Revue française d’allergologie et d’immunologie clinique 43 (2003) 216–221

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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 anaphylac-
tiques et des urticaires et/ou angio-oedèmes de chronologie immédiate. Après l’interrogatoire, les tests cutanés aux bêtalactamines représen-
tent 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 (photo-
dermatoses), 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
 C. Ponvert / Revue française d’allergologie et d’immunologie clinique 43 (2003) 216–221
1. Results of epidemiological and allergological studies
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 an-
gioedema (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 betalac-
tam 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 beta-
lactams, 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].
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 contro-
versial, with positive responses in control subjects and very
Fig. 1. Diagnostic work-up in suspected betalactam allergy.
217
Table 1
Immediate-reading skin tests for betalactam allergya
(1) Controls – Positive: histamine 10 mg/ml
(prick) and 0.1 mg/ml (ID)
– Negative: saline
(2) Penicillin – PPL: pure
metabolites – MDM: 1/100, 1/10, pure
(3) Soluble Benzyl-penicillin (BP) Other betalactams
betalactams
– 100–250 UI/ml – 0.1–0.25 mg/ml
– 1000–2500 UI/ml – 1–2.5 mg/ml
– 10 000 to ≤25 000 UI/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 posi-
tive 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 rec-
ommended concentrations are indicated in Table 1. Finally,
immediate-reading skin tests diagnose cross-sensitization
between betalactams of the same class and of different
218 C. Ponvert / Revue française d’allergologie et d’immunologie clinique 43 (2003) 216–221
Table 2
Methodologies of patch testing for betalactam allergy
Authors [reference] Solvent Concentration
Neukomm et al. [54] Saline 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
Barbaud et al. [32] Saline and All betalactams = 30%
petrolatum
Romano et al. [33] Petrolatum 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 antibi-
otics, 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 toxider-
mia 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 chal-
lenge test results [11,45]. This is probably because the im-
mune 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 con-
cluded 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 tran-
sient 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
Table 3
Clinical history of children with suspected betalactam hypersensitivity
(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
infections (such as the original reactions) for which betalac-
tams 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 sub-
jects after well-tolerated treatments with betalactams [53].
3. Concluding remarks
In children reporting reactions to betalactams, the confir-
mation 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 chil-
dren 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-
 C. Ponvert / Revue française d’allergologie et d’immunologie clinique 43 (2003) 216–221
cially benign viral illnesses), independent of treatment
[54]. Various infectious agents, such as mycoplasmas
and viruses, cause urticaria, morbilliform and unidenti-
fied rashes in children [55], and MPR and Stevens–
Johnson Syndrome (SJS) may result from the destruc-
tion of infected epidermal cells by cytotoxic T lympho-
cytes [46]. Skin reactions may also result from interac-
tions between infectious agents and antibiotics, as
described in Epstein–Barr virus, influenza virus, and
HIV infections [56,57], with subjects generally tolerat-
ing 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 sup-
pressor cells [59]. Thus, betalactams may induce exac-
erbation of the anti-viral immune response.
• Skin tests with betalactams are safe, especially in chil-
dren. In our experience, a few children only reported
mild to moderate reactions induced by skin tests, prob-
ably 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 per-
formed 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 chal-
lenge (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) betalac-
tam(s).
• In children reporting mild to moderate urticaria and
angioedema, an allergologic work-up is also recom-
mended. 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 cepha-
losporins in children reacting during penicillin treat-
ments; 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 contra-
indicated, with no contra-indication for the other beta-
lactams in the same and other classes [5,61,62].
• A microbial etiology (mycoplasmas, herpes virus, cox-
sackies, 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 contra-
indicated, with no contra-indication for other betalac-
tams.
219
• 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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