The diagnosis and management of antibiotic allergy in children: Systematic review to inform a contemporary approach Tom Marrs, 1,2 Adam T Fox, 1,2 Gideon Lack, 1,2 George du Toit 1,2 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2014-306280). 1 Division of Asthma, Allergy and Lung Biology, Department of Paediatric Allergy, King’s College London, London, UK 2 Department of Paediatric Allergy, Guys and St Thomas’ Hospitals NHS Foundation Trust, London, UK Correspondence to Dr George du Toit, Division of Asthma, Allergy and Lung Biology, Department of Paediatric Allergy, King’s College London at St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK; george.dutoit@kcl.ac.uk Received 23 September 2014 Accepted 26 November 2014 To cite: Marrs T, Fox AT, Lack G, et al. Arch Dis Child Published Online First: [ please include Day Month Year] doi:10.1136/ archdischild-2014-306280 ABSTRACT Background Adverse drug reactions (ADRs) to antibiotics are commonly reported among children, with some representing genuine drug allergies. Accurate diagnostic tests are required. Drug provocation testing (DPT) is accepted as the gold standard investigation among children with suspected antibiotic allergy. We conducted this review to ascertain the strength of current evidence for using DPT as the first-line investigation for suspected antibiotic allergy among children. Methods Medline was searched in June 2014 for publications investigating antibiotic allergy among children. Results 865 publications were retrieved and 76 studies selected. ADRs are most common among children of 0–4 years, however only some reveal drug allergies. The best evidence demonstrates that around 0.21% of general paediatric outpatients demonstrate positive antibiotic intradermal (ID) testing or DPTs, while 6.8% of children attending emergency departments for suspected β-lactam allergy may fulfil DPT reactions. Four studies used DPT- based protocols to investigate suspected antibiotic allergy, with two of these conducting ID testing and DPTs across all participants. β-lactam and clarithromycin ID testing had sensitivities of 66.7% and 75%, with positive predictive values of 36% and 33%, respectively, when compared with DPT data. Conclusions Our literature review found four (6%) publications that performed DPTs to subjects’ index antibiotic across all participants. No rigorous evidence supports using skin prick, ID or in vitro diagnostic testing; indeed, the testing regimens, extracts and positivity criteria used are inconsistent. We recommend that suspected non- serious antibiotic allergy should be primarily investigated using DPT-based clinical protocols. Data examining their safety, acceptability and diagnostic performance are required. INTRODUCTION Adverse drug reactions (ADRs) to antibiotics are commonly reported among children and young people. Allergic mechanisms are frequently sus- pected and alternative agents routinely prescribed. Altered antibiotic choices may impact on the health of both the individual and wider society, where antibiotic resistance and increasing health costs are becoming more burdensome. 1 A substantial proportion of children develop rashes, urticaria, angio-oedema and respiratory symptoms while unwell, frequently while taking antibiotics. 2 Thus many children are diagnosed with ‘suspected antibiotic allergy’. This is understand- able, since 51 (36.7%) of the anaphylactic deaths in the UK over a 6 year period were due to medication. Sixteen (31.4%) of these deaths resulted from anti- biotics, including a 5-year-old child. 3 However, only a small proportion of ADRs result from reprodu- cible allergic immunological mechanisms. One meta-analysis found that up to 24% of inpatient ADRs were characterised as ‘allergic and or idiosyn- cratic’ reactions, without requiring further investiga- tion for more detailed determination. 4 Despite this, prevailing caution has allowed a substantial propor- tion of children experiencing ADRs to be labelled with ‘suspected antibiotic allergy’, without further investigation or confirmation. Identifying and managing suspected antibiotic allergy has now become a clinical imperative, as current practice requires that we have reliable systems in place to mitigate iatrogenic harm and manage risks associated with healthcare interven- tions. In September 2014, the National Institute of Health and Care Excellence recommended that indi- viduals warrant referral to specialist services if “they are likely to need β-lactam antibiotics frequently in the future”. 5 It can be argued that all children then qualify for investigation as many antibiotic courses may be required over a lifetime, usually in an acute setting. The National Institute of Health and Care Excellence guideline emphasises the need for all healthcare workers to recognise, record and make referrals for suspected antibiotic allergy, while the antibiotic prescription rate among UK general prac- tices is soaring. 6 The few specialist paediatric allergy services in the UK are widely dispersed and have limited capacity to cope with increased demand for the investigation of suspected drug allergy. 7 Allergic reactions to antibiotics may be caused by a variety of mechanisms and raise a considerable diag- nostic challenge. 8 The World Health Organisation (WHO) defines ADRs as being either Predictable (type A) or Unpredictable (type B). The Unpredictable type are subclassified into pharmacological drug intolerance, idiosyncratic pharmacodynamic reactions and allergic reactions. Immediate, type 1 hypersensi- tivity and IgE-mediated drug allergic reactions com- monly cause urticaria, angio-oedema and potentially airway and systemic compromise, whereas non- immediate syndromes may manifest either as localised cutaneous responses, or systemic signs associated with more serious syndromes ( figure 1). 9 Drug provocation tests (DPTs) are recommended as the first-line gold standard investigation among children with mild allergic reactions and rashes to β-lactams. 10 However, clinical pathways using patients’ histories, skin prick testing (SPT) and intradermal (ID) testing have not been validated against DPT outcome data. Rigorous appraisal of Marrs T, et al. Arch Dis Child 2014;0:1–6. doi:10.1136/archdischild-2014-306280 1 Review ADC Online First, published on December 19, 2014 as 10.1136/archdischild-2014-306280 Copyright Article author (or their employer) 2014. 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