Systemic reaction during intradermal skin tests with beta-lactams
- Joana Carvalho and
- Georgeta Oliveira
- Pediatric Department, Local Health Unit of Matosinhos, EPE, Senhora da Hora, Portugal
- Correspondence to Dr Joana Carvalho; joana.teixeiracarvalho@gmail.com
Abstract
Beta-lactam (BL) antibiotics are the most frequent cause of drug hypersensitivity in children, inducing both immediate and non-immediate reactions. Here we report a case of a 4-year-old child with a disseminated maculopapular exanthema 7 days after the first dose of amoxicillin–clavulanate, referred to our paediatric allergy department. Skin prick tests were negative. Intradermal tests were performed and, after 10 hours, indurated wheals larger than 10×10 mm with progressive erythema and disseminated maculopapular eruption were developed, related to amoxicillin and amoxicillin–clavulanate. Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions. This case illustrates a rare example of a non-immediate systemic reaction to intradermal tests, underlying the importance of skin testing before drug provocation tests in cases of moderate to severe non-immediate reactions.
Background
Beta-lactam (BL) antibiotics are the most frequent cause of antibiotic hypersensitivity in children, more specifically amoxicillin alone or amoxicillin–clavulanate. The estimated prevalence of antibiotic hypersensitivity to BL ranges from 1% to 10%.1–3
They can induce immediate and non-immediate reactions. Immediate reactions are induced by an IgE-mediated mechanism and occur within an hour of the last drug administration. Non-immediate reactions are induced by a delayed T cell-dependent type of allergic reaction and generally occur 1–48 hours after the last dose, but they can also appear later. Maculopapular exanthema is the most common non-immediate reaction.1 2
The diagnostic methods of BL allergic reactions consist of clinical history, skin tests, laboratory tests and drug provocation test.1 The authors present a clinical report of a rare systemic non-immediate reaction to a BL intradermal test.
Case presentation
We present a case of a 4-year-old girl admitted to our paediatric allergy clinic due to a BL antibiotic allergy suspicion. The child was born G3P1, birth weight 3455 g and Apgar score of 9/10 points. Her neonatal period was uncomplicated. Since the beginning of preschool at 3 years old, she never had respiratory infections requiring antibiotics. She was vaccinated according to the schedule. There was no family history of atopic disease. According to the interview collected from her mother, oral amoxicillin–clavulanate was given to the child due to a suppurative otitis in December 2019. Seven days after the first dose of this antibiotic and about 2 hours after the last drug intake, a disseminated maculopapular eruption appeared without other symptoms (figure 1). The child was seen at the emergency department, and intravenous corticosteroids and antihistamines were administered with improvement of the symptoms. The antibiotic was suspended and she was referred to our paediatric allergy clinic for drug allergy diagnosis. The investigation was performed 6 months after the adverse event, according to the European Academy of Allergology and Clinical Immunology guidelines.1
Disseminated maculopapular exanthema 7 days after the first dose of amoxicillin–clavulanate.
Investigations
Skin prick and intradermal tests were performed with antibiotic concentrations as recommended in previous studies,4–6 with penicilloyl-polylysine (benzylpenicilloyl poly-L-lysine 0.04 mg and mannitol 20 mg per 1.0 mL of diluent), minor determinant mixture (sodium benzylpenicillin 0.5 mg, benzylpenicilloyl acid 0.5 mg, sodium benzylpenicilloate 0.5 mg and mannitol 20 mg per 1.0 mL of diluent) (Diater TM, Madrid, Spain), amoxicillin (20 mg/mL) and amoxicillin–clavulanate (20 mg/mL). Skin prick tests were negative after 15 min. Intradermal tests were performed in full-strength concentrations due to the non-immediate nature of the reaction. Responses were evaluated at 15 min and at 1, 24 and 48 hours. About 10 hours after the intradermal tests, the patient exhibited positive responses with both concentration of amoxicillin and amoxicillin–clavulanate, showing indurated wheals larger than 10×10 mm with erythema (figure 2), accompanied by the gradual appearance of a generalised maculopapular exanthema, beginning in the upper trunk and lower limbs (figure 3). She was treated with oral corticosteroids and antihistamines, with clinical improvement and complete resolution at 72 hours.
Positive responses to amoxicillin and amoxicillin–clavulanate intradermal tests.
Progressive erythema to the lower limbs after intradermal tests.
Outcome and follow-up
Drug provocation tests with the suspected BL were not performed due to the positive intradermal tests. Five weeks later, a drug provocation test with an alternative BL (cefuroxime) was performed. During the whole provocation test, we did not notice any adverse reaction. The parents were informed that cefuroxime may be used safely in case of infections needing therapy with antibiotics.
Discussion
BLs are the most common antibiotics prescribed and are responsible for the majority of drug allergies, followed by non-steroidal anti-inflammatory drugs and non-BL antibiotics. Hypersensitivity reactions to drugs are a frequent problem in clinical practice and have a significant impact on patient health. Clinical manifestations range from maculopapular and non-immediate urticarial exanthemas to anaphylaxis or severe cutaneous adverse reactions. Viral and bacterial infections with exanthemas are important differential diagnoses to consider in drug hypersensitivity reactions management.1 2
Drug allergies diagnosis approach differs for immediate and non-immediate reactions. For immediate reactions (within an hour of the last drug administration), it includes skin prick tests and immediate-reading intradermal tests. Regarding non-immediate or delayed reactions (appearing after 1 hour of drug administration, the majority after 6 hours), management includes skin prick tests, delayed-reading intradermal tests and, if negative, drug provocation tests.7 Intradermal tests are the most sensitive skin tests, but are more painful and less tolerated by younger children. Therefore, in mild exanthemas resulting from non-immediate reactions, it has been proposed to perform drug provocation tests without prior skin tests. It is important to note that the clinician should be certain that the child does not show any signs associated with a potential severe reaction, highlighting the importance of an accurate description of the reaction. For patients with a history of severe reactions, the use of a drug provocation test is contraindicated, due to the potential risk of triggering a severe systemic reaction. Therefore, the diagnostic procedure should start with a patch test and if negative, intradermal tests can be performed, starting with the highest dilutions.1 In our case, the reaction appeared 7 days after the first dose, but with a maculopapular eruption, therefore a more cautious approach was chosen with skin tests first.
Systemic reactions to BL skin tests are rarely reported and the majority are immediate reactions.8 9 In the literature, generalised reactions after BL skin tests are rare, from 0.1% to 2% of all patients tested and from 0.7% to 9.4% of positive skin-tested patients.10 11 An analysis of reported (suspected) cases of adverse drug reactions conducted by the Paul Ehrlich Institute yielded 26 reported cases following skin tests, 16 after prick tests, 2 after intradermal testing. A 10% risk of experiencing potential systemic reactions during skin tests has been reported for patients with a history of penicillin allergy associated with severe anaphylactic reactions.12 13 To our knowledge, there are no reports of systemic reactions to intradermal tests with BL in children. In this case, a generalised non-immediate reaction to BL intradermal tests has occurred in a context of a previous moderate exanthema.
As regards the sensitivity of prick and intradermal tests, the majority of studies describe a greater sensitivity for intradermal testing. In general, being more painful and less tolerated by children, intradermal tests are only carried out after a negative prick test,1 14 like in our case.
Avoidance of the culprit and cross-reactive drugs is the treatment of choice for hypersensitivity reactions to drugs. It should be provided a written list of the generic and brand names of the culprit drug, as well as possibly cross-reactive drugs. Compared with adults, this avoidance may be more difficult to achieve in children as the choice of complementary drugs is more limited due to prescription restrictions. In drug allergy-prone patients, efforts should be made to limit unnecessary exposure to antibiotics, namely treating underlying conditions that predispose to infections (like rhinitis or asthma) and having proactive efforts to obtain culture data before initiating antibiotics by avoiding treatment of viral infections and minimising mid-treatment changes in antibiotics regimens.1
In conclusion, this case illustrates that intradermal tests should be performed cautiously and the importance of their late reading must not be underestimated. It also illustrates that non-immediate systemic reactions can occur after intradermal tests, although they are rare. Drug provocation tests without prior skin testing appear to be safe in non-immediate mild exanthemas, but a more cautious approach should be advocated in cases of moderate to severe non-immediate reactions.
Learning points
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Beta-lactams are the most common antibiotics prescribed and the most frequent cause of drug hypersensitivity in children.
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The diagnostic approach includes a detailed clinical history, followed by skin tests and drug provocation tests. In mild exanthemas resulting from non-immediate reactions, drug provocation tests have been proposed to be safe without prior skin tests.
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Although rare, systemic reactions can occur after beta-lactam intradermal tests.
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A more conservative approach using skin testing prior to drug provocation tests should be recommended in the management of moderate to severe non-immediate reactions.
Footnotes
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Contributors JC and GO—bibliographical search, drafting of the article and critical reviewing of the content of the article.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Parental/guardian consent obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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