Acetyl Salicylic Acid Challenge in Children with Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs Differentiates Between Cross-Intolerant and Selective Responders

doi:10.1016/j.jaip.2017.08.029

The Journal of Allergy and Clinical Immunology: In Practice

Volume 6, Issue 4, July–August 2018, Pages 1226-1235

https://doi.org/10.1016/j.jaip.2017.08.029 Get rights and content

Background

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children are becoming a great concern. Most studies have focused on adults, with noted discrepancies observed in the classification of hypersensitivity reactions to NSAIDs in children when compared with adults.

Objective

To phenotype a group of children with hypersensitivity reactions to NSAIDs, including paracetamol, and analyze the degree of agreement with the entities reported in adults and how they fit the proposed classifications.

Methods

The study comprised 116 children aged 0.5 to 14 years, with a clinical history indicative of hypersensitivity reactions to NSAIDs. They all underwent a single-blind oral provocation test with acetyl salicylic acid, except in those cases when this was the suspected drug, in which case the challenge was done first with ibuprofen. If positive, cross-intolerance was established and if negative, an oral provocation test with the culprit drug was performed to establish a selective response or exclude allergy.

Results

Of the 26% diagnosed as hypersensitive to NSAIDs, 83% were cross-intolerant and 17% selective reactors. The highest significant differences between reactors and nonreactors were observed in the time to reaction after drug intake and the clinical entity (P < .0001), followed by drug involved and age (P < .01).

Conclusions

From the total number of cases confirmed with NSAID hypersensitivity, 83% were cross-intolerant. In cross-intolerant reactions, both cutaneous and respiratory manifestations are common. Acetyl salicylic acid challenge as the first approach proved to be safe and useful to establish the diagnosis.

Section snippets

Patient evaluation

Children aged 14 years or younger referred to our service were evaluated prospectively for HR-NSAIDs over 4 years (2012-2015). After the workup (Figure 1) they were classified as hypersensitive to NSAIDs (group A, cases) or tolerant (group B). Challenge with ASA was made in all cases and if good tolerance occurred challenge was made with the culprit drug. Children with positive skin test results to dipyrone were not challenged. Informed written consent was obtained before the allergological

Results

The study included 116 children (67 [58%] boys and 49 [42%] girls) evaluated for a reaction attributed to 1 or more NSAID. The mean and median ages were 7.15 and 7.5 years, the youngest being 6 months and the oldest 14 years. The indications for NSAIDs were fever (44%), headache (19%), pharyngitis (16%), respiratory infection (14%), pain (4%), and otitis (3%). The clinical entities reported were urticaria with/without angioedema (46%), isolated angioedema (29%), exanthema (14%), facial

Discussion

We evaluated 116 children aged 14 years or younger who reported symptoms after intake of NSAIDs, with 26% having confirmed NSAID sensitivity. In the remaining cases, although they reported similar symptoms in the clinical history, hypersensitivity was ruled out. Many children often develop urticaria during acute infectious (frequently viral) episodes, with these reactions often being falsely attributed to the NSAID. This is the largest series evaluating confirmed cases with the youngest group

Acknowledgements

We thank Ian Johnstone for English language assistance.

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Nonsteroidal anti-inflammatory drug (NSAID) outpatient challenge protocols are not standardized. They vary in clinical practice and can be time- and resource-intensive to perform.
To investigate the safety and outcomes of two-step outpatient NSAID challenges to evaluate patients with non–aspirin-exacerbated respiratory disease (AERD)-related NSAID hypersensitivity.
We conducted a retrospective study of patients with a history of NSAID allergy who underwent outpatient NSAID challenges under allergist supervision. Individuals with AERD were excluded. Patient demographics, NSAID reaction history, and drug challenge details and outcomes were collected.
A total of 249 patients (mean age, 51.6 years; 63.5% female) underwent 262 NSAID challenges. Of these, 224 challenges were negative (85.5%). Thirty challenges resulted in an immediate reaction during the challenge procedure (11.5%) and eight resulted in delayed reactions (3.1%). Three individuals with immediate reactions required treatment with intramuscular epinephrine. Factors associated with a positive NSAID challenge included a prior reaction occurring within 5 years of drug challenge (odds ratio [OR] = 3.66; 95% confidence interval [CI], 1.67-8.44), a prior immediate reaction within 3 hours of NSAID ingestion (OR = 2.45; 95% CI, 1.12-5.57), a history of cross-reactive NSAID hypersensitivity to multiple NSAIDs (OR = 2.97; 95% CI, 1.23-6.91), and the presence of comorbid chronic spontaneous urticaria (OR = 2.95; 95% CI, 1.35-6.41).
More than 85% of two-step non-AERD NSAID drug challenges were negative for an immediate or delayed reaction, which allowed patients to use at least one clinically indicated NSAID. Challenge reactions were generally mild. Two-step NSAID challenge protocols can be safely performed in the outpatient setting.
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Citation Excerpt :
Similarly, we were unable to classify 12 patients younger than 10 years and 8 patients older than 10 years (42.5%), mainly because of our inability to perform aspirin provocation in all patients. In contrast, Blanca-Lopez et al20 tested their patients with aspirin first, proceeding to provocation with the suspected drug as a second step if there was no reaction to aspirin. However, this 2-step approach may be useful for patients in the older-than-10-years group.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in children and can frequently cause hypersensitivity reactions. Rates of confirmed NSAID hypersensitivity (NSAID-H) in children are low.
To evaluate the results of drug provocation tests (DPTs) with NSAIDs and to evaluate the difficulties encountered in the classification of NSAID-H in children.
The study included patients with suspected NSAID-H who were examined in our clinic between January 1, 2015, and December 31, 2018. Oral provocation tests with NSAIDs were performed and reactions were classified according to the European Academy of Allergy and Clinical Immunology position paper on NSAID-H.
A total of 243 patients (57.2% male patients) presented with suspected NSAID-H during the study period. Of these, 168 patients (69.1%) had a history of reaction to ibuprofen. Isolated skin involvement was the most frequent symptom (86%). A total of 238 DPTs were performed with the suspected agents and 34 had positive results. The families of 12 patients refused provocation testing with the suspected agent or aspirin and these patients could not be diagnosed. Of the 231 patients, 47 patients (20.3%) received a diagnosis of NSAID-H. Twenty patients with NSAID-H could not be classified because their guardians did not consent to further testing with aspirin.
Performing diagnostic tests is important in patients with no contraindications. Characterizing these reactions in children can be difficult because of the coexistence of indistinguishable symptoms in their history and DPTs, as well as the need for multiple provocation tests. Therefore, further research is needed on this subject.
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Nevertheless, the prevalence of proven NSAID HS varies greatly among studies depending on whether it has been proven by DPTs or only based on the clinical history. In more recent studies, children and adolescents with a suspected history of NSAID-induced HS reaction have been challenged with the culprit drug, with a prevalence of NSAIDs assessed at around 20% to 25% (8% to 68%) in different populations.5,7,9,14,16,17,23-27 To our knowledge, this is the largest study published so far including only patients younger than 18 years with a percentage of confirmed NSAID HS of 19.6% based on 526 DPTs performed with the culprit NSAID or a stronger one.
Diagnosis of hypersensitivity (HS) reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in children is complex. The real prevalence of NSAID HS remains unknown because a drug provocation test (DPT) is not always performed with the culprit NSAID.
To describe and compare the diagnostic workup among different European centers and to find out the real proportion of NSAID HS by performing a DPT with the culprit drug.
We retrospectively collected data from children (0-10 years) and adolescents (10-18 years) with a history of NSAID reactions and who underwent a complete allergy workup including DPTs with the culprit in 6 different pediatric centers: Belgrade, Florence, Geneva, Madrid, Porto, and Rome.
A total of 693 children with a history of NSAID reactions were enrolled, and a total of 526 DPTs were performed with the culprit NSAID. The diagnosis of NSAID HS was confirmed in 19.6% (103 of 526) of children by performing a DPT with the culprit drug. The major differences in the allergy workup among the 6 centers concerned the duration of the DPT and the practical use of skin tests for diagnosing NSAID HS. In addition, the use of acetyl salicylic acid to differentiate single reactor or cross-intolerance patients is not common, except in Spain.
The value of this study is that although different approaches are used around Europe to diagnose NSAID HS, we found that the percentage of confirmed NSAID HS is less than 20%. This highlights the importance of the DPT in confirming or excluding NSAID HS in the pediatric population.
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: This study was supported by the ISCIII (Carlos III Health Institute) with grant numbers PI15/00726, PI15/00303, and RD16/0006, and by Services Research on Chronic Diseases Network-REDISSEC, Spain.

: Conflicts of interest: The authors declare that they have no relevant conflicts of interest.

View full text

Original ArticleAcetyl Salicylic Acid Challenge in Children with Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs Differentiates Between Cross-Intolerant and Selective Responders

Background

Objective

Methods

Results

Conclusions

Section snippets

Patient evaluation

Results

Discussion

Acknowledgements

Immunol Allergy Clin North Am

Ann Allergy Asthma Immunol

Immunol Allergy Clin North Am

Therapie

An Pediatr (Barc)

Allergol Immunopathol

Allergol Int

J Allergy Clin Immunol Pract

J Allergy Clin Immunol

Epidemiology of ACE inhibitor angioedema utilizing a large electronic health record

J Allergy Clin Immunol Pract

Drug hypersensitivity reactions: response patterns, drug involved and temporal variations in a large series of patients

J Investig Allergol Clin Immunol

Selective immediate hypersensitivity reactions to NSAIDs

Curr Opin Allergy Clin Immunol

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs

Allergy

Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction

Ann Intern Med

Characteristics of subjects experiencing hypersensitivity reactions to drugs: pattern of response

Clin Exp Allergy

Time for more clinical research on non-steroidal anti-inflammatory drug-induced urticaria/angioedema and anaphylaxis

Clin Exp Allergy

Original Article
Acetyl Salicylic Acid Challenge in Children with Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs Differentiates Between Cross-Intolerant and Selective Responders