Antibiotic Allergy in Pediatrics Abstract the Overlabeling of Pediatric Antibiotic Allergy Represents a Huge Burden NIH in Society

Allison Eaddy Norton, MD,a​ Katherine Konvinse, MS,​b Elizabeth J. Phillips, MD,​a,​b,​c,​d,​e Ana Dioun Broyles, MDf Antibiotic Allergy in Pediatrics abstract The overlabeling of pediatric antibiotic allergy represents a huge burden NIH in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the – aDivision of Allergy, Immunology and Pulmonology, cutaneous symptoms that are interpreted as drug allergy are likely Monroe Carell Jr. Children's Hospital at Vanderbilt, and viral induced or due to a drug virus interaction, and they usually do not cJohn A. Oates Institute for Experimental Therapeutics and Department of Pharmacology, School of Medicine, represent a long-lasting, drug-specific, adaptive immune response to the Vanderbilt University School of Medicine, Nashville, antibiotic that a child received. Because most antibiotic allergy labels Tennessee; Departments of dDivision of Infectious Disease, Medicine and bPathology, Microbiology, and Immunology, acquired in childhood are carried into adulthood, the overlabeling of Vanderbilt University Medical Center, Nashville, Tennessee; antibiotic allergy is a liability that leads to unnecessary long-term health eInstitute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia; and fDivision of Allergy and care risks, costs, and antibiotic resistance. Fortunately, awareness of this Immunology, Boston Children’s Hospital, Harvard Medical growing burden is increasing and leading to more emphasis on antibiotic School, Boston, Massachusetts allergy delabeling strategies in the adult population. There is growing Dr Norton conceptualized and outlined the article, literature that is used to support the safe and efficacious use of tools such drafted the initial manuscript, and reviewed and as skin testing and drug challenge to evaluate and manage children with revised the manuscript; Ms Konvinse aided in the conception and outline of the article, drafted antibiotic allergy labels. In addition, there is an increasing understanding of sections of the article, and reviewed and revised antibiotic reactivity within classes and side-chain reactions. In summary, a the manuscript; Drs Phillips and Broyles aided better overall understanding of the current tools available for the diagnosis in conceptualizing and outlining the article, and and management of adverse drug reactions is likely to change how pediatric critically reviewed and revised the manuscript; and all authors approved the final manuscript primary care providers evaluate and treat patients with such diagnoses and as submitted and agree to be accountable for all prevent the unnecessary avoidance of antibiotics, particularly penicillins. aspects of the work. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​2497

1 Accepted for publication Dec 13, 2017 Antibiotic allergy labeling leads to their third birthday. The prevalent Address correspondence to Allison Eaddy Norton, significant individual and public health carriage of these childhood allergy MD, Division of Pediatric Allergy, Immunology, consequences. Unlike vaccination, labels into adulthood perpetuates and Pulmonology, Vanderbilt Children’s Hospital, there is no systematic approach to the use of alternative antibiotics, Vanderbilt University, 2200 Children’s Way, 11215 DOT, Nashville, TN 37232. E-mail: allison.norton@ address antibiotic allergy during which are often more expensive, vanderbilt.edu routine office visits, and allergy labels less effective,– and contribute to PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, persist into adulthood. Antibiotic an increase2 4 in antibiotic-resistant 1098-4275). allergy usually comes to light when bacteria. ‍ ‍ However, studies reveal Copyright © 2018 by the American Academy of treatment is imminent, and physicians that when children are tested and/– Pediatrics often find themselves choosing or undergo drug challenging, >90% 5 7 FINANCIAL DISCLOSURE: Dr Phillips has received more expensive and time-intensive are able to tolerate the antibiotic. ‍ ‍ consultancy fees from Xcovery and BioCryst; Drs procedures, such as desensitization, Unfortunately, even when the Norton, Konvinse, and Broyles have indicated they or using higher-cost alternative diagnosis of drug allergy is excluded by have no financial relationships relevant to this antibiotics with potentially more side such procedures, not only parents but article to disclose. effects. These measures may satisfy the many providers are still8, resistant9​ to FUNDING: Ms Konvinse is supported by the National immediate need for treatment but do drug allergy delabeling. ‍ Institutes of Health (1P50GM115305, 2T32GM7347, not address the primary problem. and F30 AI131780). Dr Phillips is supported by Prescription costs are 30% to 40% 1P50GM115305-01, 1R01AI103348-01, 1P30AI110527- Antibiotic allergy labels are often higher in patients10 with suspected 01A1, 5T32AI007474-20, and 1 R13AR71267-01 from acquired because of rashes reported penicillin allergy. If just half of by parents, and most children never the children who visit a physician To cite: Norton AE, Konvinse K, Phillips EJ, et al. undergo an allergy evaluation to for acute otitis media annually Antibiotic Allergy in Pediatrics. Pediatrics. 2018; address the diagnosis. In a recent were to receive amoxicillin instead 141(5):e20172497 study, 75% of children diagnosed with of cefdinir (a common alternative penicillin allergy were labeled before prescribed for treating patients with Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018:e20172497 STATE-OF-THE-ART REVIEW ARTICLE a history of penicillin allergy), the Researchers in 1 large study in the adults and children– and is as high estimated annual savings11 would United States evaluating 411 543 as 20% in those18,38​ linked41 to ongoing exceed $34 million. Researchers adult and pediatric medical records medical care. ‍ ‍ An allergy to in a recent cohort study were able found that the overall incidence amoxicillin is the most32 common drug to match 51582 subjects with and of self-reported antibiotic24 allergy allergy in children. Although the without penicillin allergy at hospital was as high as 15.3%. Despite epidemiology in the United States is admission. It confirmed that patients the high number of reported cases, currently unknown, hypersensitivity who require alternative drugs, such <10% of cases– are confirmed to to clavulanic acid appears prevalent as fluoroquinolones, clindamycin,Clostridium and be allergic25 after31 testing and/or in southern Europe and26, 42,​has43​ been vancomycin,difficile because of a penicillin challenge,​ ‍ ‍ indicating that true described in children. ‍ ‍ allergy haveStaphylococcus 23.4% more aureus allergy to antibiotics32,​33 is rare and Of ADRs in pediatric patients, –β , 14.1% more methicillin- overdiagnosed. ‍ 23% are reported to be caused by resistant , and The drug allergy box is the major non -lactam antibiotics. Although 30.1% more vancomycin-resistant place in most medical records where rarely confirmed in pediatric enterococci infections compared 4 ADRs are documented, often without studies, macrolides are reported to with controls. The accumulation of reference to the immunologic basis cause drug allergy, mostly44 benign adverse drug labels is more limiting of the reaction. This label does not cutaneous reactions. Among in populations that are susceptible typically discriminate between macrolides, the 15-membered ring to frequent infections, such as cystic – pharmacological effects, side effects, azalide (azithromycin) may be more fibrosis, particularly when drug 12 14 temporally associated observations, allergenic than clarithromycin and resistance develops. ‍ or true drug allergies, making without consistent cross-reactivity with clarithromycin, erythromycin, In this state-of-the-art review, we aim the drug allergy box subject to 34 to provide clinicians with an evidence- overestimation of true allergy risk. and other 14-membered45, 46​ring based toolbox for the diagnostic traditional macrolides. ‍ This overestimation has been workup of children with antibiotic Sulfonamide antimicrobial agents demonstrated in multiple studies in infrequently cause IgE-mediated allergy. The ultimate goal is to improve – which the initial drug allergy label was patient and provider education to symptoms in children but are known based on questionnaires and/or the address and reconcile allergy labels to cause a wide array of T-cell opinions of experienced physicians, early to prevent children from carrying mediated symptoms, most commonly but subsequent drug challenges these potentially false antibiotic allergy – mild cutaneous exanthems, but were used to disprove the majority labels into adulthood. 35 37 more severe reactions such as of them. ‍‍ In a large study of drug reaction with eosinophilia EPIDEMIOLOGY OF ANTIBIOTIC consecutive patients with or without ALLERGY and systemic symptoms (DRESS) a history of penicillin allergy, the rate syndrome, fixed drug eruption, of positive skin testing results in those Stevens-Johnson syndrome (SJS), who were labeled as penicillin allergic toxic epidermal necrolysis (TEN), Epidemiologic studies in children with vague histories was 1.7%, which drug-induced liver disease, and with antibiotic allergy are scarce is the same as in those without23 a cytopenia– have been reported as and fraught with inconsistencies. It history of penicillinç ğ allergy. well,12, especially47​ 50 in patients with is challenging to accurately assess 33 HIV. ‍ ‍ Allergic reactions the incidence of true allergy in the In 1 study, Erko o lu et al found “ ” to quinolones, vancomycin, United States, particularly because that of the 10096 questionnaires returned, in 792 (7.87%), parents aminoglycosides, and tetracyclines the term allergic has been used are rare except in certain patient frequently without definition, reported a history of drug allergy, but only 117 (1.1%) of these were populations with chronic diseases, which allows one to conclude that – such as cystic fibrosis, likely because consistent with an immunoglobulin E 44,​51 nonallergic reactions were included15 of repeated exposure to antibiotics. in many epidemiologic studies. (IgE) mediated reaction by history. CLASSIFICATION OF ADRS Antibiotics are responsible for up to There were 101 children for whom ∼ one-third of reported adverse drug further workup was done, and only 7 (0.11%) of those with suggestive reactions (ADRs), and 35%– of ADRs ADRs are clinically classified as histories had positive testing results. seen in the emergency department16 18 type A and type B reactions. Type are reported as allergic. ‍ ‍ In Penicillin allergy, which is the most A (on-target) reactions are dose addition, as many as 10% of parents common reported drug allergy, dependent and pharmacologically – ’ report that their children 19are23 allergic has a prevalence rate of 5% to predictable on the basis of the to 1 or more medications. ‍ ‍ 10% in community populations of accentuation of the drug s on-target Downloaded from www.aappublications.org/news by guest on October 1, 2021 2 NORTON et al – therapeutic effect. They comprise

Table 3) but >80% of ADRs, including drug drug (

a a interactions, and may52, 53​be subject to genetic variation. ‍ Common Timing examples include bleeding with warfarin or tremor associated with albuterol. Antibiotic-associated type A

the specific phenotype generally 24 h to 1 wk after first exposure and can be quicker (h) on rechallenge exposure reactions in pediatric practice include Nonimmediate: differs according to 1 – 2 wk after exposure Immediate: <1 h after drug exposure 1 – 2 wk after exposure antibiotic-associated diarrhea because of an on-target effect dependent on dose and duration secondary to the alteration of the bacterial microbiome or dose-dependent adrenal

suppression associated47,54​ with azole antifungal agents. ‍ Type B (off-target) reactions are not predictable on the basis of the known target of therapeutic effect but are often dose dependent and

Clinical Features subject to host genetic variation. A minority are dose independent, including antibody- and IgE-mediated 52,53,​ 55,​ 56​ –

61 reactions. ‍ ‍ ‍ The off-target mechanism of non IgE-mediated mast cell activation for many drugs (such as opiates, neuromuscular (typically infection, not drug) and/or TEN, generalized-bullous FDE cardiovascular, and neurologic symptoms cardiovascular, Allergic contact dermatitis, maculopapular exanthema, FDE, EM Allergic More severe cutaneous skin rashes Acute generalized exanthematous pustulosis, DRESS syndrome, SJS Benign, delayed skin rashes Serum sickness, vasculitis Drug-induced hemolytic anemia, thrombocytopenia Anaphylaxis, urticaria, angioedema, gastrointestinal, respiratory, blocking agents, fluoroquinolones, and potentially vancomycin) entails – the dose-dependent activation of

a specific mas-related G protein57,58​ ​ 61 ‍ b, coupled receptor on mast cells. ‍ – Red man syndrome because of non IgE-mediated mast cell activation secondary to vancomycin administration is a clinical example of a type B reaction in children.

Immune Mechanism Drug allergies comprise <15% of all ADRs; however, patients and physicians often erroneously refer 19,51,​ 56​ – to all ADRs as allergic. ‍ ‍ The a drug or metabolite), forming circulating immune complex receptor in the a peptide interacts with T-cell presence of a drug or metabolite coated cells that are directed against the drug or drug metabolite on the patient ’ s cells by drug interaction and/or cross-linking of drug- specific IgE bound to these cells Antibody (IgG>IgM) binds to soluble antigen (often Natural killer cells and macrophages kill IgG- or IgM- Gell and Coombs mechanism based system (Table 1) classifies ADRs into 4 types (I, II, III, and IV) and, more recently, subtypes– IVa, IVb, IVc, and

IVd on the 57,basis59​ 63 of their immune mediators. ‍ ‍ Other proposed classification systems are used to establish biomarkers depending on the  Classification, Clinical Features, and Management of Classic Hypersensitivity Reactions to Antibiotics patient phenotype and endotype. hypersensitivity hypersensitivity Phenotype is determined on the basis Type IVa Type IVb Type IVc Type IVd Gell and Coombs Classification Type III: immune complex – mediated Type IV: delayed-type hypersensitivities An antigen-presenting cell expressing HLA bound to Type II: cytotoxic or antibody dependent, Type I: immediate-type hypersensitivity Mast cell and/or basophil mediator release directed de repertoire model. In the hapten/prohapten model, a drug/drug metabolite covalently bound to larger protein Multiple models have been proposed including hapten/prohapten model, pharmacological interaction (p-i) model and altered pepti de repertoire model. In the hapten/prohapten model, a drug/drug metabolite covalently bound to larger May be sooner if preformed antibodies. undergoes intracellular processing to generate modified peptides that are incorporated onto HLA proteins for presentation to T cells. intracellular processing to generate modified peptides that are incorporated onto HLA undergoes TABLE 1 EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte antigen; IgG, immunoglobulin G; IgM, immunoglobulin M. EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte antigen; IgG, immunoglobulin a b of timing (immediate or delayed onset) and associated symptoms. Endotypes include IgE-mediated Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018 3 – reactions, T-cell mediated reactions, pharmacologic interactions, and genetic predisposition. Biomarkers include in vivo, in vitro and/or ex vivo testing, mediators, and genetic markers (such as64 human leukocyte antigen typing). CROSS-REACTIVITY

Cross-reactivity is a clinically relevant topic because clinicians are often faced with alternative antibiotic choices when a patient develops a rash during an antibiotic course. β Most studies have been focused on -lactam cross-reactivity; however, other antibiotics, such as macrolides– and quinolones, are also known46, to65​ 68 cross-reactβ within their group. ‍ ‍ FIGURE 1 Penicillin-cephalosporin cross-reactivity based on side-chain similarity. Penicillin G, benzylpenicillin; -lactams (penicillins, cephalosporins, β penicillin VK, phenoxymethylpenicillin potassium. Approximately 2% of penicillin allergic patients carbapenems, monobactams, would be expected to react to a cephalosporin, however this number may exceed 30% when oxacephems, and -lactamase administered cephalosporins with identical R1 side chains. Cefditoren and cefpodoxime are oral β cephalosporins with the same side chain. inhibitors) are a group of drugs that β share a 4-membered -lactam ring. The -lactam ring opens spontaneously in vivo into benzylpenicillin without to react to a cephalosporin; however, cephalosporins, and accumulating active metabolism, resulting in the this number may exceed 30%– when evidence supports that patients with formation of the major determinant, administered cephalosporins47,71​ 73 have IgE-mediated– reactions to cefazolin benzylpenicilloyl. Additionally, identical R1 side chains. ‍ ‍ The may tolerate77 other80 cephalosporins and 2% figure is based on the statistic penicillins. ‍‍ Researchers in some benzylpenicillin (the native penicillin β drug) and the minor determinants that only 10% of individuals with studies have reported on subjects who (penicilloate and penilloate) can be a history of penicillin allergy are are allergic >1 -lactam drug, although β ∼ immunogenic. There is a side chain expected to test positive to penicillins, their sensitivity cannot be70, 75​explained that arises from the -lactam ring and of those, 2% will develop a by side-chain similarity. ‍ Ideally, (R1). Cephalosporins additionally reaction to cephalosporins. The testing to cephalosporins should be pursued along with penicillin reagents have a 6-membered47,69​ ring and another mechanism behind this is unknown side βchain (R2). ‍ but may be secondary to coexisting in children with a strong history of allergy. In the Practice Parameter penicillin allergy or positive penicillin The -lactam ring was initially 47,70​ on drug allergy, the Joint Task Force skin testing results. ‍ The rate of believed to be the predominant recommends skin testing individuals cross-reactivity between penicillins cause of cross-reactivity between 69 with penicillin allergy to penicillin and both carbapenems and aztreonam cephalosporins and penicillins. in children has been determined However, the R1 side chain and, less and its major and minor determinants to be <1%, so it is safe for a patient frequently, the R2 side chain have (although the percentage is low) – with penicillin allergy to receive been demonstrated to contribute before administering a cephalosporin 75,81​ 84 these drugs. ‍‍ The tolerability significantly to cross-reactivity because fatal47 anaphylaxis has been of carbapenems in individuals with within the penicillin class itself reported. When skin testing is not penicillin allergy has also recently and also between penicillins and available, there is clinical evidence been demonstrated in delayed-type cephalosporins in vitro, in vivo to support choosing a cephalosporin– 83 with a different R1 side chain to CLINICALdrug allergy PHENOTYPING. through skin testing and challenge, – 69 76 – reduce reaction risk. ‍‍ and clinically through selective 63,69​ 72 tolerance or reactivity (Figs 1 5). ‍ ‍‍ Cefazolin, which is a common cause Approximately 2% of patients with of perioperative anaphylaxis, does An accurate and detailed history penicillin allergy would be expected not share R1 or R2 groups with other helps identify the nature of the Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 NORTON et al an immediate reaction potentially6,33,​ 87​ associated with anaphylaxis. ‍ ‍ “ ” – Pseudoallergic reactions, also known as anaphylactoid reactions or non IgE-mediated mast cell activation,

can resemble type I 47,hypersensitivity57,​ 88,​ 89​ reactions (Table 2). ‍ ‍ Delayed or nonimmediate reactions range from benign to severe and can be

classified by timing47, and88,​ 89​ clinical features (Table 3). ‍ Delayed urticaria that occurs several hours to days after drug exposure is often non-IgE mediated. The underlying cause of cutaneous drug reactions during viral infections may involve a viral-induced polyclonal activation FIGURE 2 of lymphocytes, an enhancement of First-generation cephalosporin cross-reactivity. Approximately 2% of penicillin allergic patients cellular immunity,90 or changes in drug would be expected to react to a cephalosporin, however this number may exceed 30% when metabolism. administered cephalosporins with identical R1 side chains. Cefditoren and cefpodoxime are oral cephalosporins with the same side chain. In children, rashes during antibiotic treatment can be difficult to assess because they often result from a variety of triggers that are common in the pediatric population. Maculopapular rashes have been observed in

3% to 7% of92 children who are on ampicillin. In fact, researchers in recent studies have attempted to reveal the underlying viral causes of rashes by performing viral diagnostic

studies with31,35​ simultaneous allergy workup31 . ‍ In a 2011 study by Caubet et al,​ of 88 children with a history of nonimmediate drug allergy, only 6 had positive challenge results, and 5 of these were confirmed to have an underlying infection known to cause rash. Delayed-onset urticarial or maculopapular rashes are also β frequently observed in children who are treated with -lactam, with an FIGURE 3 estimated frequency of 1% to 5% Second-generation cephalosporin cross-reactivity. Approximately 2% of penicillin allergic patients 39 would be expected to react to a cephalosporin, however this number may exceed 30% when experiencing rashes per prescription. administered cephalosporins with identical R1 side chains. Cefditoren and cefpodoxime are oral AVAILABLE GUIDELINES AND cephalosporins with the same side chain. CONSENSUS STATEMENTS

– Most information on pediatric drug adverse reaction and the most85 as non IgE-mediated15,32,​ 86​ mast cell allergy is tailored for specialists appropriate management. activation. ‍ ‍ When it occurs and extrapolated from guidelines ’ Urticaria is the most common within an hour of exposure to a for adults. Specialists refer to both – – clinical symptom of a drug reaction, drug, particularly if it s reproducible American and European guidelines44,47,​ 89,​ 93​ 98 drug viral interaction, as well on drug challenge, it can represent and consensus statements. ‍ ‍ ‍ ‍‍ Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018 5 The accurate documentation of medications taken at the time of the reaction is crucial because the presence of cofactors or coprescribed drugs may change

the onset47, or89​ progression of a reaction ‍ and could also be causal. The mechanism could be a true allergic reaction associated – with immunologic memory or an off-target effect, such as non IgE- mediated mast cell activation exacerbated by multiple inciting

drugs administered concurrently52 (eg, opiates and vancomycin). Previous exposure to the same antibiotic or structurally similar antibiotics is important in determining the FIGURE 4 immunologic mechanism. The Third-, fourth-, and fifth-generation cephalosporin cross-reactivity. Approximately 2% of penicillin physician should gather particular allergic patients would be expected to react to a cephalosporin, however this number may exceed signs and symptoms as precisely as 30% when administered cephalosporins with identical R1 side chains. Cefditoren and cefpodoxime are oral cephalosporins with the same side chain. possible and consider, on the basis of these symptoms, whether the reaction should be considered severe, benign, immediate, or nonimmediate. The provider should determine if treatment was required for the

reaction as32, well55,​ 102,​ as103​ the response to treatment. ‍ ‍ If a provider is suspicious that an IgE-mediated allergic reaction occurred (Table 1), workup should be considered (Fig 6). Immediate reactions that typically occur within 1 hour of exposure to oral drugs or within 15 to 20 minutes for parenteral drugs should prompt referral to an allergist for further workup. In reality, the immunologic – mechanisms of the reactions may be accelerated in nature (1 72 hours after dosing), and these overlap considerably in time or may not be FIGURE 5 clearly differentiated by the medical Third-, fourth-, and fifth-generation cephalosporin cross-reactivity (continued). Approximately 2% history, which is why if there is any of penicillin allergic patients would be expected to react to a cephalosporin, however this number suspicion of drug allergy,80 referral may exceed 30% when administered cephalosporins with identical R1 side chains. Cefditoren and should be considered. cefpodoxime are oral cephalosporins with the same side chain. IN VIVO TESTING: IMMEDIATE REACTIONS DIAGNOSIS AND TREATMENT OF ANTIBIOTIC ALLERGY IN CHILDREN information available is key in When performed by trained the diagnostic evaluation– of professionals, skin prick and

An accurate history that combines children38, with44,​ 55,​ 56,​antibiotic89,​ 99​ 101 intradermal skin testing are safe and all subjective and objective allergy. ‍ ‍ ‍ ‍ ‍ ‍ efficacious procedures to aid in the Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 NORTON et al diagnosis of immediate reactions β to antibiotics,26,102,​ particularly104,​ 105​ in -lactams. ‍ ‍ ‍ If possible, skin testing should be Management delayed for 2 to 3 weeks after an inciting reaction because of the syndrome) drugs potential depletion of mediators, Slow infusion speed (with Red man Antihistamines Desensitize in some cases Pretreatment Desensitization which may temporarily55 lead to false- negative results. Most guidelines

b suggest waiting 4 to 6 weeks after the complete resolution of all clinical

Testing symptoms and signs of a suspected l a delayed hypersensitivity44,47,​ 89,​ 106​ reaction leve and possible tests testing before testing. ‍ ‍ Serum histamine Serum total tryptase Acute testing as above Avoid drugs and/or cross-reacting referral testing Allergy Skin prick testing Serum-specific IgE Drug provocation Standardized antibiotic skin testing protocols exist for penicillin, although the only labeled skin testing reagent currently available Antibiotics in the United States is penicillin syndrome) aminopenicillins) (macrolides) Vancomycin (Red man β -lactams (ie, Rarely non- β -lactams major determinant (Pre-Pen). There are also published data regarding nonirritating concentrations and test specificity to other antibiotics that

allergists may107, choose108​ to use before challenging. ‍ IN VIVO TESTING: NONIMMEDIATE cell activation anaphylaxis Differential Diagnosis Commonly Involved Anaphylaxis IgE-mediated reaction Quinolones Non – IgE-mediated mast Food allergy Venom allergy Idiopathic urticaria and REACTIONS

Some researchers suggest delayed intradermal testing reads at 24 to 48 cell tryptase cell tryptase Acute Setting

Laboratories in hours or patch testing with reads at Elevated mast Elevated mast 48 hours, 72 hours, 96 hours, and 1 week for nonimmediate reactions. However, sensitivity has been reported to be <50% in many studies and is likely to be dependent on the

specific antibiotic and35,98​ the pretest clinical probability. ‍ instances hypotension Urticaria Angioedema (occasionally) Hypotension Mild fever Muscle pain in severe Angioedema Flushing Urticaria Rhinitis Conjunctivitis Hypotension Laryngeal edema Gastrointestinal symptoms Bronchospasm Cardiovascular shock and FEASIBILITY OF SKIN TESTING IN CHILDREN

Skin prick testing is performed during infusion administration of the drug course of drug easily in109 children of any age, even in Immediate or 1 – 6 h after Can occur on first infancy. Although intradermal skin testing is less well tolerated because of the discomfort from injections, when indicated, it is possible to perform this  Immediate Reactions: Clinical Features and Management test in young children with adequate reaction, mast cell activation (anaphylactoid, pseudoallergic) anaphylactic- producing, immediate reaction preparation. In routine clinical Non – IgE-mediated Type of Reaction Timing of Reaction Symptoms of Reaction Possible IgE-mediated, Obtain 2-15 minutes after reaction. Obtain serum total tryptase 15 minutes to 3 hours after reaction. TABLE 2 a b practice, the risk of resensitization to

a drug after a negative 27,testing110​ result is extremely uncommon. ‍ Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018 7 c drugs and/or cross-reacting drugs and/or drug class testing drugs and/or cross-reactive drugs and/or cross- reactive drugs testing and/or cross- reactive drug Management Avoidance of Drug provocation Avoidance of Avoidance drugs Drug provocation Avoidance of drug Testing testing Patch testing LTT and/or ELISPOT HLA screening ​ 91 ‍ a, Antibiotics drugs sulfones acne) TetracyclinesRifampin Antituberculosis HLA screening Sulfonamides and/or β -lactams β -lactams Sulfonamides LTT and/or ELISPOT Avoidance drug Clindamycin Sulfonamides Aminopenicillins Delayed intradermal Sulfonamides Patch testing β lactams Quinolones Fluconazole psoriasis skin syndrome SJS and/or TEN dermatosis Differential Diagnosis Commonly Involved Severe eczema or FDE DRESS syndrome Early SJS and/or TEN Staphylococcal scalded EM Early DRESS syndrome or IgE-mediated drug allergy Sulfonamides Subcorneal pustular DRESS syndrome Quinolones EM Bullous pemphigoidSJS and/or TEN Tetracyclines Acute Setting lymphocytes Laboratories in Renal impairment Hepatitis Eosinophilia Viral or drug exanthem Vancomycin Eosinophilia Bullous impetigo Clindamycin None (occasionally) Fever Pneumonitis Malaise Prodrome Anemia High fever Neutrophilia Pustular psoriasis Aminopenicillins Patch testing Pruritus None lesions, scaling, and purpura BSA with purpuric or dusky centers pustules on erythematous background round, dusky-to-violaceous macules or plaques limited mucositis hyperpigmentation ≥ 2 facial edema, infiltrated Morbilliform eruption >50% Nonerosive mucositis Lymphadenopathy Atypical Mucositis in ≥ 2 surfaces Painful erythematous macules Superficial sloughing High fever Lymphopenia Bullous pemphigoid Minocycline (used for Dozens to hundreds of Flexural accentuation Edema Maculopapular exanthema Low-grade fever Eosinophilia (mild) Viral exanthem Urticaria 1 or more well-demarcated, Blistering may occur Mucosal predilection but Postinflammatory b 4 – 28 d 7 – 14 d 2 – 8 wk 1 – 14 d 24 – 48 h  Nonimmediate Reactions: Clinical Features and Management

exanthematous pustulosis reaction DRESS syndrome SJS and/or TEN Acute generalized Type of Reaction Timing Cutaneous Symptoms Systemic Symptoms Possible FDE Delayed drug TABLE 3

Downloaded from www.aappublications.org/news by guest on October 1, 2021 8 NORTON et al d IN VITRO AND/OR EX VIVO TESTING –

false-negative and false-positive95,121​ testing123 β results have been reported. ‍ ‍ specific drug Management

Avoidance of Serum-mature tryptase ( tryptase), Enzyme-linked immunospot a mast cell mediator, can be used (ELISPOT) assays are used to as an adjunct for suspected IgE- analyze low-frequency, antigen- mediated reactions during which specific, cytokine-producing cells peak levels will be reached within in the peripheral blood of patients

Testing 30 minutes to 2 hours of the onset with a type IV hypersensitivity – of symptoms and typically return to reaction after stimulation with

None normal within 24 hours. Non IgE- pharmacological drug concentrations. mediated mast cell activation can ELISPOT can be used to measure ∼ γ produce a positive111 mast cell tryptase cytokine responses, including interleukin (IL)-13, interferon , in 10% of cases. Although a α normal tryptase level does not IL-10, IL-5, granzyme B, granulysin,

Antibiotics rule out anaphylaxis and/or IgE- and tumor necrosis factor . ELISPOT

cefaclor) mediated drug allergy, an elevated has been reported to have better β lactams (especially level compared with baseline can sensitivity than LTT in detecting

be helpful47 in the diagnosis of such drug-specific T-cell– responses and reactions. a specificity112, 124​ranging131 from 95% DRUG-SPECIFIC TESTS to 100%. ‍ ‍ ‍ Intracellular cytokine staining is used to measure the production of targeted cytokines by T cells in response to drug Differential Diagnosis Commonly Involved There are currently no validated 122 in vitro or ex vivo tests that have stimulation. adequate sensitivity and/or Tests such as the ELISPOT assay – specificity to be widely applied in and intracellular cytokine staining clinical practice. The in vitro specific potentially could be of great utility, IgE testing that is commercially particularly because many children Acute Setting Laboratories in available for penicillin has a low are on multiple antibiotics at the Mild eosinophiliaMild proteinuria Rheumatic fever Other drug reactions Sulfonamides Macrolides sensitivity, ranging from 0% to 25%, time they develop a severe reaction

and in some studies, false-positive112, ​ such as DRESS syndrome or SJS and/ 113testing results have been found. or TEN, when delayed intradermal ‍ Researchers in multiple studies skin testing or patch testing may have reported false-negatives when be riskier or lack sensitivity. The polyarthritis extent to which these tests remain High fever Neutropenia Vasculitis Malaise Polyarthralgia or testing was done close to the acute reaction and –when testing is delayed positive over time is not known, and

beyond 6 months114 116 despite a lack of differences may exist132 between drugs tolerance. ‍ and classes of drugs. There are other ex vivo and in vitro DRUG CHALLENGE assays that are potentially clinically useful but are currently only used in research settings. The basophil The drug challenge, also referred

serpiginous plaques (usually at injection site) activation test is an in vitro test for to as a graded challenge or drug Pruritic urticarial or antibiotics using flow cytometry provocation test, is considered to to detect basophil surface (CD63 be a gold standard for drug allergy

1 – 2 wk and/or CD203c) and intracellular – diagnosis. It can be administered

(phospho-p38 mitogen-activated85,112,​ 117​ 120 as a single dose or in multiple protein kinases) markers. ‍ ‍ ‍ ‍ doses. Drug challenge strategies to Lymphocyte transformation testing reduce the risk of severe reaction, Continued

(LTT) is used to measure T-cell when the pretest probability of an proliferation to a drug in vitro and IgE-mediated reaction is high and reaction Serum-sicknesslike Type of Reaction Timing Cutaneous Symptoms Systemic Symptoms Possible Rapid recurrence on drug re-exposure. just recommend avoiding culprit drug. Controversial. Some sources recommend avoiding drug and class while others (ie cefaclor) Sulfonamides include trimethoprim-sulfamethazole and sulfones dapsone. There is no cross reactivity between sulfa anti microbials non-antibiotic sulfonamides (such as acetazolamide, bumetanide, celecoxib, chlorothiazide, diazoxide, Contraindicated in generalized FDE. is possibly useful for the diagnosis the negative predictive value of BSA, Body Surface Area; EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte antigen. BSA, Body Surface Area; EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte a b c d TABLE 3 dorzolamide, furosemide, glyburide, hydrochlorothiazide, indapamide, metolazone, sumatriptan, torsemide and zonisamide). dorzolamide, furosemide, glyburide, hydrochlorothiazide, indapamide, metolazone, sumatriptan, of drug-induced type IV (delayed) skin testing is low, include a 2-step hypersensitivities, although both graded challenge in which 10% of Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018 9 FIGURE 6 Stepwise approach to the evaluation and treatment of patients with type I IgE-mediated drug allergy (see Table 1). This approach cannot be used in the case of severe reactions, including SJS, TEN, DRESS syndrome, nephritis, hepatitis, and hemolysis. Adapted from Turvey SE, Cronin B, Arnold AD, Dioun AF. Antibiotic desensitization for the allergic patient: 5 years of experience and practice. Ann Allergy Asthma Immunol. 2004;92(4): p. 430 and Dioun AF. Management of multiple drug allergies in children. Curr Allergy Asthma Rep. 2012;12(1): p. 81.See Figs 1–5 for cross reactivity. aPursuing skin testing is dependent on negative predictive value of testing and reagent dependent. Consider going straight to challenge if reaction was mild and inconsistent with

Downloaded from www.aappublications.org/news by guest on October 1, 2021 10 NORTON et al – a weight-based dose is given and of a drug to a patient who has either particularly141 144 with sulfa antimicrobial then the remaining 90% is given a proven or is highly likely to have agents. ‍ ‍ Desensitization is also – after a specified observation time of a drug allergy as opposed to drug frequently employed and effective 30 to 60 minutes with an additional challenge, which is a diagnostic in the setting of suspected non IgE- observation time of 60 minutes. For procedure performed in cases23,47​ of low mediated reactions14,135,​ 145​in children with instance, if a penicillin testing result probability of drug allergy. ‍ cystic fibrosis. ‍ ‍ is negative, then it is reasonable to In addition, drug challenge and ANTIBIOTIC STEWARDSHIP PROGRAMS proceed with a single-dose challenge desensitization should be done because the negative predictive in a monitored setting and are – value of penicillin testing has been contraindicated in patients with Patients requiring frequent medical well established at 97% to 99%. For severe non IgE-mediated reactions, care or hospitalization are at all other antibiotics, the predictive such as SJS, TEN, DRESS syndrome, high risk to be labeled 3,as146​ allergic values have not been determined in interstitial nephritis,47 hepatitis, or to multiple antibiotics. ‍ In large population studies; therefore, hemolytic anemia. addition, labels frequently stick if a testing result is negative, a Drug desensitization procedures despite negative9 testing results and graded challenge23,31,​ 47​ is the safest way vary depending on several factors, challenge. In fact, it is estimated that ’ to proceed. ‍ ‍ If >3 doses are such as the drug itself, the route of 36% to 49% of patients with negative administered, a graded challenge can administration, and the patient s penicillin testing results may have a be used to downregulate mast cells reaction and its severity. The persistence or redocumentation– of and runs the risk of desensitizing 47 starting dose is typically in fractions their allergy despite147 149 proven negative patients. of a milligram, doubling every 15 testing results. ‍ The majority of studies in which to 30 minutes until a cumulative Current evidence reveals that researchers evaluate drug challenges therapeutic dose has been achieved. an interactive and electronically reveal that they are safe and well The goal of desensitization is to accessible drug allergy box in a tolerated in the pediatric population. render the individual nonreactive medical record that is regularly Researchers in several studies to the drug as long as he or she is reconciled improves the management report that if reactions were to receiving treatment with the drug. of patients labeled with drug occur as a result of drug challenge, Once the drug is no longer present allergies. In 1 study, the electronic they are similar or less* severe than in the serum, the individual loses medical record was used proactively the original reaction. Researchers the tolerance to the drug, and repeat to identify patients for testing, which support the use of allergy testing desensitization is usually indicated47,55​ if was then performed in the inpatient and challenge in special populations, there is a delay of >2 half-lives. ‍ unit by a trained pharmacist. such as oncologic and immune- There are few studies on antibiotic Researchers in this study reduced the compromised patients, and have desensitization in children, so most of use of second-line antibiotics during150 comparable positive and negative our knowledge of this procedure135, is 136​ hospitalization and discharge. predictive values133,134​ to the general extrapolated from adult studies. ‍ Researchers in another small pilot population. ‍ β A high efficacy and safety rate– has study prevented redocumentation DRUG DESENSITIZATION –β been reported in both47, 50,​ -lactam137​ 140 and with several interventions, including non -lactam drugs. ‍ ‍ ‍ Case an electronic alert notifying β reports of successful desensitization providers when a penicillin allergy Drug desensitization is described in children to other -lactam drugs is added back for a patient with as a temporary induction of drug (including meropenem, cefotaxime, documented negative testing –β 148 tolerance by the administration47 of ceftriaxone, and ceftazidime) as results. incremental doses of the drug. well as non -lactam drugs (such– It is important to realize that drug Targeting prospective antibiotic as macrolides or sulfa antimicrobial50,138​ 140 allergy management in adults has led desensitization is a therapeutic agents) have been reported. ‍ ‍ measure for the safe administration to a positive impact on151 antibiotic use Desensitization is most effective in and 152appropriateness. Blumenthal IgE-mediated reactions; however, et al used a quasi-experimental * Refs 25,​‍26,​‍28,​‍31,​35–‍37,​‍43,​‍154,​155. – there is evidence for its use in design to measure the impact of some non IgE-mediated reactions, different strategies over discreet time FIGURE 6 Continued IgE mediated drug allergy. b Consider graded challenge for milder reactions or desensitization for more severe reactions. cConsider graded challenge for milder reactions. dConsider desensitization regardless of skin test, particularly if index reaction was severe.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 141, number 5, May 2018 11 ACKNOWLEDGMENTS periods among an internal medicine promote appropriate referrals and β – service and showed that inpatient procedures, such as skin testing and Thank you to Zohaib Lakhani for skin testing to -lactam drugs drug challenging, that will prevent contributing to Figs 1 5. Thank directed by an allergist and the use the overlabeling of drug allergy. you also to Dr Melissa Fuller for of previously adopted, computerized Education directed at community reviewing the article and steering guidelines resulted in an increase providers to make a more accurate the content toward general pediatric in penicillin153 and cephalosporin146 diagnosis of drug allergy could providers. use. Trubiano et al measured potentially improve global health. the impact of an integrated and An interactive electronic medical ABBREVIATIONS responsive outpatient antibiotic record that is regularly reconciled allergy testing and antimicrobial could help improve the management stewardship program at 2 Australian of patients with drug allergy. In the ADR: adverse drug reaction centers and determined that after future, accessibility to preventive DRESS: drug reaction with eosin- testing, appropriate antibiotics were genetic testing and more sensitive ophilia and systemic more likely to be prescribed. To diagnostic tests for both immediate symptoms date studies using antibiotic allergy and delayed antibiotic allergy could ELISPOT: enzyme-linked management as an antimicrobial be invaluable. These tests would immunospot stewardship tool have focused ideally aid in preventing reactions, IgE: immunoglobulin E on adults. Programs in which unraveling the diagnostic complexity IL: interleukin researchers prioritize pediatric of multiple antibiotic allergies, or LTT: lymphocyte transformation populations, in which the majority determining the underlying cause of – testing of antibiotic allergy labels are first a reaction and whether it is the drug, β R1: side chain that arises from realized, are warranted. a virus, or a drug virus interaction. If the -lactam ring FUTURE DIRECTIONS sufficiently sensitive and/or specific R2: side chain that arises from and widely available, such testing the dihydrothiazine ring on would also greatly reduce the risks cephalosporins Educating the public and health in drug challenges, decrease the use SJS: Stevens-Johnson syndrome care providers about the differences of the more time-intensive and costly TEN: toxic epidermal necrolysis in ADRs and drug allergies procedure of desensitization, and could reduce overdiagnosis and increase the use of first-line antibiotics. Australia’s National Health and Medical Research Council and the Australian Centre for HIV and Hepatitis Virology Research. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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