Drug Allergy in Children: Adverse Reactions after Skin Testing

Drug allergies are reported in almost 10% of children. Nonsteroidal anti-inflammatory drugs (NSAIDs) and β-lactam antibiotics are among the most common causative agents [1, 2]. A detailed history and physical examination are the initial steps in evaluation of drug allergies. The classification of drug hypersensitivity reactions is based on the morphological and chronological features of the reactions. Reactions that appear within the first 1 h after the last dose of the culprit drug is classified as “immediate type reactions,” while the hypersensitivity reactions occurring after the first 1 h are classified as “non-immediate type reactions” [3, 4]. Although immediate drug hypersensitivity reactions nearly occur always within the first hour, they can occasionally occur within first 6 h after the last dose of culprit drug [3, 4]. There may be overlaps regarding the durations.

In general, urticarial lesions and angioedema favor immediate-type reactions, while maculopapular rash favors delayed-type reactions. Detailed histories taken from patients can be confusing in the conclusive diagnosis of drug allergy, especially when a long time has been passed. Often, lesions could not be described precisely, unless images of the lesions were taken and, the time interval in between the drug intake and onset of the symptoms could be chaotic [5‒7].

Skin tests are practical, reliable, and generally well-tolerated tests used in the diagnosis of immunoglobulin (Ig) E mediated type-1 hypersensitivity reactions [8]. In evaluation of patients with suspected drug allergies, skin tests with the culprit drugs are among the diagnostic tools for a decision [6, 7, 9, 10]. Besides, a small number of drug-specific IgE measurement assays, skin tests with the drugs are standardized and validated for a limited number of drugs in today’s allergy practice [10, 11]. In addition to these limitations, irritant doses of some drugs pose a drawback to use drug skin test are as a decisive diagnostic tool for drug allergy diagnosis. Thus, as a final point drug provocation test is acknowledged as the “gold standard” test for a definite diagnosis of drug allergy in the absence of contraindications [10, 11]. Although severe adverse reactions after allergy skin testing are rare, there were few reported fatal reactions [12‒14]. Symptoms such as syncope/pre-syncope and those associated with anxiety may possibly appear more frequently, which necessitate differential diagnosis with hypersensitivity reactions [15].

Studies on the safety of drug skin tests are limited. Mostly pediatric and adult patients who underwent skin testing with a group of allergens (aeroallergens, foods, drugs) were evaluated together [16]. To the best of our knowledge, there is no large-scale study evaluating the adverse reactions observed in patients undergoing drug skin tests only in children. This study evaluated the adverse reactions that can be seen after skin testing in the clinics in patients undergoing skin tests for suspected drug allergies.

Children who were referred to Istanbul University, Istanbul Faculty of Medicine, Division of Pediatric Allergy and Immunology with suspected drug allergies between May 2017 and June 2022 were evaluated retrospectively. Demographic and clinical data of the patients were obtained according to European Network for Drug Allergy (ENDA) questionnaire [9]. Detailed history about the suspected drug allergy with the culprit drug, including the spectrum and time interval of the symptoms, in addition to presence of previous drug reactions and family history of drug allergy, concomitant chronic diseases, and atopic diseases were retrieved from the patients’ medical recordings. Patients who could not be tested for drug allergy due to uncontrolled asthma, suspicious of severe cutaneous drug allergy or parental disapproval were excluded from the study.

Drug skin tests were performed by the same experienced nurse, at the earliest 4 weeks after the suspected reaction. Prior to the tests, medications that could interfere with the results were discontinued as recommended [17]. A skin prick test (SPT) was performed at full-strength concentrations with the culprit drug. SPT was considered positive when the wheal diameter was at least 3 mm or larger than the negative control with surrounding erythema after 20 min. In case of a negative SPT, intradermal tests (IDTs) were performed on the volar forearm. After 20 min, the IDT was evaluated and considered positive if the mean diameter of the wheal increased by 3 mm or more with surrounding erythema. In patients with a suspected history of anaphylaxis, IDT was initiated at a concentration of 1:1,000 and reached its maximum non-irritant concentration in gradual increments (1:100 and 1:10, respectively). Skin test concentrations for the beta lactams and other drugs were used according to ENDA/EAACI position paper [5, 7]. Drug concentrations used for skin testing are given in Table 1.

The patients were observed for immediate reactions up to 2 h after skin testing. Histamine 10 mg/mL was used as the positive control and 0.9% NaCl was used as the negative control. In addition, in patients who described non-immediate type of reactions, skin test was reevaluated at the 72nd hour and on the 7th day of the procedure.

Data were analyzed using SPSS for Windows version 23.0 (IBM Corp, Armonk, NY, USA). Normal distribution of continuous variables was assessed using skewness and kurtosis with Kolmogorov-Smirnov test or Shapiro Wilks test. Continuous variables with non-normal distribution were expressed as median and interquartile range (IQR) and were compared using non-parametric tests (Mann-Whitney U test or Kruskal Wallis test). Categorical variables were compared using Pearson’s χ² test or Fisher’s exact test. A p value of <0.05 was considered significant.

A total of 1,073 children (488 [45.5%] girls and 585 [54.5%] boys) with a median age of 7.5 years (IQR 5–12 years) who underwent skin testing due to suspected drug allergies were evaluated. Atopic disease history was detected in 360 (33.6%) patients and chronic urticaria in 5 (0.5%) patients. Demographic and clinical characteristics of the patients are shown in Table 2.

Out of the total number of patients (n = 1,073), 53% (n = 567) reported an immediate reaction, while 47% (n = 506) reported a delayed reaction. The difference between the two groups was not statistically significant (p = 0.67). Median time between the last suspected reaction and drug skin test was 12 months (IQR: 6–24 months). Drug skin test was conducted with β-lactam antibiotics in 622 (58%), with non-β-lactam antibiotics in 169 (15.8%), with NSAIDs (mostly paracetamol and ibuprofen) in 214 (19.9%), with local anesthetic drugs in 41 (3.8%), with general anesthetic drugs in 7 (0.7%), and with other drugs in 17 (1.6%) of the patients (Table 3).

Adverse reactions were observed in 12 patients (1.1%) after the drug skin tests. Of these, allergic reactions were detected in 4 patients (0.4%), among which three were anaphylaxis and treated with intramuscular epinephrine and one was urticaria. The drugs responsible for two of the anaphylactic reactions were beta lactams (benzylpenicillin and ceftriaxone), and the third one was clarithromycin. The drug responsible for urticaria was a local anesthetic, prilocaine. Drug concentrations used in skin tests of the offending drugs that caused allergic reactions and their skin test results are given in Table 4. Symptoms such as pre-syncope or fear reaction were detected in 8 patients, all of which were incompatible with allergic reactions. There was no significant difference between the ages of patients with allergic and nonallergic reactions (median ages 12.2 [13.7–15.5] and 14.7 [12.5–17] years, respectively, p = 0.570).

In statistical analysis, no significant correlation was found between the occurrence of adverse reactions and the onset of the reaction (within 1 h), clinical type of the reaction (r = 0.36, p = 0.241), presence of anaphylaxis (r = 0.008, p = 0.799), family history of drug allergy (r = −0.031, p = 0.303), and personal history of atopy (r = −0.38, p = 0.213). There was a positive correlation between adverse reactions and age (r = 0.12, p ≤ 0.001), and a negative correlation between adverse reactions and male gender (r = −0.081, p = 0.008). In addition, adverse reactions were not correlated either with serum total Ig E levels (r = −0.008 p = 0.799) or with percentage of serum eosinophilia (r = −0.008 p = 0.799).

Patient 1: A 12.5-year-old female patient presented with urticaria, angioedema, and shortness of breath within 10–15 min after intravenous ceftriaxone and paracetamol 6 months ago. Generalized urticaria, angioedema, and respiratory distress developed within 5 min after the ceftriaxone skin prick test at undiluted, full concentration (100 mg/mL). The test was stopped, and intramuscular epinephrine was administered immediately; nebulized beta-2 agonists and intravenous steroid were given at the same time. Reaction totally resolved within minutes; the patient was observed for 6 h, uneventfully.

Patient 2: A 16-year-old female patient presented with urticaria and angioedema within 1 h after using oral amoxicillin-clavulanic acid 1 year ago. Her complaints had regressed within 2 h after using oral antihistamine (cetirizine dihydrochloride). In the first step, the patient underwent skin prick test and intradermal test with penicillin G, respectively. Since these tests were negative, in the second step, the patient underwent skin prick test at full concentration and intradermal test with ampicillin (1/1,000, 1/100, and 1/10 dilution), respectively. About 30 min after the intradermal test (at 1/10 dilution, 2 mg/mL), the patient developed runny nose, sneezing, shortness of breath, and urticarial rash. Intramuscular epinephrine was administered immediately; intravenous antihistamine and steroid were given. Reaction totally resolved within minutes; the patient was observed for 6 h, uneventfully.

Patient 3: A 16-year-old girl presented with urticaria and angioedema within 20 min after taking oral clarithromycin 4 months ago. Her complaints had regressed within 1 h after using oral antihistamine (cetirizine dihydrochloride). In the first step, the patient underwent skin prick test with clarithromycin at full concentration (50 mg/mL). As skin prick test was negative intradermal test (1:100 dilution) was performed. The patient developed urticarial rash, abdominal pain, and vomiting in approximately 30 min after the procedure. Intramuscular epinephrine was administered, and also systemic steroid was given to the patient.

Patient 4: A 13-year-old male patient presented with urticaria within 20 min after a local anesthetic administration during a dental procedure, 6 months ago. He had been treated with an oral antihistamine. The patient underwent skin prick test with prilocaine at full concentration (20 mg/mL) and developed generalized urticarial 15 min after the test. The test stopped, intravenous antihistamine was administered and observed for 2 h. Clinical findings of the patients with adverse allergic reactions are presented in Table 5.

In this study, we evaluated the adverse reactions observed in the course of drug skin testing in the clinic in children with suspected drug hypersensitivity. Our results indicated that drug skin tests in children were generally well-tolerated, and allergic reactions were remarkably rare. Furthermore, we did not find any association between patient-reported history of immediate reactions with the culprit drug, including anaphylaxis and adverse reactions in skin testing.

Drug skin tests are one of the most widely used diagnostic tools to demonstrate IgE-mediated sensitization. In drug skin testing, SPT should be done in the first step; if the result is negative, then IDT should be performed. Reported allergic reactions for SPT with common allergens such as aeroallergens and food allergens ranged from 0.02% to 0.4% [18‒20]. In a prospective study including 31,000 SPTs with aeroallergens, foods, venoms, and drugs, the rate of systemic reactions was reported as 0.08%, most of which were related to food allergens, but one severe case of anaphylaxis was related SPT with drug (piperacillin tazobactam) SPT [16]. In our study, the overall reaction rate in patients who underwent skin tests with drugs was found to be 1.1%, and the allergic reaction rate was 0.4%. These rates are higher than those reported in previous studies, which could be explained in several ways. First, most of the reactions reported in previous studies were performed with foods and aeroallergens, not with drugs. Second, IDTs with aeroallergens are not currently performed due to their additional little diagnostic value and not being as practical and well-tolerated as SPTs [21].

Skin prick test is often more reliable and provides a lower adverse reaction rate when compared to IDT [22, 23]. In a previous study performed in 1,456 patients, the incidence of systemic reactions to SPTs and IDTs was found to be 3.6% (0.4% for SPT and 3.2% for IDT) [19]. These high rates could be attributed to the fact that the tests were performed in only adult patients with a wide variety of allergens including food allergens, aeroallergens, drugs, and venoms.

In our study, there were only 2 adverse reactions to SPTs, 10 reactions occurred during IDT. Most of the reactions were nonallergic. In our clinic, after a negative SPT, IDTs were performed in incremental concentrations at least in two steps as 1:100 dilution and 1:10 dilution, if applicable. The increased number of interventions may have increased the likelihood of symptoms related to fear of injections and anxiety. In a large-scale study conducted in 5,063 patients with suspected penicillin allergy, the rate of adverse reactions to IDTs (with major and minor determinants) was found to be 0.2%. No severe reaction was reported that supports the safety of intradermal drug skin tests [24].

Although it is well known that a history of drug allergy is an unreliable marker for establishing the diagnosis, previous data have shown that having a positive history of drug anaphylaxis may possibly increase the rate of reactions during skin testing. Additionally, rare fatal reactions have also been reported in patients undergoing drug skin tests [13, 22, 25]. On the other hand, in a study covering a period of 5 years with 497,656 skin tests performed in adults, 6 systemic mild reactions were reported that fully recovered within 1 h, which supported that skin tests are relatively safe procedures. Overall, the rate of systemic reactions for skin tests was reported as 33 reactions per 100,000. Systemic reaction rate for penicillin and antibiotic skin tests (SPT and IDT) was reported as 72 reactions per 100,000, which was markedly higher than seen during SPTs with aeroallergens (30 reactions per 100) [26].

The most important limitation of our study is its retrospective design. Another limitation is the low number of patients with adverse reactions after the drug skin tests. Therefore, our findings will not reflect the general population. The strength of our study was that the drug skin tests were applied to a large group of pediatric patients and the tests were performed by experienced healthcare professionals in the same tertiary center. It should be highlighted that despite safety and well-toleration of drug skin tests, due to rare severe reaction risk, these tests should be performed by experienced staff in allergy centers that are well-equipped to recognize and deal with emergency situation.

Written informed consent from the participants’ parents/legal guardian/next of kin to participate in the study and for publication of the details of their medical case and any accompanying images for all participants aged under 18 years was obtained. The study protocol was approved by the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (No: 2022/1497). The study was performed according to the Declaration of Helsinki.

The authors have no conflict of interest in relation with this publication.

There is no funding.

Cagla Karavaizoglu conceptualization (lead), writing original draft (lead), formal analysis (lead), and writing review and editing (equal); Ayse Suleyman conceptualization (supporting), writing original draft (supporting), formal analysis (lead), and writing – review and editing (equal); Roza Yavuz, Kazım Okan Dolu, Esra Yucel, Zeynep Hızlı Demirkale, and Sevgi Sipahi Cimen conceptualization (supporting), writing original draft (supporting), and writing review and editing (equal); Cevdet Ozdemir drafted and revised the manuscript; Zeynep Ulker Tamay: conceptualization (equal), writing – original draft (equal), and writing – review and editing (equal).