Diagnosis of drug causality in non-immediate drug hypersensitivity in children
GRAHAM, François, CAUBET, Jean-Christoph Roger J-P
GRAHAM, François, CAUBET, Jean-Christoph Roger J-P. Diagnosis of drug causality in non-immediate drug hypersensitivity in children. Expert Review of Clinical Pharmacology , 2018, vol. 11, no. 7, p. 655-658
DOI : 10.1080/17512433.2018.1494570 PMID : 29949394
Disclaimer: layout of this document may differ from the published version.
1 / 1
Full Terms & Conditions of access and use can be found at
Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: https://www.tandfonline.com/loi/ierj20
Diagnosis of drug causality in non-immediate drug hypersensitivity in children
François Graham & Jean-Christoph Caubet
To cite this article: François Graham & Jean-Christoph Caubet (2018) Diagnosis of drug causality in non-immediate drug hypersensitivity in children, Expert Review of Clinical Pharmacology, 11:7, 655-658, DOI: 10.1080/17512433.2018.1494570
To link to this article: https://doi.org/10.1080/17512433.2018.1494570
Accepted author version posted online: 27 Jun 2018.
Published online: 06 Jul 2018.
Submit your article to this journal
Article views: 444
View related articles
View Crossmark data
Diagnosis of drug causality in non-immediate drug hypersensitivity in children
François Graham and Jean-Christoph Caubet
Pediatric Allergy Unit, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.
ARTICLE HISTORYReceived 30 March 2018; Accepted 26 June 2018
KEYWORDSAllergy; delayed drug hypersensitivity; non-immediate reactions; drug provocation test; children; beta-lactam antibiotics; penicillin; non-steroidal anti-inflammatory drugs; non-beta-lactam antibiotics; skin test
Drug hypersensitivity reactions are an important public health concern and are frequently suspected in children, with a self- reported prevalence of up to 6% . Non-immediate drug hyper- sensitivity reactions are defined as drug reactions occurring more than 1 h after the administration of the drug dose . Mild non- immediate reactions generally consist of uncomplicated macu- lopapular exanthemas or delayed urticaria/angioedema and are devoid of danger signs [2,3]. Severe non-immediate reactions include severe cutaneous adverse reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms, Stevens- Johnson syndrome, toxic epidermal necrolysis, and acute gener- alized exanthematous pustulosis .
Beta-lactam (BL) allergy is the most common cause of drug allergy related consultations in children , with an incidence of 1–5% of skin eruptions per BL prescription . Most rashes occur- ring during BL treatment are thought to be viral, as the majority are not reproduced with drug provocation tests (DPTs) .
However, in clinical practice, most of these patients are labeled as allergic without an appropriate allergic work-up to exclude or confirm a real allergy. Physicians and patients generally refuse to reuse the culprit drug once a suspected reaction has occurred, usually by fear of reproducing a similar or more severe reaction .
Unfortunately, use of alternative antibiotics may lead to higher costs, treatment failures, and adverse reactions .
Traditionally, the evaluation of non-immediate mild reactions to BL involved delayed-reading intradermal tests (IDTs), followed by DPTs in patients with negative skin tests (STs). However, multiple studies have shown that IDTs have a low sensitivity [5,7–10] in non-immediate mild reactions to BLs. In addition, recent studies have found a low positive predictive value (PPV) of STs in both children [5,11] and populations consisting mainly of adults [12,13] when evaluating non-immediate mild reactions to BLs. Considering that these IDTs are not standardized, painful, and difficult to interpret, multiple centers have performed direct DPTs in children without skin testing before or without taking into account the result of STs [5,12,14–17], with no severe reac- tions being documented. Nonetheless, this approach is still con- troversial, and some centers  continue to perform STs in mild non-immediate reactions in children to reduce the risk of having even one positive DPT, arguing that patients with positive IDTs have a higher rate of positive DPTs . From another point of view, a large number of painful IDTs need to be performed to
detect only a very small amount of positive reactions on DPT, which have been shown to be mild in numerous studies [5,11,12]. Furthermore, in our experience, many parents refuse painful IDTs to be performed on their children whereas the DPT is well accepted . Therefore, direct DPT without STs in children with mild non-immediate reactions is increasingly accepted, and this approach has recently been outlined by the European Academy of Allergy and Clinical Immunology  and British Society of Allergy and Clinical Immunology . However, addi- tional multicentric studies are still required to validate the safety of such an approach and increase overall consensus.
Thus, DPTs play a central role in the management of children with a suspicion of non-immediate BL allergy. However, DPTs are not standardized and multiple different protocols are used among centers, even in the same country. In particular, the optimal length of DPTs remains highly debated, ranging from 1 to 10 days [5,12,14,17,21–23]. It has been shown that longer protocols can increase the sensitivity, with up to 6.2% of patients reacting after the first day of DPT [5,7–9,14,17,21]. In addition, some authors have suggested that compliance to BLs may be increased after extended DPTs when compared to shorter pro- tocols [14,23]. On the other hand, the negative predictive value (NPV) of 1-day DPTs is relatively similar to the NPV of prolonged DPTs (89.1 to 97.6%) [5,14,22,24–26]. Of note, the percentage of patients that will react after a negative DPT is similar to the incidence of cutaneous rashes during antibiotic treatments in children, which is estimated around 5% . In addition, an important concept is the number needed to harm ; many children need to be exposed to a prolonged course of antibiotics to screen a few patients who would present a mild reaction when retaking the antibiotic. Although this may seem innocuous, tak- ing antibiotics for no validated reason is not benign; studies have shown that gut microbiota is significantly altered during anti- biotic course , and long-term effects of multiple antibiotic courses in children are numerous, including obesity , anti- microbial resistance , and possibly increased atopy .
Another possible confounding factor in studies is the delay between the index reaction and the DPT. The delay is variable, with some studies having a delay of only a few months , and others a mean of 2 to 3 years [14,24]. When the delay is longer, parents often cannot recall the reaction, and it is often difficult to classify the patients as immediate or non-immediate reactions. In
CONTACTJean-Christoph Caubet, Jean-Christoph.Caubet@hcuge.ch Pediatric Allergy Unit, University Hospitals of Geneva, 6 rue Willy-Donze, 1211, Geneva, 14, Switzerland
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 2018, VOL. 11, NO. 7, 655–658
© 2018 Informa UK Limited, trading as Taylor & Francis Group
addition, a longer DPT may be required to reactivate an immune response with a longer interval between DPT and index reaction.
Another question is the ideal way to perform the first day DPT in children with mild delayed reactions. Studies have proposed DPTs ranging from a graded challenge divided in 7 to 8 doses  to one single dose [5,24]. In our Geneva cohort we have performed more than 350 single dose DPTs in patients with mild non-immediate reactions to BLs with no serious adverse reac- tions (unpublished data). This has also been supported by Ponvert et al.  who give a 5- to 7-day BL prescription directly at home without performing a DPT at the hospital the first day when children have a clear history of mild delayed reactions.
Based on the current literature and taking into account the risk-benefit balance, a single dose , single day  challenge appears to be the optimal protocol when evaluating non- immediate mild reactions to BLs in children. These DPTs should be performed in a supervised setting with experienced personnel able to treat allergic reactions. Head-to-head stu- dies with a fixed interval between the initial reaction and DPT are still needed to confirm that this approach is optimal.
Non-BL antibiotics are another common cause of drug allergy in children, the most frequently incriminated being cotrimoxazole and macrolides . In addition, quinolone allergies are increas- ingly reported due to their frequent use in children with cystic fibrosis . The value of STs for non-BLs in children remains largely unknown, although non-irritating doses have been described in adult populations . Delayed reading IDTs followed by DPT remain the classical approach when evaluating children with non- immediate mild reactions to non-BLs, even if the sensitivity and PPV of these STs is not well established. Future studies are urgently required to evaluate whether direct DPTs without STs is safe for non-immediate mild reactions to non-BLs, and to determine the optimal DPT protocols for non-BLs.
Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed during viral infections and in some centers represent the number one cause of drug hypersensitivity reactions in chil- dren . They are generally divided in cross-intolerant and non- cross-intolerant reactions . The most frequent non-immediate reactions in children are cross-intolerant reactions involving angioedema and/or urticaria [35–37], which can occur up to 24 hours after drug intake . On the other hand, mild exanthe- mas after NSAID therapy are not as common, representing 14–23%
of children in studies [37,38]. STs to NSAIDS are not validated [37,39], and DPTs are the gold standard to determine NSAID tolerance or selective responders, and/or to eliminate cross- intolerance reactions. Most children with a history of mild exanthe- matous reactions to NSAIDs on history have negative DPTs [37,38,40,41] and studies have shown that patients with a history of reaction after 1 h of drug intake are less at risk of reacting on DPT [36,37]. As with BLs, standardization of DPTs is required concerning number of doses, the optimal dose itself, length, and type of NSAID challenged. Some authors propose a direct DPT with the culprit NSAID [38,39,41], whereas others start with aspirin to exclude cross-intolerance [37,42]. Starting with aspirin is beneficial since it can help distinguish selective and cross responders with one single DPT.
Finally, management of children with suspicion of SCARs, although rare in children, remains difficult. The majority are
caused by antibiotics and antiepileptic drugs . Based on current international guidelines, patch tests should be consid- ered as the first line diagnostic method in the evaluation of SCARs . However, the diagnostic value of patch tests in SCARs remains relatively unknown since there are few studies to validate their result considering that DPTs are contraindi- cated in SCARs . Althoughin vitrotests such as lymphocyte transformation tests, the flow cytometric lymphocyte activa- tion test, and the enzyme linked immunospot assays have been useful to identify culprit drugs in adults, they still need validation in children.
The natural history of delayed drug hypersensitivity reac- tions in children is relatively unknown; a recent study demon- strated that most children with DPT confirmed BL allergies acquire tolerance to the index antibiotic after a 3-year period , although future studies are needed to confirm these findings. Another study showed that the natural history of NSAID induced urticaria/angioedema was favorable, with the majority of patients losing their allergy after 5 years, although this was an adult cohort . Future multicentric and prospec- tive studies are needed in children.
In conclusion, there are still many caveats regarding our knowledge of drug allergy in children and there is an urgent need for large multicentric studies to improve the manage- ment of those patients. In particular, the optimal protocol for DPTs needs to be determined for the diagnosis of non- immediate drug allergy to BLs. The diagnostic value of STs for non-BLs needs to be evaluated. Recent data suggesting a favorable evolution of drug allergy in children needs to be confirmed. There is also a need to develop new diagnostic tests to reduce the number of DPTs, which remain the most important test to diagnose non-immediate hypersensitivity reactions.
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
This manuscript was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
1. Rebelo Gomes E, Fonseca J, Araujo L, et al. Drug allergy claims in children: from self-reporting to confirmed diagnosis. Clin Experimental Allergy: Journal Br Soc Allergy Clin Immunol.2008;38(1):191–198.
2. Demoly P, Adkinson NF, Brockow K,et al. International consensus on drug allergy. Allergy.2014;69(4):420–437.
656 F. GRAHAM AND J.-C. CAUBET
•• International consensus on the diagnosis and management of drug allergy.
3. Gomes ER, Brockow K, Kuyucu S, et al. Drug hypersensitivity in children: report from the pediatric task force of the EAACI drug allergy interest group. Allergy, 71(2),149–161 (2016).
•• Guidelines from the European Academy of Allergy and Clinical Immunology which summarize the management of children with drug hypersensitivity reactions.
4. Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes in chil- dren: a survey in a private practice setting. Arch Dermatol.
5. Caubet J-C, Kaiser L, Lemaître B, et al. The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge. J Allergy Clin Immunol.2011;127(1):218–222.
6. Blumenthal KG, Li Y, Banerji A, et al., The cost of penicillin allergy evaluation. J Allergy Clin immunol.In Pract.2018;6(3):1019–1027.e2.
7. Atanaskovic-Markovic M, Gaeta F, Medjo B, et al. Non-immediate hypersensitivity reactions to beta-lactam antibiotics in children– our 10-year experience in allergy work-up. Pediatr Allergy Immunol.2016;27(5):533–538.
8. Zambonino MA, Corzo JL, Muñoz C, et al. Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children. Pediatr Allergy Immunol.2014;25(1):80–87.
9. Ponvert C, Perrin Y, Bados-Albiero A, et al. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol.2011;22 (4):411–418.
10. Barni S, Mori F, Sarti L, et al. Utility of skin testing in children with a history of non-immediate reactions to amoxicillin. Clin Experimental Allergy: Journal Br Soc Allergy Clin Immunol.
11. Vyles D, Adams J, Chiu A, et al. allergy testing in children with low-risk penicillin allergy symptoms. Pediatrics.2017;140:2.
12. Confino-Cohen R, Rosman Y, Meir-Shafrir K,et al. Oral challenge without skin testing safely excludes clinically significant delayed-onset penicillin hypersensitivity. J Allergy Clin immunol.In Pract.2017;5(3):669–675.
• Large study emphasizing the safety of performing DPTs with- out preceding skin testing in patients with mild non-immedi- ate penicillin hypersensitivity.
13. Goldberg A, Confino-Cohen R. Skin testing and oral penicillin chal- lenge in patients with a history of remote penicillin allergy. Ann Allergy, Asthma Immunol. Official Publication American College Allergy, Asthma, Immunology.2008;100(1):37–43.
14. Labrosse R, Paradis L, Lacombe J, et al. Efficacy and safety of five-day challenge for the evaluation of non-severe amoxicillin allergy in children. J Allergy Clin immunol.In Pract. 2018. [Epub ahead of print]
• This study supports increased future compliance after a 5-day DPT compared to a 1-day DPT in children with a suspicion of amoxicillin allergy.
15. Prieto A, Doña I, Muñoz C, et al. Value of drug provocation test in non-immediate hypersensitivity reactions to betalactams in pedia- tric age. J Allergy Clin Immunol.2018;141(2):AB37.
16. Koosakulchai V, Wantanaset D, Jessadapakorn W, et al. Safety of amoxicillin provocation test using the PSU 2-step challenge in children with a history of non-immediate reactions. J Allergy Clin Immunol.2018;141(2, Supplement):AB39.
17. Vezir E, Dibek Misirlioglu E, Civelek E,et al. Direct oral provocation tests in non-immediate mild cutaneous reactions related to beta-lactam antibiotics. Pediatr Allergy Immunology: Official Publication Eur Soc Pediatr Allergy Immunol.2016;27(1):50–54.
18. Sogn DD, Evans R 3rd, Shepherd GM,et al. Results of the national institute of allergy and infectious diseases collaborative clinical trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med.
19. Gomes ER, Kvedariene V, Demoly P, et al. Patients’satisfaction with diagnostic drug provocation tests and perception of its usefulness.
Int Arch Allergy Immunol.2011;156(3):333–338.
20. Mirakian R, Leech SC, Krishna MT,et al. Management of allergy to penicillins and other beta-lactams. Clin Experimental Allergy:
Journal Br Soc Allergy Clin Immunol.2015;45(2):300–327.
21. Mori F, Cianferoni A, Barni S, et al. Amoxicillin allergy in children:
five-day drug provocation test in the diagnosis of nonimmediate reactions. J Allergy Clin immunol.In Pract.2015;3(3):375–380 e371.
22. Mill C, Primeau MN, Medoff E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr.2016;170(6):e160033.
• Large study providing evidence for the safety of direct graded DPTs without skin testing in children with a history of mild reactions to amoxicillin.
23. Ratzon R, Reshef A, Efrati O, et al. Impact of an extended challenge on the effectiveness of beta-lactam hypersensitivity investigation. Ann Allergy, Asthma Immunol. Official Publication American College Allergy, Asthma, Immunology.
24. Ponvert C, Weilenmann C, Wassenberg J, et al. Allergy to betalac- tam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests. Allergy.2007;62(1):42–46.
25. Chiriac A-M, Rerkpattanapipat T, Bousquet P-J, et al. Optimal step doses for drug provocation tests to prove beta-lactam hypersensitivity. Allergy.2017;72(4):552–561.
• Interesting article determining optimal step doses for beta- lactam drug provocation tests.
26. Demoly P, Romano A, Botelho C, et al. Determining the negative predictive value of provocation tests with beta-lactams. Allergy.
27. Brunser O, Gotteland M, Cruchet S, et al. Effect of a milk formula with prebiotics on the intestinal microbiota of infants after an antibiotic treatment. Pediatr Res.2006;59(3):451–456.
28. Korpela K, De Vos WM. Antibiotic use in childhood alters the gut microbiota and predisposes to overweight. Microbial Cell (Graz, Austria).2016;3(7):296–298.
29. Gibson MK, Crofts TS, Dantas G. Antibiotics and the developing infant gut microbiota and resistome. Curr Opin Microbiol.2015;27:51–56.
30. Ahmadizar F, Vijverberg SJH, Arets HGM,et al. Early-life antibiotic exposure increases the risk of developing allergic symptoms later in life: a meta-analysis. Allergy.2018;73(5):971–986.
31. Kuyucu S, Mori F, Atanaskovic-Markovic M, et al. Hypersensitivity reactions to non-betalactam antibiotics in children: an extensive review. Pediatr Allergy Immunology: Official Publication Eur Soc Pediatr Allergy Immunol.2014;25(6):534–543.
32. Atanaskovic-Markovic M, Caubet JC. Management of drug hyper- sensitivity in the pediatric population. Expert Rev Clin Pharmacol.
33. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs – an ENDA/EAACI drug allergy interest group position paper. Allergy.2013;68(6):702–712.
34. Kidon M, Blanca-Lopez N, Gomes E, et al. EAACI/ENDA Position Paper: diagnosis and management of hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in children and adolescents. Pediatr Allergy Immunology: Official Publication Eur Soc Pediatr Allergy Immunol.2018. [Epub ahead of print]
•• Recent position paper from the European Academy of Allergy and Clinical Immunology on the diagnosis and management of NSAID hypersensitivity reactions in children.
35. Zambonino MA, Torres MJ, Muñoz C, et al. Drug provocation tests in the diagnosis of hypersensitivity reactions to non-steroidal anti-inflammatory drugs in children. Pediatr Allergy Immunology:
Official Publication Eur Soc Pediatr Allergy Immunol. 2013;24 (2):151–159.
36. Arikoglu T, Aslan G, Yildirim DD, et al. Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersen- sitivity reactions in children. Allergol Int.2017;66(3):418–424.
37. Blanca-López N, Haroun-Diaz E, Ruano FJ, et al. Acetyl salicylic acid challenge in children with hypersensitivity reactions to nonsteroidal anti-inflammatory drugs differentiates between EXPERT REVIEW OF CLINICAL PHARMACOLOGY 657
cross-intolerant and selective responders. J Allergy Clin Immunology: In Pract.2017. [Epub ahead of print]
38. Alves C, Romeira AM, Abreu C, et al. Non-steroidal anti-inflammatory drug hypersensitivity in children. Allergol Immunopathol (Madr).
39. Cousin M, Chiriac A, Molinari N, et al. Phenotypical characterization of children with hypersensitivity reactions to NSAIDs. Pediatr Allergy Immunology: Official Publication Eur Soc Pediatr Allergy Immunol.2016;27(7):743–748.
40. Guvenir H, Dibek Misirlioglu E, Vezir E, et al. Nonsteroidal anti-inflammatory drug hypersensitivity among children. Allergy Asthma Proc.2015;36(5):386–393.
41. Cavkaytar O, Arik Yilmaz E, Karaatmaca B, et al. Different pheno- types of non-steroidal anti-inflammatory drug hypersensitivity dur- ing childhood. Int Arch Allergy Immunol.2015;167(3):211–221.
42. Pérez-Alzate D, Cornejo-García JA, Pérez-Sánchez N, et al.
Immediate reactions to more than 1 NSAID must not be considered
cross-hypersensitivity unless tolerance to ASA is verified. J Investig Allergol Clin Immunol.2017;27(1):32–39.
43. Dibek Misirlioglu E, Guvenir H, Bahceci S, et al. Severe cuta- neous adverse drug reactions in pediatric patients: a multi- center study. J Allergy Clin Immunol Pract.2017;5(3):757–763.
44. Bergmann M, Caubet J-C. Specific aspects of drug hypersensi- tivity in children. Curr Pharm Des.2016;22(45):6832–6851.
45. Tonson La Tour A, Michelet M, Eigenmann PA, et al. Natural history of benign nonimmediate allergy to beta-lactams in children: a prospec- tive study in retreated patients after a positive and a negative provocation test. J Allergy Clin Immunology: In Pract.2017. [Epub ahead of print]
• This is the first study to assess the natural history of mild beta- lactam allergy in children.
46. Doña I, Barrionuevo E, Salas M, et al. Natural evolution in patients with nonsteroidal anti-inflammatory drug-induced urticaria/angioedema. Allergy. 2017;72(9):1346–1355.
658 F. GRAHAM AND J.-C. CAUBET