1542/peds.2017-3466.\u003c/li\u003e\n \u003cli\u003eDelli Colli L, Gabrielli S, Abrams EM, O\u0026rsquo;Keefe A, Protudjer JLP, Lavine E, et al. Differentiating Between \u0026beta;-Lactam-Induced Serum Sickness\u0026ndash;Like Reactions and Viral Exanthem in Children Using a Graded Oral Challenge. Journal of Allergy and Clinical Immunology: In Practice 2021;9:916\u0026ndash;21. https://doi.org/10.1016/j.jaip.2020.08.047.\u003c/li\u003e\n \u003cli\u003eGateman DP, Rumble JE, Protudjer JLP, Kim H. Amoxicillin oral provocation challenge in a primary care clinic: a descriptive analysis. CMAJ Open 2021;9:E394\u0026ndash;9. https://doi.org/10.9778/cmajo.20200077.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Penicillin allergy, Amoxicillin, Pediatrics, Oral challenge, Allergy delabelling, Retrospective review, Northwestern Ontario, Delayed rash","lastPublishedDoi":"10.21203/rs.3.rs-8845785/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8845785/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003cbr\u003e\nTo find out how many children labelled as allergic to amoxicillin are truly allergic, and to assess whether a direct oral amoxicillin challenge, without prior skin testing, is a safe and effective way to remove incorrect allergy labels in low-risk pediatric patients in Northwestern Ontario.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nWe conducted a retrospective review of pediatric patients (6 months-15 years) referred for suspected amoxicillin allergy at two Northwestern Ontario hospitals between 2015 and 2025. Eligible patients underwent oral amoxicillin challenge. Clinical data were summarized, and group comparisons were performed using Fisher’s exact and Wilcoxon tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nOf 96 patients, 93 (96.9%) tolerated the oral amoxicillin challenge, while 3 (3.1%) developed mild, delayed rashes. Notably, all three had previously reported delayed reactions (5-10 days) after their initial amoxicillin exposure, and two reproduced the same rash type following the challenge. This reproducibility suggests that the timing and nature of index reactions may help predict outcomes during oral challenge.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nThe prevalence of true penicillin allergy among paediatric patients labelled as penicillin-allergic in Northwestern Ontario was 3.1%. Oral amoxicillin challenge without prior skin testing proved to be a safe and effective approach for de-labelling low-risk children. Broader implementation of this strategy could enhance antibiotic stewardship, reduce healthcare-related costs, and improve patient care.\u003c/p\u003e","manuscriptTitle":"De-labelling Penicillin Allergy in Paediatric Patients Using Oral Challenge: A Retrospective Study from Northwestern Ontario","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 12:34:05","doi":"10.21203/rs.3.rs-8845785/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-10T06:26:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-22T17:23:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106574992041917765282372589865467730618","date":"2026-02-18T15:23:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300824129118920841693055036350993993030","date":"2026-02-13T16:12:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-13T15:45:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-12T15:44:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-12T04:47:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2026-02-10T23:59:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1ef0ece0-053d-4b3f-be97-671b65f602b4","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T10:54:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 12:34:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8845785","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8845785","identity":"rs-8845785","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}