Exacerbated Respiratory Disease Research Articles

Clinical benefits of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease are not related to urinary eicosanoid release and are accompanied with decreased urine creatinine.

Treatment with acetylsalicylic acid (ASA) after desensitization may be a therapeutic option in patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD). The mechanisms that lead to improvement in rhinosinusitis and asthma symptoms remain unknown. To attribute the documented clinical effects of ASA treatment of chronic rhinosinusitis and/or asthma to the release of eicosanoid metabolites in urine. Fourteen patients with NERD were successfully desensitized, and, eventually, eight patients were treated with 650 mg of ASA daily for 3 months. In addition to clinical assessments, nuclear magnetic resonance imaging and smell test were performed before and after treatment with ASA. Venous blood and urine were collected before desensitization and after 1 and 3 months of treatment. The levels of urinary leukotrienes (LT) (cysteinyl LT and LTE4) and tetranor PGDM (metabolite of prostaglandin D2) were measured by enzyme-linked immunosorbent assay. Treatment with ASA after desensitization alleviated symptoms of rhinosinusitis, improved nasal patency (mean, 50% decrease in peak nasal inspiratory flow) and sense of smell (fourfold increase in smell test score) in as early as 4 weeks. Clinical improvements were not accompanied by any change in sinonasal mucosa thickness as assessed with nuclear magnetic resonance. Urinary cysteinyl LTs, LTE4, and prostaglandin D2 metabolite remained relatively stable during ASA treatment and did not correlate with clinical improvements. Desensitization was associated with a progressive decrease of urinary creatinine. Clinical improvement in rhinosinusitis and/or asthma after ASA desensitization was not related to concentrations of urinary eicosanoid metabolites. A decrease of urinary creatinine requires further study to determine the renal safety of long-term treatment with ASA after desensitization.

A novel treatment adjunct for aspirin exacerbated respiratory disease: the low-salicylate diet: a multicenter randomized control crossover trial.

Aspirin-exacerbated respiratory disease (AERD) is a clinical triad consisting of aspirin/acetylsalicylic acid (ASA) sensitivity, bronchial asthma, and nasal polyposis. Although respiratory reactions following ingestion of ASA and other nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a hallmark of the condition, respiratory inflammation persists despite patients' avoidance of NSAIDs. Treatment of this condition remains challenging and includes both medical and surgical options. A prospective crossover single-blind multicenter study involving 4 tertiary rhinology care centers (n = 30) was conducted in which patients were randomized to start with either 6 weeks of a regular diet or 6 weeks of a low-salicylate diet and then crossed-over for a total study duration of 12 weeks. Patients were evaluated at baseline, 6 weeks (at crossover) and 12 weeks using subjective measures (22-item Sino-Nasal Outcome Test-22 [SNOT-22], Nasal Sinus Symptom Scale [NSSS], and 7-item Asthma Control Questionnaire [ACQ-7]) and objective outcome instruments (Perioperative Sinus Evaluation [POSE] and Lund-Kennedy Endoscopic Score [LKES]). Data was analyzed for 30 patients. Wilcoxon rank sum tests determined that patients had improvement in their median difference in scores, which were all statistically significant, when they followed the low-salicylate diet compared to their regular diet: SNOT-22: 15 (95% confidence interval [CI], 10 to 23.25), p < 0.001; NSSS: 3 (95% CI, 1.75 to 4), p < 0.001; ACQ-7: 4.5 (95% CI, 1.5 to 8.5), p < 0.001; POSE 6 (95% CI, 2.5 to 10), p < 0.001; and LKES: 2.5 (95% CI, 1.5 to 4), p < 0.001). The low-salicylate diet may offer a novel treatment adjunct to the current management of AERD. Clinically and statistically significant improvements on both subjective and objective outcome measures were noted for the upper and lower respiratory tracts.

An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease

Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day.

Aspirin provocation increases 8-iso-PGE2 in exhaled breath condensate of aspirin-hypersensitive asthmatics

BackgroundIsoprostanes are bioactive compounds formed by non-enzymatic oxidation of polyunsaturated fatty acids, mostly arachidonic, and markers of free radical generation during inflammation. In aspirin exacerbated respiratory disease (AERD), asthmatic symptoms are precipitated by ingestion of non-steroid anti-inflammatory drugs capable for pharmacologic inhibition of cyclooxygenase-1 isoenzyme. We investigated whether aspirin-provoked bronchoconstriction is accompanied by changes of isoprostanes in exhaled breath condensate (EBC). MethodsEBC was collected from 28 AERD subjects and 25 aspirin-tolerant asthmatics before and after inhalatory aspirin challenge. Concentrations of 8-iso-PGF2α, 8-iso-PGE2, and prostaglandin E2 were measured using gas chromatography/mass spectrometry. Leukotriene E4 was measured by immunoassay in urine samples collected before and after the challenge. ResultsBefore the challenge, exhaled 8-iso-PGF2α, 8-iso-PGE2, and PGE2 levels did not differ between the study groups. 8-iso-PGE2 level increased in AERD group only (p=0.014) as a result of the aspirin challenge. Urinary LTE4 was elevated in AERD, both in baseline and post-challenge samples. Post-challenge airways 8-iso-PGE2 correlated positively with urinary LTE4 level (p=0.046), whereas it correlated negatively with the provocative dose of aspirin (p=0.027). ConclusionA significant increase of exhaled 8-iso-PGE2 after inhalatory challenge with aspirin was selective and not present for the other isoprostane measured. This is a novel finding in AERD, suggesting that inhibition of cyclooxygenase may elicit 8-iso-PGE2 production in a specific mechanism, contributing to bronchoconstriction and systemic overproduction of cysteinyl leukotrienes.

Influence of maternally-derived antibodies on live attenuated influenza vaccine efficacy in pigs

Vaccination during pregnancy is practiced in swine farms as one measure to control swine influenza virus (SIV) infection in piglets at an early age. Vaccine-induced maternal antibodies transfer to piglets through colostrum and stabilize the herd: however, maternally derived antibodies (MDA) interfere with immune response following influenza vaccination in piglets at the later stage of life. In addition, MDA is related to enhanced respiratory disease in SIV infection. Previously, we have developed a bivalent live attenuated influenza vaccine (LAIV) which harbors both H1 and H3 HAs. We demonstrated vaccination of this LAIV provided protection to homologous and heterologous SIV infection in pigs. In this study we aimed to investigate the influence of MDA on LAIV efficacy. To this end, SIV sero-negative sows were vaccinated with a commercial vaccine. After parturition, nursery piglets were vaccinated with LAIV intranasally or intramuscularly, and were then challenged with SIV. We report that MDA hampered serum antibody response induced by intramuscular vaccination but not by intranasal vaccination of the LAIV. Viral challenge in the presence of MDA caused exacerbated respiratory disease in unvaccinated piglets. In contrast, all LAIV vaccinated piglets were protected from homologous viral infection regardless of the route of vaccination and the presence of MDA. Our results demonstrated that LAIV conferred protection in the presence of MDA without inciting exacerbated respiratory disease.

NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity.

The prevalence and mean provocative dose of oral aspirin (MPDA) triggering respiratory reactions in people with asthma have been inconsistently reported, and the relationship between NSAID-exacerbated respiratory disease (NERD) and asthma morbidity was less well quantified. A systematic review was performed by identifying studies diagnosing NERD using blinded, placebo-controlled oral provocation challenge tests (OPCTs) or by self-reported history in people with asthma. Data were extracted, and effect estimates for changes in respiratory function, MPDA and asthma morbidity were pooled using random-effects meta-analysis. The prevalence of NERD in adults with asthma was 9.0% (95% CI 6-12%) using OPCTs and 9.9% (95% CI 9.4-10.5%) using self-reported history from questionnaires. The MPDA in adults with NERD was 85.8 mg (95% CI 73.9-97.6). In people with NERD, the risk of: uncontrolled asthma was increased twofold (RR 1.96 (95% CI 1.25-3.07)); severe asthma and asthma attacks was increased by 60% (RR 1.58 (95% CI 1.15-2.16) and RR 1.59 (95% CI 1.21-2.09), respectively); emergency room visits was increased by 80% (RR 1.79 (95% CI 1.29-2.49)); and asthma hospitalization was increased by 40% (RR 1.37 (95% CI 1.12-1.67)) compared to people with NSAID-tolerant asthma. Respiratory reactions triggered by oral aspirin in people with asthma are relatively common. At the population level, the prevalence of NERD was similar when measured using appropriately conducted OPCTs or by self-reported history. On average, respiratory reactions were triggered by clinically relevant doses of oral aspirin. Asthma morbidity was significantly increased in people with NERD who potentially require more intensive monitoring and follow-up.

ASA-intolerance syndrome and persistent rhinosinusitis : Differential diagnosis and treatment

A differential diagnosis of persistent chronic rhinosinusitis is ASA-intolerance syndrome (AIS), also known as Aspirin®‑exacerbated respiratory disease (AERD), Samter-Trias (Samter's disease, Morbus Widal). Particularly in cases of frequent recurrency of nasal polyps in combination with bronchial asthma and hypersensitivity reactions to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAR) can often be referred to an underlying AIS. The pathogenesis of this syndrome is attributed to a misallocation of the arachidonic acid metabolism, resulting in an increased leukotriene production. The diagnosis may be difficult in the early stages of the disease with incomplete triad of symptoms. Therapy may consist of paranasal sinuses surgery, drug therapy and adaptive deactivation as the only causal treatment option for patients with AIS. For adaptive desactivation, positive effects were actually shown even in patients with long-term recurrent or persistent complaints of chronic rhinosinusitis.

Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease in adolescents.

There has been no study investigating nonsteroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (NERD) exclusively in childhood. Therefore, in the current study, the authors aimed to evaluate the diagnostic features, clinical characteristics, and follow-up of adolescents diagnosed with NERD. The patients who were consecutively diagnosed with NERD between January 2011, and November 2013, included in the study. Oral provocation test (OPT) with at least 2 different NSAIDs was used to confirm NSAID hypersensitivity in patients with underlying asthma/chronic rhinosinusitis/nasal polyps. All patients were followed regularly in 3-month intervals by the Pediatric Allergy and Otorhinolaryngology Department for asthma, allergic rhinitis, or chronic rhinosinusitis with or without nasal polyps. A total of 10 adolescents with NERD were included in the study. The mean age of the patients at the time of diagnosis was 14.9 ± 1.5 years. Hives or angioedema accompanied respiratory complaints induced by NSAIDs. The mean duration of follow-up was 28.9 ± 12.4 months. All patients had asthma except 1 with asymptomatic bronchial hyperreactivity. Asthma of patients was well-controlled with moderate dose of inhaled corticosteroids. Chronic rhinosinusitis with or without nasal polyps developed in 2 patients. Aspirin desensitization was required in these 2 patients with recurrent nasal polyps. NERD in childhood has much more favorable clinical characteristics and course than in adulthood. Few adolescents with NERD refer with typical chronic upper respiratory tract complaints. The asthma component seems to be mild and is well controlled in the short-term follow-up.

An Alternative Aspirin Desensitization Protocol for Patients with Aspirin- Exacerbated Respiratory Disease

Background:Aspirin exacerbated respiratory disease (AERD) affects up to 5% to 15% of asthmatics. While aspirin desensitization is a safe treatment option and allows for aspirin to be used to control AERD symptoms, not all patients diagnosed with AERD are able to complete the standard desensitization protocol. Objective: For patients who cannot complete the standard desensitization protocol, we sought to create an alternative method that allows patients to reach a therapeutic maintenance dose of aspirin. Methods: We retrospectively analyzed patients that underwent AERD desensitization, identifying 5 patients that failed the standard desensitization protocol and 6 that elected to complete the alternative aspirin desensitization. Subjects started at a dose lower than their reaction dose and subsequently increased their dosage by 40.5 mg or 81 mg every 2 to 4 weeks, with the goal of reaching a dose of 325 mg BID. Results: Among the five patients that initially failed the standard desensitization protocol, our alternative desensitization protocol took an average of 6.1 months to reach a maintenance dose of 307 mg BID with an increase of 47.5 mg aspirin every two weeks. Of the six patients who elected to complete our alternative protocol, it took an average of 4.6 months to reach a maintenance dose of 244 mg BID with an increase of 38.7 mg every two weeks. Six patients successfully increased their aspirin dosage to 325 mg BID by following the alternative protocol. Conclusion: Based on the data, it seems possible that a graduated approach to the administration of aspirin could benefit a majority of those who fail or do not wish to complete the standard desensitization protocol.

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for research on gene-environment interactions in asthma.

Extrabronchial symptoms and late phase reaction enhance the diagnostic value of aspirin bronchial challenge.

IntroductionLysine aspirin (l-ASA) bronchial challenge can be used in the diagnostics of aspirin exacerbated respiratory disease. It is safer than oral challenge, however it is characterized by a lower sensitivity.AimWe sought to investigate whether additional indicators of the positive result of l-ASA bronchial challenge, i.e. late phase reaction (LPR) and extrabronchial symptoms (EBS), may enhance its diagnostic value.Material and methodsSixty-seven patients with a positive history of asthma exacerbated by aspirin and/or other non-steroidal inflammatory drugs underwent l-ASA bronchial challenge. The control groups comprised 15 aspirin tolerant asthmatics and 15 healthy subjects. Forced expiratory volume in 1 s (FEV1) and 24-hour peak expiratory flow (PEF) measurements were performed in all subjects in order to recognize early and late response to l-ASA. All subjects underwent oral ASA challenge 2 weeks after l-ASA bronchial challenge.ResultsBasing on FEV1 and PEF results, early reaction was present in 50.7% of patients, early and LPR in 29.9% and LPR in only 10.4% of aspirin exacerbated respiratory disease patients. The EBS were noted in 31.3% of subjects. Inclusion of LPR and EBS as positive criteria of the challenge increased sensitivity to 94.0%.ConclusionsThese results indicate that both LPR and EBS should be considered as positive criteria of aspirin bronchial challenge as they enhance its diagnostic value.

Expression of the Receptor for Advanced Glycation End Products, a Target for High Mobility Group Box 1 Protein, and its Role in Chronic Recalcitrant Rhinosinusitis with Nasal Polyps

A receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) protein has been linked to several chronic diseases, and acts as a trigger for inflammation signaling. Here, we study RAGE and HMGB1 expression in chronic, recalcitrant rhinosinusitis with nasal polyps (CRSwNP) to determine its potential clinical significance, i.e., disease recurrence and severity. RAGE and HMGB1 expression in CRSwNP was evaluated by immunohistochemistry in epithelial cells of fresh sinonasal mucosa samples obtained from the patients diagnosed with recalcitrant CRSwNP (n = 25) and normal control mucosa (NC) (n = 26). RAGE and HMGB1 expression levels in tissues were correlated with disease severity assessed by nasal endoscopy, CT scan, number of previous sinus surgeries, allergy status and nasosinusal microbiology. RAGE and HMGB1 were moderately or strongly expressed in CRSwNP tissue. No or weak RAGE expression was found in NC. HMGB1 was equally strongly expressed in NC. We observed a strong correlation between RAGE and disease severity, recurrence, undergone operations, asthma and aspirin exacerbated respiratory disease (AERD). Elevated RAGE expression is associated with increased disease severity, as well as allergy and AERD in patients with recalcitrant CRSwNP. It is possible that the explanation for recurrent CRSwNP pathogenesis might be related to RAGE overexpression with subsequent sinus mucosa hyperproliferation, necessitating several operations.

Treatment of aspirin exacerbated respiratory disease with a low salicylate diet: a pilot crossover study.

Aspirin exacerbated respiratory disease (AERD) is comprised of aspirin/acetylsalicylic acid (ASA) sensitivity, bronchial asthma, and nasal polyposis. Treatment of this condition is challenging and may include topical/systemic steroids, endoscopic sinus surgery, and/or aspirin desensitization. A prospective crossover pilot study (n = 10) was conducted in which patients were randomized into either of 2 groups with 6 weeks of regular diet (R) or 6 weeks of a low salicylate diet (LS). The study was conducted in a tertiary otolaryngology clinic. Patients with AERD were enrolled in the study. Subjective (Sino-nasal Outcome Test-22 [SNOT-22], Nasal Sinus Symptom Scale [NSSS], and the Asthma Control Questionnaire-7 [ACQ-7]) and objective outcome instruments (Peri-Operative Sinus Evaluation [POSE] and Lund-Kennedy Endoscopic Score [LKES]) were used to evaluate patients at baseline, 6 weeks (at crossover), and 12 weeks. Wilcoxon rank sum tests demonstrated that patients on the low salicylate diet had improved scores compared to their regular diet when evaluated by 4 of the 5 outcome measures (SNOT-22 pLS = 0.0059, NSSS pLS = 0.0195, LKES pLS = 0.0039, POSE pLS = 0.005). Results of the pilot study indicate that implementation of a low salicylate diet improves the nasal symptoms and nasal endoscopy findings of individuals with AERD. Further research is required to support these findings.

Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity

Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently coexist and are always present in patients with aspirin exacerbated respiratory disease (AERD). Although the pathogenic mechanisms of this condition are still unknown, AERD may be due, at least in part, to an imbalance in eicosanoid metabolism (increased production of cysteinyl leukotrienes (CysLTs) and reduced biosynthesis of prostaglandin (PG) E2), possibly increasing and perpetuating the process of inflammation. PGE2 results from the metabolism of arachidonic acid (AA) by cyclooxygenase (COX) enzymes, and seems to play a central role in homeostasis maintenance and inflammatory response modulation in airways. Therefore, the abnormal regulation of PGE2 could contribute to the exacerbated processes observed in AERD. PGE2 exerts its actions through four G-protein-coupled receptors designated E-prostanoid (EP) receptors EP1, EP2, EP3, and EP4. Altered PGE2 production as well as differential EP receptor expression has been reported in both upper and lower airways of patients with AERD. Since the heterogeneity of these receptors is the key for the multiple biological effects of PGE2 this review focuses on the studies available to elucidate the importance of these receptors in inflammatory airway diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-014-0100-7) contains supplementary material, which is available to authorized users.

Long-term sinonasal outcomes of aspirin desensitization in aspirin exacerbated respiratory disease.

This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS). Case series with chart review. University hospital. A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization. Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted. Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

Aspirin hypersensitivity in Iranian patients with chronic rhinosinusitis and nasal polyposis: prevalence and comorbid factors

Background Aspirin (ASA) hypersensitivity is frequent in patients with chronic rhinosinusitis and nasal polyps (CRSwNP), which is called aspirin exacerbated respiratory disease (AERD). However, there are few studies on evaluating the prevalence of ASA hypersensitivity in patients with nasal polyps (NPs), using the oral aspirin challenge test. This study was designed to determine the frequency of ASA hypersensitivity and factors associated with ASA hypersensitivity in patients with CRSwNP. Methods Eighty Iranian patients (43 women and 37 men) with CRSwNP were enrolled in this study. Extension of NPs was evaluated by endoscopic examination. A single day, oral aspirin challenge (OAC) was used to detect ASA hypersensitivity. Atopic evaluation was performed, using skin prick test, nasal smear, blood eosinophil count, and serum total IgE. Results

A survey of physician practice and knowledge of drug allergy at a university medical center

A survey of physician practice and knowledge of drug allergy at a university medical center

Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity

Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity

Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (CEP68) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest p-value = 1.13×10−6), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that CEP68 gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs.

Alcohol-induced Respiratory Symptoms Are Common in Patients With Aspirin Exacerbated Respiratory Disease

A large percentage of patients with aspirin exacerbated respiratory disease (AERD) report the development of alcohol-induced respiratory reactions, but the true prevalence of respiratory reactions caused by alcoholic beverages in these patients was not known. We sought to evaluate the incidence and characteristics of alcohol-induced respiratory reactions in patients with AERD. A questionnaire designed to assess alcohol-induced respiratory symptoms was administered to patients at Brigham and Women's Hospital and Scripps Clinic. At least 50 patients were recruited into each of 4 clinical groups: (1) patients with aspirin challenge-confirmed AERD, (2) patients with aspirin-tolerant asthma (ATA), (3) patients with aspirin tolerance and with chronic rhinosinusitis, and (4) healthy controls. Two-tailed Fisher exact tests with Bonferroni corrections were used to compare the prevalence of respiratory symptoms among AERD and other groups, with P ≤ .017 considered significant. The prevalence of alcohol-induced upper (rhinorrhea and/or nasal congestion) respiratory reactions in patients with AERD was 75% compared with 33% with aspirin-tolerant asthma, 30% with chronic rhinosinusitis, and 14% with healthy controls (P < .001 for all comparisons). The prevalence of alcohol-induced lower (wheezing and/or dyspnea) respiratory reactions in AERD was 51% compared with 20% in aspirin-tolerant asthma and with 0% in both chronic rhinosinusitis and healthy controls (P < .001 for all comparisons). These reactions were generally not specific to one type of alcohol and often occurred after ingestion of only a few sips of alcohol. Alcohol ingestion causes respiratory reactions in the majority of patients with AERD, and clinicians should be aware that these alcohol-induced reactions are significantly more common in AERD than in controls who are aspirin tolerant.