Nonsteroidal Anti-inflammatory Drugs Hypersensitivity Research Articles

An update on nonsteroidal anti-inflammatory drug-induced urticaria.

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (HR-NSAIDs) are common adverse events related to the widespread use of over-the-counter NSAIDs for the treatment of a variety of inflammatory conditions. Urticaria is the most commonly reported immediate cutaneous clinical sign of HR-NSAIDs, but it can be a manifestation of pathophysiologically different clinical entities that require different therapeutic strategies. The aim of this study is to ease the identification of the correct phenotype of HR-NSAIDs in patients reporting urticaria associated with the intake of NSAIDs and provide updated information about their diagnosis and management. The study is a narrative review conducted by collecting the most relevant and up-to-date data related to the classification, pathophysiology, severity, and prognosis of NSAID hypersensitivity reactions. PubMed and Embase scientific databases were used as search engines to select relevant articles. Patients developing HR-NSAIDs can be divided into two categories: selective responders (SR), who develop reactions after the administration of a single specific NSAID due to an underlying IgE or T-cell mediated hypersensitivity mechanism, or cross-intolerant (CI), who develop reactions to more than one chemically unrelated NSAIDs due to abnormalities in the biochemical pathways related with prostaglandin metabolism, independently from an underlying immunological mechanism. Five major different categories of HR-NSAIDs have been identified: NSAIDs-exacerbated cutaneous disease (NECD), NSAIDs-induced urticaria/angioedema with/without respiratory and systemic symptoms of anaphylaxis (NIUAA), and NSAIDs-exacerbated respiratory disease (NERD), which are developed by CI patients, and single NSAIDs-induced urticaria, angioedema and/ or anaphylaxis (SNIUAA) and single NSAIDs-induced delayed hypersensitivity reactions (SNIDHR), which are developed by CI patients. In vivo and in vitro diagnostic tests have rarely been shown to be reliable in all these entities and therefore are not routinely used in clinical practice. The management in SR patients consists of strict avoidance of the culprit drug, while for cross-intolerance reactions oral tolerance tests with safe alternative drugs (e.g. weak COX-1 inhibitors or selective COX-2 inhibitors) can be performed. HR-NSAIDs are being observed with increasing frequency, however, the pathogenesis behind some NSAIDS-associated clinical entities is still unclear. Diagnosis is mostly based on a thorough clinical history and confirmed by a drug challenge test. Clinical management is based on strict avoidance and use of alternative tolerated medications. Overall, all therapeutic decisions depend on the correct identification of the type of reaction the patient experienced.

Importance of aspirin challenges in patients with NSAID-exacerbated respiratory disease

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is often characterized by asevere course of chronic rhinosinusitis with nasal polyps (CRSwNP), comorbid asthma, and NSAID hypersensitivity. The gold standard for N-ERD diagnosis is challenge with acetylsalicylic acid (ASA). In expert recommendations, the diagnosis of N-ERD is established based on aplausible positive history of NSAID hypersensitivity and CRSwNP with asthma. The following review describes the performance of ASA challenges and their sensitivity and specificity. It also examines the extent to which apositive history of NSAID hypersensitivity correlates with ASA challenge results in clinical trials and when ASA challenges should be performed. ASA challenges have high sensitivity and specificity. In clinical ASA challenge studies, there is ahigh concordance between apositive history of NSAID hypersensitivity obtained by rhinologists and the measured data of ASA challenge in patients with CRSwNP and comorbid asthma. Therefore, ASA challenge is primarily indicated in patients with an unclear history of NSAID hypersensitivity.

Asthma-chronic obstructive pulmonary disease overlap: Results from a national-multicenter study.

Patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) have a greater disease burden than those with COPD or asthma alone. In this study, it was aimed to determine the prevalence, risk factors, and clinical features of ACO because there are limited national data in Türkiye. The study was conducted in a cross-sectional design in nine tertiary-care hospitals. The patients followed with a diagnosis of asthma or COPD for at least one year were enrolled in the study. The frequency of ACO and the characteristics of the patients were evaluated in the asthma and COPD groups. The study included 408 subjects (F/M= 205/203, mean age= 56.24 ± 11.85 years). The overall prevalence of ACO in both groups was 20.8% (n= 85). The frequency was higher in the COPD group than in the asthma group (n= 55; 33.3% vs. n= 22; 9.8%), respectively (p= 0.001). Patients with ACO had similarities to patients with COPD in terms of advanced age, sex, smoking, exposure to biomass during childhood, being born in rural areas, and radiologic features. Characteristics such as a history of childhood asthma and allergic rhinitis, presence of chronic sinusitis, NSAID hypersensitivity, atopy, and high eosinophil counts were similar to those of patients with asthma (p<0.001). The annual decline in FEV1 was more prominent in the ACO group (mean= -250 mL) than in the asthma (mean change= -60 mL) and COPD (mean change= -230 mL) groups (p= 0.003). This study showed that ACO was common among patients with asthma and COPD in tertiary care clinics in our country. ACO should be considered in patients with asthma and COPD who exhibit the abovementioned symptoms.

Safety of partial selective COX-2 inhibitors in patients with cross-reactive NSAID hypersensitivity and factors affecting safety

Aims: Partial selective COX-2 inhibitors, such as nimesulide, or meloxicam are tolerated by the majority of the patients with cross-reactive NSAID hypersensitivity. This study aimed to obtain more information about the safety of partial selective COX-2 inhibitors; nimesulide and meloxicam in non-immunologic type, cross-reactive NSAID hypersensitivity and to detect risk factors for intolerance to these drugs.&#x0D; Methods: This is a retrospective study of patients with suggestive of cross-reactive NSAID hypersensitivity who admitted to our clinic over a period of 10 years. Patients who had a reliable history of immediate type NSAIDs hypersensitivity with at least 2 chemically unrelated class and/or positive ASA provocation test and who underwent alternative drug provocation test with partial selective COX-2 inhibitors (nimesulide and/or meloxicam) were included to study. Patients’ demographics, comorbidities, atopy status, duration of NSAID hypersensitivity, total number of reactions, reaction grades, clinical phenotypes, pulmonary function test parameters and results of alternative drug provocation test results are recorded. Patients with and without reactions during alternative provocation tests with nimesulide and/or meloxicam were compared in terms of these data. &#x0D; Results: A total of 560 patients were included in the study, 378 (67.5%) of them were female. Allergic comorbidities were detected in 394 (72.6%) patients. Asthma, other drug allergies and nasal polyp were the most common comorbidities. Alternative drug provocation test positivity with nimesulide and/or meloxicam was detected in 50 of 560 (8.9%) patients. Provocation test positivity was 33/541 (6.1%) with nimesulide, 30/517 (5.8%) with meloxicam and 13/498 (2.3%) with both nimesulide and meloxicam. Duration of NSAID hypersensitivity was shorter and allergic comorbidities, asthma, nasal polyp and the coexistence of asthma and nasal polyp were more common in patients with a positive provocation test.&#x0D; Conclusion: The partial selective COX-2 inhibitors nimesulide and meloxicam are well tolerated alternatives in patients with cross-reactive NSAID hypersensitivity. Hypersensitivity to these drugs is significantly higher in patients with asthma and/or nasal polyp than other group of cross-reactive NSAID hypersensitive patients and also in patients with a shorter duration of NSAID hypersensitivity.

Evaluation of different protocols for classification of pediatric hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: Children with underlying allergic disease should be a separate subgroup.

Background: Different recommendations for the classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions (NSHSR) in children have been reported but a shortage still exists. Objective: The aim of the present study was to evaluate the inclusivity of two European Academy of Allergy and Clinical Immunology (EAACI) position paper classifications and to characterize the factors that underlie classification discordance in children. Methods: Patients with a history of NSHSR were evaluated with a standardized diagnostic protocol according to EAACI/ European Network for Drug Allergy (ENDA) recommendations. Children were classified and compared according to the EAACI 2013 and the pediatric EAACI/ENDA 2018 classifications. Subjects who were unclassified and those who were classified were compared. Results: Of 232 patients (median [interquartile range] age 6 years (4-11 years) with a history of NSHSR, 52 (22.4%) were confirmed with diagnostic tests. Thirty-six (69.2%) were classified as having cross-intolerance, whereas 16 patients (30.8%) were classified as selective responders. Eleven of the confirmed cases (21.2%) could not be categorized according to the 2013 EAACI classification, whereas this number was six adolescents (11.5%) when the 2018 EAACI/ENDA pediatric classification was used. Patients who were unclassified and who were all cross-intolerant were more likely to have atopic sensitization (p = 0.001) and asthma as an underlying disease (p = 0.03), higher serum eosinophil count (p = 0.022), and total immunoglobulin E levels (p = 0.007) compared with those who fit well into the classification. In multivariate regression analysis, the presence of atopic sensitization (adjusted odds ratio 20.36 [95% confidence interval, 2.14-193.48]; p = 0.009) was found to be the only significant underlying factor for an unclassified and/or blended phenotype. Conclusion: The 2013 EAACI classification resulted in a high rate of subjects who were unclassified. Despite better clinical utility, the recent pediatric EAACI/ENDA classification system still has shortcomings in terms of inclusivity for adolescents. Mostly, children with underlying allergic diseases could not be classified by the current guidelines. We propose to classify them as a separate pediatric cross-intolerance subgroup because the underlying mechanism may involve more than cyclooxygenase 1 inhibition.

Genetic Susceptibility of HLA Alleles to Non-Steroidal Anti-Inflammatory Drug Hypersensitivity in the Taiwanese Population.

Human leukocyte antigen (HLA) genes are important in many immune processes and contribute to many adverse drug reactions. Whether genetic variations in the HLA region are associated with non-steroid anti-inflammatory drug (NSAID) hypersensitivity remains uncertain. Therefore, the aim of our study was to identify HLA genetic variations in patients with NSAID hypersensitivity in the Taiwanese population. This hospital-based, retrospective case-control study enrolled 37,156 participants with NSAID exposure from the Taiwan Precision Medicine Initiative (TPMI), who were all genotyped and imputed to fine map HLA typing. Our study assigned 1217 cases to the NSAID allergy group and 12,170 controls to a matched group. Logistic regression analyses were utilized to explore associations between HLA alleles and NSAID hypersensitivity. Overall, 13,387 patients were genotyped for eight major HLA alleles. Allele frequencies were different between the two groups. In the NSAID allergy group, the genotype frequencies of HLA-A*02:01, HLA-A*34:01, and HLA-DQA1*06:01 were found to be markedly elevated compared to the control group, a significance that persisted even after applying the Bonferroni correction. Furthermore, the risk of NSAID allergy demonstrated a significant association with HLA-A*02:01 (OR = 1.29, p < 0.001) and HLA-A*34:01 (OR = 9.90, p = 0.001), in comparison to their respective counterparts. Notably, the genotype frequency of HLA-B*46:01 exhibited a significant increase in the severe allergy group when compared with the mild allergy group. We identified HLA genotypes linked to the onset and severity of NSAID hypersensitivity. Our findings establish a basis for precision prescription in future clinical applications.

Acetylsalicylic acid challenge or desensitization in sensitive patients with cardiovascular disease

Abstract Background The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. Purpose To evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs. Methods We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110 mg), while those from group III were desensitized (cumulative dose of 100.1 mg). Results We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized. Conclusions LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS.

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) in the pediatric population

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) is predominantly encountered in adults and rarely documented and less well-defined clinically and epidemiologically in children. The cause remains unclear, with the main pathogenic mechanism being represented by a decrease in prostaglandin E2 production, increased production of cysteinyl-leukotrienes, and eosinophilic inflammation. N-ERD symptoms in the pediatric population are similar to those in adults: chronic eosinophilic rhinosinusitis with nasal polyps, asthma and respiratory symptoms upon aspirin/NSAID administration, but they can initially present with gastrointestinal or cutaneous symptoms or be more subtle, making early diagnosis difficult and requiring rigorous differential diagnosis. Pediatric onset of N-ERD should be considered by specialists when faced with cases of asthma associated with chronic rhinosinusitis and nasal polyps. Studies involving a larger number of patients are needed to determine the frequency of non-steroidal anti-inflammatory drug hypersensitivity in children with asthma and to establish the evolutionary and therapeutic characteristics of this patient category.

Clinical management of plant food allergy in patients sensitized to lipid transfer proteins is heterogeneous: identifying the gaps.

Patients sensitized to lipid transfer protein (LTP) present a wide clinical variability. The lack of practical diagnostic and therapeutic guidelines complicate their management. The aim of the study was to describe the clinical approach of Spanish allergists to this pathology using a survey designed by PICO method and subsequent Delphi approach validation. Designed survey was answered by 224 allergists (75% women; 57.1% with >20 years of professional experience). Homogeneity regarding clinical practice on the main points of LTP allergy diagnosis was observed, except for patients with suspected NSAID hypersensitivity (44.6% frequently include LTP skin testing). Oral food challenges were not frequently performed (63.6% occasionally to never), and they were generally (75.5%) used to confirm tolerance. It was common to recommend fruit skins avoidance (77.2%) and maintaining consumption of foods to which patients are sensitised but tolerant (99.1%). There was heterogeneity on other dietary indications, modifications due to co-factors, or traces avoidance. Peach sublingual immunotherapy (SLIT) was considered very/quite effective by 55.9% of allergists. The majority (79.5%) consider SLIT indicated in <25% of LTP allergic patients, based on severity (95.2%), frequency of reactions (99.4%), allergy to multiple food families (97.4%), and the quality of life/nutrition impairment (91.5%). There was different practice on SLIT prescription based on co-factor involvement. These data suggest that there is a need to increase evidence to reduce the clinical practice heterogeneity in the management of LTP allergy.

A case of possible anaphylaxis to ASA and structurally unrelated NSAIDs

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications, and are among the leading causes of drug hypersensitivity. NSAIDs hypersensitivity reactions are classified by symptom involvement and NSAIDs subclass cross-reactivity. Reactions varying from cutaneous involvement to respiratory symptoms can be triggered by multiple NSAIDs subclasses. Anaphylaxis, while rare, can be induced by a single NSAID, with tolerability of other structurally unrelated subclasses. Reactions that fall outside of these traditional categories are deemed “blended reactions”. We report a unique case of possible anaphylaxis to acetylsalicylic acid (ASA) and ibuprofen, two structurally dissimilar NSAIDs, indicating a severe blended reaction outside of the typical NSAIDs hypersensitivity reaction categories.Case presentationAn otherwise healthy 45 year old woman was referred to the Allergy and Immunology clinic after developing acute onset dyspnea, lip swelling, and generalized urticaria with ibuprofen use requiring treatment with intramuscular epinephrine in the emergency department. She previously tolerated ibuprofen, naproxen, and acetaminophen and had no history of urticaria, angioedema, asthma, or nasal polyps. She underwent an oral challenge to ASA whereby she developed urticaria and throat irritation with rebound symptoms requiring 2 doses of intramuscular epinephrine. On subsequent visits she passed treatment dose acetaminophen and celecoxib challenges. She was counseled to avoid all other NSAIDs and ASA desensitization was offered should this medication be clinically indicated in the future.ConclusionsNSAIDs hypersensitivity reactions can be triggered by individual NSAIDs with tolerance of other subclasses or by multiple structurally unrelated NSAIDs due to COX-1 inhibition. Determining the type of reaction (NERD, NECD, NIUA, SNIUAA, or SNIDHR) allows for appropriate oral challenges and safe alternative therapy recommendations. However, not all clinical reactions fit perfectly into these categories. Patients may also develop blended reactions. Our case highlights a severe blended reaction to multiple unrelated NSAIDs, including likely anaphylaxis to ASA. We note the utility of drug provocation tests (DPTs) to identify safe alternative medication options, as well as the importance of performing DPTs in settings properly equipped to assess and manage severe hypersensitivity reactions including anaphylaxis.

Practical Approach to Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Children.

We aimed to assess the real-life prevalence, patient profile, and clinical presentation of drug hypersensitivity to NSAIDs in children after an incidence of an adverse event during treatment, verified by a drug challenge test. We included 56 children, aged 4-18 years, referred to our allergy clinic due to the incidence of adverse reaction during treatment. Skin prick tests and a drug provocation test were performed in all patients. Diagnostics for persistent urticaria were performed. In 56 patients suspected of drug allergy, we proved NSAID hypersensitivity in 17 patients (30.1%). In 84.9% (n = 47) of patients, the clinical manifestations of hypersensitivity revealed angioedema and urticaria. The most common culprit drug among NSAIDs in children was ibuprofen. Thirty-one (55.4%) reactions were immediate, and 25 (44.6%) were delayed or late. Previous history of allergy was a risk factor for NSAID hypersensitivity (p = 0.001). Vitamin D deficiency in the blood serum was a risk factor for NASID hypersensitivity (OR = 5.76 (95% Cl: 1.42-23.41)). Hypersensitivity to NSAIDs is a difficult diagnostic problem in pediatric allergy. The most common manifestation of hypersensitivity to ibuprofen in children is acute urticaria and angioedema. Two important problems in the differential diagnosis are cofactors such as vitamin D levels and viral infections, which require further research.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment—Results From CURE

Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

Sex, Ethnicity, Body Mass Index, and Environmental Exposures Associated With NSAID-Exacerbated Respiratory Disease Symptom Sequence

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has a triad of symptoms: nasal polyposis, asthma, and NSAID hypersensitivity. Little is known about symptom timing and disease progression. The aim of this study is to characterize disease progression in N-ERD. Patients with N-ERD were prospectively interviewed and classified into 4 groups based on their first symptom at initial N-ERD onset (asthma, nasal polyps, NSAID hypersensitivity, or all concurrently). Associations of patient characteristics with the 4 groups were examined, along with associations within the "asthma first" group. Patients (N= 240) were mostly female (68%) and self-identified as non-White (77%). Half (N= 119) reported asthma as the earliest symptom in the N-ERD triad. Compared with other groups, "asthma first" was associated with younger age of onset (25 years, standard error ±1.3, P < .001) and higher body mass index (BMI) (odds ratio [OR]= 1.3, 95% confidence interval [CI]: 1.06-1.7, P= .02). In this group, age of onset <20 years was associated with female sex, Latino ethnicity, and higher BMI (all P < .05). The "NSAID sensitivity first" group was significantly associated with male sex (OR= 3.3, 95% CI: 1.5-7.4, P= .004) and pollution exposure (OR= 4.4, 95% CI: 1.6-11.9, P= .003). At the initial presentation, 27% of patients were unaware of their N-ERD diagnosis. Black and Latino patients were more likely to be unaware of their N-ERD diagnosis compared with White (P= .003). The median diagnostic delay was 3 years (interquartile range: 0-5 years). In this cohort, N-ERD is highly variable in onset and progression, with sex, BMI, race and ethnicity, and environmental exposures significantly associated with disease patterns and diagnostic delay.

Evaluation and Updated Classification of Acute Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAID-Exacerbated or -Induced Food Allergy (NEFA/NIFA).

There are hypersensitivity reactions (HRs) to foods in which nonsteroidal anti-inflammatory drugs (NSAIDs) act as aggravating factors (NSAID-exacerbated food allergy, NEFA) or cofactors (NSAID-induced food allergy, NIFA), often misdiagnosed as HRs to NSAIDs. Urticarial/angioedematous and/or anaphylactic reactions to ≥ 2 chemically unrelated NSAIDs do not meet the current classification criteria. However, they may be considered as part of a cross-reactive type of acute HR, which is NSAID-induced urticaria/angioedema with/without respiratory and/or systemic symptoms of anaphylaxis (NIUAA). To evaluate patients reporting acute HRs to NSAIDs and classify them according to updated criteria. 414 patients with suspected HRs to NSAIDs were studied prospectively. NEFA/NIFA was diagnosed in those who met all the following criteria: 1) mild reactions to (NEFA) or tolerance of (NIFA) the suspected foods without taking NSAIDs; 2) cutaneous and/or anaphylactic reactions to the combination foods + NSAIDs; 3) positive allergy tests to the suspected foods; 4) negative drug challenges (DCs) with the NSAIDs involved. 252 patients (60.9%) were diagnosed with NSAID hypersensitivity, 108 of whom had NIUAA. NSAID hypersensitivity was excluded in 162 patients (39.1%) who tolerated DCs with the suspected NSAIDs, 9 of whom were diagnosed with NEFA and 66 with NIFA. Pru p 3 was implicated in 67 of these 75 cases. NEFA/NIFA accounts for about 18% of patients reporting HRs to NSAIDs, with Pru p 3 as the main responsible food allergen. Therefore, patients with cutaneous and/or anaphylactic reactions to NSAIDs should be carefully questioned about all foods ingested within 4 hours before or after NSAID exposure, and targeted food allergy tests should be considered in the diagnostic workup of these patients. If testing is positive, DCs with the suspected NSAIDs should also be considered.

Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs on a pediatric Portuguese cohort.

Background. Non-steroidal anti-inflammatory drugs (NSAID)/analgesics (paracetamol) are among the most common causes of drug hypersensitivity reactions in children, with a reported prevalence of around 0.3% in the pediatric population. Paracetamol and ibuprofen are the most commonly reported culprits in the pediatric population. Our objective was to describe the allergy workup to NSAID/paracetamol of a pediatric population monitored in an allergy outpatient clinic. Methods. Retrospective observational study by consulting the medical records of patients evaluated in a pediatric outpatient clinic with history of NSAID/paracetamol, between January 2016 to August 2022. Results. A total of 43 patients have been evaluated for NSAID/paracetamol suspected allergy: 53.5% females, mean age of 9.8 ± 5.1 years, 47.7% atopic. The drugs reported as culprits were: ibuprofen (75.6%), paracetamol (17.8%), metamizole (4.4%) and naproxen (2.2%) and clinical manifestations were mainly urticaria/angioedema and maculopapular exanthema. Skin tests were performed in 7 patients: paracetamol (n = 5) and metamizole (n = 2), which were all negative. Fourty-six drug provocation tests were performed: 28 with the culprit drug and 18 with an alternative one; only 2 were positive (ibuprofen - culprit NSAID group): one immediate periorbital angioedema and one delayed lip edema with oropharyngeal tightness. Conclusions. The investigation of allergy to NSAID/paracetamol in children remains a challenge. In our population, ibuprofen was the most common NSAID reported. There were only 2 (4.3%) mild reactions on DPT. We could allow the use of the culprit NSAID/analgesic in 11 patients and an alternative one in 9 patients. This study highlights the importance of DPT in children for a correct diagnosis of NSAID hypersensitivity and selection of an alternative drug.

Safety and outcomes of “at-home self-provocation tests” in patients with mild nonsteroidal anti-inflammatory drug–induced urticaria/angioedema

BackgroundNonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is common; however, many patients do not receive an accurate diagnosis and are using unnecessary alternative drugs or have medication restrictions. ObjectiveTo establish a protocol for provocation tests that can be performed safely and effectively at home to give patients an accurate diagnosis, whereas also delabeling NSAID hypersensitivity. MethodsWe retrospectively analyzed the medical records of 147 patients with NSAID hypersensitivity. All patients had NSAID-induced urticaria/angioedema with less than 10% body surface area skin involvement. One specialist developed the protocol through history taking and chart review. If NSAID hypersensitivity was confirmed, an oral provocation test was performed to confirm the safe alternative medications (group A). If it was undetermined, an oral provocation test was performed to confirm the diagnosis and alternative medications (group B). All oral provocation tests were performed by patients in their homes according to the protocol. ResultsApproximately 26% of group A patients had urticaria or angioedema symptoms with alternative drugs, whereas the remaining 74% was safe. In group B, 34% of the patients were diagnosed with having NSAID hypersensitivity. However, 61% did not respond to the culprit drug; therefore, NSAID hypersensitivity had been misdiagnosed. During this at-home self-provocation test, no severe hypersensitivity reactions occurred. ConclusionMany patients originally suspected of having NSAID hypersensitivity were confirmed to have been misdiagnosed. We successfully conducted an effective and safe at-home self-provocation test.

Recent Updates in Understanding NSAID Hypersensitivity.

To provide a review of available literature regarding nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with an emphasis on more recent findings. Oral provocation tests with aspirin are important for diagnosis and management in adult and pediatric populations with reported NSAID hypersensitivity. Risk of cross-reactivity to COX-2 inhibitors varies by NSAID hypersensitivity phenotype. COX-2 inhibitors are tolerated in aspirin-exacerbated respiratory disease. Reported NSAID allergy is associated with a higher risk of a substance use disorder. Effective treatment of underlying chronic spontaneous urticaria can allow tolerance of NSAIDs in NSAID-exacerbated cutaneous disease. The pathophysiology, cross-reactivity, and appropriate diagnostic evaluation differ between the 5 distinct NSAID hypersensitivity phenotypes. Further research into the pathophysiology of NSAID hypersensitivity in patients with and without underlying disease is needed.

Acetylsalicylic acid challenge or desensitization in sensitive patients with cardiovascular disease.

The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We sought to evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs. We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110mg), while those from group III were desensitized (cumulative dose of 100.1mg). We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized. In this pragmatic study,LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS. Study flow-chart. ASCVD atherosclerotic cardiovascular disease; CCS chronic coronary syndrome; ACS acute coronary syndrome; ASA acetylsalicylic acid; DAPT dual antiplatelet therapy; PCI percutaneous coronary intervention; NSAIDs nonsteroidal anti-inflammatory drugs; NERD NSAID-exacerbated respiratory disease; NECD NSAID-exacerbated cutaneous disease; NIUAA NSAID-induced urticaria-angioedema or anaphylaxis; SNIUAA single NSAID-induced urticaria-angioedema or anaphylaxis; SNIDHR single NSAID-induced delayed hypersensitivity reaction.

Association of NSAID hypersensitivity with opioid prescribing following total joint arthroplasty

Nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for post-operative pain management, but medication use may be precluded by report of adverse drug reactions (ADRs). The impact of NSAID allergy labeling on opioid prescribing following total joint arthroplasty is unknown.

Drug Allergy Practice Parameter Updates to Incorporate Into Your Clinical Practice

The drug allergy practice parameter was developed to provide guidance on the diagnosis and management of drug hypersensitivity reactions. It was last updated in 2010. With the growth of research and evidence-based data since then, experts came together to update the practice parameter with a focus on sections that the work group deemed to have significant changes (or were not addressed) in the previous practice parameter. This review is a focused update on aspects of the practice parameter deemed to have the greatest impact on clinical practice and includes significant updates on diagnosis of antibiotic allergyincluding penicillin, cephalosporin, sulfonamide, fluoroquinolone, and macrolide allergies. Other topics include the evolution in our management approach to patients with aspirin/nonsteroidal anti-inflammatory drug allergy, diagnostic testing for delayed drug hypersensitivity and allergy to chemotherapeutics and biologics, and the key consensus-based statements for clinical practice. Specifically, the updated practice parameter helps allergists understand the place of 1- or 2-step drug challenges that are valuable tools often without the need for skin testing in many clinical situations. A proactive approach to delabeling penicillin allergy as well as unnecessary avoidance of safe antibiotic alternatives for patients with proven penicillin allergy is emphasized. New guidance is provided on management of patients with different phenotypes of aspirin and nonsteroidal anti-inflammatory drug hypersensitivity reactions. Approaches to delayed drug hypersensitivity and use of delayed intradermal and patch testing for specific phenotypes are reviewed. Lastly, practical approaches to management of patients with reactions to chemotherapeutics and biologics are discussed.