Attitudes of caregivers of children labeled with drug allergy after delabeling by provocation tests

Abstract

Background

Mislabeling children as drug‐allergic leads to suboptimal, costly, and potentially harmful treatments. Although drug provocation tests (DPTs) are the gold standard for excluding drug hypersensitivity, the impact of these interventions on caregivers' willingness to reuse delabeled drugs remains elusive. We evaluated DPT outcomes and post‐DPT drug use and caregiver attitudes in pediatric patients.

Methods

We analyzed children who underwent DPTs for suspected drug allergy at a tertiary pediatric allergy center between January 2019 and June 2023. Demographic and clinical data were reviewed, and caregivers were contacted ≥6 months after DPT to assess subsequent drug use and concerns.

Results

A total of 254 DPTs were performed in 198 children (55.1% male; median age: 58 months). Drug allergy was confirmed in 25.3% of patients (50/198), corresponding to 22.0% of tests (56/254). Among 162 negative DPTs with follow‐up, the suspected drug was reused in 56.8% of cases; 92.4% were tolerated while 7.6% resulted in mild reactions.

Multivariable logistic regression identified predictors of drug reuse: paracetamol (aOR: 7.40; 95% CI: 1.73–31.63; p = .007), concomitant allergic disease (aOR: 2.51; 95% CI: 1.12–5.64; p = .026), self‐referral (aOR: 3.81; 95% CI: 1.12–12.95; p = .032), and younger age (aOR per month: 0.99; 95% CI: 0.98–1.00; p = .017). Anaphylaxis at index reaction was associated with reduced reuse likelihood (aOR: 0.21; 95% CI: 0.06–0.76; p = .018).

Conclusion

Despite negative DPT results, almost half of caregivers did not reuse the suspected drug, mostly due to fear or miscommunication. These findings highlight the importance of post‐DPT education and structured follow‐up to optimize delabeling outcomes.

Despite negative drug provocation tests excluding allergy in 74.7% of children, nearly half of caregivers avoided reusing the delabeled drug—primarily due to fear. Paracetamol use, self‐referral, and younger age predicted reuse, while prior anaphylaxis was the strongest barrier.

Abbreviations

aOR

adjusted odds ratio

CI

confidence interval

DHR

drug hypersensitivity reaction

DPT

drug provocation test

EAACI

European Academy of Allergy and Clinical Immunology

IgE

immunoglobulin E

IQR

interquartile range

NSAID

non‐steroidal anti‐inflammatory drug

OR

odds ratio

SCAR

severe cutaneous adverse reaction

SD

standard deviation

STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

Key message.

Negative drug provocation testing excluded drug allergy in most children, but nearly half of caregivers still avoided reusing the delabeled drug due to persistent fear. Reuse was more likely with paracetamol, in self‐referred families, and in younger children, whereas prior anaphylaxis was the main barrier.

1. INTRODUCTION

Drug hypersensitivity reactions (DHRs) affect up to 7% of the general population and remain a major source of concern for clinicians and families, although their incidence is lower in children. ¹ , ² The prevalence of DHRs varies across populations, with beta‐lactam antibiotics and non‐steroidal anti‐inflammatory drugs (NSAIDs) being the most frequently implicated agents. ³ Novel therapies, including monoclonal antibodies and enzyme‐based treatments, have also been linked with hypersensitivity reactions. ⁴ , ⁵

Although cutaneous manifestations such as maculopapular rashes and urticaria are the most common presentations, severe reactions including anaphylaxis and severe cutaneous adverse reactions (SCARs) may occur. ⁶ Precise diagnosis is crucial to avoid future reactions and ensure safe, effective therapy. However, when children are labeled as drug‐allergic, clinicians may prescribe suboptimal, potentially more costly alternatives, while caregivers may avoid not only the suspected drug but also many unrelated medications. ⁷ , ⁸ Such mislabeling can lead to anxiety, increased healthcare costs, emergence of antimicrobial resistance, and failure to access optimal treatment. ⁹ , ¹⁰

Diagnostic evaluation typically includes a detailed history and physical examination, supported by some selected laboratory tests (e.g., serum‐specific immunoglobulin E (IgE), skin prick, intradermal, basophil activation, and lymphocyte transformation tests). In addition, drug provocation testing (DPT) is considered the gold standard for confirming or excluding hypersensitivity and identifying safe alternatives. ¹¹ , ¹² Although a negative DPT should theoretically “delabel” the child and restore caregiver confidence in the drug's safety, real‐world studies have reported post‐delabeling drug reuse rates around 40%–70%, often limited by caregiver anxiety, insufficient counseling, and inadequate follow‐up. ¹³ , ¹⁴ , ¹⁵

Despite the high burden of pediatric drug use and the growing network of allergy centers, data on post‐delabeling behaviors in this population remain scarce. ¹⁶ Addressing these behavioral barriers is critical for developing targeted counseling strategies and supporting antimicrobial stewardship initiatives.

This study evaluated consecutive children who underwent DPT for suspected drug allergy at a tertiary pediatric allergy center. In addition to clinical data, structured caregiver surveys assessed post‐DPT drug use and attitudes. The primary aim was to determine the proportion of families who reused delabeled drugs after a negative DPT and secondarily identify factors associated with continued avoidance. By integrating clinical and caregiver‐reported outcomes, this study seeks to inform strategies for effective counseling and safe reintroduction of previously suspected drugs in pediatric care.

2. METHODS

2.1. Study design and population

This bidirectional observational study was conducted at the Division of Pediatric Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. Children aged 0–18 years who underwent DPT for suspected drug hypersensitivity between January 2019 and June 2023 were included. Inclusion criteria were: (i) a DPT performed within the study period and (ii) availability of follow‐up data ≥6 months post‐DPT.

DPTs were performed according to European Academy of Allergy and Clinical Immunology (EAACI) / European Network on Drug Allergy (ENDA) position paper. ¹² In addition, children with a history of delayed reactions to the culprit drug (antibiotics or NSAIDs) and a negative DPT continued the drug at regular doses at home for 5 days to observe possible delayed‐type reactions.

Children with negative DPT results who reused or did not reuse the delabeled drug were compared for several risk factors. Demographic and clinical data were retrospectively extracted from electronic medical records, including sex, age at index reaction, suspected culprit drug, drug tested during DPT, reaction type (immediate [1–6 h] or delayed [>6 h]), reaction management, comorbid allergic/chronic diseases, family history of drug allergy, skin prick test results, serum total IgE, absolute eosinophil count, prescription of adrenaline auto‐injectors, and DPT outcomes.

For patients with negative DPT results and follow‐up ≥6 months, caregiver‐reported attitudes regarding reuse of previously suspected drugs were evaluated using a structured survey during routine follow‐up visits. Informed consent was obtained from all participants or their legal guardians. The patient flow diagram is presented in Figure 1.

FIGURE 1.

Flow diagram of drug provocation tests (DPTs) and post‐test drug usage among pediatric patients between January 2019 and June 2023. A total of 371 tests were initially invited; after exclusions, 232 DPTs were included in the final analysis. Confirmed drug allergy comprised positive skin tests (n = 3) and positive DPTs (n = 53). Tests involving alternative drug groups or structurally similar drugs were excluded because the suspected culprit drug was not directly tested. Among 179 negative DPTs, 56.8% were followed by actual drug reuse. Reasons for non‐use included lack of clinical indication, ongoing caregiver hesitation, and unawareness that allergy had been ruled out. The unit of analysis was DPTs rather than unique patients; therefore, patient counts may not sum across branches because some children underwent more than one test.

2.2. Statistical analysis

Demographic and clinical characteristics of children with positive DPT results were analyzed at the patient level and comparisons between those who reused or did not reuse the delabeled drug were conducted at the test level.

Data analyses were performed using SPSS version 30 (IBM Corp., Armonk, NY, USA); figures were created in GraphPad Prism version 10 (GraphPad Software, San Diego, CA, USA). Continuous variables are presented as mean ± standard deviation (SD) or median (interquartile range [IQR]), and categorical variables as frequencies and percentages.

Normality was assessed with the Kolmogorov–Smirnov test. For categorical variables, the chi‐square test or Fisher's exact test (as appropriate) was used. For continuous variables, Student's t‐test or one‐way ANOVA was applied for normally distributed data; otherwise, the Mann–Whitney U or Kruskal–Wallis H test was used. Correlations between continuous variables were evaluated using Pearson's correlation coefficient (for normally distributed data) or Spearman's rank correlation coefficient (for non‐normal data). Correlation coefficients with p < .05 were denoted with *, and those with p < .01 with **. A two‐tailed p‐value <0.05 was considered statistically significant.

This study was reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (Data S1).

2.3. Ethics

Ethical approval was obtained from the Clinical Research Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (Approval Date: 05 January 2024; Approval Number: 2332348).

3. RESULTS

A total of 198 children were included, undergoing 254 DPTs. Of all participants, 181 patients were tested with the suspected culprit drug, while 17 patients were tested with a structurally similar drug from the identical pharmacological group. In these 17 patients, all tests were negative; however, since the suspected drug was not tested directly, DHR could not be definitively excluded. These patients were excluded from the DPT‐negative cohort. Fifty‐two patients underwent DPTs for more than one drug. Fourteen patients (17 tests) did not provide post‐DPT drug use information; their data were included only in demographic analyses.

3.1. Demographic and clinical characteristics

At the patient level, the mean age at the time of the index hypersensitivity reaction was 69 ± 56 months, with a median of 58 months (range: 1–203 months). Of the 198 patients included, 109 (55.1%) were male and 89 (44.9%) were female. Concomitant allergic diseases were identified in 109 of 193 patients with available data (56.5%; Supplementary Figure S1), and a family history of allergic disease was reported in 119 of 198 patients (60.1%). The mean total serum IgE level was 135 ± 270 IU/mL, and the mean absolute eosinophil count was 255 ± 229 cells/μL.

At the reaction‐ and test‐based level, beta‐lactam antibiotics (penicillins and cephalosporins) and NSAIDs were the most frequently implicated drug groups among the 254 evaluated drug provocation tests (Figure S2). Based on clinical history, the data of 224 documented index reactions were available for classification; of these, 88.2% were immediate‐type and 11.8% were delayed‐type reactions.

Across the documented reactions, the most common presenting symptom was urticaria (n = 92, 36.4%), followed by angioedema (n = 44, 17.4%), maculopapular eruption (MPE) (n = 42, 16.6%), anaphylaxis (n = 37, 14.6%), combined urticaria and angioedema (n = 34, 13.4%), vomiting (n = 3, 1.2%), and wheezing (n = 1, 0.4%). Angioedema was most frequently associated with NSAIDs (38.7%), whereas urticaria was most commonly associated with penicillin exposure (46.2%).

Serum IgE levels were significantly higher in patients with suspected paracetamol allergy compared to other drug groups (p < .001). IgE levels were also elevated in patients experiencing anaphylaxis or angioedema versus other reaction types (p = .008). Patients with confirmed drug allergy showed higher IgE levels than those with negative DPT results (231 ± 417 IU/mL vs. 104 ± 175 IU/mL; p = .013). Adrenaline auto‐injectors (AAIs) were prescribed in 70 of 254 tests (27.6%), corresponding to 51 of 198 patients (25.8%), with 64 prescriptions issued prior to DPT and 6 following test outcomes.

3.2. Diagnostic tests and outcomes

The mean interval between the index reaction and DPT was 34 ± 39 months (median: 19 months; range: 1–180 months). The mean interval between DPT and caregiver survey administration was 30 ± 18 months (median: 24 months; range: 1–63 months).

Among participants with available data, 118 patients (85.5%) were referred for allergy testing by a physician, while 20 patients (14.5%) self‐referred. Of all tests performed, 153 (85%) followed physician referral, and 27 (15%) involved voluntary applications.

Skin testing was performed in 57 patients prior to DPT, with positive results in 3 (5.3%). These three patients were classified as having confirmed drug allergy. The remaining 178 DPTs were performed without prior skin testing. Of 232 DPTs, 53 (23.1%) yielded positive results. Among these, 84.9% were immediate‐type reactions and 15.1% were delayed‐type reactions. Ultimately, 50 of the 198 patients (25.3%) were confirmed to have a drug allergy, accounting for 56 positive drug provocation tests. Some patients had more than one positive drug provocation test; therefore, test‐level and patient‐level positivity rates differ.

3.3. Post‐DPT drug use

Of the 146 patients with negative DPT results, 14 patients (17 tests) were excluded due to incomplete post‐DPT data. Among the remaining 162 tests, 92 tests (56.8%) involving 70 patients resulted in reuse of the previously suspected drug, while 70 tests (60 patients) (43.2%) did not (Figure 2). Of the 92 tests (70 patients) who reused the drug, 85 tests (63 patients) (92.4%) tolerated it without incident. However, 7 tests (7 patients) (7.6%) experienced mild to moderate reactions: urticaria (n = 3), angioedema (n = 2), maculopapular eruption (n = 1), and nausea with dizziness (n = 1). The implicated drugs were antibiotics—amoxicillin‐clavulanate (n = 3) and cefuroxime axetil (n = 1)—and NSAIDs—ibuprofen (n = 2) and paracetamol (n = 1).

FIGURE 2.

Proportions of patients who reused or did not reuse the delabeled drug after negative DPT, stratified by drug group. The most common groups were penicillins (n = 74), NSAIDs (n = 38), paracetamol (n = 23), cephalosporins (n = 12), other antibiotics (n = 14), and other drugs (n = 1). Paracetamol was significantly more likely to be reused compared to all other drug groups combined (82.6% vs. 50.7%, p = .013). The overall association between drug group and reuse showed a trend toward significance (p = .060).

Reasons for avoiding drug use despite a negative DPT included lack of clinical indication (37.1%), persistent caregiver concerns (58.6%), and failure to recognize that allergy had been ruled out (4.3%).

3.4. Comparison of patients who reused or did not use the delabeled drug

The median age at index reaction was significantly lower among patients who reused the delabeled drug compared to those who did not (36 months vs. 69 months; p = .021). No significant difference was observed in the interval between the index reaction and DPT, (p = .866).

The presence of concomitant allergic diseases was associated with higher rates of drug reuse after a negative DPT (65.3% vs. 44.8%; p = .010). Moreover, patients who self‐referred for drug allergy testing were more likely to reuse the delabeled drug compared to those referred by a physician (84.6% vs. 52.5%; p = .002).

In the multivariable logistic regression analysis (Figure 3, Table S1), independent predictors of drug reuse included paracetamol (adjusted OR: 7.40; 95% CI: 1.73–31.63; p = .007), presence of concomitant allergic disease (adjusted OR: 2.51; 95% CI: 1.12–5.64; p = .026), self‐referral (adjusted OR: 3.81; 95% CI: 1.12–12.95; p = .032), and younger age (adjusted OR per month: 0.99; 95% CI: 0.98–1.00; p = .017). Conversely, a history of anaphylaxis at the index reaction was associated with a decreased likelihood of drug reuse (adjusted OR: 0.21; 95% CI: 0.06–0.76; p = .018).

FIGURE 3.

Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with reuse of the delabeled drug after negative drug provocation testing (DPT). Significant predictors of reuse included paracetamol (OR: 7.40, 95% CI: 1.73–31.63), presence of comorbid allergic disease (OR: 2.51, 95% CI: 1.12–5.64), and self‐referral (OR: 3.81, 95% CI: 1.12–12.95), while anaphylaxis at index reaction was associated with a decreased likelihood of reuse (OR: 0.21, 95% CI: 0.06–0.76). Red dots indicate statistically significant predictors in the multivariable analysis. Odds ratios are presented on a logarithmic scale. Full p‐values for all variables are provided in Table S1.

Table 1 presents the univariable comparisons, and the multivariable analysis is summarized in Figure 3; Table S1.

TABLE 1.

Comparison of patients who reused or did not use the delabeled drug after negative DPT.

	Did not use, n = 70 (62 pts) b	Reused, n = 92 (70 pts) b	p
Demographics and clinical parameters a
Age at index reaction, months (mean ± SD)	70 ± 46	57 ± 53	0.021
Male sex, n (%)	40 (57.1%)	53 (57.6%)	0.953
Interval: reaction to DPT, months (mean ± SD)	38 ± 45	33 ± 37	0.866
Interval: DPT to survey, months (mean ± SD)	28 ± 19	31 ± 18	0.210
Concomitant allergic disease, n (%)	33 (47.1%)	62 (67.4%)	0.010
Family allergy history	47 (67.1%)	61 (66.3%)	0.911
Family drug allergy history	13 (18.6%)	18 (19.6%)	0.873
Adrenaline auto‐injector, n (%)	19 (27.1%)	18 (19.6%)	0.255
Referral Status
Physician referral, n (%)	57 (93.4%)	63 (74.1%)	0.002
Self‐referred, n (%)	4 (6.6%)	22 (25.9%)
Index reaction
Anaphylaxis, n (%)	13 (18.6%)	5 (5.4%)	0.027
Urticaria or angioedema, n (%)	43 (62.8%)	66 (71.8%)
Maculopapular eruption, n (%)	12 (17.1%)	20 (21.7%)
Reaction Type at Index Reaction
Immediate	60 (85.7%)	81 (88.0%)	0.662
Delayed	10 (14.3%)	11 (12.0%)
Treatment During Index Reaction
Adrenaline administered, n (%)	11 (16.9%)	5 (5.9%)	0.047
Antihistamine only, n (%)	38 (58.5%)	63 (74.1%)
Antihistamine+steroid, n (%)	6 (9.2%)	5 (5.9%)
Skin prick test
Performed (all negative)	12 (17.1%)	22 (23.9%)	0.295
Not performed	58 (82.9%)	70 (76.1%)
Laboratory values
Total serum IgE, IU/mL (mean ± SD)	85 ± 99	117 ± 222	0.765
Eosinophil count, cells/μL (mean ± SD)	262 ± 234	239 ± 163	0.991

Note: p values in bold are statistically significant.

Abbreviations: DPT, drug provocation test; IgE, immunoglobulin E; SD, standard deviation.

^a Values are mean ± SD or n (%).

^b Analyses were performed at the test level (individual DPTs); some patients contributed more than one test.

3.5. Factors associated with persistent caregiver concerns after delabeling

To investigate predictors of persistent caregiver concerns following delabeling, we conducted a multivariable logistic regression analysis. Patients without subsequent medical need for the delabeled drug and those who misunderstood the implications of their negative DPT result were excluded. This analysis included 92 tests (70 patients) who reused the delabeled drug and 41 tests (37 patients) who avoided reuse solely due to ongoing caregiver apprehension.

In the univariable analyses, anaphylaxis at the index reaction was significantly more common among patients who avoided reuse (26.8% vs. 5.4%; p < .001). Concomitant allergic diseases were also more prevalent in those who avoided reuse (67.4% vs. 51.2%; p = .075). Patients referred by a physician were less likely to reuse the drug compared to those who applied voluntarily (10.8% vs. 25.9%; p = .047).

In the multivariable logistic regression (Figure 4; Table S2), a history of anaphylaxis at the index reaction (adjusted OR: 0.17; 95% CI: 0.05–0.57; p = .004) was independently associated with persistent caregiver concerns. Comorbid allergic disease showed a trend toward significance (adjusted OR: 2.15; 95% CI: 0.90–5.13; p = .085).

FIGURE 4.

Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with persistent caregiver concerns after delabeling. The analysis included patients who reused the delabeled drug (n = 92) and those who avoided reuse solely due to ongoing caregiver apprehension (n = 41). Anaphylaxis at index reaction was independently associated with persistent caregiver concerns (OR: 0.17, 95% CI: 0.05–0.57; p = .004), and comorbid allergic disease showed a trend toward significance (OR: 2.15, 95% CI: 0.90–5.13; p = .085). Red dots indicate statistically significant predictors in the multivariable analysis. Odds ratios are presented on a logarithmic scale. Full p‐values for all variables are provided in Table S2.

4. DISCUSSION

Drug hypersensitivity reactions represent a significant clinical challenge, particularly in pediatric populations where mislabeling as “drug allergic” can lead to avoidance of first‐line therapies, increased healthcare costs, and potential adverse outcomes. ¹⁷ The EAACI/ENDA guidelines reaffirm that DPTs remain the diagnostic gold standard and support omitting skin tests in selected low‐risk cases to streamline diagnosis safely. ¹² In this study, we evaluated 254 DPTs performed in 198 children with suspected drug allergy. Our findings provide insight into the epidemiology of DHRs in children, DPT outcomes, and post‐delabeling drug use behaviors among caregivers.

Consistent with previous studies, beta‐lactam antibiotics were the most common culprits in suspected DHRs, with amoxicillin‐clavulanate alone accounting for 34.6% of cases and cephalosporins (10.6%), followed by NSAIDs (37.7%). ¹¹ , ¹⁸ This aligns with data from Portugal and Türkiye, where beta‐lactams and NSAIDs are frequently implicated in pediatric DHRs. ³ , ¹⁶ NSAIDs were often associated with angioedema and penicillins with urticaria, reflecting classification patterns described in EAACI/ENDA guidelines. ¹² Moreover, 88.2% of the reactions were immediate type, while only 11.8% were delayed type, consistent with the predominance of IgE‐mediated mechanisms in children. ¹¹

In line with Turkish multicenter data from the ADAPT study, which reported approximately 27% positivity via DPT, ¹⁶ and findings by Schrüfer et al., who documented a 25.6% rate of confirmed beta‐lactam allergy in a large cohort ¹⁹ ; our study confirmed drug allergy in 25.3% of patients, while 22.0% of drug provocation tests yielded positive results. These findings demonstrate that the majority of suspected drug hypersensitivity reactions can be excluded through careful clinical evaluation and DPT, reaffirming the critical role of DPT as the diagnostic gold standard for drug allergy and for avoiding unnecessary drug restrictions. ¹² , ²⁰ The high negative predictive value of provocation testing in children has been demonstrated for both single‐day and extended beta‐lactam protocols, further supporting its use to safely exclude hypersensitivity. ²¹ , ²²

Among the 92 drug reuses (70 unique patients), 7 (7.6%) were associated with mild reactions, including urticaria, angioedema, and maculopapular eruptions, classified as mild adverse drug reactions. One patient experienced nausea and dizziness, likely attributable to side effects rather than hypersensitivity. Subsequent reactions despite a negative DPT may result from concurrent infections or other cofactors that increase reaction risk. Similar observations were reported by Lachover‐Roth et al., where 5.5% of patients experienced mild reactions upon reusing penicillin after delabeling. ¹³ Notably, a negative provocation test does not invariably predict long‐term tolerance, and resensitization has been described in some children. ²³

Delabeling not only holds diagnostic value but also impacts prescribing behavior. While DPT safely ruled out drug allergy in most patients, only 56.8% of families reported reintroducing the drug. Hesitations were rooted in persistent anxiety (59%), absence of clinical need (37%), and misunderstanding that allergy had been ruled out (4%). Similar post‐delabeling hesitancy has been reported in other pediatric cohorts, with reuse rates ranging from 40% to 70%. ¹³ , ¹⁴ Vyles et al. observed that only 44% of patients reused penicillin after delabeling, while 10% felt inadequately informed about the removal of their allergy label. ⁷ Gerace et al. also found that 41% of patients remained reluctant to use beta‐lactams despite negative testing. ⁹ In line with these observations, a Turkish pediatric cohort similarly reported that a substantial proportion of caregivers continued to avoid nonsteroidal anti‐inflammatory drugs after a negative provocation test. ²⁴

In multivariable logistic regression, independent predictors of drug reuse included paracetamol, concomitant allergic disease, self‐referral, and younger age. Paracetamol was more likely to be reused, likely because it is a commonly prescribed and easily accessible medication in children, and caregivers may feel more comfortable administering it. Self‐referral was associated with higher reuse rates, possibly reflecting increased caregiver motivation, higher health literacy, and stronger trust in allergy evaluations among families who proactively seek testing. Younger age at the index reaction also predicted higher reuse, potentially because caregivers are more inclined to follow medical advice for younger children and avoidance behaviors may be less entrenched. In contrast, a history of anaphylaxis at the index reaction was associated with reduced reuse, likely due to persistent caregiver anxiety despite negative DPT results.

A negative DPT did not always change behavior, as many caregivers continued to avoid the drug. This gap between objective and perceived risk is well recognized in research on medication‐related behavior, where fear and earlier adverse experiences often weigh more heavily than test results. Our data fit this pattern: a history of anaphylaxis at the index reaction was the strongest barrier to reuse, even though allergy had been formally excluded. The nocebo response is also relevant here. During provocation testing, a meaningful proportion of patients report subjective, non‐allergic symptoms even after receiving an inert substance ²⁵ ; and in children these expectations can be reinforced by an anxious parent, a so‐called “nocebo‐by‐proxy” effect. ²⁶ Reassuring families with statistics alone is therefore often not enough, and how the information is framed also matters; telling parents that most children tolerate the drug, rather than that a few react, may ease anxiety and build confidence. ²⁷ These observations suggest a few practical steps. A supervised first dose, a clear verbal and written message that the drug can be used again, and simple guidance on what to do if symptoms appear may help more than reassurance alone. Strengthening caregivers' sense of control in this way could turn a negative test into real‐world drug reuse and should be tested in future interventional studies.

These findings highlight the importance of proactive counseling and education, as structured interventions have been shown to improve patient confidence and support antimicrobial stewardship, ¹⁴ , ¹⁵ , ²⁸ particularly for families of patients with severe index reactions. Implementing DPT‐driven delabeling protocols in line with EAACI/ENDA guidance, alongside structured follow‐up programs, may help alleviate caregiver fears and improve drug reuse rates. Given the rise in antimicrobial resistance and the risks of second‐line therapies, such interventions are crucial.

Our study's strengths include a large pediatric cohort, real‐world diagnostic outcomes, and caregiver‐reported post‐DPT behaviors. Limitations include its retrospective design, potential recall bias, and absence of formal anxiety or health literacy assessment. Prospective studies incorporating educational strategies are warranted to address these gaps.

In conclusion, accurate diagnosis of suspected drug allergy, avoidance of unnecessary drug restrictions, and tailored treatment approaches will enhance healthcare quality and reduce costs. While DPTs effectively exclude drug allergy in most pediatric patients, nearly half of caregivers remain hesitant to reuse delabeled drugs. Multidisciplinary strategies involving allergists, primary care providers, and pharmacists are essential to translate negative DPT results into confident and safe drug reintroduction.

AUTHOR CONTRIBUTIONS

Şeyma Kaya Ağargün: Data curation; methodology; formal analysis; writing – original draft; writing – review and editing. Besim Fazıl Ağargün: Formal analysis; writing – review and editing; writing – original draft. Ayse Süleyman: Writing ‐ review and editing. Sophia Tsabouri: Conceptualization; writing – review and editing. Zeynep Ülker Altınel: Data curation; conceptualization; writing – review and editing. Cevdet Ozdemir: Conceptualization; supervision; methodology; formal analysis; writing – review and editing; project administration.

FUNDING INFORMATION

No external funding supported this study.

CONFLICT OF INTEREST STATEMENT

CO is the European Academy of Allergy and Clinical Immunology (EAACI) Allied Health and Primary Care Section Chair (2024‐2026), EAACI ExCom member (2024‐2026), and Assistant Editor of Allergy. ST is Editor‐in‐Chief of Pediatric Allergy and Immunology. These editorial and society roles are unrelated to the present work and had no influence on the study design, data analysis, or interpretation of results. The remaining authors declare no actual or potential conflicts of interest.

Supporting information

Figure S1. Venn diagram showing the distribution and overlap of concomitant allergic diseases in the study cohort (n = 193). Allergic rhinitis, asthma, chronic urticaria, food allergy, and atopic dermatitis are displayed with overlaps indicating co‐occurrence among patients.

Figure S2. Distribution of suspected culprit drugs among pediatric patients undergoing drug provocation testing (DPT) between January 2019 and June 2023. Pie charts show the frequencies of specific drugs within the main pharmacological groups: penicillins, cephalosporins, NSAIDs, other antibiotics, and other drugs.

Table S1. Univariable and multivariable logistic regression analyses for factors associated with post‐DPT drug reuse (n = 162). Odds ratios (ORs) with 95% confidence intervals (CIs) and p‐values are shown for each predictor.

Table S2. Univariable and multivariable logistic regression analyses for factors associated with persistent caregiver concerns after delabeling (n = 133). Odds ratios (ORs) with 95% confidence intervals (CIs) and p‐values are shown for each predictor.

Data S1. Supporting Information.

Kaya Ağargün Ş, Ağargün BF, Süleyman A, Tsabouri S, Altınel ZÜ, Ozdemir C. Attitudes of caregivers of children labeled with drug allergy after delabeling by provocation tests. Pediatr Allergy Immunol. 2026;37:e70435. doi: 10.1111/pai.70435

DATA AVAILABILITY STATEMENT

De‐identified data can be obtained from the corresponding author on reasonable request.