The use of direct oral challenge to confirm allergies to penicillin class antibiotics in Danish children

Only a small minority of children with suspected IgE-mediated allergy to penicillin is confirmed to be hypersensitive in direct oral challenge, which is the current reference standard. This study investigates the historical use of direct oral challenges at three specialist pediatric departments in Denmark. We speculated that most of the children referred with allergy to penicillin would show not to be.

Many children are referred to pediatric departments with a suspected allergic reaction to antibiotics. The prevalence of true allergy is considered to be significantly lower than indicated from the clinical history and symptoms alone. Among children, allergic reactions have been reported with an incidence as high as 10% of all prescriptions for antibiotics [1, 2]. However, drug-related side effects or disease-related symptoms are often mistaken for being an allergic reaction to antibiotics [3]. Examples of this are low risk symptoms, such as rashes or itching, which are rarely related to allergic reactions [4]. A large study from 2016 at the allergy clinic of the Montreal Children’s Hospital showed that among 818 patients suspected for amoxicillin allergy, only 5.8% tested positive in a graded drug challenge (DC) [5].

Penicillin is among the most commonly used antibiotics in children and thus often suspected to lead to allergic reactions in children [6]. These mistaken suspicions and often not validated diagnosis of allergy to penicillin increase the risk of doctors prescribing broad-spectrum antibiotics, which could potentially lead to a higher risk of antibiotic resistance. The American Academy of Allergy, Asthma and Immunology (AAAI) and European Network for Drug Allergy (ENDA)/ European Academy of Allergy and Clinical Immunology (EAACI) have recommend that investigation of suspected IgE-mediated penicillin allergy includes skin testing followed by an oral challenge with a therapeutic dose in skin test-negative individuals [7]. The usefulness of in vitro tests as commercial anti-penicillin IgE flurometric enzyme immunoassay is questionable [8]. This study investigated potential predictive symptoms and findings and discussed the diagnostics process in allergy to penicillin among children.

This is a retrospective medical record review with no prospective interventional component. According to The Central Denmark Region Committee on Health Research Ethics, no formal ethics approval was required for this study. The study subjects were children followed in outpatient clinics at three Danish hospitals in Central Denmark Region, with a history of alleged allergy to a penicillin class antibiotic within the period from December 2007 to October 2011. In total, 141 children (69 boys and 72 girls) with an average age of 4.2 years (range, 0.33–15.3) were included. The local guideline was a graded two-step direct oral challenge/drug challenge (DC), with two total hours of observation to confirm antibiotic allergy or current tolerance, along with completion of a standardized ENDA drug allergy questionnaire. There was variable use of skin prick testing (SPT) (only in a subgroup (n = 52)), in vitro anti-penicillin and anti-cephalosporin specific IgE testing (n = 141), and measurements of total IgE level (104 individuals). The setup with SPT, DC and in vitro measurements of anti-penicillin and anti-cephalosporin specific IgE was in accordance with the European Network for Drug Allergy (ENDA) guidelines [9‐11]. Specific IgE testing was done for penicillin G and V, amoxicillin, ampicillin, cefuroxime, ceftriaxone, cefamandole, cefotaxime, ceftazidime and penicillin minor determinant in all patients using ImmunoCAP Specific IgE 0–100 (Phadia APS, Allerød, Denmark) and a value > 0.35 kUA/L was considered positive. Total IgE was measured at the same time in 104 of the patients (74%) using ImmunoCAP Total IgE (Phadia APS, Allerød, Denmark). A standardized questionnaire (ENDA) for drug allergy was completed at the beginning of the investigation [12].

SPT was performed in 52 (37%) of the children, primarily at one of the study hospitals (98%). SPT with benzylpenicillin, ampicillin and amoxicillin (1.25 mg/ml) was performed together with SPT with the culprit drug according to the patient history; histamine 10 mg/ml (ALKAbello, Nordic, Hoersholm, Denmark) and isotonic sodium chloride were used as controls. SPT was used on the volar forearm and read after 20 min. If the increase of the largest diameter of the rash was > 3 mm, the test was considered positive.

The DC was performed as a graded oral challenge in all patients, including patients with positive SPT and/or positive specific IgE. Both a doctor and nurse were present all the time and the DC was performed following local anaphylaxis preparedness guidelines. The first dose was administered as one tenth of a normal treatment dose of penicillin/antibiotics (normal treatment dose: Amoxicillin, Penicillin V, Dicloxacillin and Amoxicillin + clavulanic acid = 16.7 mg/kg; Ampicillin = 25 mg/kg). If no reaction was seen, a second full dose was administered 60 min after the first dose. The patients were observed for 2 h before leaving the hospital. Afterwards, the parents observed the child at home for 7 days and reported by telephone if late onset symptoms requiring evaluation occurred. At another study hospital, Amoxicillin was used in the DC. If the DC was positive, a new test with the culprit drug was performed. At the other two study hospitals, the culprit drug was used from the beginning. In both scenarios the oral challenge was stopped if a clinical reaction occurred.

Hypothesis testing for continuous variables was done using the t test. Nominal statistical significance was set at a p-value < 0.05. All statistical analyses were performed using Sigmaplot 11.0, Systat Software.

We concluded that allergy to penicillin in children is rare and probably overestimated. Only 2.8% of the patients referred due to suspected allergy in our study had a positive DC.

In children reacting to antibiotics with a simple rash (itching or not) alone, our study indicates that the rash is most likely not related to allergy; antibiotic treatment should thus be continued.

In diagnosing allergy, measuring specific IgE provided no useful information in our study. We suggest that all patients should undergo a three- to seven-day DC to increase the sensitivity of the diagnosis of non-IgE β-lactam allergy.