Allergic and pseudoallergic reactions to betalactam antibiotics in children

Revue française d’allergologie et d’immunologie clinique 43 (2003) 216–221 www.elsevier.com/locate/revcli

Allergic and pseudoallergic reactions to betalactam antibiotics in children Réactions allergiques et pseudo-allergiques aux bétalactamines chez l’enfant Claude Ponvert * Pédiatrie 6, Allergologie, Pneumologie, Asthmologie, Hôpital Necker, Enfants Malades, 149–161, rue de Sèvres, 75015 Paris, France Received 14 March 2003; accepted 17 March 2003

Abstract Fifteen to 20% of patients of all ages treated with anti-infectious drugs report symptoms suggestive of a hypersensitivity reaction, most often related to a betalactam. Allergy studies show that most reactions to betalactams reported in children do not result from anti-microbial drug hypersensitivity. Nevertheless, the risk of hypersensitivity to these drugs is high in children who have previously had anaphylaxis, immediate urticaria and/or angioedema. Following an initial medical history, skin tests with betalactams are the next diagnostic step. Immediate skin tests to betalactams have been standardized and have good diagnostic and predictive values, whereas the predictive value of in vitro tests for immediate and non-immediate hypersensitivity to betalactams has not been proven. Immediate skin tests are indicated mainly in patients reporting reactions suggestive of immediate hypersensitivity, and they provide confirmation or rejection of a diagnosis of sensitization to betalactams and at the same time provide evidence for sensitization to one or more betalactams of the same and/or different class. Except for patch tests (for eczema) and photopatch-tests (for photodermatoses), the predictive values of delayed skin tests to anti-microbial drugs remain uncertain, and a large proportion of such delayed reactions must be diagnosed by challenge tests. Note that challenge tests are strictly contraindicated in children reporting symptoms suggestive of (pseudo-) serum sickness or a (potentially) severe toxic epidermal necrolysis (TEN) reaction. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Résumé Tous âges confondus, 15 à 20% des sujets traités par des médicaments anti-infectieux rapportent des réactions susceptibles d’évoquer une hypersensibilité à ces médicaments, les anti-infectieux les plus fréquemment accusés étant les bêtalactamines. Les résultats des études ayant comporté un bilan allergologique montrent que, chez l’enfant, la plupart des réactions attribuées aux bêtalactamines ne résultent pas d’une allergie à ces antibiotiques. Toutefois, le risque d’allergie aux bêtalactamines est élevé chez les enfants rapportant des réactions anaphylactiques et des urticaires et/ou angio-oedèmes de chronologie immédiate. Après l’interrogatoire, les tests cutanés aux bêtalactamines représentent le premier temps de la démarche diagnostique, les tests in vitro n’ayant pas fait la preuve de leur valeur diagnostique et prédictive. Les TC à lecture immédiate aux bêtalactamines sont bien standardisés, et ont une bonne valeur diagnostique et prédictive. Ils sont essentiellement indiqués chez les patients rapportant des symptômes fortement évocateurs d’une hypersensibilité immédiate, chez lesquels ils permettent de confirmer ou d’infirmer une sensibilisation aux bêtalactamines, et de déterminer si le patient est sensibilisé à une seule ou à plusieurs bêtalactamines de la même classe ou de classes différentes. A l’exception des patch-tests (eczémas) et des photo-patch-tests (photodermatoses), la valeur diagnostique et prédictive des TC à lecture retardée reste incertaine, et une importante proportion des réactions d’hypersensibilité non-immédiate est diagnostiquée par les tests de réintroduction. Toutefois, ces tests sont formellement contre-indiqués chez les enfants rapportant des symptômes à type de (pseudo) maladie sérique ou de toxidermie (potentiellement) sévère. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Antibiotic; Betalactam; Allergy; Skin tests; Challenge tests; Children Mots clés : Allergie médicamenteuse ; Bêtalactamines ; Tests cutanés ; Tests de réintroduction ; Enfant

* Corresponding author. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. DOI: 10.1016/S0335-7457(03)00101-1

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1. Results of epidemiological and allergological studies

Table 1 Immediate-reading skin tests for betalactam allergya

Between 1% and 10% of patients treated with betalactam antibiotics report reactions that suggest an allergy to these drugs [1–4]. The most frequently reported reactions are maculopapular rashs (MPR: 70–75%), urticaria and angioedema (20–25%). Other reactions are rare, except for serum sickness-like disease (SSLD) that occurs primarily in young children treated with first generation cephalosporins [5]. Allergological studies show that only 3–23.5% of the children with suspected betalactam allergy are really allergic to betalactams [6–12]. We have shown that anaphylaxis and immediate reactions were significant risk factors for betalactam allergy and for cross-reactivity between penicillins and cephalosporins in children. In contrast, a few children only reporting other reactions were diagnosed allergic on the basis of skin and challenge tests. Finally, we also showed that age, sex, personal history of atopy, number of reactions to betalactams, and history of reactions to other anti-microbial drugs were not significant risk factors for betalactam HS [11], consistent with previous studies [10,13]. However, other studies have suggested that atopy may be a risk factor for betalactam-induced anaphylaxis [14–16].

(1) Controls

2. Diagnostic work-up The diagnostic and predictive values of in vitro tests for immediate HS to betalactams are low. The sensitivity of CAP-Rast-FEIA for penicillin G, ampicillin and amoxicillin does not exceed 50% [17], and the specificity of histamine and leukotriene release is lower than 75% [18]. Moreover, the diagnostic and predictive values of in vitro tests for non immediate HS to betalactams (lymphocyte proliferation and cytokine production by blood mononuclear cells) are controversial, with positive responses in control subjects and very

Fig. 1. Diagnostic work-up in suspected betalactam allergy.

(2) Penicillin metabolites (3) Soluble betalactams

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– Positive: histamine 10 mg/ml (prick) and 0.1 mg/ml (ID) – Negative: saline – PPL: pure – MDM: 1/100, 1/10, pure Benzyl-penicillin (BP)

Other betalactams

– 100–250 UI/ml – 1000–2500 UI/ml – 10 000 to ≤25 000 UI/ml

– 0.1–0.25 mg/ml – 1–2.5 mg/ml – 10 to ≤25 mg/mlb

a Increasing concentrations of the reagents are tested initially by the prick method. If prick test results are negative, 0.02 ml of the solutions are injected intradermally at increasing concentrations. b Concentrations above 10–25 mg/ml give false-positive results for several betalactams such as cefotaxime and imipenem.

similar pattern of reactivity in patients with immediate and non immediate HS, respectively [19–23]. Thus, diagnosis of betalactam HS is based above all on clinical history and in vivo tests (skin tests and challenge: Fig. 1). Immediate responses to prick and intradermal (ID) tests with major allergenic determinants (benzyl-penicilloyl polylysine: PPL) and minor determinant mixture (MDM) have good diagnostic and predictive values in patients with reactions suggestive of immediate HS to penicillins [1,14,24,25]. The sensitivity of prick-tests is low, being positive in less than 30% of the allergic patients. In contrast, ID tests diagnose immediate allergy in 85–95% of the patients. However, skin tests with PPL and MDM may fail to detect specific sensitizations to individual betalactams [26–28]. In contrast, skin tests using soluble betalactams diagnose a significant number of immediate sensitizations to penicillins, cephalosporins and other betalactams [19,29–33]. The recommended concentrations are indicated in Table 1. Finally, immediate-reading skin tests diagnose cross-sensitization between betalactams of the same class and of different

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Table 2 Methodologies of patch testing for betalactam allergy

Table 3 Clinical history of children with suspected betalactam hypersensitivity

Authors [reference] Neukomm et al. [54]

Solvent Saline

Barbaud et al. [32]

Saline and petrolatum Petrolatum

(1) Nature and localization of symptoms ⇒ cutaneous symptoms: – isolated pruritus – urticaria and/or angioedema – EM (with or without bullae), erythroderma, skin detachment – rash: maculopapular, morbilliform, etc. ⇒ other symptoms: – faintness, hypotension/shock – respiratory distress (laryngeal or bronchial), dysphonia, dysphagy – fever – arthralgias, etc... (2) Chronology in relation to beginning of treatment – immediate (≤2 h) – accelerated (≤48 h) – delayed (>48 h) (3) Chronology in relation to the last ingestion of the drug (minutes or hours?) (4) Length of the reaction after stopping the drug (number of hours or days?) (5) Worsening of symptoms – during subsequent treatments – after subsequent ingestions during the same treatment (6) Drug personal history – previous treatments tolerated with the suspected or other drugs in the same family – further treatments tolerated with other anti-microbial drugs in the same family – reactions to other drugs or biological substances (7) Others: ⇒ personal history: atopy, etc ⇒ family history: atopy, suspected or proven drug allergy, etc

Romano et al. [33]

Concentration Penicillin G = 200 000 UI/ml Ampicillin = 1000 mg/ml Amoxicillin = 375 mg/ml Cefazolin = 500 mg/ml Cefuroxime = 500 mg/ml Ceftriaxone = 250 mg/ml Imipenem = 750 mg/ml All betalactams = 30% Penicillin G = 5000 UI/ml Other betalactams = 5%

classes. In our experience, the frequency of positive skin test results to both penicillins and cephalosporins is significantly higher in children with betalactam-induced anaphylaxis than in allergic children reporting other reactions [10], suggesting that anaphylaxis is a major risk factor for sensitization to cross-reactive allergenic determinants of betalactam antibiotics, as shown previously in adults [25,28,29,34]. Semi-late and late responses to betalactams in skin tests (ID and patch tests) have been reported in adult patients and children with non immediate reactions to betalactams, such as urticaria, angioedema, MPR, potentially harmful toxidermia and unidentified rash [11,35–38]. Most patients were sensitized to a particular or a limited number of betalactams [11,12,36,37,39–41], although cross-sensitizations have been reported in a few patients [41–43]. In general use, the concentrations used for ID tests are similar in late- and immediate-reading skin tests. In contrast, the solvent and concentrations used for patch-tests are not standardized [35,36,44] (Table 2). The diagnostic and predictive values of non immediate responses in skin tests with betalactams are controversial, with false positive results [36], and with a large number of children diagnosed allergic on the basis of challenge test results [11,45]. This is probably because the immune response is directed rather against metabolites of the betalactams than against the native or poorly metabolized drugs [46,47]. When skin tests are negative, diagnosis of immediate and non immediate betalactam HS is based on challenge tests. Recent studies suggested that challenge with the suspected betalactams, even if negative, could boost IgE synthesis in 5–10% of patients with negative skin tests [10,48,49], and be responsible for severe relapses on subsequent treatment with the same or very similar betalactams [50]. The authors concluded that it was necessary to repeat skin testing 2–4 weeks later in patients with negative skin tests and challenge, and to diagnose allergy if a conversion of skin tests from negative to positive was observed. However, several studies suggest that most sensitizations detected at the second work-up are transient and non pathogenic: (1) the frequency of suspected allergic relapses is below 4–6% in patients with negative skin tests and challenge [6,48,50,51]; (2) we have shown that most relapses in children were rather a consequence of the

infections (such as the original reactions) for which betalactams have been prescribed than a result of antibiotic HS [52]; (3) a transient sensitization has been shown by in vitro tests (lymphocyte proliferation, cytokine production, specific IgE determination and hemagglutination assay) in numerous subjects after well-tolerated treatments with betalactams [53]. 3. Concluding remarks In children reporting reactions to betalactams, the confirmation or invalidation of the allergic nature of the reactions is not based on in vitro tests, but on a rigorous allergological work-up based on detailed analysis of clinical history (Table 3) and, if necessary, skin and challenge tests. In clinical practice: • few children only reporting reactions to betalactams are really allergic to these antibiotics. In our experience, only 12% of the children were diagnosed allergic based on skin and challenge tests [11]. Except for a few children with allergy or intolerance to other drugs (i.e. antipyretics and NSAIDs), excipients or foods, most of the reactions reported were rather a consequence of the infections for which betalactams have been prescribed than a result of betalactam HS. Acute urticaria and angioedema are caused primarily by infections (espe-

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cially benign viral illnesses), independent of treatment [54]. Various infectious agents, such as mycoplasmas and viruses, cause urticaria, morbilliform and unidentified rashes in children [55], and MPR and Stevens– Johnson Syndrome (SJS) may result from the destruction of infected epidermal cells by cytotoxic T lymphocytes [46]. Skin reactions may also result from interactions between infectious agents and antibiotics, as described in Epstein–Barr virus, influenza virus, and HIV infections [56,57], with subjects generally tolerating subsequent exposure to the drugs concerned [57,58]. It has been shown in vitro that penicillins activated T helper lymphocytes and inhibited activation of T suppressor cells [59]. Thus, betalactams may induce exacerbation of the anti-viral immune response. • Skin tests with betalactams are safe, especially in children. In our experience, a few children only reported mild to moderate reactions induced by skin tests, probably attributable to inadvertent subcutaneous injection of the reagents [11]. However, cases of anaphylaxis, including fatal reactions, have been reported in adults [25]. Thus, skin testing with betalactams must be performed in a hospital with a critical care unit. • In children reporting anaphylactic reactions, all classes of betalactams are contra-indicated because there is a high risk of cross-sensitization to several betalactams in the same and different classes. An allergologic work-up, based on skin tests with the suspected betalactam(s) and with other betalactams from different classes, and challenge (if necessary), must be performed between 3 and 6–12 months after the clinical reaction, to confirm or refute the diagnosis of allergy, and to determine if the child is sensitized to one or several (classes of) betalactam(s). • In children reporting mild to moderate urticaria and angioedema, an allergologic work-up is also recommended. However, the risk of sensitization is low, and cross-reactivity to several betalactams is rare [11,60]. Thus, betalactams from other classes than that suspected are not contra-indicated (i.e. third generation cephalosporins in children reacting during penicillin treatments; penicillin A or M in children reporting a reaction during a cephalosporin treatment). • In children reporting SSLD, allergologic work-up is useless, but the suspected betalactam is contraindicated, with no contra-indication for the other betalactams in the same and other classes [5,61,62]. • A microbial etiology (mycoplasmas, herpes virus, coxsackies, etc.) must be searched as soon as possible for children reporting erythema multiforme (EM) and SJS. When diagnosis of infection by these microorganisms has been ruled out, ID and patch-tests can be performed. However, negative skin tests do not exclude risk of allergy to the suspected betalactams that must be contraindicated, with no contra-indication for other betalactams.

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• Late-reading ID and patch-tests can be performed in children reporting potentially harmful skin reactions such as erythroderma, toxic epidermal necrolysis (TEN), acute generalized exanthematic pustulosis (AGEP), etc. However, as in the case of EM and SJS, negative tests do not exclude an allergy to the suspected betalactams. Challenge tests are forbidden because there is a high risk of severe relapse. Thus, suspected (and very similar) betalactams are contra-indicated, with no contra-indication for other betalactams. • In the other cases, such as unidentified delayed rashs and MPR, skin tests are probably useless, and the diagnosis of HS to betalactams is often ruled out on the basis of tolerance of the challenge with the suspected drug. However, an allergologic work-up is needed in the rare children relapsing during challenge.

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