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Diagnostic flow chart for 106 patients with suspected NSAID hypersensitivity.
Source publication
Background:
Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently encountered in daily clinical practice. The aim of this study was to determine the confirmation rates, risk factors of NSAID hypersensitivity in children and to try to classify them with a standardized diagnostic protocol.
Methods:
All patients with a su...
Context in source publication
Context 1
... 31 were confirmed with tests. Of the 31 patients with confirmed reactions, 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPT. NSAID hypersensitivity in two patients with a his- tory of doctor diagnosed anaphylaxis was confirmed by medical records and DPTs were not performed in such high risk patients based on ENDA recommendations ( Fig. 1) (Table ...
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Background:
Suspicion of beta-lactam (BL) hypersensitivity is often based on parental report. Evaluation is important as incorrect labelling has clinical consequence.
Objective:
To describe the outcomes of drug provocation test (DPT) in children with suspected hypersensitivity.
Methods:
A retrospective study of patients who completed BL DPT fr...
Since overdiagnosis of beta‐lactam (BL) allergy is common in the pediatric population, delabeling is a critical part of antimicrobial stewardship. Undesirable consequences of inaccurate BL allergy labeling can be handled by incorporating traditional delabeling or newer risk‐based strategies into antibiotic stewardship programs. Conventional assessm...
Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity reactions (HSRs) are often nonimmunologically mediated reactions which present with immediate HSR type manifestations. These are mediated by cyclooxygenase inhibition resulting in shunting towards the excessive production of leukotrienes. Important disease associations include asthma, nas...
Background:
The European Network for Drug Allergy (ENDA) proposed a consensus document for hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) in 2011. A subgroup of patients with NSAIDs-exacerbated respiratory disease (NERD) develop urticaria/angioedema type reactions in response to NSAIDs. The Kalyoncu classification migh...
Objective A misdiagnosed “penicillin allergy” is a common problem in childhood. Recently, skipping skin tests (STs) and performing a direct oral challenge test (OCT) have become an increasingly common approach in children with suspected β-lactam (BL) allergy. In our study, we aimed to evaluate the safety and efficacy of OCT without using ST in chil...
Citations
... 11 Although the EAACI/ENDA classification provides evidence-based recommendations for managing hypersensitive patients, recent data suggest that certain patients cannot be classified into the phenotypes described by the EAACI/ENDA group, indicating critical unmet needs in understanding and managing NSAID hypersensitivity reactions. 9,[12][13][14][15] This study aims to assess NSAID HSRs that do not fit the latest EAACI classification, focusing on potential new phenotypes and describing the culprit drugs in Turkey. ...
... In a study involving 106 children, one patient with cross-intolerance could not be classified according to pathomechanisms, and seven patients with cross-intolerance could not be categorized based on the underlying disease and clinical manifestations using the EAACI/ENDA method. 12 It can be argued that the validity of these studies may be limited, as the ENDA classification primarily focuses on adult populations. This has led to some studies done in the adult population questioning the efficacy of the ENDA classification and even proposing alternative classification systems. ...
Background:
Hypersensitivity reactions (HSRs) to nonsteroidal anti-inflammatory drugs (NSAIDs) are a significant clinical issue. Several classifications have been proposed to categorize these reactions, including the current European Academy of Allergy and Clinical Immunology/European Network for Drug Allergy (EAACI/ENDA) classification. This study aimed to evaluate the applicability of this classification in a real-world clinical setting.
Methods:
We conducted a national multicenter study involving patients from nine hospitals in four major urban centers in Turkey. All patients had a suggestive clinical history of hypersensitivity reactions to NSAIDs. Researchers collected data using a structured form and classified reactions based on the EAACI/ENDA classification. Oral provocation tests with several NSAIDs were performed using a single-blind challenge per EAACI/ENDA guidelines.
Results:
Our retrospective study included 966 adult patients with a history of hypersensitivity to NSAIDs. The most common triggers were Acetylsalicylic Acid (ASA), paracetamol, and metamizole. The most prevalent acute NSAID hypersensitivity group was NSAID-induced urticaria/angioedema (NIUA) (34.3%). However, 17.3% of patients did not fit neatly into the current EAACI/ENDA classification. Notably, patients with underlying asthma or allergic rhinoconjunctivitis exhibited unusual reactions, such as urticaria and/or angioedema induced by multiple chemical groups of NSAIDs, blended mixed reactions, and isolated periorbital angioedema in response to multiple chemical groups of NSAIDs.
Conclusions:
While the EAACI/ENDA classification system stratifies NSAID-induced hypersensitivity reactions into five distinct endotypes or phenotypes, it may not fully capture the diversity of these reactions. Our findings suggest a need for further research to refine this classification system and better accommodate patients with atypical presentations.
... Hypersensitivity to NSAIDs can be safely diagnosed by drug provocation tests, but different phenotypes that do not fit into the current classification might exist [232,234,236,237]. ...
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in infants, children, and adolescents worldwide; however, despite sufficient evidence of the beneficial effects of NSAIDs in children and adolescents, there is a lack of comprehensive data in infants. The present review summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available, and includes ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, ketorolac, indomethacin, niflumic acid, meloxicam, celecoxib, parecoxib, rofecoxib, acetylsalicylic acid, and nimesulide. The efficacy of NSAIDs has been documented for a variety of conditions, such as fever and pain. NSAIDs are also the main pillars of anti-inflammatory treatment, such as in pediatric inflammatory rheumatic diseases. Limited data are available on the safety of most NSAIDs in infants. Adverse drug reactions may be renal, gastrointestinal, hematological, or immunologic. Since NSAIDs are among the most frequently used drugs in the pediatric population, safety and efficacy studies can be performed as part of normal clinical routine, even in young infants. Available data sources, such as (electronic) medical records, should be used for safety and efficacy analyses. On a larger scale, existing data sources, e.g. adverse drug reaction programs/networks, spontaneous national reporting systems, and electronic medical records should be assessed with child-specific methods in order to detect safety signals pertinent to certain pediatric age groups or disease entities. To improve the safety of NSAIDs in infants, treatment needs to be initiated with the lowest age-appropriate or weight-based dose. Duration of treatment and amount of drug used should be regularly evaluated and maximum dose limits and other recommendations by the manufacturer or expert committees should be followed. Treatment for non-chronic conditions such as fever and acute (postoperative) pain should be kept as short as possible. Patients with chronic conditions should be regularly monitored for possible adverse effects of NSAIDs.
... 71 The most commonly implicated NSAID is ibuprofen. [72][73][74][75][76] The main identified risk factors for NSAID hypersensitivity are older age, atopy, chronic urticaria, a previous anaphylaxis history, the number of concomitant drugs, and a family history of NSAID allergy. 72,[75][76][77][78][79][80][81][82] Approach and Diagnosis ...
... [72][73][74][75][76] The main identified risk factors for NSAID hypersensitivity are older age, atopy, chronic urticaria, a previous anaphylaxis history, the number of concomitant drugs, and a family history of NSAID allergy. 72,[75][76][77][78][79][80][81][82] Approach and Diagnosis ...
... 74,76,83 In general, SPT has been described with approximately 5% to 33% positivity rate. 70,73,75,80,81,84,85 Ingestion challenge remains the gold standard for NSAID assessment allowing to confirm or rule out the allergy. The rate of positive ingestion challenge reported in the literature varies from 11% 74,80 to 30% 70,72,73,75,81,85 for the majority of the studies. ...
Drug allergies are reported in approximately 10% of children and carry significant health and economic impacts. However, only a minority of these reported drug allergies are established on diagnostic workup. Classically, drug allergies were diagnosed by skin prick and/or intradermal tests. However, recent data reveal that a direct ingestion challenge is often an appropriate diagnostic strategy in cases of reported nonsevere reactions to penicillin derivatives in children. This article will review the prevalence, diagnosis, and management of the main culprits of pediatric drug allergies: antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs). We will also review severe cutaneous adverse reactions to drugs in children.
... The rate of NSAID-H, as confirmed with oral provocation tests (OPT), was measured between 4% and 68% in various patient groups with histories of suspected reactions (Table 2). 25,27,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Considering the general pediatric population, the rate of actual ASA-hypersensitivity (ASA-H) in 1632 control subjects was detected as 0.55% according to the OPT performed independent of suspected ASA-H history. 45 However, in a very recent study in which OPT with ASA was performed if there was a positive clinical history, only one participant had undergone OPT, and no ASA-H was detected in 2000 control subjects (Table 2). ...
... 61 However, although it is relatively safe in terms of other adverse events, ibuprofen is the most frequent cause of NSAID-induced hypersensitivity reactions in susceptible children. 25,27,[30][31][32][33]35,36,38,41,62,63 It is a propionic acid derivative and a strong cyclo-oxygenase (COX) enzyme inhibitor like ASA. Gaffar et al reported actual ibuprofen hypersensitivity at a rate of 22.7% in children with a suspected history of ibuprofen-induced reactions, with half of the OPT resulting in anaphylactic reactions. ...
... The clinical entities that emerge during NSAID-H are mainly cutaneous symptoms such as facial angioedema with or without urticaria. 30,[36][37][38]63 Respiratory symptoms such as rhinoconjunctivitis and/or bronchospasm associated with cutaneous symptoms appear to a lesser extent. 31,37 Cutaneous and respiratory symptoms together are currently termed "blended reactions". ...
Ozlem Cavkaytar, Mustafa Arga Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, TurkeyCorrespondence: Ozlem Cavkaytar, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University Faculty of Medicine, Prof. Dr. Suleyman Yalcin City Hospital, Kadıköy, Istanbul, Turkey, Tel +90 216 6065200, Email ozlem.bircan@gmail.comAbstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently administered drugs, mainly for their anti-pyretic, but also for pain-relieving and anti-inflammatory effects in children. NSAIDs are composed of structurally divergent subgroups of drugs with similar pharmacological and adverse effects. Aspirin originates from salicin and was the first synthesized analgesic. As a prototype of NSAIDs; aspirin-induced hypersensitivity reactions were first reported, but subsequently, other phenotypes of hypersensitivity reactions were also described with aspirin and other NSAIDs. There are certain challenging aspects of NSAID-hypersensitivity in the pediatric population that need to be further investigated. These include the effect of age on drug metabolism and the natural history of the various phenotypes of NSAID-hypersensitivity, the effect of certain co-factors (infections, exercise) on NSAID-hypersensitivity, and diagnostic clinical and laboratory biomarkers clarifying the endotypes. In recent years, a non-negligible number of case series, studies and expert panel reports have been published in this field with some novel features and diagnostic modalities in the pediatric population. With the current review; the clinical phenotypes and diagnostic and management modalities of suspected NSAID-induced hypersensitivity reactions in childhood and adolescence were explained and updated by examining past and current publications.Keywords: allergy, aspirin, child, drug, ibuprofen, paracetamol
... Other studies showed that ibuprofen accounted for 63.8% and was followed by acetaminophen (59%). NSAIDexacerbated respiratory disease (NERD) was present in the form of respiratory symptoms such as asthma, rhinitis, nasal polyps, mild chest tightness, and nasal congestion (23,24) . ...
Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs to reduce pain or swelling. The use of these drugsin high doses or long-term can cause side effects or hypersensitivity problems, also known as Adverse DrugReaction (ADR). A literature review was carried out using the PubMed database by inserting the keywords‘NSAID’, ‘adverse drug reaction’, and ‘hypersensitivity’. All studies related to NSAIDs and their adversedrug reactions were included in this review, while genetic or pharmacogenomics studies and NSAIDs’effectiveness were excluded. The results showed that gastrointestinal (GI) problems such as duodenal ulcersor erosive gastritis are the most common diclofenac effects (2.05%). Cardiovascular issues, such as acutemyocardial infarction, were mostly caused by rofecoxib (2.12%). Hypersensitivity, both respiratory andskin, is commonly caused by ibuprofen with prevalence 50% and 67%, respectively. The most frequentkidney problem related to NSAIDs use is acute kidney injury. In comparison, the common hypersensitivityproblems are asthma, urticaria, and angioedema. Adverse drug reactions can be prevented or treated bylowering the dose, reducing the duration of treatment, adding companion drugs, or changing the type ofNSAID. In conclusion, it can be seen that ibuprofen severely caused kidney problems and hypersensitivity.On the other hand, diclofenac caused digestive issues, and rofecoxib caused cardiovascular problems.
... 1,2 Interestingly, in most studies, only 20%-30% of patients with a previous history suggesting a NSAID-induced hypersensitivity reaction are finally classified according to the ENDA workup approach. [3][4][5][6][7][8] The clinical history has a low predictive value because it and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) ...
Background
In up to 70%–80% of patients with a suspected non‐steroidal anti‐inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food‐dependent NSAID‐induced hypersensitivity (FDNIH).
Methods
We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID.
Results
199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%.
Conclusion
Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.
... 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][24][25][26][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. This result underlines the importance of performing DPTs with the culprit (or strong COX-1 inhibitors) to avoid a mislabeling of patients as hypersensitive to NSAIDs, even though challenging with the culprit alone does not enable a better phenotyping of patients. ...
Background:
Diagnosis of hypersensitivity (HS) reactions to non-steroidal anti-inflammatory drugs (NSAIDs) in children is complex. The real prevalence of NSAIDs HS remains unknown because a drug provocation test (DPT) is not always performed with the culprit NSAID.
Objective:
To describe and compare the diagnostic workup among different European centers and to find out the real proportion of NSAIDs HS by performing a DPT with the culprit drug.
Methods:
We retrospectively collected data from children (0-10 years) and adolescents (10-18 years) with a history of NSAIDs reactions and who underwent a complete allergy workup including DPTs with the culprit in six different pediatric centers: Belgrade, Florence, Geneva, Madrid, Porto, and Rome.
Results:
A total of 693 children with a history of NSAIDs reactions were enrolled and a total of 526 DPTs were performed with the culprit NSAID. The diagnosis of NSAIDs HS was confirmed in (103/526) 19.6% of children by performing a DPT with the culprit drug. The major differences in the allergy workup among the six centers concerned the duration of the DPT and the practical use of skin tests for diagnosing NSAIDs HS. In addition, the use of acetyl salicylic acid (ASA) to differentiate single reactors (SR) or cross-intolerance (CI) patients is not commonly used except in Spain.
Conclusion:
The value of this study is that although different approaches are used around Europe to diagnose NSAIDs HS, we found that the percentage of confirmed NSAIDs HS is less than 20%. This highlights the importance of the DPT in confirming or excluding NSAIDs HS in the pediatric population.
... [62][63][64][65] Precise definitions and provision of background, in a standardized available questionnaire, are helpful to correctly classify DHRs. 5,66,67 Although in NSAID hypersensitivity, the current classification needs a revision 68,69 including new entities as blended reactions. 55 Predictive models have been designed for the diagnosis of BL allergy, based only on clinical history. ...
Drug hypersensitivity reactions (DHRs) are nowadays the third cause of allergy after rhinitis and asthma with a significant increase in prevalence in both adults and paediatric population with new drugs included as culprit. For this, DHRs represent not only a health problem but also a significant financial burden for affected individuals and health systems. Mislabelling DHRs is showing to be a relevant problem for both, false label of drug allergic and false label of nonallergic. All this reinforces the need to improve accurate diagnostic approaches that allow an appropriate management. Moreover, there is a need for training both, nonallergist stakeholders and patients to improve the reaction identification and therefore decrease the mislabelling. The use of allergy cards has shown to be relevant to avoid the induction of DHRs due to the prescription of wrong medication.
Recent developments over the last 2 years and highlights about risk factors, diagnostic approaches, mechanisms involved as well as prevention actions, and management have been reviewed. In these papers, it has been outlined the need for correct diagnosis and de‐labelling of patients previously false‐reported as allergic, which will improve the management and treatment of patients with DHRs.
... [115][116][117] Focusing on the clinical entities included within the CI groups, a number of claims have been raised, especially with NIUAA, indicating that particularly in children and adolescents both cutaneous and respiratory manifestations may occur. 60,118 These reactions also occur in adults although in a lower percentage. 3 Further queries can be raised concerning this classification that rather than invalidating it actually contributes to improving the classification, providing more detailed information on the clinical entities outlined above. ...
... Time interval is implicit in clinical manifestations, 14,29 so to use this variable as discriminative for a new classification is not needed. 118 Within each group several entities can be identified although more will emerge or be segregated from these as more research is done. ...
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.
... They rank second in reported allergies with prevalence in children of approximately 0.3% but more frequent in asthmatics and patients with chronic urticaria [35,36]. Other risk factors include family history of atopy, clinical reactions to multiple NSAIDs, and reaction within the first hour [95]. Confirmation rate of NSAID hypersensitivity is greater than β-lactams, ranging from 21 to 68% [95]. ...
... Other risk factors include family history of atopy, clinical reactions to multiple NSAIDs, and reaction within the first hour [95]. Confirmation rate of NSAID hypersensitivity is greater than β-lactams, ranging from 21 to 68% [95]. There is a spectrum of presentations, but primary symptoms are typically cutaneous or respiratory (Fig. 2) [35, 36, 60•, 95, 96]. ...
Purpose of Review
Pediatric drug hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric drug hypersensitivity and highlight new developments in diagnosis and management.
Recent Findings
This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for β-lactam reactions. We review unique aspects of pediatric drug challenges and desensitizations.
Summary
It is important to accurately diagnose pediatric drug hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient’s treatment. Utilization of weight-based dose and infusion rate adjustments for current drug challenge and desensitization protocols optimize success.
