Nonsteroidal Anti-inflammatory Drugs Hypersensitivity Research Articles

Establishing a Safe Administration of ASA in Cardiovascular Patients with Nonsteroidal Anti-Inflammatory Drug Hypersensitivity with Skin and/or Respiratory Involvement

Background: A history of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity with cross-intolerance to several drugs is common in some patients with coronary artery disease. We present a series of patients with acute coronary syndrome undergoing ASA desensitization prior to a possible stent to evaluate the short- and long-term efficacy and safety. The aim was to evaluate the outcomes of an ASA desensitization protocol developed by our center based on the guidelines proposed by the EAACI drug allergy expert recommendations. Methods: We developed a desensitization protocol that was based on both the patient characteristics and onset of reaction after NSAIDs, including premedication with a leukotriene antagonist and the H1-antagonist antihistamine. The clinical entities were NSAID-induced urticaria and/or angioedema in the absence of chronic spontaneous urticaria (NIUA) and NSAID-exacerbated respiratory disease (NERD). Results: A total of 23 patients were challenged or desensitized with ASA: 19 NIUA and 4 NERD. All patients tolerated the protocol at the different times of 30, 45, 90, and 120 min. The dosages of oral ASA that were given included 10, 21, 41, 81, and 162 mg (cumulative dose 315 mg). One patient reacted during the procedure and 1 during follow-up. Symptoms were limited to the skin without manifestations in other organs. All patients tolerated the required dose of ASA within 30–120 min. Those requiring urgent catheterization were desensitized within 90 min. Conclusions: Our protocol addresses challenge or desensitization with the contribution of a specialist allergist. It provides an effective, dynamic, safe, and short administration of 81 mg or higher of ASA in patients with a history of NSAID hypersensitivity with skin involvement.

Aspirin exacerbated respiratory disease: Current topics and trends.

Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets. In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option.

Nonsteroidal anti-inflammatory drug hypersensitivity in the Asia-Pacific.

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, nasal polyposis, and chronic spontaneous urticaria, especially among adults. The European Network on Drug Allergy/Global Allergy and Asthma European Network 2013 classification of NSAID HSR comprises nonselective HSR i.e., NSAID exacerbated respiratory disease (NERD), NSAIDs exacerbated cutaneous disease (NECD), NSAIDs induced urticarial-angioedema (NIUA); and selective (allergic) HSR i.e., single NSAID induced urticaria/angioedema or anaphylaxis, NSAIDs-induced delayed HSR. Much of the literature on genetic associations with NSAID HSR originate from Korea and Japan; where genetic polymorphisms have been described in genes involved in arachidonic acid metabolism, basophil/mast cell/eosinophil activation, various inflammatory mediators/cytokines, and different HLA genotypes. The Asian phenotype for NSAID HSR appears to be predominantly NIUA with overlapping features in some adults and children. NECD also appears to be more common than NERD, although both are not common in the Asian paediatric population. Between adults and children, children seem to be more atopic, although over time when these children grow up, it is likely that the prevalence of atopic adults with NSAID HSR will increase. Low-dose aspirin desensitization has been shown to be effective in the treatment of coronary artery disease, especially following percutaneous coronary intervention.

The historical factors associated with the true non-steroidal anti-inflammatory drug hypersensitivity in children

The historical factors associated with the true non-steroidal anti-inflammatory drug hypersensitivity in children

NSAIDs hypersensitivity reactions – truth or dare?

NSAIDs hypersensitivity reactions – truth or dare?

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

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. 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. 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. 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). 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.

Current diagnostics in NSAID hypersensitivity

Non-steroidal anti-inflammatory drugs (NSAID) are the second most common trigger of drug hypersensitivity in adults and children and are considered the most common or second most common cause of drug-induced anaphylaxis. NSAID hypersensitivity reactions are classified according to the latency of symptoms in relation to ingestion and on the basis of symptoms, potential underlying disease (chronic urticaria, bronchial asthma/chronic rhinosinusitis/nasal polyps), cross-reactivity to other NSAID, and the suspected pathomechanism. The diagnosis and management of NSAID hypersensitivity depend on the confirmed or suspected type of reaction. The pathomechanism for the majority of hypersensitivity reactions to NSAID has not been elucidated in detail; preferential COX-1 inhibition, which causes a shift in arachidonic acid metabolism, is considered relevant to an extent in immediate-type reactions. Delayed reactions to NSAID are rarer, diverse, and considered to be T cell mediated. All NSAIDs are essentially able to trigger all types of reaction. Immediate-type reactions involving cutaneous (urticaria/angioedema) and/or respiratory symptoms (rhinitis, bronchial asthma), as well as anaphylactic reactions are the most common. A careful allergy diagnostic work-up enables hypersensitivity to be excluded in the majority of affected individuals. In vitro testing and skin testing, as well as the gold standard, provocation testing with the suspected NSAID, or exposure testing to identify safe alternatives are used in a stepwise approach. It is important to bear in mind that standardized and validated in vitro test methods (e. g., specific IgE determination, basophil activation test, lymphocyte transformation test) and skin testing are not available for most NSAID and often prove negative. Except in the case of severe index reactions, provocation testing (with emergency response measures in place) to establish the diagnosis, evaluate possible cross-reactivity, and identify safe alternatives should be performed. Avoidance measures should only be recommended if the diagnosis has been reliably established. Patients should receive recommendations (avoidance measures, alternatives) in written form.

Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross‐Reactive Nonsteroidal Anti‐inflammatory Drug Hypersensitivity

Our aim was to evaluate genetic polymorphism of molecules involved in immunoregulatory/allergic processes in patients who presented with cutaneous hypersensitivity caused by chemically unrelated nonsteroidal anti-inflammatory drugs. Polymorphisms at IL10 (-1082 G>A), IL4 (-589 C>T), CTLA4 (+49A>G), and DAO (+8956 C>G) genes were studied in 55 cases and 97 controls by the polymerase chain reaction-restriction fragment length polymorphism technique. With regard to the polymorphism at IL10 -1082, higher frequencies of the AG genotype (57% vs 39%) and G allele carriers (70% vs 48%) were found among the patients, indicating a risk effect (odds ratio [OR] = 2.56 and P = .01 for AG genotype and OR = 2.52; P = .01 for AG/GG). For the CTLA4 +49 A/G single-nucleotide polymorphism (SNP), AG genotype (31.0%) (P = .02) and G carrier (54.0%) (P = .05) frequencies were found to be significantly lower in the patient group compared with the control group (51.0% and 69.0%, respectively). The SNP DAO +8956 C>G was associated with a strong protective effect, with OR values of 0.83 for CG and 0.11 for GG genotype (P = .04 for the codominant model), suggesting an allele dose effect. The combination of IL10 and DAO SNPs in a multivariate model did not alter the OR values, suggesting independent effects for both SNPs. The results are striking. In conclusion, these results suggest that polymorphisms in regulatory targets of the immune response and in DAO gene could modulate an individual's susceptibility to nonsteroidal anti-inflammatory drug hypersensitivity reactions. Further studies will be necessary to complement our results.

NSAIDs-Induced Anaphylaxis

Drugs are between the main triggers of anaphylaxis. They have been described as major cause of fatal anaphylaxis. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed drugs around the world because of their analgesic, anti-inflammatory, antipyretic, and antithrombotic effects. This class of drug is the first or the second after antibiotics as the cause of drug hypersensitivity reactions, including anaphylaxis. However, frequency of NSAIDs as the drug implicated in anaphylactic reactions is too variable among different countries. We believe there are discrepancies between genetics, frequency of exposure and mainly between classification of hypersensitivity reactions to NSAIDs and definition of anaphylaxis. Actual classification of NSAIDs hypersensitivity considers as anaphylaxis only those severe reactions presented by selective responders, probably IgE-mediated. Blended reactions, when respiratory plus mucocutaneous symptoms are presented after intaking NSAIDs from different groups (cross-intolerant), are not included in this classification. It can lead to underdiagnosis of non-immunological anaphylaxis. International groups of researchers must try to better define phenotypes of hypersensitivity reactions to NSAIDs, in order to include those blended reactions and better manage these cases.

Mesalamine desensitization in a patient with treatment refractory ulcerative colitis and aspirin and nonsteroidal anti-inflammatory drug hypersensitivity

Mesalamine desensitization in a patient with treatment refractory ulcerative colitis and aspirin and nonsteroidal anti-inflammatory drug hypersensitivity

Clinical Characterization of a Large Population of Subjects with Respiratory Vs Cutaneous Non-Steroidal Anti-Inflammatory Drugs (NSAID) Hypersensitivity Reactions

Clinical Characterization of a Large Population of Subjects with Respiratory Vs Cutaneous Non-Steroidal Anti-Inflammatory Drugs (NSAID) Hypersensitivity Reactions

Comparison of NSAID Hypersensitivity Between Children and Adolescents.

Comparison of NSAID Hypersensitivity Between Children and Adolescents.

Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory Drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

Systemic contact dermatitis caused by cobalt chloride and palladium in a 26-year-old woman with allergic type I reactions, non-steroidal anti-inflammatory drug hypersensitivity and autoimmune thyroiditis.

Systemic contact dermatitis caused by cobalt chloride and palladium in a 26-year-old woman with allergic type I reactions, non-steroidal anti-inflammatory drug hypersensitivity and autoimmune thyroiditis.

Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs among Adults: Clinical Features and Risk Factors for Diagnosis Confirmation

Background: Nonsteroidal anti-inflammatory drugs (NSAIDS) are among the most common causes of drug hypersensitivity (HS) reactions. The diagnosis is based on a careful clinical history, and provocation tests are considered the gold standard for diagnosis. Skin tests have some value to study reactions to pyrazolones. Laboratory investigations are mostly used for research purposes. Different phenotypes have been described. Objective and Methods: Our aim was to describe the most common clinical manifestations of NSAID HS in a large population of adult patients, the drugs involved, the association with previously described risk factors, and the outcome of diagnostic procedures. The classification of reactions proposed by the European Academy of Allergy and Clinical Immunology (EAACI) Drug Allergy Interest Group was adopted. Results: Acetylsalicylic acid was the drug most often involved in reactions (34%), isolated cutaneous symptoms were the most reported (60%), and immediate reactions (58%) were the most common. There was an overall female predominance (64%) and 35% of the patients were atopic. HS to NSAIDs was confirmed in 21% of the patients. The most common phenotypes encountered among HS patients were NSAID-induced urticaria/angioedema and single-NSAID-induced urticaria/angioedema or anaphylaxis. Logistic regression analysis showed that gender and atopy were not significant risk factors for HS confirmation, but diagnosis depended on the number of previous reactions, the type of reaction, and the time interval between drug intake and reaction. Conclusion: Only 21% of suspected HS reactions were confirmed after diagnostic workup. Patients describing >1 previous reaction and suffering immediate reactions had a higher probability of a positive investigation.

Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity.

Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization. Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel. Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%. In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization.

Periostin in Exhaled Breath Condensate and in Serum of Asthmatic Patients: Relationship to Upper and Lower Airway Disease.

PurposePeriostin is considered a biomarker for eosinophilic airway inflammation and have been associated with NSAID-Exacerbated Respiratory Disease (NERD) and chronic rhinosinusitis (CRS). In this study, we aimed to evaluate periostin in exhaled breath condensate (EBC) and in serum of patients with various asthma phenotypes.MethodsThe study included 40 asthmatic patients (22 with NERD) and 17 healthy controls. All the procedures (questionnaire, spirometry, FeNO, nasal swabs, EBC collecting, and blood sampling) were performed on the same day. Periostin concentrations were measured using an ELISA kit.ResultsPeriostin was detected in EBC from 37 of 40 asthmatics and in 16 from 17 of controls. The concentration of periostin in EBC did not differ between the study groups and was not associated with NERD or asthma severity. However, the EBC periostin was significantly higher in asthmatics with CRS as compared to those without (3.1 vs 2 ng/mL, P=0.046). Patients with positive bacterial culture from nasal swabs had higher EBC periostin concentrations than those without (3.2 vs 2.1 ng/mL; P=0.046). The mean serum periostin level was higher in asthmatics with a 1-year history of exacerbation than in those without (3.2 vs 2.3 ng/mL, P=0.045). Asthmatics with skin manifestation of NSAIDs hypersensitivity had higher serum periostin levels as compared to those without (3.5 vs 2.3 ng/mL; P=0.03).ConclusionsEBC periostin levels seem to reflect intensity of upper airway disease in asthmatics, while serum levels of periostin are associated with asthma activity (exacerbations or FeNO) or NERD subphenotypes.

Discrepancies in the diagnosis and classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions in children

BackgroundHypersensitivity 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. MethodsAll patients with a suspicion of NSAID-induced hypersensitivity were evaluated with European Network for drug Allergy (ENDA) recommendations. The children were classified as selective responders (SRs) or cross-intolerant (CI) depending on the drug provocation test (DPT) results. ResultsWe evaluated 106 children with a suspicion of NSAID hypersensitivity. NSAID hypersensitivity was confirmed with tests in 31 patients; 4 (12.9%) were diagnosed by skin tests and 27 (87.1%) by DPTs and two patients with a history of anaphylaxis by medical records. Eleven patients (33.3%) were classified as SRs, whereas twenty-two (66.6%) children as CIs. SRs and CIs were further classified as NSAID-induced urticaria/angioedema (n = 8), NSAID-exacerbated cutaneous disease (n = 6) and NSAID-exacerbated respiratory disease (n = 1) and single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 11). Eight (24.2%) patients could not be categorized according to ENDA/GA2LEN classification; one CI patient could not be classified based on pathomechanisms, seven CIs could not be categorized based on the underlying disease and clinical manifestations. A reaction within an hour of drug intake (aOR:3.0, 95% confidence interval: 1.18–7.67, p = 0.021), a history with multiple NSAIDs hypersensitivity (aOR:2.9, 95% confidence interval: 1.16–7.60, p = 0.022), and family history of atopy (aOR:4.0, 95% confidence interval: 1.50–10.82, p = 0.006) were found as the independent risk factors related to confirmed NSAID hypersensitivity. ConclusionsThis study suggests the presence of different phenotypes which do not fit into the current classifications in children with NSAID hypersensitivity.

FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS.

The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P < 0.001 and P = 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P = 0.011), and the detrimental DAO SNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P = 0.039).

Weighted Epistatic Analysis of NSAIDs Hypersensitivity Data

Complex diseases such as allergy are thought to partly result from combinations of particular genetic variants, as well as additive effects of single variations acting independently. As a result, employing an epistatic interaction approach that focuses on identifying multiple single nucleotide polymorphism (SNP) interactions can build on genome wide association studies that focus on discovering associations between disease and individual variants, and can provide insights about the underlying disease mechanisms. In previous work, we identified a number of SNPs and genes potentially involved in nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity through the application of an epistatic analysis approach. In this study, we build on these approaches and use a weighted approach to identify additional SNPs and genes associated with this disorder. This is achieved through the implementation of a novel two stage weighted epistatic analysis approach. In the first step, epistatic analysis is carried out to identify SNP pairs associated with NSAIDs hypersensitivity, and weighted SNP interaction networks inferred based on their p-value. In the second step, these SNPs are mapped to their closest protein coding gene within a 500Kb flanking distance, with a penalty applied to interactions involving SNPs not located within a gene, and gene interaction networks are constructed from this data. These networks are analysed using graph theory metrics, leading to the identification of several combinations of SNPs and genes potentially involved in and predictive of NSAIDs hypersensitivity. A number of potential asthma and atopy related genes are identified, such as KCNB2, as well as the gene CGNL1, which is differentially expressed following aspirin intake. In addition, subsequent pathway analysis of the gene interaction subnets uncovers significant enrichment for a number of biological pathways with a potential role in NSAIDs hypersensitivity, such as ALK1 and TGF-beta signalling, both associated with allergy. This study shows that applying a weighted epistatic analysis approach can provide further insights into the underlying mechanisms of NSAIDs hypersensitivity.