Introduction: Beta-lactam (BL) antibiotics are the most often involved drugs in allergic reactions. Mild cutaneous reactions such as maculopapular exanthema or urticaria are the most common presenting complaints of BL allergy in the pediatric population. However, it can be challenging to distinguish BL-induced allergy from reactions due to infections or other reasons. In this study, we aimed to determine the clinical characteristics and potential risk factors of true BL allergy in children with suspected mild cutaneous reactions to BLs. Methods: We evaluated children who were admitted to our pediatric allergy clinic with suspected BL allergy in between January 2015 and March 2020. Patients with a history suggestive of immediate and non-immediate mild cutaneous reactions were included in the study. The oral challenge test (OCT) with the culprit drug was performed on all patients to confirm the diagnosis. Results: Two hundred fourteen (119 male and 95 female) patients with a median age of 4.9 years were evaluated. BL allergy was confirmed in 10.7% (23) of the patients, according to the OCT results. Most of the proven allergic reactions were of the immediate type (73.9%), and urticaria was the most common presenting complaint (60.8%) in proven BL-allergic patients. The negative predictive value of penicillin-G skin testing was 89.7% for immediate-type penicillin allergy and 93.4% for non-immediate reactions. Also, positive predictive value of penicillin-G skin testing was 50% for immediate and 25% for non-immediate reactions. In the multivariate logistic regression analysis, a history of proven drug allergy (Exp (B): 7.76, 95% CI: 1.88–31.97, p = 0.005) was found to be the risk for BL allergy. Conclusion: This study highlighted that OCTs should be performed to confirm the diagnosis in patients suspected of immediate and non-immediate mild cutaneous reactions to BLs and remove the overestimated “BL allergy” label. In these patients, a history of proven drug allergy might be a risk factor for true BL allergy.

1.
Azevedo J, Gaspar Â, Mota I, Benito-Garcia F, Alves-Correia M, Chambel M, et al. Anaphylaxis to beta-lactam antibiotics at pediatric age: six-year survey. Allergol Immunopathol. 2019;47(2):128–32.
2.
Abrams EM, Atkinson AR, Wong T, Ben-Shoshan M. The importance of delabeling β-lactam allergy in children. J Pediatr. 2019;204:291–7.e1.
3.
Gomes ER, Brockow K, Kuyucu S, Saretta F, Mori F, Blanca-Lopez N, et al. Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group. Allergy. 2016;71(2):149–61.
4.
Graham F, Tsabouri S, Caubet JC. Hypersensitivity reactions to beta-lactams in children. Curr Opin Allergy Clin Immunol. 2018;18(4):284–90.
5.
Lucas M, Arnold A, Sommerfield A, Trevenen M, Braconnier L, Schilling A, et al. Antibiotic allergy labels in children are associated with adverse clinical outcomes. J Allergy Clin Immunol Pract. 2019;7(3):975–82.
6.
Blanca-Lopez N, Atanaskovic-Markovic M, Gomes ER, Kidon M, Kuyucu S, Mori F, et al. An EAACI Task Force report on allergy to beta-lactams in children: clinical entities and diagnostic procedures. Pediatr Allergy Immunol. 2021;32(7):1426–36.
7.
Brockow K, Ardern-Jones MR, Mockenhaupt M, Aberer W, Barbaud A, Caubet JC, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy. 2019;74(1):14–27.
8.
Calamelli E, Caffarelli C, Franceschini F, Saretta F, Cardinale F, Bernardini R, et al. A practical management of children with antibiotic allergy. Acta Biomed. 2019;90(3–S):11–9.
9.
Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, et al. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol. 2011;22(4):411–8.
10.
Zambonino MA, Corzo JL, Munoz C, Requena G, Ariza A, Mayorga C, et al. Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children. Pediatr Allergy Immunol. 2014;25(1):80–7.
11.
Mill C, Primeau MN, Medoff E, Lejtenyi C, O’Keefe A, Netchiporouk E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr. 2016 Jun 6;170(6):e160033.
12.
Eser Simsek I, Tuba Cogurlu M, Aydogan M. Suspected reaction with cephalosporin may be a predictive factor for β -lactam allergy in children. Int Arch Allergy Immunol. 2019;178(3):248–54.
13.
Norton AE, Konvinse K, Phillips EJ, Broyles AD. Antibiotic allergy in pediatrics. Pediatrics. 2018;141(5):e20172497.
14.
Blumenthal KG, Li Y, Banerji A, Yun BJ, Long AA, Walensky RP. The cost of penicillin allergy evaluation. J Allergy Clin Immunol Pract. 2018;6(3):1019–27.e2.
15.
Wu JHC, Langford BJ, Schwartz KL, Zvonar R, Raybardhan S, Leung V, et al. Potential negative effects of antimicrobial allergy labelling on patient care: a systematic review. Can J Hosp Pharm. 2018;71(1):29–35.
16.
Doña I, Romano A, Torres MJ. Algorithm for betalactam allergy diagnosis. Allergy. 2019;74(9):1817–9.
17.
Jeimy S, Ben-Shoshan M, Abrams EM, Ellis AK, Connors L, Wong T. Practical guide for evaluation and management of beta-lactam allergy: position statement from the Canadian Society of Allergy and Clinical Immunology. Allergy Asthma Clin Immunol. 2020 Nov 10;16(1):95.
18.
Moral L, Caubet JC. Oral challenge without skin tests in children with non-severe beta-lactam hypersensitivity: time to change the paradigm? Pediatr Allergy Immunol. 2017 Dec;28(8):724–7.
19.
Mustafa SS, Conn K, Ramsey A. Comparing direct challenge to penicillin skin testing for the outpatient evaluation of penicillin allergy: a randomized controlled trial. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2163–70.
20.
Felix MMR, Kuschnir FC. Direct oral provocation test is safe and effective in diagnosing beta-lactam allergy in low-risk children with mild cutaneous reactions. Front Pharmacol. 2020 Aug 7;11:1223.
21.
Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. Allergy. 1999;54(9):999–1003.
22.
Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food challenges. J Allergy Clin Immunol. 2004;114(5):1164–8.
23.
Barbaud A. Skin testing and patch testing in non-IgE-mediated drug allergy. Curr Allergy Asthma Rep. 2014 Jun;14(6):442.
24.
Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420–37.
25.
Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, et al. Skin test concentrations for systemically administered drugs: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68(6):702–12.
26.
Misirlioglu ED, Guvenir H, Toyran M, Vezir E, Capanoglu M, Civelek E, et al. Frequency of selective immediate responders to aminopenicillins and cephalosporins in Turkish children. Allergy Asthma Proc. 2017 Sep 1;38(5):376–82.
27.
Zagursky RJ, Pichichero ME. Cross-reactivity in β-lactam allergy. J Allergy Clin Immunol Pract. 2018 Jan–Feb;6(1):72651–81.e1. Epub 2017 Oct 7. Erratum in: J Allergy Clin Immunol Pract. 2022 Feb;10(2):651.
28.
Brockow K, Romano A. Skin tests in the diagnosis of drug hypersensitivity reactions. Curr Pharm Des. 2008;14(27):2778–91.
29.
Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58(9):854–63.
30.
Ben Romdhane H, Ben Fredj N, Ben Fadhel N, Chadli Z, Abderrahmen A, Boughattas NA, et al. Beta-lactam hypersensitivity in children: frequency and risk factors. Br J Clin Pharmacol. 2023;89(1):150–7.
31.
Dias de Castro E, Carolino F, Carneiro-Leão L, Barbosa J, Ribeiro L, Cernadas JR. Allergy to beta-lactam antibiotics in children: risk factors for a positive diagnostic work-up. Allergol Immunopathol. 2020;48(5):417–23.
32.
Caubet JC, Kaiser L, Lemaître B, Fellay B, Gervaix A, Eigenmann PA. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol. 2011;127(1):218–22.
33.
Suleyman A, Yararli Aİ, Yucel E, Tamay Z, Guler N. β-Lactam allergy in children. Sisli Etfal Hastan Tip Bul. 2021;55(3):374–81.
34.
Joint Task Force on Practice ParametersAmerican Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and ImmunologyJoint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010 Oct;105(4):259–73.
35.
Picard M, Paradis L, Bégin P, Paradis J, Des Roches A. Skin testing only with penicillin G in children with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2014;113(1):75–81.
36.
Solensky R, Phillips EJ. Drug allergy. 9th ed. In: Burks WA, Holgate ST, O'Hehir RE, Broide DH, Bacharier LB, Khurana Hershey GK, editors. Middleton’s allergy:principles and practice. Elsevier; 2020. p. 1261–81.
37.
Faitelson Y, Boaz M, Dalal I. Asthma, family history of drug allergy, and age predict amoxicillin allergy in children. J Allergy Clin Immunol Pract. 2018;6(4):1363–7.
38.
Ibáñez MD, Rodríguez Del Río P, Lasa EM, Joral A, Ruiz-Hornillos J, Muñoz C, et al. Prospective assessment of diagnostic tests for pediatric penicillin allergy: from clinical history to challenge tests. Ann Allergy Asthma Immunol. 2018;121(2):235–44.e3.
39.
Atanasković-Marković M, Velicković TC, Gavrović-Jankulović M, Vucković O, Nestorović B. Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy Immunol. 2005;16(4):341–7.
40.
Pichichero ME, Pichichero DM. Diagnosis of penicillin, amoxicillin and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge. J Pediatr. 1998;132(1):137–43.
41.
Romano A, Gaeta F, Valluzzi RL, Alonzi C, Viola M, Bousquet PJ. Diagnosing hypersensitivity reactions to cephalosporins in children. Pediatrics. 2008;122(3):521–7.
42.
Rubio M, Bousquet PJ, Gomes E, Romano A, Demoly P. Results of drug hypersensitivity evaluations in a large group of children and adults. Clin Exp Allergy. 2012;42(1):123–30.
43.
Goh SH, Chong KW, Chiang WC, Goh A, Loh W. Outcome of drug provocation testing in children with suspected beta-lactam hypersensitivity. Asia Pac Allergy. 2021 Jan 14;11(1):e3.
44.
Blanca-Lopez N, Perez-Alzate D, Ruano F, Garcimartin M, de la Torre V, Mayorga C, et al. Selective immediate responders to amoxicillin and clavulanic acid tolerate penicillin derivative administration after confirming the diagnosis. Allergy. 2015;70(8):1013–9.
45.
Antúnez C, Martín E, Cornejo-García JA, Blanca-Lopez N, R-Pena R, Mayorga C, et al. Immediate hypersensitivity reactions to penicillins and other betalactams. Curr Pharm Des. 2006;12(26):3327–33.
46.
Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016;16(3):24.
47.
Kim MH, Lee JM. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins. Allergy Asthma Immunol Res. 2014 Nov;6(6):485–95.
48.
Mori F, Liccioli G, Piccorossi A, Sarti L, Barni S, Giovannini M, et al. The Diagnosis of ceftriaxone hypersensitivity in a paediatric population. Int Arch Allergy Immunol. 2019;178(3):272–6.
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