Oral challenge without skin tests in children with non-severe beta-lactam hypersensitivity: Time to change the paradigm?

Suspected allergy to penicillins and cephalosporins is very common in childhood. After a proper evaluation, allergy will be confirmed only in a small portion of them. Intradermal tests are usually part of the allergy workup, but they are painful for children and time-consuming, and their role has been debated. A systematic review found only two studies reporting a positive predictive value of skin tests in children of 36% and 33%, respectively, leading to a high rate of inaccurate diagnosis. Moreover, considering that skin tests are negative in more than 90%-95% of cases, an oral provocation test (OPT) is finally needed to confirm tolerance in most of these children. Positive OPT are rare, and even where children demonstrate reproducible signs on challenge, they rarely constitute immediate or serious symptoms. Therefore, OPT to the index antibiotic without skin tests are increasingly being considered an accepted procedure for children with a suspected mild non-immediate reaction related to a beta-lactam antibiotic. Furthermore, a recent research has taken the same approach including children with suspected mild immediate reactions, with similar safety and positive results. In light of recent evidence highlighted, it is now the time for large and multicentric studies to confirm that OPT with the index antibiotic, without skin tests, are safe and convenient for children with a history of a mild reaction with a beta-lactam antibiotic before it can be recommended in pediatric allergy guidelines.

Beta-lactam hypersensitivity in children with cystic fibrosis: a study in a specialized pediatric center for cystic fibrosis and drug allergy.

BACKGROUND: Beta-lactam hypersensitivity (HS) is suspected in 5-12% of the children, but proven in only 10-15% of those children, based on skin and challenge tests results. In contrast, 30-60% of patients with cystic fibrosis (CF) are diagnosed allergic to beta-lactams, based mainly on the clinical history of the patients. OBJECTIVES: To confirm or rule out a suspected beta-lactam HS in CF children and to determine the prevalences of suspected and confirmed beta-lactam HS in those children. PATIENTS AND METHODS: Children with CF and suspected beta-lactam HS were explored by means of skin and challenge tests with the suspected and alternate beta-lactams. The results in CF children were compared with those reported in the literature in non- CF children. RESULTS: Eight of the 701 CF children followed in our center between 1990 and 2011 (1.14%), and 11 other children from other centers were explored for suspected beta-lactam HS. Beta-lactam HS was diagnosed in nine of these children (47.3%). Based on the results in the children followed in our center, the prevalence of beta-lactam HS was 0.71% (5/701) in CF children vs. a mean estimated prevalence of 1-1.5% in the general pediatric population. CONCLUSION: Our results contrast with those of most previous studies. Although half of the CF children with suspected beta-lactam HS were truly allergic to beta-lactams, the general prevalence of beta-lactam HS in CF children was very low. This may result from tolerance induced by frequent and/or prolonged treatments with beta-lactams.

Is a Prolonged Drug Provocation Test Better Than a Single-Day Drug Provocation Test? A Systematic Review and Meta-Analysis.

BACKGROUND: There is currently no standardized duration of drug provocation test (DPT) for confirming/delabeling beta-lactam hypersensitivity reaction (BL-HSR). OBJECTIVES: This meta-analysis and systematic review aimed to investigate the added diagnostic value of extended-day over single-day DPT for confirming/delabeling BL-HSR in adults and children. METHODS: The MEDLINE, EMBASE, Web of Science, and CINAHL online databases were searched from inception to March 15, 2023, for studies that performed extended-day DPT to confirm/delabel BL-HSR. Risk difference and risk ratio were used to compare the proportions of patients with confirmed BL-HSR by single-day or extended-day DPT. RESULTS: A total of 10,371 DPTs from 42 studies were included. Extended-day DPTs ranged from 2 to 7 days, or as long as index reactions were reported (maximum 10 days). The overall prevalence of confirmed BL-HSR was 6.96% (3.31% during the first-day DPT, and 3.65% during extended-day DPT). Approximately half of the positive reactions during extended-day DPT occurred during the second/third day. The increased detected pool prevalence of confirmed BL-HSR yielded by extended-day DPT was 0.03 (95% CI, 0.02%-0.04%; I2 = 57.69%; P < .001), and the risk ratio of positive reactions between extended-day and single-day DPT was 1.94 (95% CI, 1.62-2.33; I2 = 36.26%; P < .001). The risk difference increased per 1% increase in prevalence of BL-HSR by 0.6% (95% CI, 0.4%-0.7%; P < .001). Twenty-three severe reactions occurred during DPT, and only 2 severe reactions (0.02%) occurred during extended-day DPT. An additional 28 extended-day DPTs were needed to identify 1 mild reaction. CONCLUSIONS: The increased prevalence of confirmed BL-HSR observed during extended-day DPT could be attributed to the first-day DPT. As a result, our findings do not conclusively support the use of extended-day DPT over single-day DPT. Further studies, incorporating a washout period, are required to comprehensively compare these 2 approaches.

The Safety of the Direct Drug Provocation Test in Beta-Lactam Hypersensitivity in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Direct drug provocation test (DPT) without prior skin testing (ST) has been investigated in children suspected of being at risk for beta-lactam (BL) hypersensitivity reaction (HSR). However, no systematic review and meta-analysis has investigated the efficacy and safety of direct DPT for BL-HSR in children. OBJECTIVE: To investigate the prevalence of BL-HSR by direct DPT and the safety of direct DPT in children. METHODS: We searched MEDLINE, EMBASE, Web of Science, and CINAHL from their inception to July 23, 2022, for studies that performed direct DPT in children with suspected BL-HSR, or for studies that performed DPT in all cases with ST results, but they ignored the ST results. The true prevalence was defined as the proportion of children who experienced an HSR during direct DPT. Safety was determined according to the proportion of children who developed a dangerous reaction following DPT. RESULTS: Twenty-eight studies with 8,334 direct challenges were included. Fifteen studies included patients who presented with either immediate or nonimmediate HSR, and the majority of the index reactions were nonsevere. Amoxicillin/amoxicillin-clavulanic acid was the most commonly used during the DPT. The pooled prevalence of confirmed BL-HSR was 5.23% (95% CI 4.17-6.39; I2 = 72%). Immediate and nonimmediate HSR were reported in 0.8% (95% CI 0.43-1.25; I2 = 55.1%) and 3.69% (95% CI 2.66-4.87; I2 = 79.77%), respectively. Severe reactions were found in 3 cases with the frequency of 0.036% (95% CI 0.012-0.112; I2 = 0%). CONCLUSIONS: The prevalence of BL-HSR by direct DPT was 5.23%, and the frequency of severe reactions from direct DPT was very low (0.036%). Our findings support direct DPT as a safe and effective delabeling tool in children with suspected nonsevere BL-HSR.