Clinical and behavioral determinants in pediatric non‐immediate drug hypersensitivity: Low confirmation but persistent avoidance

Abstract

Background

Non‐immediate drug hypersensitivity reactions (DHRs) in children are frequently overdiagnosed, leading to unnecessary drug avoidance. Evidence regarding predictors of more extensive reactions, drug provocation test (DPT) outcomes, and re‐exposure behavior and avoidance remains limited.

Methods

This retrospective cohort study included 161 children referred for suspected non‐immediate‐type DHRs. Clinical characteristics, reaction features, laboratory findings, and DPT outcomes were collected from medical records. Re‐exposure behavior and avoidance were assessed at 6 and 12 months. Logistic regression was used to identify predictors of more extensive reactions, DPT outcomes, and avoidance of re‐exposure.

Results

Beta‐lactam antibiotics were the most frequently implicated drugs in 154 (95.7%) cases. Generalized cutaneous reactions occurred in 79 (49.1%) and were associated with male sex (OR: 2.70, 95% CI 1.31–5.56, p = .007), concomitant rhinitis/conjunctivitis (OR: 2.41, 1.02–5.71, p = .045), atopic dermatitis (OR: 2.55, 1.05–6.19, p = .038), and symptom onset after >3.5 days of treatment (OR: 3.21, 1.57–6.49, p = .001). DPT was positive in 9.3% of tested children, with no independent predictors of positivity. A mild maculopapular rash as the index reaction independently predicted a negative DPT result. (OR: 6.74, 1.83–24.83, p = .004). At 6 months, 40.7% avoided re‐exposure despite clinical indication, associated with generalized urticaria as the index reaction (OR: 2.60, 1.00–6.72, p = .048) and having received treatment for the reaction (OR: 4.12, 1.08–15.73, p = .038). By 12 months, 86.5% of patients had reused the culprit drug.

Conclusion

Male sex, atopic comorbidities, and later‐onset reactions were associated with an increased risk of more extensive non‐immediate‐type DHRs. Despite low DPT positivity and good re‐exposure tolerance, drug avoidance remains frequent, particularly after treated or generalized reactions.

Key message.

Most children with suspected non‐immediate drug hypersensitivity reactions tolerate the culprit drug on re‐exposure. However, despite low rates of confirmed allergy, drug avoidance remains common and appears to be influenced more by the perceived severity of the initial reaction than by objective diagnostic results.

1. INTRODUCTION

Non‐immediate drug hypersensitivity reactions (DHRs) are a frequent reason for referral to pediatric allergy clinics and represent a common cause of antibiotic allergy labeling in childhood. ¹ , ² Although most non‐immediate reactions are mild and self‐limited, the resulting fear of re‐exposure often persists for years, influencing prescribing practices, antimicrobial stewardship, and parental behaviors. ³ Distinguishing true drug hypersensitivity from benign, infection‐related rashes remains a major diagnostic challenge in pediatric practice. ⁴ Moreover, reducing parental and patient‐related avoidance after exclusion of drug allergy is crucial to prevent unnecessary long‐term drug avoidance.

Non‐immediate DHRs cover a heterogeneous clinical spectrum, ranging from mild cutaneous eruptions to more extensive reactions that raise concern for severity and recurrence. ⁵ Early recognition of clinical predictors of more extensive non‐immediate reactions may facilitate risk stratification, tailor follow‐up strategy, and guide decisions on re‐exposure and diagnostic testing. However, data in children are limited, and the contribution of factors such as sex, atopic comorbidities, and timing of reaction onset during treatment courses has not been sufficiently defined. ⁶

Drug provocation testing (DPT) is considered the gold standard for confirming or excluding drug hypersensitivity in children. ⁷ Nevertheless, DPT is frequently avoided or delayed due to safety concerns, parental anxiety, and uncertainty regarding patient selection. Given that most children with suspected non‐immediate DHRs ultimately tolerate the culprit drug, identifying clinical features associated with negative DPT outcomes could optimize diagnostic pathways, reduce unnecessary testing, and facilitate safe de‐labeling. ⁸

Importantly, diagnostic clarification alone does not always translate into successful drug reuse. Drug avoidance by patients, parents, or caregivers may persist even after negative allergy evaluations, causing continued restriction of first‐line therapies. ⁹ This behavioral dimension of drug allergy has been insufficiently explored in pediatric non‐immediate DHRs, particularly with respect to how initial reaction characteristics and management influence long‐term re‐exposure behavior. ¹⁰ , ¹¹

Therefore, this study aimed to identify clinical predictors of reaction extent, determinants of DPT outcomes, and factors associated with drug avoidance and re‐exposure behavior in children with suspected non‐immediate drug hypersensitivity reactions.

2. METHODS

This retrospective cohort study included children referred to Pediatric Allergy Clinic of University Hospital of Ioannina, Greece, for evaluation of suspected non‐immediate drug hypersensitivity reactions between January 2023 and January 2025. Eligible patients were aged 1–15 years and presented with cutaneous and/or systemic symptoms occurring >1 h after drug intake and attributed to medication exposure.

Patients with a history of definite immediate‐type reactions (≤1 h), incomplete clinical records, or reactions unrelated to medications were excluded. Patients who were receiving multiple medications simultaneously and in whom the culprit drug could not be clearly identified, either because the same drug was not subsequently tolerated without symptoms or because an appropriate DPT was not performed, were also excluded. Severe cutaneous adverse drug reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS) or Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or acute generalized exanthematous pustulosis (AGEP), were not included in the study.

Clinical data were obtained from electronic medical records and standardized drug allergy evaluation forms completed at presentation. Collected variables included demographic characteristics, personal and family history of allergic diseases, the indication for antibiotic treatment, reaction type and timing, concomitant medication use, eosinophil count, and total serum IgE levels. The suspected culprit drug, prior exposures to the same medication, clinical features of the hypersensitivity reaction, treatment administered for the reaction, and clinical resolutions were documented.

Cutaneous reactions were classified according to phenotype and extent rather than clinical severity. For urticaria, extent was categorized as “mild” (<20 wheals) or “generalized” (≥20 wheals). ¹² Mild maculopapular exanthema (MPE) was defined as involvement of <50% of body surface area, absence of systemic symptoms, and requiring no treatment or only antihistamines; these cases were considered low risk in DPT. Intermediate‐risk reactions included non‐severe immediate reactions (e.g., generalized pruritus), moderate MPE (involvement of >50% body surface area without systemic symptoms) and delayed urticaria (>1 h after drug exposure). Patients presenting with systemic symptoms (e.g., respiratory, gastrointestinal or cardiovascular involvement) were classified as high risk. ¹³

DPT was performed in accordance with the EAACI/ENDA position paper on drug provocation testing. ¹³ DPT was indicated in children with a clinical history suggestive of a non‐severe non‐immediate drug hypersensitivity reaction if no contraindications were present. All tests were performed at least 4 weeks after complete resolution of the index reaction. Provocation was carried out in a supervised hospital setting with immediate access to emergency equipment and personnel trained in the recognition and management of hypersensitivity reactions. Written informed consent was obtained from parents prior to testing. The suspected drugs were administered using a 3‐step incremental dosing protocol, aiming to reach at least the full single therapeutic dose with intervals of at least 30 min between steps. All DPTs were completed within a single day, without the use of prolonged or multi‐day provocation protocols. In patients classified as high risk, particularly given the late onset of symptoms and the fact that the clinical history was based solely on parental reports, DPT was administered after a careful individual risk–benefit assessment, when available, after a negative skin test.

Patients were observed for a minimum of 2 h after the final dose, with longer observation when clinically indicated based on the characteristics of the index reaction. Parents were instructed to actively monitor delayed symptoms for several days following provocation and to report any reactions occurring after discharge. Follow‐up calls were performed within 72 h after provocation to capture delayed reactions.

A positive DPT was defined as the reproducible occurrence of objective clinical signs consistent with the index reaction, including delayed‐onset cutaneous symptoms, following drug provocation. Subjective symptoms without objective findings were not considered positive.

Follow‐up information regarding re‐exposure to the suspected drug at 6 and 12 months was obtained through structured telephone interviews with parents or caregivers. Based on re‐exposure behavior, patients were classified into two groups: Group 1; “Drug avoidant group” defined as those who avoided re‐exposure due to parental or patient concern despite negative or absent diagnostic confirmation, and Group 2 “Non‐avoidant group,” consisting of patients who reused the culprit drug with or without antihistamines. Avoidance was assessed behaviorally, rather than through psychological assessment tools.

Descriptive statistics were used to summarize demographic and clinical variables. Categorical variables were compared using the chi‐square or Fisher's exact test, and continuous variables were analyzed using the Mann–Whitney U test or Student's t‐test, depending on data distribution. Risk factors associated with more extensive reactions, DPT positivity, and avoidance of re‐exposure were explored using univariate analysis followed by multivariate logistic regression. Patients with overlapping phenotypes were classified according to the most extensive manifestation for regression analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the day of treatment on which the reaction occurred for generalized reactions. A p‐value <.05 was considered statistically significant. All analyses were performed using SPSS version 25.0. Artificial intelligence (AI)‐based tools were only used to support graphical elements and visual presentation of the figures. No AI tools were used in data collection or statistical analysis.

The study was conducted in accordance with the Declaration of Helsinki. Approval was obtained from the 8/7‐5‐2023, Topic 26, University Hospital of Ioannina Ethics Committee, and parental consent was obtained for follow‐up interviews and drug provocation procedures as per institutional policy.

3. RESULTS

A total of 161 children with suspected non‐immediate drug hypersensitivity reactions were included in the study. The median age was 5 years (min–max: 1–15), and 90 (55.9%) were male. Eighty‐one patients (50.3%) had a personal history of allergy, including rhinitis/conjunctivitis in 39 (24.2%), asthma in 15 (9.3%), atopic dermatitis in 35 (21.7%), Hymenoptera venom allergy in 3 (1.9%), chronic urticaria in 3 (1.9%), and food allergy in 12 (7.5%). A family history of allergic disease was present in 97 (60.2%) children (Table 1).

TABLE 1.

Demographic and clinical characteristics of the study population.

Demographic and clinical characteristics	Value
Age, median (min–max)	5.0 (1.0–15.0)
Weight, median (min–max)	22.0 (7.0–71.0)
Gender, n (%)	90 (55.9)
Personal history of allergy, n (%)	81 (50.3)
Rhinitis‐conjunctivitis, n (%)	39 (24.2)
Asthma, n (%)	15 (9.3)
Atopic Dermatitis, n (%)	35 (21.7)
Allergy to Hymenoptera, n (%)	3 (1.9)
Chronic urticaria, n (%)	3 (1.9)
Food allergy, n (%)	12 (7.5)
Family history of allergies, n (%)	97 (60.2)
Drug group, n (%)
Penicillin	110 (68.3)
Cephalosporin	44 (27.3)
Macrolide	4 (2.5)
NSAID	3 (1.9)
Hours after the last dose, median (min–max)	2.0 (1.0–50.0)
Day of treatment when reaction took place, median (min–max)	4.0 (1.0–12.0)
Extention and phenotype of skin reaction, n (%)
Mild urticaria	52 (32.2)
Generalized urticaria	64 (39.7)
Mild MPE	26 (16.1)
Moderate MPE	13 (8.1)
Generalized urticaria + Mild MPE	2 (1.2)
Mild pruritus and erythema	4 (2.5)

Most reactions (154, 95.7%) were associated with beta‐lactam antibiotics. Penicillins were the most common culprit drugs with 110 (68.3%) patients, followed by cephalosporins in 44 (27.3%) patients. Non–beta‐lactam triggers included macrolides in 4 patients (2.5%) and non‐steroidal anti‐inflammatory drugs (NSAIDs) in 3 (1.9%). The median time from the last administered dose to the onset of reaction was 2 h (min–max: 1–50), and the median day of treatment on which the reaction occurred was day 4 (min–max: 1–12). The most common indication for antibiotic treatment was upper respiratory tract infections (URTIs), including acute otitis media, sinusitis, and pharyngotonsillitis infection (77, 48.4%), followed by respiratory infections (66, 41.5%), urinary tract infections (6, 3.8%), skin infections (4, 2.5%), and dental abscess (6, 3.8%) (Table 1).

The most frequent phenotype was generalized (≥20 wheals) urticaria (64, 39.7%), followed by mild urticaria (52, 32.3%), mild MPE (26, 16.1%), moderate MPE (13, 8.1%), generalized urticaria with mild MPE (2, 1.2%), and mild pruritus & erythema in 4 (2.5%) patients. Six (3.7%) patients had non‐immediate reactions with multi‐system involvement. These included non‐severe, patient reported gastrointestinal symptoms (abdominal pain) (n = 4), respiratory symptoms (dyspnea) (n = 1), and cardiovascular symptoms (tachycardia) (n = 1) in addition to cutaneous findings. Based on risk stratification according to the EAACI/ENDA, the majority of patients were classified as intermediate risk (n = 126 (78.2%)), followed by low risk (n = 29 (18%)) and high risk (n = 6 (3.7%)). ¹³ None of these cases met criteria for SCARs or other absolute contraindications to DPT (Figure 1).

FIGURE 1.

Flow diagram illustrating the clinical course of children with suspected non‐immediate drug hypersensitivity reactions, including reaction phenotype, diagnostic confirmation by drug provocation testing, and re‐exposure behavior during follow‐up. *Percentages for persistent drug avoidance were calculated using the number of patients with negative DPT results in each group as the denominator.

Sixty‐two patients (38.5%) had previously taken the culprit drug without issues. Concurrent medication use included NSAIDs in 18 (11.1%), inhalers in 4 (2.48%), additional antibiotic in 1 (0.62%), antihistamines in 6 (3.72%), and herbal/mucolytic agents in 4 patients (2.48%). All patients who had taken these concomitant drugs during the index reaction subsequently tolerated the same medications. Mean eosinophil count during reaction was 278.9 ± 147.7/μL, and median serum total IgE level was 40.5 IU/mL (5.0–1170.0).

A total of 121 (75.2%) reactions were treated, while 40 (24.8%) resolved spontaneously. Of those treated, 87 (54%) received antihistamines alone and 29 (18%) received combined antihistamine and systemic corticosteroid therapy. Fever accompanied the rash in 31 patients (19.2%).

When generalized and mild reactions were compared, generalized reactions occurred more frequently in males (52 [65.8%] vs. 35 [46.1%], p = .013). A history of rhinitis/conjunctivitis and atopic dermatitis was also more common in the generalized group (p = .021 and p = .01, respectively). The onset of the reaction was later in generalized cutaneous reactions (median 5.0 [1.0–10.0] vs. 3.0 [1.0–12.0], p = .007). Spontaneous resolution was more frequent in mild reactions (p = .045). In ROC analysis, the day of treatment on which the reaction occurred showed predictive value for generalized reactions (AUC: 0.625, 95% CI: 0.537–0.713, p = .007). A reaction onset at ≥3.5 days predicted generalized reactions with 63% sensitivity and 62% specificity. Logistic regression identified male gender (OR: 2.70, 95% CI: 1.31–5.56, p = .007), rhinitis/conjunctivitis (OR: 2.41, 95% CI: 1.02–5.71, p = .045), atopic dermatitis (OR: 2.55, 95% CI: 1.05–6.19, p = .038), and reaction occurring after >3.5 days of treatment (OR: 3.21, 95% CI: 1.57–6.49, p = .001) as significant risk factors for generalized reactions (Figure 2).

FIGURE 2.

Logistic regression analysis for predictors of generalized, non‐immediate drug hypersensitivity reactions in children.

DPT was performed with penicillins in 110 patients (68.3%), cephalosporins in 44 (27.3%), macrolides in 4 (2.5%) and NSAIDs in 3 (1.9%). Fifteen patients (9.3%) had a positive DPT. In the comparison of DPT positive and negative patients, those with mild maculopapular lesions were more likely to have a negative DPT result (p = .015). In univariate analysis, rhinitis/conjunctivitis and atopic dermatitis were associated with DPT positivity (p = .023 and p = .011), although these did not remain significant in multivariate analysis. Mild maculopapular rash was an independent predictive factor for DPT negativity (OR: 6.74, 95% CI: 1.83–24.83, p = .004).

At 6 months, follow‐up information was obtained from 125 patients. Eighty‐one patients (64.8%) required a medication from the same drug class; of these, 48 (59.2%) re‐used the drug. Among patients who avoided re‐exposure (n = 33), 13 (39.4%) refused to reuse themselves, 19 (57.6%) were withheld the drug by their parents, and 1 (3.0%) avoided re‐exposure due to non‐specific symptoms during the challenge test. These 33 patients (40.7%) constituted the “Drug‐avoidant group”.

The “Non‐avoidant group” included 48 patients who reused the drug: 32 (66.6%) used it directly, 14 (29.1%) used it together with antihistamines, and 2 (4.1%) developed a mild rash during reuse that resolved with antihistamines. At 12 months, 156 individuals were contacted, and 135 patients (86.5%) had taken the medication without any reaction.

In the low‐risk group, 27 (93.1%) patients had a negative DPT, and persistent drug avoidance was observed in 1 (3.7%). In the intermediate‐risk group, 114 (90.5%) out of 126 patients had a negative DPT, among whom 29 (25.4%) exhibited persistent drug avoidance. In the high‐risk group, 5 (83.3%) patients had a negative DPT, and 3 (60%) of them demonstrated persistent drug avoidance (Figure 1).

In logistic regression analysis, generalized urticaria during the index reaction was significantly associated with avoidance of re‐exposure (p = .022) as having received treatment for the initial reaction (p = .029). Having received treatment for the reaction remained a significant predictor for avoidance of re‐exposure in univariate analysis (OR 4.12, 95% CI 1.08–15.73; p = .038), and generalized urticaria remained significant in the multivariate model (OR 2.60, 95% CI 1.00–6.72; p = .048), (Figure 3).

FIGURE 3.

Logistic regression analysis for predictors of drug avoidance of re‐exposure at 6 months.

4. DISCUSSION

This retrospective cohort study of 161 children with suspected non‐immediate drug hypersensitivity reactions identified clinical predictors of generalized cutaneous reactions, characterized DPT outcomes, and documented persistent drug avoidance despite diagnostic clarification. Our main findings include: (1) male sex, atopic comorbidities, and history of a delayed onset of reaction (>3.5 days) independently predicted more extensive cutaneous reactions; (2) DPT confirmed hypersensitivity in only 9.3% of tested children, with mild maculopapular rash predicting negative outcomes; and (3) drug avoidance persisted in 40.7% of families at 6 months, associated with generalized urticaria and having received treatment for the index reaction. These findings may inform clinical risk stratification; however, the proposed time threshold should be interpreted as exploratory. While several pediatric studies reports no gender association for drug associated reactions, other studies have observed that reactions to certain medications, such as NSAIDs, may be more frequent in males, as also observed in our study. ¹⁴

The rate of positive DPT was low in our study, supporting the observation that most children labeled with non‐immediate drug hypersensitivity do not have a true drug allergy and can safely tolerate upon re‐exposure. This aligns with the previous pediatric studies reporting high tolerance rates after re‐challenge and highlights how frequently non‐immediate/delayed drug reactions are overdiagnosed in daily routine practice. ³ , ¹⁵ , ¹⁶

In our cohort, patients with atopic conditions tended to have more extensive non‐immediate drug eruptions. While the role of atopy in drug hypersensitivity remains uncertain and appears to differ across drug classes, our findings suggest that an atopic immune milieu may influence the clinical expression of these reactions. While atopy is a well‐established risk factor for immediate hypersensitivity, its role in non‐immediate reactions remains less clearly defined, particularly in pediatric populations. ¹⁴

Optimizing patient selection for DPT may reduce unnecessary testing, alleviate parental anxiety, while also facilitating earlier removal of incorrect drug allergy labels. A notable observation in our study was that mild maculopapular eruptions were independently associated with negative DPT outcomes. This suggests that limited cutaneous involvement may serve as a reassuring clinical marker when considering re‐exposure and could support more focused diagnostic approaches in selected low‐risk patients. Current literature emphasizes that most pediatric rashes occurring during antibiotic treatment are viral in origin and not reproducible with DPT. ¹⁷

Reactions occurring after more than 3.5 days of treatment were more frequently generalized rather than mild, highlighting the importance of treatment duration as a potential marker of reaction extent. This observation may reflect cumulative drug exposure or immune priming over time and has practical implications for risk stratification and follow‐up planning.

An important finding of this study is that 40.7% of families continued to avoid the culprit drug 6 months after evaluation. These findings highlight that removal of a drug allergy label does not automatically translate into behavioral acceptance of the medication, emphasizing that successful delabeling requires not only diagnostic confirmation but also effective communication and counseling of families. Drug avoidance was independently associated with more extensive urticaria at presentation and with having received treatment for the initial reaction in the current study. This suggests that visible extent of the reaction and the need for medical intervention may disproportionately shape parental risk perception, even when objective evidence does not support continued drug avoidance. Interestingly, medical interventions such as prescribing antihistamines or corticosteroids may themselves constitute a “frightening experience,” reinforcing perceptions of severity and contributing to persistent reluctance to reuse the drug despite confirmed tolerance. ¹⁸ At the 12‐month follow‐up, the high rate of drug reuse (86.5%) may suggest that interim follow‐up consultations and continued counseling may play a supportive role in facilitating safe re‐exposure. To our knowledge, this is one of the first pediatric studies to specifically evaluate parental drug avoidance persisting despite a negative DPT, and to identify clinical factors associated with this behavior. Successful de‐labeling programs must move beyond the “test and tell” model to include targeted psychological counseling for families in selected cases, particularly those whose children had visible, treated reactions like generalized urticaria.

Another important consideration is the duration of DPT. In the present study, all DPTs were performed using a single‐day protocol, without prolonged exposure over multiple days. Although single‐day DPT is widely used and considered safe, previous studies have suggested that extended provocation protocols (e.g., 3–5 days) may increase diagnostic sensitivity for non‐immediate reactions and improve patient and parental confidence in future drug reuse. For instance, Labrosse et al. demonstrated that a 5‐day amoxicillin challenge increased detection of delayed reactions and supported safe reintroduction of the drug in children. ¹⁹ The lack of prolonged DPT in our study may therefore have influenced both the detection of late reactions and the persistence of drug avoidance observed at 6–12 months.

This study has limitations, including its retrospective design, reliance on parental reporting during follow‐up, and performance in a single center, which may limit generalizability. Additionally, psychological factors underlying avoidance were not assessed using validated instruments. Nevertheless, the structured follow‐up and comprehensive evaluation of clinical, diagnostic, and behavioral outcomes represent key strengths. Reactions were defined as occurring >1 h after drug intake, representing a heterogeneous group of non‐immediate reactions rather than strictly T‐cell–mediated delayed hypersensitivity. This heterogeneity represents a limitation and may have influenced phenotype classification. In addition, reaction extent was categorized using adapted thresholds rather than validated drug hypersensitivity severity scales, introducing potential misclassification bias.

In conclusion, generalized non‐immediate cutaneous reactions in children are associated with identifiable clinical predictors, while true drug hypersensitivity confirmed by DPT remains uncommon. Drug avoidance persists in a substantial proportion of families and represents a critical target for intervention. Addressing both medical and behavioral dimensions of non‐immediate drug hypersensitivity is essential to improve de‐labeling efforts in pediatric practice.

AUTHOR CONTRIBUTIONS

Sophia Tsabouri: Conceptualization; investigation; writing – original draft; methodology; validation; visualization; writing – review and editing; formal analysis; supervision. Marios Papadopoulos: Conceptualization; writing – review and editing; supervision. Ozge Can Bostan: Conceptualization; writing – original draft; methodology; validation; visualization; writing – review and editing; formal analysis; investigation. Ozge Soyer: Conceptualization; methodology; validation; visualization; writing – review and editing; supervision.

FUNDING INFORMATION

No funding was obtained for the study.

CONFLICT OF INTEREST STATEMENT

None of the authors have a conflict of interest related to this manuscript.

Can Bostan O, Soyer O, Papadopoulos M, Tsabouri S. Clinical and behavioral determinants in pediatric non‐immediate drug hypersensitivity: Low confirmation but persistent avoidance. Pediatr Allergy Immunol. 2026;37:e70390. doi: 10.1111/pai.70390

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.