Current diagnostics in NSAID hypersensitivity

Background: The eosinophil/neutrophil/platelet-to-lymphocyte ratios (ELR, NLR, and PLR) have been used as clinical markers of systemic inflammation. However, they have not yet been tested in various subtypes of immediate hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs). Objectives: To assess the ELR, NLR, and PLR in various types of hypersensitivity to NSAIDs. Materials and Methods: A retrospective analysis of complete blood cell count and the ELR, NLR, and PLR was performed. Appropriate types of hypersensitivity to NSAIDs were diagnosed based on the anamnesis and drug provocation tests. The analysis covered 97 patients. Twenty were diagnosed with NERD (NSAID-exacerbated respiratory disease), 20 with NECD (NSAID-exacerbated cutaneous disease), 38 with NIUA (NSAID-inducted urticaria/angioedema), and 19 with SNIUAA (single-NSAID-induced urticaria/angioedema or anaphylaxis). Two controls groups were included: the first covered 15 patients with bronchial asthma and the second 28 patients with chronic spontaneous urticaria without NSAID hypersensitivity. Results: The NLR did not differ significantly between the NSAID hypersensitivity types. The ELR was significantly higher in NERD patients, and the PLR was significantly lower in NECD patients than in patients with other types of NSAID hypersensitivity and in controls. Conclusions: The ELR and PLR may be useful in differentiating various types of immediate hypersensitivity to NSAIDs. Moreover, the ELR may be helpful in differentiating patients with bronchial asthma with and without NSAID hypersensitivity and PLR in differentiating patients with chronic spontaneous urticaria from NECD.

A Multicenter Retrospective Study on Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Children: A Report from the European Network on Drug Allergy (ENDA) Group

Provocation tests (PTs) with the suspected compounds are considered the 'gold standard' for establishing or excluding a diagnosis of hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs). However, only a few studies have evaluated the potential determinants of positive responses to PTs. The aims of this study are to assess the reliability of clinical histories as indicators of NSAID hypersensitivity, as well as the risk factors for a positive PT. Two hundred and seventy-five subjects with an unequivocal history of NSAID hypersensitivity reactions underwent PTs with the suspected drugs. To establish the potential determinants of positive PTs, we examined the following variables: gender, age at the time of reaction (<40 or ≥40 years), family and personal histories of atopy, patients who had reacted to one or more NSAIDs, time interval between drug intake and symptom onset (immediate or non-immediate reactions), time interval between the last drug reaction and the allergologic examination (≤12 or >12 months), and inclusion in a category of the Stevenson et al. classification. Two hundred and fourteen (77.8%) subjects tolerated the suspected drugs and 61 (22.2%) reacted. Age <40 years, male gender, immediate reactions, and time interval ≤12 months were significant risk factors for a positive PT. Our study confirms that clinical histories are not reliable tools for diagnosing NSAID hypersensitivity. Therefore, we recommend that suspected cases should undergo drug PTs. However, further studies on large samples of NSAID-sensitive patients are necessary to establish the risk factors that allow the number of candidates for PTs to be reduced.

Hypersensitivity to non-steroidal anti-inflammatory drugs(NSAID) is a distinct phenomenon of severe asthma. Eosinophils play a key role in NSAID hypersensitivity as a main source of prostanoides. The aim of the analysis is to assess the effect of omalizumab(OMA) on blood eosinophils count(Eo) in asthmatic patients with NSAID hypersensitivity compare to those who tolerate NSAID(non-NSAID). Out of 38 patients who started OMA therapy the positive history of NSAID hypersensitivity was reported by 14 patients, 24 tolerated NSAID. We evaluated Eo level and OMA clinical effectiveness in 16thweek and 52ndweek of therapy (P-value The baseline characteristic(demographic data, asthma severity) did not differ between study groups. The mean Eo did not differ between study groups at the baseline (mean±SD NSAID vs non-NSAID respectively: 578±681/μl vs 348±301/μl), although patients hypersensitive to NSAID had Eo≥500/μl almost 2 times more frequent. At 16thand 52ndweek the mean Eo did not change significantly. 4 patients(NSAID/non-NSAID=2/2) stopped the therapy due to subjective lack of benefit. In both groups, we observed significant improvement in ACQ and AQLQ scale, the reduction of annual exacerbations rate and the daily OCS dose in 16th and 52nd week. The improvement in asthma control parameters in 16thand 52ndweek did not differ between study groups. OMA therapy did not affect Eo blood in patients with NSAID-intolerance, regardless of good clinical response. OMA seems to be effective in patients suffering from severe allergic asthma independently of NSAID hypersensitivity status.(2015/19/B/NZ5/00096)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main cause of drug-induced hypersensitivity in children. Many classifications have been proposed, focusing on adults. So far, no large study has deeply investigated a pediatric cohort. The aim of the present study was to describe a population of NSAID hypersensitive patients reporting a reaction during their childhood and to verify whether it is possible to classify pediatric patients, following the EAACI/ENDA classification. We conducted a historical prospective study including patients evaluated from 1996 to 2015 in the allergy unit of the Montpellier University Hospital. We included 635 patients. For each patient, we recorded clinical manifestations and possible comorbidities and tried to identify possible risk factors. NSAID hypersensitivity was diagnosed in 107 of 635 patients (16.9%). In this group, 43 patients (40.2%) could not be classified following the ENDA recommendations. The main discrepancies were on the patients' clinical manifestations and on their possible underlying diseases. We identified, on a multivariate analysis, some risk factors for NSAID hypersensitivity: chronic urticaria (OR 7.737, 3.375-18.296 95%CI), atopic status (OR 2.514, 1.504-4.364 95%CI), and allergic rhinoconjunctivitis (OR 1.799, 1.138-2.837 95%CI). On the basis of our results, we are proposing an adapted classification for NSAID hypersensitivity in children. The current ENDA classification does not seem to be adapted for pediatric patients; a modified version does. Our study could help allergists better understand the differences between adults and children in developing hypersensitivity reactions to NSAIDs, but further large-scale prospective longitudinal analyses are required to validate this new classification.

A Quantitative Analysis of NSAID-Induced Small Bowel Pathology by Capsule Enteroscopy

Urticaria, angioedema and anaphylaxis are common adverse reactions to non-steroidal anti-inflammatory drugs (NSAIDs). To investigate the clinical characteristics of NSAID-induced acute hypersensitivity reactions with structured oral drug challenges. Patients with NSAID-induced urticaria, angioedema or anaphylaxis were challenged with either the homologous NSAID to confirm diagnosis or a heterologous NSAID to investigate cross-reactivity. Data were analysed retrospectively and supplemented by a telephone questionnaire. Sixty-eight patients (mean age 48.3, 53 females) reported a total of 75 instances of NSAID-induced reactions of which 64% were purely cutaneous and 36% were systemic anaphylaxis. Ibuprofen was the most frequent cause of reactions (35%), however, diclofenac was the most frequent cause of anaphylaxis (48%). Seventeen out of 40 (43%) homologous NSAID challenges were positive; presentation with anaphylaxis or reaction to diclofenac predicted a positive challenge. Only 7 of 28 (25%) of heterologous NSAID challenges were positive. Structured challenges enabled us to identify 23 (34%) patients with selective reactivity to a single NSAID, 19 (28%) patients with cross-reactivity to multiple NSAIDs and 23 (34%) patients in whom NSAID hypersensitivity was not reproduced. Selective reactors presented most often with anaphylaxis and some had a background of beta-lactam antibiotic allergy. Cross-reactive patients often had a background of chronic urticaria and presented with milder reactions. In the absence of a reliable in vitro test, structured drug challenges allow identification of selective and cross-reactive NSAID hypersensitivity syndromes. NSAID-induced anaphylaxis is often associated with selective hypersensitivity and patients may not need to avoid other NSAIDs.

The aim of this study was to examine the pathophysiological mechanisms, epidemiology, diagnostic strategies, and treatment approaches for non-steroidal anti-inflammatory drug (NSAID) allergy based on clinical data obtained in routine allergy practice. The study combined an analysis of the scientific literature with a retrospective clinical analysis of adult patients who presented to an allergy department with suspected NSAID hypersensitivity. Clinical data were derived from patient medical records and included documented reactions to NSAIDs, diagnostic procedures performed as part of standard care (medical history assessment, skin testing, laboratory investigations, basophil activation testing, and drug provocation tests), and applied therapeutic strategies. The clinical analysis identified two principal reaction mechanisms: immediate-type hypersensitivity mediated by IgE-dependent immune activation and immediate non-immunological hypersensitivity associated with cyclooxygenase-1 (COX-1) inhibition. Clinical manifestations ranged from cutaneous reactions to severe systemic responses, including anaphylaxis, as well as chronic conditions such as aspirin-exacerbated respiratory disease. The diagnostic value and practical limitations of the applied methods were evaluated in the clinical setting. Individualised management strategies, including avoidance of the causative NSAID, the use of alternative agents such as selective COX-2 inhibitors, pharmacological treatment of acute reactions, and desensitisation protocols, were summarised based on observed clinical practice. By integrating real-world clinical data with current scientific evidence, this study provides a clinically grounded overview of NSAID allergy and highlights the importance of personalised diagnostic and therapeutic approaches in everyday medical practice. The findings may be useful for allergists, immunologists, and general practitioners involved in the management of patients with suspected NSAID hypersensitivity.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in the pediatric age group as pain relievers, antipyretics and anti-inflammatory drugs. Since NSAIDs are used in many medical conditions, there is a need for alternative NSAIDs to be used safely in people with hypersensitivity reactions. Selective and partially selective COX-2 inhibitors and weak COX-1 inhibitors are generally used as safe alternative drugs. The aim of this study was to evaluate safe NSAIDs determined by oral provocation tests (OPTs) according to phenotypes in children with NSAID hypersensitivity reactions. Methods: The results of the oral provocation test performed with alternative NSAIDs (paracetamol, meloxicam, nimesulide, celecoxib) in patients followed up with the diagnosis of NSAID hypersensitivity reaction in the Pediatric Immunology and Allergy Department between January 2015 and February 2023 were evaluated retrospectively. Results: During the study period, 91 patients underwent OPTs with 109 alternative drugs 48 (52.7%) of whom were girls, with a median age of 15 years. 91 patients had a history of reactions to 117 drugs. As an alternative NSAID; OPT was performed with paracetamol in 58 patients, meloxicam in 44 patients, nimesulide in 5 patients, and celecoxib in 2 patients. Since 15 patients used paracetamol safely at home, no tests were performed with paracetamol. Reactions were observed in 3 of the 73 patients (4.1%) who underwent OPT with paracetamol and in 2 of the 44 (4.5%) who underwent OPT with meloxicam. Reactions to nimesulide were also observed in the latter 2 patients (2/5, 40%), but they appeared to tolerate celecoxib. No reaction was observed in the 2 patients who were tested with celecoxib. Conclusion: Paracetamol, meloxicam, and nimesulide can be used as safe alternative drugs in most children with NSAID hypersensitivity. Selective COX-2 inhibitors should be tried as an alternative in patients who cannot tolerate them.

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs), manifested by cutaneous symptoms and/or airway manifestations represent 20-25% of all hypersensitivity reactions to drugs. Today, it is still claimed that no in vitro diagnostic tests exist for that condition and that the only way to confirm the diagnosis is a provocation challenge. The objective of this study was to assess whether NSAIDs may provoke blood basophil activation in vitro in such patients, as detected by a flowcytometric technique. Sixty NSAID hypersensitive patients (38 with cutaneous, 20 with airway and two with cutaneous and airway symptoms) and 30 control patients (15 asthmatics) were selected. Their hypersensitivity was confirmed by documented history indicating at least two clinical episodes to two or more different NSAIDs or by positive oral provocation challenge. Isolated buffy coat leukocytes were stimulated in vitro with aspirin, paracetamol, metamizol, diclofenac, and naproxen. The percentage of activated basophils was evaluated by an anti-CD63. Aspirin showed a sensitivity of 43.3%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99.4%. For the other NSAIDs, the sensitivity and specificity values were: for paracetamol 11.7% and 100%, for metamizol 15% and 100%, for diclofenac 43.3% and 93.3% and for naproxen 54.8% and 74.1%. When considering the first four NSAIDs, the global sensitivity raised to 63.3% and specificity to 93.3%. If the number of tests is to be limited for practical reasons, the combination of acetylsalicylic acid and diclofenac at two concentrations yields a sensitivity of 58.3% and a specificity of 93.3%. Flowcytometric determinations of basophil activation following stimulation with NSAIDs show a high sensitivity (60-70%) with specificity above 90%. So this test may help avoiding some cumbersome and dangerous provocation challenges.

Nonsteroidal anti-inflammatory drug (NSAID) exacerbated respiratory disease phenotype: Topical NSAID and asthma control – A possible oversight link

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause different types of allergic and pseudo allergic reactions. This results in difficulties in clinical practice. Most cases of NSAID hypersensitivity are mediated by the inhibition of cyclooxygenase-1 enzyme (COX-1), which results in depletion of the protective prostaglandin E2, and promotes the unrestrained synthesis of inflammatory mediators from mast cells. Selective COX-2 inhibitors are considered safe alternatives in patients with NSAID allergy, although hypersensitivity reactions to COX-2 inhibitors have also been reported. Our study aimed to report the experience in Qatar for using COX2 inhibitors as an alternative treatment for nonselective NSAID allergy.Methods: Data of patients who underwent open challenge with a single dose of oral celecoxib 200 mg were retrieved from the procedure log of the Allergy and immunology Division in Hamad medical corporation, Doha, Qatar, from 2013 to 2022. The challenge was considered positive if the patient developed cutaneous or respiratory symptoms.Results: A total of 31 patients were identified; 4 with a history of celecoxib allergy. The remaining 27 (23 females and 4 males); with mean ( ± SD, range) age of 42 ( ± 12, 20–65) years had hypersensitivity to one (n = 11) or more than one (n = 16) nonselective NSAID, manifested as cutaneous, respiratory, or anaphylactic symptoms. Those 4 patients with celecoxib allergy were challenged and only one with a historical reaction of anaphylaxis developed anaphylaxis during the challenge. Celecoxib was well tolerated in all 27 patients with hypersensitivity reactions to nonselective NSAIDs. Also, patients were contacted by telephone call at 24 hours and after 1 week with no evidence of delayed reactions.Conclusions: Selective COX-2 and nonselective NSAIDs have similar overall efficacy as analgesic, anti-inflammatory, and antipyretic agents. Hypersensitivity reaction to COX-2 inhibitors has been reported; however, it is rare. So, it is safer to challenge the patients with COX-2 inhibitors before prescribing them as alternative medication in patients with Nonselective NSAID allergies. We plan to conduct a single-/double-blind placebo-controlled study for more patients, especially using graded challenges for high-risk profile candidates. Also, it may be of significance to test more than one type of selective COX-2 to avoid drug-specific reactions.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the medications most frequently involved in hypersensitivity drug reactions. Because NSAIDs are prescribed for many conditions, this is a world-wide problem affecting patients of all ages. Various hypersensitivity reactions have been reported, mainly affecting the skin and/or the respiratory airways. The most frequent of these is acute urticaria, which can be induced by several different NSAIDs. Both specific and non-specific immunological pathways have been proposed as underlying mechanisms. This review presents the clinical phenotypes and the drugs involved in NSAID hypersensitivity. Five major clinical syndromes can be distinguished: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated cutaneous disease (AECD), multiple NSAID-induced urticaria/angioedema (MNSAID-UA), single NSAID-IgE reactions and single NSAID T cell responses. However, further classification is possible within these five major entities, by detailed descriptions of the clinical characteristics enabling more phenotypes to be defined. This detailed differentiation now seems required in order to undertake appropriate pharmacogenetic studies.

Advances in hypersensitivity drug reactions.