Acetylsalicylic Acid Challenge Research Articles

[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.

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.

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 ATP8B3 gene polymorphisms with aspirin-exacerbated respiratory disease in asthmatics.

Aspirin-exacerbated respiratory disease (AERD), an asthma phenotype, often presents with severe manifestations and it remains widely underdiagnosed because of insufficient awareness of the relationship between the ingestion of nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid (ASA), and asthma exacerbation. Our previous genome-wide association study demonstrated an association between a single nucleotide polymorphism (SNP) of the ATP8B3 gene and the risk of AERD. This study examined AERD-related SNPs of the ATP8B3 gene in a large population. Twenty-five SNPs of ATP8B3 were genotyped with the GoldenGate assay using VeraCode microbeads in 141 asthmatics with AERD and 995 Aspirin-tolerant asthma (ATA). The genotype distribution was analyzed using logistic regression models. The declines in forced expiratory volume in 1 second (FEV1)following an ASA challenge were compared among the genotypes and haplotypes using a type III generalized linear model. The minor allele frequencies (MAFs) of rs10421558 A>G in the 5'UTR and rs10403288 G>A in the intron were significantly lower in the AERD than the ATA [34.0% vs. 43.8%, OR = 0.66 (0.62-0.92), Pcorr = 0.03 and 28.4% vs. 35.4%, OR = 0.62 (0.59-0.89), Pcorr = 0.016, respectively]. BL1ht5 was significantly higher in the AERD [7.6% vs. 1.6%, OR = 12.23 (0.2-0.51), P = 4.7 × 10 -4 , Pcorr = 0.001]. Among them, rs10421558 A>G and BL1ht5 were associated with the percent decline in FEV1 on the oral ASA challenge test. The minor allele of rs10421558 A>G in the 5'UTR may protect against the development of AERD via the increased production of ATP8B3.

Omalizumab in patients with NSAIDs-exacerbated respiratory disease.

The association of acetylsalicylic acid (ASA) intolerance, chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, or chronic urticaria is known as NSAID-exacerbated respiratory disease (N-ERD). N-ERD patients often suffer from recurrent nasal polyps, severe asthma or also from urticaria. The aim of the present study was to retrospectively analyze the clinical efficacy of anti-IgE antibody treatment with omalizumab in patients with confirmed N-ERD. In the open trial with patients receiving verum patients with CRSwNP, confirmed N-ERD by oral or nasal ASA challenges, asthma or chronic urticaria were included in the study. Rhinological and pulmonary parameters were evaluated before and after 3, 6 and 9 months of therapy by rhinological questionnaires (CRS VAS-scores and RSOM-31), nasal polyp (NP)-, ACT-scores and FEV1 values. Urticaria activity was monitored clinically. N-ERD patients with aspirin desensitization were included as control group (follow-up 9 months). In the omalizumab group 16 patients were included (10 female, 6 male, mean age 51 yrs). CRS symptoms, RSOM-31- and NP-score decreased significantly following omalizumab therapy compared to baseline. The ACT-score (MV 16.5 to 20.6) and FEV1values (MV 80 % to 89 %) improved significantly. No urticaria symptoms were reported after 3 months. Oral prednisolone therapy was required in one case and a repeated nasal sinus surgery in an additional case due to progression of NP. In the control group (8 female, 8 male, mean age 45 yrs) the NP-score was unchanged. Omalizumab is an effective therapy option in N-ERD patients in a 9 month study period.

Can nasal acetylsalicylic acid challenge predict the severity of non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD)?
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Background: Non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD) complicates the clinical course of chronic rhinosinusitis with nasal polyps (CRSwNP) and severe asthma. We aimed to determine the detection rate of NERD in patients with CRSwNP, asthma, and history of NSAID intolerance using nasal challenge with acetylsalicylic acid (ASA) and the relationship between the severities of response to ASA challenges and the grade of N-ERD. Materials and methods: Three groups of patients were included: CRSwNP with asthma and clinical history of analgesics intolerance (CRSwNP-AAI n = 18), CRSwNP with asthma but without a clinical history of analgesics intolerance (CRSwNP-A n = 20), and CRSwNP without asthma or analgesics intolerance (n = 18). All subjects were challenged nasally with 16 mg ASA and monitored with active anterior rhinomanometry. Rhinological (nasal polyp score), pulmonary (spirometry, Asthma Control Test (ACT), and asthma treatment), and psychometric questionnaire scores were recorded and correlated with rhinomanometric data following nasal challenges (flow depressions and symptom scores). Results: Nasal ASA challenge detected N-ERD in 96.7% of CRSwNP-AAI patients and 45% of CRSwNP-A patients. No N-ERD was seen in the CRSwNP group. The control grade of asthma measured with ACT scores was significantly lower in the groups CRSwNP-AAI (MV 18.22) and CRSwNP-A (MV 19.75) when compared to the CRSwNP group (MV 24.39) (p = 0.000). In the CRSwNP-AAI group, 11 patients had uncontrolled asthma (61%), and in the CRSwNP-A group, 9 patients had uncontrolled asthma (45%). No correlation was found between rhinology and pulmonary parameters, nasal symptoms, and the severity of nasal ASA challenges. Specific reactions were detectable under the therapy of prednisolone and omalizumab. Conclusion: N-ERD might not always be detected by screening a patient’s medical history. Nasal ASA challenges are recommended in patients with CRSwNP and asthma. The nasal challenge with ASA positively confirms the N-ERD diagnosis. Moreover, N-ERD is a differential diagnosis in patients with severe asthma with the need for prednisolone or omalizumab therapy. The severity of the reaction to the ASA challenge in controlled and uncontrolled asthma patients is independent of the grade of N-ERD.

[Nasal provocation with increased ASA dose: improved "non-steroidal anti-inflammatory drugs (NSAIDs)-exacerbated disease" (N‑ERD) detection rate in chronic rhinosinusitis patients].

Analgesic intolerance (AI) is an important diagnostic feature of disease progression in patients with chronic rhinosinusitis (CRS) accompanied by nasal polyps (CRSwNP) and asthma. The aim of the present study was to determine whether increasing the concentration of acetylsalicylic acid (ASA) used in the diagnostic nasal challenge would improve detection of ASA intolerance (NSAIDs-exacerbated respiratory disease, N‑ERD). Patients with CRSwNP, asthma, and with (CRSwNP-AAI, n = 20) or without (CRSwNP-A, n = 15) anamnestically reported AI, as well as control subjects with CRS but no nasal polyps, asthma, or AI (n = 15), were challenged nasally with 16 mg ASA and, in case of a negative result, with 25 mg of ASA. In CRSwNP-AAI subjects, the challenge with 16 mg ASA resulted in detection of AI in 80% of cases; increasing the challenge of ASA to 25 mg improved the AI detection to 95%. In CRSwNP-A subjects, the detection of AI increased from 40% (16 mg ASA) to 53% (25 mg ASA). In the control group, no reaction to nasal ASA challenge was detected. No difference in the diagnosis of positive reactions after provocation was found when using the German vs. the European recommended evaluation criteria. Mild pulmonary symptoms occurred in 2 (10%) CRSwNP-AAI patients following the 16 mg ASA challenge. In patients with CRSwNP, asthma, and anamnestic AI, nasal provocation can effectively confirm the diagnosis of N‑ERD and can also be recommended for patients with recurrent CRSwNP and asthma but without reported AI. Increasing the ASA challenge to 25 mg increases the overall detection rate.

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.

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.

Nonsteroidal Anti-Inflammatory Drug Hypersensitivity in Preschool Children

Although extensively studied in adults, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children, especially in young children, remains poorly defined. Pediatricians, prescribing antipyretics for children, rarely encounter significant problems, but the few epidemiologic studies performed show conflicting results. Although it is clear that some patients with acetylsalicylic acid (ASA)-sensitive asthma have their clinical onset of disease in childhood and bronchoconstriction after ASA challenge is seen in 0 to 22% of asthmatic children so challenged, ibuprofen at antipyretic doses may cause acute respiratory problems only in a very small number of mild to moderate asthmatics. The recently elucidated mechanism of action of acetaminophen may explain some occurrences of adverse reactions in patients with cross-reactive NSAID hypersensitivity on the basis of its inhibitory activity on the newly described enzyme, cyclooxygenase (COX)-3. This nonspecific sensitivity to inhibition of COX is most likely genetically determined and shows a remarkable association with atopic disease even in the very young age group and possibly an increased predilection in specific ethnic groups. This review summarizes state-of-the-art published data on NSAID hypersensitivity in preschool children.

Safety of Meloxicam in Aspirin-Hypersensitive Patients with Asthma and/or Nasal Polyps

Background: The anti-inflammatory actions of acetylsalicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be due to inhibition of COX-2, whereas the side effects such as gastric damage and aspirin-induced asthma are mediated through inhibition of COX-1. Therefore, a new class of drugs with COX-2 selectivity may be well tolerated by patients with ASA/NSAIDs hypersensitivity. Objective: We investigated whether subjects with asthma and/or nasal polyps (NP) and analgesic intolerance proven by oral ASA provocation test tolerated the selective COX-2 inhibitor, meloxicam. Methods: All subjects were first challenged with ASA using a 2-day, single-blind, placebo-controlled oral provocation test. Thereafter, the subjects showing positive response to ASA provocation underwent a single-blind, placebo-controlled challenge with a cumulative dose of 7.5 mg of meloxicam on 2 separate days. One and three fourths of the divided doses of placebo and the active drug were given at 1-hour intervals. Clinical symptoms, lung function, and blood pressure were monitored during these challenge protocols. Results: Twenty-one patients with asthma and/or NP (10 males and 11 females; mean age: 38.4 ± 2.9 years) who reacted to ASA challenges were enrolled in the study. Response to ASA provocation was rhinitis + bronchospasm in 13, and extrabronchial reactions in 8 (isolated rhinitis in 3) patients. Mean PD₂₀ was 163.4 ± 39.9 mg ASA among patients who reacted with bronchospasm to ASA. Only 1 patient reacted to meloxicam challenge at a cumulative dose of 7.5 mg. Conclusion: This study indicates that 7.5 mg of meloxicam is a safe alternative treatment for ASA-hypersensitive asthma and/or NP patients with proven hypersensitivity via oral ASA challenges.

Nasal secretions in response to acetylsalicylic acid

Background: Acetylsalicylic acid (ASA) induces rhinorrhea in a subset of patients with asthma or chronic rhinosinusitis or both and nasal polyps. The underlying mechanism of the reaction is obscure. Methods: To assess the nasal response to ASA challenge, four groups of patients were challenged orally with ASA: group A (10 ASA-sensitive patients); group B (nine patients with nasal polyps and histories of tolerance to ASA); group C (nine ASA-tolerant patients with chronic allergic rhinitis); and group D (eight healthy nonatopic subjects). Results: Nasal lavages obtained before and after ASA challenge were assayed for proteins (total protein, lactoferrin, lysozyme, albumin) and inflammatory mediators (histamine, prostaglandin D 2, and leukotriene C). ASA challenges induced severe rhinorrhea and congestion and significant increases in mean concentrations of all measured nasal proteins in group A. Histamine and prostaglandin D 2 rose, but not significantly. In the two control groups with chronic rhinitis, ASA induced increases in the concentration of proteins and histamine. Leukotriene C, concentrations were significantly elevated in nasal lavages after ASA challenge in groups A and C only. In group D no symptoms or changes in nasal proteins were observed after aspirin challenge. Conclusions: These observations suggest that production of lipoxygenase products of arachidonate may induce glandular secretions that may participate in the clinical changes associated with ASA sensitivity.