Oral Aspirin Challenge Research Articles

Aspirin hypersensitivity diagnostic index (AHDI): Invitro test for diagnosing of N-ERD based on urinary 15-oxo-ETE and LTE4 excretion.

15-oxo-eicosatetraenoic acid (15-oxo-ETE), is a product of arachidonic acid (AA) metabolism in the 15-lipoxygenase-1 (15-LOX-1) pathway. 15-oxo-ETE was overproduced in the nasal polyps of patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). In this study we investigated the systemic biosynthesis of 15-oxo-ETE and leukotriene E4 (LTE4) and assessed their diagnostic value to identify patients with N-ERD. The study included 64 patients with N-ERD, 59 asthmatics who tolerated aspirin well (ATA), and 51 healthy controls. A thorough clinical characteristics of asthmatics included computed tomography of paranasal sinuses. Plasma and urinary 15-oxo-ETE levels, and urinary LTE4 excretion were measured using high-performance liquid chromatography and tandem mass spectrometry. Repeatability and precision of the measurements were tested. Plasma 15-oxo-ETE levels were the highest in N-ERD (p < .001). A receiver operator characteristic (ROC) revealed that 15-oxo-ETE had certain sensitivity (64.06% in plasma, or 88.24% in urine) for N-ERD discrimination, while the specificity was rather limited. Modeling of variables allowed to construct the Aspirin Hypersensitivity Diagnostic Index (AHDI) based on urinary LTE4-to-15-oxo-ETE excretion corrected for sex and the Lund-Mackay score of chronic rhinosinusitis. AHDI outperformed single measurements in discrimination of N-ERD among asthmatics with an area under ROC curve of 0.889, sensitivity of 81.97%, specificity of 87.23%, and accuracy of 86.87%. We confirmed 15-oxo-ETE as a second to cysteinyl leukotrienes biomarker of N-ERD. An index based on these eicosanoids corrected for sex and Lund-Mackay score has a similar diagnostic value as gold standard oral aspirin challenge in the studied group of patients with asthma.

Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

The value of aspirin challenge tests in the diagnosis of non-steroidal anti-inflammatory drugs-exacerbated respiratory disease

Objective: To investigate the value of aspirin challenge tests in the diagnosis of non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (NERD). Methods: Fifty patients (28 females; age, 16-61 years) who were diagnosed with chronic rhinosinusitis with nasal polyps (CRSwNP) with/without asthma, and underwent NERD standardized diagnosis in the Allergy Centre of West China Hospital, Sichuan University from December 2021 to November 2022 were included in the study. The first step was asking about the history of exacerbation respiratory symptoms after intake of any non-steroidal anti-inflammatory drug, including aspirin; the second step was performing intranasal aspirin challenge (IAC); the third step was performing oral aspirin challenge (OAC). The diagnosis of NERD was made if any of the above steps was positive, and the subsequent steps were not performed, otherwise the diagnosis was made to OAC. If OAC was negative, the diagnosis was non-NERD. All patients completed the sino-nasal outcome test 22 (SNOT 22) score, Lund-Kennedy score by nasal endoscopic, allergen skin prick test, blood routine and serum total IgE test. SPSS version 20.0 was used for statistical analysis. Results: The diagnosis of NRED was confirmed in 27 patients (27/50, 54%). Seven (7/50, 14%) of them were diagnosed by clinical history and 20 (20/50, 40%) were diagnosed by aspirin challenge tests, of which 17 (17/20, 85%) were positive to IAC and 3 (3/20, 15%) to OAC. Of the 43 patients who underwent IAC testing, only 2 (2/43, 5%) developed asthma attacks during challenge. Comparing the clinical characteristics of patients in NERD and non-NERD group, there were significant differences between the two groups in gender (P=0.001), hyposmia (P=0.003), history of repeated CRSwNP surgeries (P=0.028), comorbid asthma (P=0.013), SNOT-22 score (P=0.004) and the percentage of peripheral blood eosinophil (P=0.043). Conclusions: Patients may be underdiagnosed if the diagnosis of NERD is made only by medical history, and it is necessary to carry out aspirin challenge tests. IAC is an important means to diagnose NERD with high accuracy and good safety. However, If IAC is negative, further OAC is required.

Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E2 (PGE2) are hallmarks of AERD. Amouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD. Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production. Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P= .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8%± 3.6% with ifetroban vs -8.4%± 2.1% with placebo [P= .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis. Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.

POSSIBLE ANAPHYLAXIS TO ASPIRIN IN A PEDIATRIC PATIENT

<h3>Introduction</h3> Aspirin challenges are often used to characterize NSAID hypersensitivity, as there have been no confirmed reports of anaphylaxis to aspirin. <h3>Case Description</h3> A 6-year-old boy with history of allergic rhinitis and asthma received oral ibuprofen for fever and within 1 hour developed isolated eye and lip swelling, which persisted for several days despite taking diphenhydramine. At age 8, he underwent an oral graded ibuprofen challenge. About 30 minutes after the third dose (240 mg ibuprofen), he developed nasal congestion, throat discomfort, periorbital angioedema, and generalized pruritis. He was treated with cetirizine, and his symptoms resolved. Two months later, he underwent an oral graded aspirin challenge (cumulative dose 324 mg). While asymptomatic during the 2-hour observation period, he developed cough, throat clearing, eye itching, and nasal congestion shortly after discharge. He initially received his daily inhaled corticosteroid (fluticasone) and nasal corticosteroid (fluticasone), as well as albuterol, with partial improvement in cough. He presented to an ED with throat itching and nasal congestion and was treated with diphenhydramine and discharged. That night, he developed upper eyelid swelling, treated with diphenhydramine, followed by lower eyelid swelling and nasal congestion the next day, for which he was started on twice-daily cetirizine 10 mg. Full avoidance of all NSAIDs was recommended. <h3>Discussion</h3> Although IgE mediated anaphylaxis to aspirin has not been reported, this patient experienced symptoms suggestive of anaphylaxis after a graded oral challenge to aspirin. Alternatively, symptoms may represent a blended non-IgE mediated reaction.

Machine learning in the diagnosis of asthma phenotypes during coronavirus disease 2019 pandemic.

BackgroundDuring the coronavirus disease 2019 (COVID‐19) pandemic, it has become a pressing need to be able to diagnose aspirin hypersensitivity in patients with asthma without the need to use oral aspirin challenge (OAC) testing. OAC is time consuming and is associated with the risk of severe hypersensitive reactions. In this study, we sought to investigate whether machine learning (ML) based on some clinical and laboratory procedures performed during the pandemic might be used for discriminating between patients with aspirin hypersensitivity and those with aspirin‐tolerant asthma.MethodsWe used a prospective database of 135 patients with non‐steroidal anti‐inflammatory drug (NSAID)–exacerbated respiratory disease (NERD) and 81 NSAID‐tolerant (NTA) patients with asthma who underwent OAC. Clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant and urine were extracted for the purpose of applying ML techniques.ResultsThe overall best ML model, neural network (NN), trained on a set of best features, achieved a sensitivity of 95% and a specificity of 76% for diagnosing NERD. The 3 promising models (i.e., multiple logistic regression, support vector machine, and NN) trained on a set of easy‐to‐obtain features including only clinical characteristics and laboratory data achieved a sensitivity of 97% and a specificity of 67%.ConclusionsML techniques are becoming a promising tool for discriminating between patients with NERD and NTA. The models are easy to use, safe, and achieve very good results, which is particularly important during the COVID‐19 pandemic.

Mediator production and severity of aspirin-induced respiratory reactions: Impact of sampling site and body mass index

Patients with aspirin-exacerbated respiratory disease can experience severe reactions during aspirin challenge that are associated with high levels of mast cell mediators. The tissue source and clinical factors contributing to systemic mediator levels are unknown. We sought to determine the concordance between respiratory tract and systemic inflammatory mediator levels and identify clinical factors associated with these mediators. We performed an oral aspirin challenge in 30 subjects with aspirin-exacerbated respiratory disease. Respiratory symptoms and function, nasal mucosal fluid, blood, and urine were collected at baseline, at the onset of a respiratory reaction, and over a 3-hour observation period. Changes in nasal and systemic mediator levels were compared. Neither tryptase nor leukotriene E4 levels in nasal fluid correlated with serum tryptase or urinary leukotriene E4 levels at baseline or during reactions. We observed no association between the baseline or aspirin-induced change in nasal versus urinary leukotriene E4 and serum tryptase levels. Body mass index inversely correlated with baseline and aspirin-induced urinary leukotriene E4, prostaglandin D2 metabolite, and serum tryptase levels, as well as with aspirin-induced symptoms and respiratory function, but not with nasal mediators. The levels of nasal and systemic aspirin-induced mast cell products are discordant in aspirin-exacerbated respiratory disease. Systemically detected levels are likely derived from mast cells outside of the sinonasal cavity and do not accurately reflect upper respiratory tract production. Increased body mass index decreases systemic mast cell mediator production and reaction severity, supporting a contribution of metabolic regulation in aspirin-induced systemic reactions.

Aspirin Exacerbated Respiratory Disease and Nasal Polyp Phenotyping.

Aspirin exacerbated respiratory disease (AERD) is known by the triad of chronic rhinosinusitis with nasal polyposis (CRSwNP), aspirin hypersensitivity, and asthma, but its etiology and physiopathogenesis are still unclear. This cross-sectional study was designed to investigate allergy and inflammatory cells (neutrophils vs. eosinophils) dominancy in nasal polyp tissue of patients with AERD compared to non-AERD patients. CRSwNP patients scheduled for endoscopic sinus surgery were recruited in this study. Nasal polyp tissue was analyzed for infiltrating cells, and Eosinophil dominant and neutrophil dominant polyps were determined. AERD was confirmed by oral aspirin challenge (OAC). Demographics data; history of asthma, exacerbation by using NSAIDs, routine use of aspirin, type of surgery (primary or revision), and results of skin prick test and spirometry were recorded. Pathology results and contributing factors compared between AERD and non-AERD patients. Sixty-five patients (39 women, 26 men) were enrolled in the study (mean age 38.83 ± 12.43 years). Thirty (46%) patients had positive OAC tests. Totally 41 patients (63.1%) had eosinophilic polyps. 80% of patients with eosinophilic polyp had positive OAC and were AERD (P < 0.05). There was no significant difference in demographics, revision surgery, and concomitant asthma between AERD and non-AERD groups (P > 0.05). The positive skin prick test was higher in AERD and also in eosinophilic polyp patients, but it was not statistically significant (P = 0.086 and P = 0.177). Eosinophilic polyps are more common in AERD. A positive skin prick test is associated with AERD and eosinophilic polyp.

Aspirin Sensitivity in Patients with Moderate to Severe Asthma.

Asthma induced by ingestion of aspirin occurs when symptoms arise within 30 minutes to three hours after aspirin consumption. Previous data indicate that sensitivity to aspirin may be associated with poorly controlled asthma. This study aims to evaluate the frequency of aspirin sensitivity in patients with moderate to severe asthma receiving conventional asthma therapy. This clinical trial was conducted on 65 patients aged 18 to 65 years with moderate to severe asthma from February 2015 to February 2016 at the Allergy Department, Hazrat-e-Rasoul Hospital, Iran University of Medical Sciences, Tehran. To assess treatment responses in patients, forced expiratory volume in the first second (FEV1) and asthma control test (ACT) scores were measuredat baseline and after 3 months. The results of the oral aspirin challenge revealed a prevalence of 35.38% for sensitivity to aspirin. Hypersensitivity reactions to aspirin were detected in 60.9% of the patients with moderate asthma and 39.1% of the patients with severe asthma. All patients with positive aspirin challenge tests suffered from rhinosinusitis and in 56.5% of cases, history of previous hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) was detected. No meaningful differences were found between those patients with aspirin sensitivity and those with aspirin tolerance neither in mean pre-bronchodilator FEV1 nor in ACT scores pre- and post-treatment. To conclude, aspirin sensitivity was not found to have an association with an unfavorable response to conventional treatment in patients with uncontrolled asthma.

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20–79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5–59.8]) than in the placebo phase (80.8 [interquartile range, 65.4–87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Assessment of selected parameters of the circulatory system in patients undergoing oral aspirin challenge.

IntroductionIt is known that the administration of the drug during the oral aspirin challenge (OAC) can cause hypersensitivity symptoms not only from the respiratory system or skin, but also from the cardiovascular system.AimTo assess the occurrence and nature of cardiovascular adverse events during the OAC in patients suspected of hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).Material and methodsThe study included 52 patients with symptoms of hypersensitivity to aspirin (ASA) or other NSAIDs in the form of skin reactions or respiratory response in anamnesis. Patients were treated with OAC and simultaneously were subject to monitoring of clinical manifestations of hypersensitivity to ASA/NSAIDs, ventilation disorders and cardiovascular functions.ResultsThe most common reaction of the cardiovascular system during OAC was tachycardia or supraventricular and ventricular extrasystoles, regardless of the day of the study and the result of OAC. Supraventricular and ventricular tachycardia was recorded incidentally. Atrial or ventricular fibrillation or flutter was not observed. There was no evidence of any ischemic heart disease. In 2 patients, hypotension was registered, but only 1 of them required typical treatment of anaphylaxis.ConclusionsNo clinically significant cardiac arrhythmias were recorded during OAC. The changes observed in the records of blood pressure and ECG monitoring show that OAC performed in accordance with the current guidelines does not pose a high risk to the patient’s health and life as a result of cardiovascular reactions.

A One-day, 90-minute Aspirin Challenge and Desensitization Protocol in Aspirin-Exacerbated Respiratory Disease

Aspirin challenge and desensitization remains the gold standard in diagnosis and treatment of patients with aspirin-exacerbated respiratory disease (AERD), but the protocols can be time and resource intensive. The objective of this study is to provide evidence that oral aspirin challenge and desensitization can be safely performed in an outpatient setting in one day. Forty-four patients with confirmed diagnosis of AERD, stable asthma and baseline FEV1 ≥70% of predicted completed an oral aspirin challenge and desensitization protocol. The starting dose was 40.5mg with escalating doses of aspirin (81, 162.5, 325mg) at 90-minute intervals until symptoms were provoked. Desensitization was defined as tolerating a repeated administration of the provocative dose and at least one subsequent aspirin dose, bringing total aspirin ingested during the in-clinic desensitization to ≥325mg. Ninety-three percent of patients completed the challenge and desensitization in one day, with an average protocol completion time of 9 hours and 29 minutes. Two patients (4.6%) chose to complete the protocol over two days. One patient (2.3%) was discontinued from the protocol due to on-going abdominal discomfort and diarrhea. No patient required epinephrine, emergency department visit or hospitalization. Patients with AERD on a stable asthma regimen and with a baseline FEV1≥70% can be safely desensitized to aspirin using a 90-minute dose escalation protocol, starting at a dose of 40.5mg, and defining desensitization as tolerance of the repeated provocation dose and at least one subsequent aspirin dose, bringing total cumulative daily dose to ≥325mg. This protocol can routinely be completed in one day.

A 1-Day, 90-Minute Aspirin Challenge and Desensitization Protocol in Aspirin-Exacerbated Respiratory Disease

Aspirin challenge and desensitization remains the criterion standard in diagnosis and treatment for patients with aspirin-exacerbated respiratory disease (AERD), but the protocols can be time and resource intensive. To provide evidence that oral aspirin challenge and desensitization can be safely performed in an outpatient setting in 1 day. Forty-four patients with a confirmed diagnosis of AERD, stable asthma, and baseline FEV1 value greater than or equal to 70% of predicted completed an oral aspirin challenge and desensitization protocol. The starting dose was 40.5 mg with escalating doses of aspirin (81, 162.5, 325 mg) at 90-minute intervals until symptoms were provoked. Desensitization was defined as tolerating a repeated administration of the provocative aspirin dose and at least 1 subsequent dose, bringing the total aspirin ingested during the in-clinic desensitization to 325 mg or more. Ninety-three percent of patients completed the challenge and desensitization in 1 day, with an average protocol completion time of 9 hours and 29 minutes. Two patients (4.6%) chose to complete the protocol over 2 days. One patient (2.3%) was discontinued from the protocol because of ongoing abdominal discomfort and diarrhea. No patient required epinephrine, emergency department visit, or hospitalization. Patients with AERD on a stable asthma regimen and with a baseline FEV1 value greater than or equal to 70% can be safely desensitized to aspirin using a 90-minute dose escalation protocol, starting at a dose of 40.5 mg, and defining desensitization as tolerance of the repeated provocation dose and at least 1 subsequent aspirin dose, bringing total cumulative daily dose to 325 mg or more. This protocol can routinely be completed in 1 day.

A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions. We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD. Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4weeks of prasugrel and after 4weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded. Prasugrel did not significantly change the mean increase in TNSS of 2 points (79±15 for patients receiving placebo and 139±32 for patients receiving prasugrel, P=.10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders. In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reactionsymptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.

Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma

BackgroundWe previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype.MethodsWe recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped.ResultsIn an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P = 0.001–0.004, OR = 0.59–0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P = 0.033), but the other four SNPs in hapblock2 were not.ConclusionTo the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition.

Nasal Ketorolac Challenge Using Acoustic Rhinometry in Patients With Aspirin-Exacerbated Respiratory Disease.

Safer and less time-consuming alternatives to single-blind placebo-controlled oral challenge (SBPCOC) have been sought for the diagnosis of aspirin-exacerbated respiratory disease (AERD). Nasal challenges with various nonsteroidal anti-inflammatory drugs and assessment methods have been developed. Objective: Our objective was to evaluate the utility and safety of nasal ketorolac challenge (NKC) using acoustic rhinometry in patients with suspected AERD. The study population comprised 36 patients with suspected AERD. NKC was performed with placebo (saline) and 13 mg of ketorolac sprayed as aerosol into both nostrils. A positive challenge result was defined as an increase of ≥30% in nasal symptoms (recorded using a visual analog scale) and a 30% drop in the sum of the volumes of both nasal cavities at 2-8 cm. Patients with a negative NKC result underwent SBPCOC with aspirin (cumulative dose of 750 mg). A naso-ocular reaction during NKC was detected in 21 patients. Four patients also developed mild asthma exacerbations (although only 1 experienced a decrease in FEV1 >15%). No other significant adverse events occurred. The remaining 15 patients with a negative NKC result had a negative response during aspirin SBPCOC. NKC assessed using acoustic rhinometry is a reliable method for the study of patients with AERD. We suggest that NKC assessed with acoustic rhinometry was useful and safe for selection of candidates for safe oral aspirin challenge.

Use of a composite symptom score during challenge in patients with suspected aspirin-exacerbated respiratory disease

BackgroundAspirin-exacerbated respiratory disease is characterized by asthma, chronic rhinosinusitis, nasal polyposis, and sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. Confirmation of the diagnosis requires provocation challenge with resulting upper and/or lower airways reactivity. Currently, determination of a positive challenge result is based solely on clinical judgment that synthesizes subjective symptoms and objective measures, as a concomitant increase in nasal or bronchial airways resistance is measured in only half of patients. ObjectiveTo describe a quantitative scoring system, based on symptoms typically reported during provocation challenge, used to identify a positive challenge result. MethodsA total of 115 patients were asked to record 10 symptoms, rated on a scale from 1 (mild) to 10 (most severe), at regular intervals during intranasal ketorolac with modified oral aspirin challenge performed in our office. Composite scores, a simple sum of all individual scores, were calculated at each time point and compared with baseline, prechallenge values. ResultsOne hundred of the 115 patients were determined to have a positive challenge result. A statistically significant difference in composite scores was observed in reactors vs nonreactors. All nonreactors recorded an increase in composite score of less than 5, whereas 69% of reactors recorded an increase of 5 or more. ConclusionOur 10-symptom composite score provides a quantitative and comparable measure of symptoms that typically present during a challenge with a positive result. Although an external validation is needed to confirm its diagnostic performance characteristics, a change in composite score of 5 or more appears to be specific to reactors.

Salicylate Food Intolerance and Aspirin Hypersensitivity in Nasal Polyposis.

A clear association between allergy and nasal polyposis (NP) is not determined and the role of food intolerance in patients with NP is not investigated by oral food challenge (OFC). To investigate the relation of salicylate food intolerance and atopy in patients with NP according to recurrence and aspirin sensitivity. A cross sectional multicenter study was done in two tertiary centers for allergy in Iran. Adult patients with NP were selected for the study that had been referred to allergy clinics. The oral aspirin challenge (OAC) test was performed to identify aspirin exacerbated respiratory disease (AERD) and the OFC test was used to investigate food intolerance. Atopic evaluation was performed by skin-prick tests, nasal smear and blood eosinophil count as well as serum total IgE. One hundred and nineteen Iranian patients (female to male ratio 1.05) with NP were enrolled (mean age, 38 ± 11 years). Recurrence of nasal polyposis was 64.7%. OAC was performed in all cases; 43.79% cases had aspirin hypersensitivity. In addition, OFC tests determined that 69.9% of patients had salicylate food allergy. Salicylate food intolerance was significantly higher in NP cases with AERD than in aspirin tolerant patients (p<0.05). Yet, positive skin prick test was not associated with NP recurrence and AERD. Atopy and NSAID exacerbated respiratory disease; therefore, they can both be considered as predictors of NP recurrence. Our study also showed that salicylate food intolerance was associated with AERD in nasal polyposis.

Olfaction and sinonasal symptoms in patients with CRSwNP and AERD and without AERD: a cross-sectional and longitudinal study.

Oral aspirin challenge (OAC) reveals aspirin-exacerbated respiratory disease (AERD) in approximately 50% of unselected patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). Smell loss is one factor that predicts the outcome of OAC. The present study aims to unveil differences in olfactory function between patients with CRSwNP with and without AERD by means of a validated reliable test for odor threshold, discrimination and identification. Additionally, Beck Depression Inventory (BDI) and Sinonasal Outcome Test 22 (SNOT 22) were applied. 31 patients were tested before and 7months after OAC and aspirin desensitization in case of diagnosed AERD. AERD was diagnosed in 16 and excluded in 15 patients. Patients with AERD demonstrated significantly more olfactory loss, but no difference in BDI or SNOT 22 at baseline. Olfaction of the groups equalized at follow-up. Sinonasal complaints decreased significantly in patients with AERD, but not in the group without AERD. Olfactory loss is a valuable marker for AERD, but due to the variance of olfactory test results prediction of AERD by exclusively any of the applied olfactory tests appears unreliable.

ASCIA‐P40: PHOLCODINE‐ASSOCIATED ALLERGY AND CROSS‐REACTIVITY WITH NEUROMUSCULAR BLOCKING DRUGS

Neuromuscular blocking drugs (NMBDs) are the most common cause of intraoperative anaphylaxis in Australia.1 Pholcodine is an opioid-based antitussive agent commonly available without prescription which shares a common epitope with NMBDs. A link between pholcodine hypersensitivity and potential for NMBD-associated anaphylaxis led to pholcodine withdrawal from Norway.2 The Australian Therapeutic Goods Administration (TGA) has recently rejected applications to restrict pholcodine use. We describe two patients with pholcodine anaphylaxis who subsequently had positive skin tests (SPT) to one or more NMBD. A 76 year old ex-public servant presented with five days of cough and was given a dry cough mixture. Within ten minutes of ingestion she developed facial pruritus, rash, hoarseness and tongue swelling. She was treated with adrenaline, hydrocortisone and cetirizine. She had detectable specific IgE to pholcodine (7.14 kU/L) and morphine (1.91 kU/L) but not suxamethonium. When tested to a panel of NMBDs she had a positive intra-dermal test to atracurium. Avoidance of pholcodine, cisatracurium and atracurium was advised. A 40 year old office worker developed palmar itch, urticaria, facial oedema, throat tightness and syncope 20 minutes after ingesting a pholcodine-containing cough mixture and aspirin, for a sore throat and cough. She was treated with adrenaline. Serum specific IgE was positive to morphine and negative to suxamethonium. SPT demonstrated a 4 mm wheal to pholcodine but 0 mm to NMBDs. Intradermal testing demonstrated a 9 mm wheal to suxamethonium. The patient was advised to avoid both pholcodine and suxamethonium. Oral aspirin challenge is pending. Although its overall incidence is low, NMBD-associated anaphylaxis remains a serious clinical problem with a greater incidence in countries with high pholcodine use. Our cases demonstrate the presence of specific IgE to different NMBDs in patients presenting with pholcodine-associated anaphylaxis. We recommend that all similar cases be reported to the TGA.