Direct oral challenge for immediate and non-immediate beta-lactam allergy in children: A real-world multicenter study.

BACKGROUND: Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs. METHODS: Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT. RESULTS: The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%. CONCLUSIONS: Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care.

Single-dose prolonged drug provocation test, without previous skin testing, is safe for diagnosing children with mild non-immediate reactions to beta-lactams.

INTRODUCTION: Mild non-immediate reactions (NIRs) to beta-lactams (BLs) are the most frequent manifestation of drug allergy in children. The diagnostic approach is complex as the utility of skin tests (STs) and lymphocyte transformation tests (LTTs) is controversial. Drug provocation test (DPT) is the gold standard, although no standardized protocols exist. We aimed to investigate the utility of DPT in a unique dose without previous STs, and LTTs in the diagnosis of NIRs to BLs in children. METHODS: We prospectively evaluated children 0-14 years old referred to the Regional University Hospital of Málaga during 2017-2020 reporting NIRs to BLs. We performed a DPT with a unique dose followed by regular treatment at home. If positive, STs and LTTs were done after the reaction had disappeared. RESULTS: We included 194 children, having 24 (12.4%) a positive DPT. The main culprit was AX (70.1%) followed by AX-clavulanic acid (CLV) (26.8%) and the main symptoms maculopapular exanthema (MPE) (49.5%) and delayed-urticaria (48.5%). A decrease (p = 0.013) in the interval of days between drug administration and onset of symptoms was observed in positive DPT compared with the original reaction (3.5 vs 6 days), with no differences in the overall percentage of MPE and delayed-appearing urticaria (p = 0.551). No severe reactions occurred during DPT. Moreover, STs were positive in 13.33% and LTTs in 52.9%. CONCLUSIONS: Single-dose DPT without previous STs is a safe and useful way to assess NIRs to BLs in children. LTT has shown to be useful, confirming a T-cell mechanism involved in these reactions.

Systematic evaluation of allergic phenotypes of rhinitis in children and adolescents.

BACKGROUND: Three allergic phenotypes of rhinitis have been described in adults: allergic rhinitis (AR), local allergic rhinitis (LAR), and dual allergic rhinitis (DAR, coexistence of AR and LAR). Nevertheless, most centers follow a diagnostic approach only based on skin prick test and serum allergen-specific IgE (collectively called atopy tests, AT). This approach prevents the recognition of LAR and DAR, the diagnosis of which requires a nasal allergen challenge (NAC). Here, we investigate the existence of LAR and DAR phenotypes in children and adolescents, and the misdiagnosis rate associated with a work-up exclusively based on AT. METHODS: Clinical data were obtained during physician-conducted interviews, and AT and NAC were systematically performed in 5- to 18-year-old patients with chronic rhinitis. The misdiagnosis rate was defined as the proportion of cases where AT and NAC results were discordant. RESULTS: A total of 173 patients (mean age 15.1 years, 39.9% male) completed the study. AR (positive AT and NAC), LAR (negative AT and positive NAC), DAR (positive AT and NAC for some allergens and negative AT and positive NAC for other allergens), and non-allergic rhinitis (negative NAC) were diagnosed in 45.7%, 24.9%, 11.6%, and 17.9% of individuals, respectively. The clinical profile was comparable among allergic phenotypes, but allergic patients had a significantly earlier rhinitis onset, higher conjunctivitis prevalence, and more severe disease than NAR individuals. A diagnostic work-up exclusively based on AT misclassified 37.6% of patients. CONCLUSIONS: LAR and DAR represent relevant differential diagnosis in pediatric rhinitis. NAC increases the diagnostic accuracy of clinical algorithms for rhinitis in children and adolescents.

Egg OIT in clinical practice (SEICAP II): Maintenance patterns and desensitization state after normalizing the diet.

BACKGROUND: It is unknown which are the most suitable maintenance pattern and egg consumption to maintain the desensitization state after ending the oral immunotherapy (OIT). This multicenter, randomized, controlled trial compared two OIT maintenance patterns with pasteurized egg white (PEW), evaluating the egg consumption effect on the desensitization state after ending the OIT. METHODS: One hundred and one children with confirmed egg allergy were randomized: 25 to an egg-free diet (CG) and 76 to an OIT year with PEW and two maintenance patterns, 38 patients to daily 3.3 g proteins (AG) and 38 to every two days (BG). PEW challenge (DBPCFC), adverse reactions, and immune markers were assessed at baseline, at the end of the OIT, and at 6 and 12 months later on ad libitum egg consumption (T0, T12, T18, and T24). A questionnaire evaluated the egg consumption at T18. RESULTS: At T12, 64 of 76 (84.21%) OIT patients had reached total desensitization (32 AG and 32 BG) vs 4 of 25 (16.00%) CG who passed the PEW DBPCFC. Thirty (93.75%) AG vs 25 (78.12%) BG patients completed an OIT year. At T18, 27 of 29 (93.1%) AG vs 20 of 24 (83.3%) BG passed the PEW DBPCFC, 96% consuming at least two egg servings/week. At T24, 97.43% OIT patients passed the challenge. Most patients had adverse reactions, more frequent in the BG patients; frequency and severity of reactions decreased through the study. PEW skin prick test wheal and sIgE antibody serum levels similarly decreased in AG or BG, but AG patients had greater increase in PEW sIgG4 (P < 0.05). CONCLUSIONS: Daily OIT maintenance achieves better adherence, effectiveness, and safety. Two egg servings/week ensure maintained desensitization after the end of an OIT year.

Prospective assessment of diagnostic tests for pediatric penicillin allergy: From clinical history to challenge tests.

BACKGROUND: Diagnostic guidelines for penicillin allergy in children recommend cumbersome protocols based partially on data from adults, which may be suboptimal for pediatric use. OBJECTIVE: To assess the accuracy of tools for diagnosis of penicillin allergy in children. METHODS: A prospective, multicenter study was conducted in children with reported adverse events related to penicillin, excluding severe reactions. All patients underwent a uniform diagnostic protocol that consisted of clinical history, skin tests, serum specific IgE (sIgE), and, regardless of these results, drug provocation tests (DPTs). RESULTS: A total of 732 children (mean age, 5.5 years; 51.2% males) completed the allergy workup, including DPTs. Amoxicillin triggered 96.9% of all reactions. None of the patients with an immediate index reaction (IR) developed a reaction on DPT. Penicillin allergy was confirmed in 35 children (4.8%): 6 immediate reactions (17%) and 29 nonimmediate reactions (83%) on the DPT. No severe reactions were recorded. The allergist diagnosis based on the clinical history was not associated with the DPT final outcome. In 30 of 33 allergic patients (91%), the results of all skin tests and sIgE tests were negative. A logistic regression model identified the following to be associated with penicillin allergy: a family history of drug allergy (odds ratio [OR], 3.03; 95% confidence interval [CI], 1.33-6.89; P = .008), an IR lasting more than 3 days vs 24 hours or less (OR, 8.96; 95% CI, 2.01-39.86; P = .004), and an IR treated with corticosteroids (OR, 2.68; 95% CI, 1.30-5.54; P = .007). CONCLUSION: Conventional predictors of allergy to penicillin performed weakly. The authors propose straightforward penicillin provocation testing in controlled, experienced centers for the diagnosis of nonsevere penicillin allergy in children.

Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children.

INTRODUCTION: Hypersensitivity reactions to beta-lactams (BLs) are often reported in children, with amoxicillin and, to a lesser extent, cephalosporins being the most frequent drugs involved. Although many of these children are considered to be allergic, a careful evaluation only confirms a low percentage. OBJECTIVES: To analyse the clinical data, sensitization profile and diagnostic methods used in a large group of children with a clinical history of hypersensitivity reactions to BLs. METHODS: The study included children aged 1-14 yr with symptoms suggestive of hypersensitivity to BLs from January 2006-December 2012. Diagnosis was confirmed from a clinical history, specific IgE determination, skin testing and, if necessary, a drug provocation test (DPT). RESULTS: Of a total of 783 patients studied, only 62 (7.92%) were confirmed as being allergic, 9 (14.52%) with immediate and 53 (85.48%) with non-immediate reactions. In those with immediate reactions, 2 (22.22%) were diagnosed by in vitro test, 2 (22.22%) by skin testing and 5 (55.56%) by DPT; in those with non-immediate reactions, 2 (3.77%) were diagnosed by skin testing and 51 (96.23%) by DPT. In all cases, DPT was positive to the culprit drug (29 AX-CLV, 26 AX, 1 cefixime and 1 cefaclor), and the most usual symptoms were exanthema in 43 cases, urticaria in 12, urticaria-angio-oedema in 1 and erythema in 1 case. CONCLUSION: After an allergological work-up, over 90% of the children evaluated were finally confirmed as tolerant to BLs. Most reactions were of the non-immediate type, and DPT was an essential tool for diagnosis.

Drug provocation tests in the diagnosis of hypersensitivity reactions to non-steroidal anti-inflammatory drugs in children.

INTRODUCTION: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently reported reaction to drugs. They can be induced by pharmacological mechanisms (cyclooxygenase inhibition), with patients classified as cross-intolerant (CI), or by specific immunological mechanisms, IgE or T cell, with patients classified as selective reactors (SR). OBJECTIVE: To analyse a large group of children with a history of NSAID hypersensitivity diagnosed by drug provocation test (DPT). METHODS: A group of 63 children with a history of NSAID hypersensitivity were evaluated by DPT. The children were classified as CI or SR depending on the acetyl salicylic acid (ASA) response in DPT. The atopic status was also assessed by prick tests and total IgE in serum. RESULTS: Using DPT, 68.2% were confirmed as having hypersensitivity, 58.1% classified as CI and 41.9% as SR. Of the 119 DPT performed, 73 were positive (53.4% to ibuprofen, 37% to ASA, 8.2% to metamizol and 14% to paracetamol); angio-oedema was present in 86.3% of cases. All CI cases tolerated the administration of paracetamol. A significant number of the CI children were atopic compared with the SR children and non-allergic controls. CONCLUSION: In these children, CI hypersensitivity to NSAIDs was the most frequent type of hypersensitivity reaction. Ibuprofen was the drug most often involved, angio-oedema the most common entity, and frequently associated with atopy. DPT proved a safe approach for diagnosing these patients.