Aspirin-exacerbated Respiratory Disease Patients Research Articles

The SNP rs3128965 of HLA-DPB1 as a genetic marker of the AERD phenotype.

BackgroundTwo common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.MethodsA comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.ResultsThe minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively).ConclusionsThis implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.

Altered Inhibitory Function of the E-Type Prostanoid Receptor 4 in Eosinophils and Monocytes from Aspirin-Intolerant Patients

Prostaglandin (PG) E₂ has been implicated in the pathogenesis of aspirin-exacerbated respiratory disease (AERD). E-type prostanoid (EP) receptor 4 is known to confer inhibitory signals to eosinophils and monocytes, amongst others. In this study, we investigated whether the responsiveness of eosinophils and monocytes to PGE₂ and EP4 receptor activation is altered in AERD patients. While the expression of the EP4 receptor in eosinophils was unaltered in AERD patients, inhibition of eosinophil chemotaxis by PGE₂ or the EP4 agonist CAY10598 was less pronounced in AERD patients as compared to healthy control subjects. In monocytes, we found no changes in basal or lipopolysaccharide (LPS)-stimulated PGE₂ synthesis, but the response to EP4 receptor activation with respect to inhibition of LPS-induced tumor necrosis factor-α release was reduced in AERD patients, especially in the presence of aspirin (acetylsalicylic acid). Our data point towards a decreased sensitivity of inhibitory EP4 receptor that may play a role in AERD.

Exonic variants associated with development of aspirin exacerbated respiratory diseases.

Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10−8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10−21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be “probably damaging” to the structure and function of the protein, with a high score of ‘1’. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

State of the art: a systematic review of the surgical management of aspirin exacerbated respiratory disease.

Endoscopic sinus surgery is an important modality to the armamentarium of the otolaryngologist managing chronic rhinosinusitis (CRS). Within the spectrum of CRS, there exists a subset of patients who are recalcitrant to conventional treatment strategies, including those with aspirin-exacerbated respiratory disease (AERD). Although surgery is frequently undertaken in this group, there has been no general consensus on the efficacy or optimal extent of surgery. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of published studies was conducted. Inclusion criteria included original publications of adult patients with AERD undergoing surgery, cohorts of greater than five subjects, a minimum follow-up of 3 months, and measurable clinical outcomes. An electronic search was performed using OVID MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Sixteen studies met the criteria for analysis. For our primary objective, sinus surgery appeared to improve patient-reported quality of life (QoL) and symptom profile in AERD. Overall, most studies reported a decrease in radiographic grading, endoscopy scores, and asthma severity. Compared with aspirin-tolerant asthmatic patients, AERD patients may have worse objective measures of disease severity both pre- and postoperatively; however, patient-reported QoL and symptom improvement may be similar after sinus surgery. Finally, this review showed that patients with AERD required revision surgeries sooner and more frequently compared with other subtypes of CRS. We also discussed the role of maximal surgical techniques and additional benefit of postoperative adjunctive therapies in the management of this disease entity. The state of the art in the management of AERD patients suggests that surgery does play an important role in helping establish symptomatic control. In the future, more rigorous studies evaluating the comprehensiveness of surgery and postoperative adjuncts are required to understand their impact on long-term patient outcomes.

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.

Association of serum periostin with aspirin-exacerbated respiratory disease

BackgroundRecent studies recommend periostin as a systemic biomarker of eosinophilic airway inflammation to predict responses to novel treatments that targets eosinophilic TH2-driven inflammation in asthmatic patients. ObjectiveTo investigate the clinical implications of serum periostin levels in patients with aspirin-exacerbated respiratory disease (AERD) based on its overlapping TH2-mediated pathogenesis with the eosinophilic asthma. MethodsSerum periostin levels were measured by human periostin enzyme-linked immunosorbent assay (ELISA) in serum samples from 277 adults with asthma. Serum periostin levels were compared between patients with AERD and aspirin tolerant asthma (ATA) with other asthma phenotypes, such as severe or nonsevere asthma and eosinophilic or noneosinophilic asthma. The association of serum periostin levels with clinical parameters (including disease severity and comorbid condition) was analyzed. ResultsSerum periostin levels were significantly higher in patients with AERD vs ATA, patients with severe asthma vs nonsevere asthma, and patients with eosinophilic asthma vs noneosinophilic asthma (P=.005, P=.02, and P=.001, respectively). Multivariate regression analysis revealed serum periostin levels as a significant parameter to predict AERD phenotype (P=.006) together with severe asthma phenotype (P=.04). In addition, serum periostin levels correlated with blood eosinophil counts (Spearman ñ = 0.244, P<.001) and sputum eosinophil counts (Spearman ñ = 0.261, P < 0.001). Higher serum periostin levels were noted in comorbid AERD patients with more severe chronic rhinosinusitis (Lund-Mackay stages 3 and 4) than those with less severe chronic rhinosinusitis (Lund-Mackay stages 1 and 2) (P = .03). ConclusionSerum periostin levels are significantly elevated in AERD patients and associated with AERD phenotype and disease severity.

Aspirin Desensitization: Useful Treatment for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) in Aspirin-Exacerbated Respiratory Disease (AERD)?

Aspirin intolerance syndrome is due to disturbances in the arachidonic acid metabolism implicating both the lipoxygenase and cyclooxygenase pathways. This results in imbalances of eicosanoid, leukotriene and prostaglandin synthesis. Thus, preinflammatory cysteinyl leukotrienes increase and antiinflammatory prostaglandins (PG) such as PGE2 decrease. Clinically, intolerance reactions to nonsteroidal antiinflammatory drugs (NSAIDs) can lead to different clinical manifestations; five phenotypes of the aspirin intolerance syndrome are listed in the ENDA classification. Aspirin-exacerbated respiratory disease (AERD) is the most common phenotype characterized by an eosinophil-dominated inflammatory disease of the airways that presents clinically with nasal polyps, chronic sinusitis and bronchial asthma. About 34% of patients with aspirin-induced asthma and rhinosinusitis are thought to have AERD. Important biochemical findings in many AERD patients are increased basal leukotriene levels (at least in cell cultures) that excessively increase after intake of COX-1 inhibitors. Aspirin desensitization uses the repetitive application of aspirin to induce a tolerance to NSAIDs, especially COX-1 inhibitors. After a dose-increase phase reaching a threshold dose, a dose-continuation phase is performed. For application, the nasal, bronchial, oral and intravenous routes have been described. Aspirin desensitization has been proven to be efficacious and safe and was able to reduce the need for other medications in AERD patients.

Effect of aspirin desensitization on T-cell cytokines and plasma lipoxins in aspirin-exacerbated respiratory disease

The pathogenesis of aspirin-exacerbated respiratory disease (AERD) is thought to be based on, mainly, overproduction of eicosanoid lipid mediators and on defective anti-inflammatory regulators. Aspirin desensitization treatment, the mainstay of controlling asthma and rhinitis in AERD patients, however, is the least understood aspect of the disease. The study was designed to determine the effect of aspirin desensitization on T-lymphocyte cytokine expression and on plasma lipoxin levels in AERD. Spirometry, skin-prick test and asthma control test were documented and intracellular cytokine expression in T lymphocytes and plasma lipoxin levels were measured in 23 AERD patients, 17 aspirin-tolerant asthmatic (ATA) patients, and 16 healthy controls. In the AERD group nasal symptom and smell scores were assessed. Of the 23 AERD patients 15 accepted to undergo aspirin desensitization protocol and 14 of them were desensitized successfully. In the desensitized AERD group, cytokine and lipoxin measurements were repeated after 1-month aspirin treatment. CD4(+) IL-10 levels were higher in AERD patients than in healthy controls and CD4(+) interferon (IFN) gamma levels were higher in AERD and ATA patients than in controls. Plasma lipoxin-A4 and 15-epi-lipoxin-A4 levels were similar among the three study groups. In the AERD group, subjects underwent aspirin desensitization followed by a 1-month aspirin treatment. Clinical parameters improved and CD4(+) IFN-gamma levels decreased significantly. No significant change in lipoxin levels was recorded. CD4(+) IFN-gamma and CD4(+) IL-10 levels in AERD patients after 1-month aspirin desensitization treatment were similar to the healthy controls. The study confirms aspirin desensitization is effective clinically in AERD patients and suggests that IFN gamma and IL-10 expression in CD4(+) T lymphocytes may be related to the mechanism of action.

Audit of nasal lysine aspirin therapy in recalcitrant aspirin exacerbated respiratory disease

Background Aspirin – exacerbated respiratory disease can prove difficult to control. Oral aspirin desensitization is effective, but has adverse effects and may not be cardio-protective at the high doses needed.Objective To examine the effectiveness of aspirin administered in lower doses via the nose.Methods An audit of 121 patients with aspirin exacerbated respiratory disease (AERD), 105 of whom were treated with intranasal lysine aspirin in gradually increasing doses following positive lysine aspirin challenge.Results Treatment was associated with subjective symptomatic improvement or stabilization in 60 of 78 patients at 3 months and 19 of 27 at 12 months. Nasal inspiratory peak flow, olfaction, exhaled and nasal nitric oxide levels were significantly improved (p < 0.05 for all). Patients with positive skin prick tests and those with later onset (>40 years) AERD improved more than non-atopics and those with early onset AERD.Asthma outcomes over 1 year were assessed by questionnaire in 22 patients on lysine aspirin and in 20 who were positive on challenge but who either refused treatment or took it only briefly (less than or equal to 3 months). There was a significant decrease in emergency visits (p = 0.0182), hospitalization (p = 0.0074) and oral steroid use (p = 0.004) in those on nasal lysine aspirin for a year.Gastrointestinal side effects occurred in 3.8%, lower than those reported for oral aspirin therapy. Conclusions and Clinical Relevance This form of therapy might reduce the need for expensive monoclonal antibodies in AERD patients.

Concurrent coxibs and anti-platelet therapy unmasks aspirin-exacerbated respiratory disease

To the Editor: Aspirin-exacerbated respiratory disease (AERD) is a clinical tetrad of chronic hypertrophic eosinophilic sinusitis, nasal polyps, asthma and sensitivity to any medication that inhibits cyclooxygenase (COX)-1, namely aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. The final metabolites of the degradation of arachidonic acid via COX-1 pathway are thromboxanes, prostacyclin and prostaglandins (PG); the most crucial ones are PGE2 and PGD2. According to the classical “cyclooxygenase” hypothesis, inhibition of COX-1, but not COX-2, triggers various mechanisms leading to asthmatic and/or nasal symptoms in AERD patients. The central mechanism was regarded as the deprivation of PGE2 as a consequence of COX-1 inhibition, which would lead to an even more increased local and systemic generation of cysteinyl leukotrienes (LT). The overproduction of cysteinyl LT, due to upregulation of LTC4 synthase and/or cysteinyl LT receptors in the airways, the hallmark of the disease, occurs at baseline as well, although at a much lower degree than after aspirin/NSAIDs intake [2]. After the introduction of the selective COX-2 inhibitors, casually referred to as coxibs, several well-designed studies reported the excellent safety profile of these new NSAIDs in patients with AERD [3, 4]. Nevertheless, shortly afterwards, as the use of coxibs extended, so did the number of case reports warning the clinicians that some AERD patients may not tolerate coxibs [5, 6]. In fact, all the position papers and updates on AERD evaluation and management recommend giving the first full dose of these …

Systemic prednisone administration selectively alters granulocyte subsets in nasal polyps from aspirin‐exacerbated respiratory disease and chronic rhinosinusitis patients

Nasal polyps (NPs) are hallmark inflammatory lesions of sinusitis. Despite the spectrum of NP conditions, cellular differences between NPs from patients with chronic rhinosinusitis with NPs (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) are poorly understood. NPs are associated with abundant eosinophils; the contributions of neutrophil and basophil granulocytes are less defined. We therefore sought to assess granulocyte subpopulations, and differential effects following prednisone pretreatment, within NPs of CRSwNP and AERD patients. NPs, adjacent ethmoid sinus tissue, and peripheral blood mononuclear cells (PBMCs) were obtained from patients undergoing endoscopic sinus surgery. Samples from 5 cohorts: CRSwNP ± prednisone (n = 6 each), AERD ± prednisone (n = 6 each), and controls (n = 9), were analyzed by high-dimensional flow cytometry to gate granulocyte populations. Specimens were also assessed using immunohistochemistry (IHC) staining. Systemic prednisone administration was associated with a lower frequency of eosinophils (p < 0.0001, n = 6) in NPs in both CRSwNP and AERD patients, whereas a decrease in neutrophils (p = 0.0070, n = 6) in NPs was only observed in CRSwNP patients after prednisone treatment. In contrast, steroids do not alter basophil proportions (p = 0.48, n = 6) within NPs from either group. No significant shift in granulocyte subsets after steroid treatment was identified in the adjacent ethmoid mucosa or PBMCs from the same patients. Immunohistochemistry (IHC) staining supported these findings. Granulocyte subpopulations are focally affected within NPs by systemic steroid exposure, without notable granulocyte alterations in the surrounding regional tissues. These data provide direct insights into the cellular effects of routine prednisone exposure in CRS patients, and highlight a unique microenvironment present within NP lesions.

Aspirin desensitization for aspirin‐exacerbated respiratory disease (Samter's Triad): a systematic review of the literature

To critically review the current literature regarding aspirin desensitization treatment for nasal polyposis in patients with Aspirin-Exacerbated Respiratory Disease (AERD). Systematic review of the literature. All English literature published between January 1995 and February 2013 reporting specifically nasal outcomes following aspirin desensitization in AERD patients were eligible for inclusion. Exclusion criteria were non-investigative, non-human, and ex-vivo studies. Studies were categorized by level of evidence and evaluated for quality using the Downs and Black scale. A total of 614 citations were retrieved and eleven studies met the criteria for analysis. Outcome measurements included self-reported symptom scores, amount of corticosteroid use, rate of revision surgery, and quantitative measurements such as rhinomanometry. Overall, most studies reported a significant improvement in symptom scores, decrease in corticosteroid use, and decrease in revision surgery. A few studies showed promising results with quantitative outcomes. However, most studies were of Level 2 evidence with small samples sizes. Rates of adverse events ranged from 12.5% to 23%. Unlike traditional treatments for nasal polyposis, aspirin desensitization targets AERD etiology rather than phenotype and can be an effective therapeutic option. While the current literature shows encouraging results, additional studies are needed to better define clinical benefits.

Eosinophil activation and novel mediators in the aspirin‐induced nasal response in AERD

Eosinophil activation is the key feature of upper and lower airway inflammation in aspirin-exacerbated respiratory disease (AERD). To investigate the mechanism of eosinophil activation and identify novel inflammatory mediators using proteomics. Thirty-two asthmatic subjects were enrolled: 18 AERD patients who showed positive responses to the lysine-aspirin nasal provocation test (L-ASA NPT) and 14 aspirin-tolerant asthma (ATA) patients who showed negative responses to the L-ASA NPT (control group). Nasal lavage fluid (NLF) was collected before (baseline), at 10, 30 and 60min (early response), and at 3h (late response) after the L-ASA NPT. Eosinophil cationic protein (ECP) and cysteinyl leucotriene (CysLT) levels were measured using an ImmunoCAP system and ELISA respectively. To identify proteins involved in AERD, comparative proteomics was applied using NLFs collected before and after L-ASA NPTs in AERD patients. The clinical relevance of identified novel proteins was evaluated by ELISA using NLFs from the AERD and ATA groups. Eosinophil cationic protein and CysLT levels both increased significantly during the early response in AERD. ECP levels increased until the late response in AERD, while CysLT levels were not significantly increased during the late response. Proteomic analysis showed up-regulation of apolipoprotein A1 (ApoA1), α2-macroglobulin (α2M) and ceruloplasmin (CP), with significant increases in NLF of AERD patients, which was significantly higher in AERD patients with chronic rhinosinusitis. Significant correlations were noted between ECP and CysLT, ApoA1, α2M and CP levels during the early response in AERD patients. Eosinophil activation occurred in early and late responses after L-ASA NPT in upper airway mucosa of AERD patients, where ApoA1, α2M and CP as well as CysLT may be involved in eosinophilic inflammation.

A genetic effect of IL-5 receptor α polymorphism in patients with aspirin-exacerbated respiratory disease

Persistent eosinophil activation in both the upper and lower airway mucosa is a central feature of aspirin-exacerbated respiratory disease (AERD). Eosinophil activation and survival are profoundly influenced by interleukin 5 (IL-5) and its receptor, IL-5R. In patients susceptible to allergic disorders, IL-5 receptor α (IL5RA) polymorphisms have been reported; however, an association with AERD remains unclear. We hypothesize that IL5RA polymorphisms may contribute to eosinophil activation in AERD patients. We recruited 139 AERD patients, 171 aspirin-tolerant asthma patients and 160 normal controls. IL5RA polymorphisms (−5993G>A, −5567C>G and −5091G>A) were genotyped and functional activity of polymorphism was assessed by luciferase reporter assay and electrophoretic mobility shift assay (EMSA). There was no significant difference in the genotype frequency of the three polymorphisms among the three groups. AERD patients carrying the AA genotype at −5993G>A had a significantly higher presence of serum-specific immunoglobulin E (IgE) to staphylococcal enterotoxin A (P=0.008) than those with the GG/GA genotype. In vitro, the −5993A allele had a higher promoter activity compared with the −5993G allele in human mast cell (HMC-1; P=0.030) and human promyelocytic leukemia (HL-60; P=0.013) cells. In EMSA, a −5993A probe produced a specific shifted band than the −5993G had. These findings suggest that a functional polymorphism in IL5RA may contribute to eosinophil and mast cell activation along with specific IgE responses to staphylococcal enterotoxin A in AERD patients.

Two Patterns of Changes in Nasal Nitric Oxide after Lysine Aspirin Nasal Challenge in Patients with Aspirin-exacerbated Respiratory Disease

Nasal nitric oxide (nNO) levels after nasal lysine acetylsalicylic acid (lys-ASA) challenge have not been determined. This study was designed to determine a pattern of changes after lys-ASA challenge in aspirin-exacerbated respiratory disease (AERD) patients and to evaluate the usefulness of nNO measurements in the assessment of lys-ASA nasal challenge outcome. Eighteen patients with aspirin hypersensitivity, nasal polyps, and asthma were included. Aspirin-tolerant control groups consisted of 10 healthy volunteers without asthma and nasal polyps and 10 patients with nasal polyps without asthma. All subjects underwent nasal challenge with lys-ASA. nNO was measured before and 1, 2, 4, and 24 hours after control solution and lys-ASA administration. A significant fall in nNO levels was noted in AERD patients with a positive result to challenges at time points 1 hour (p = 0.0033), 2 hours (p = 0.0033), and 3 hours (p = 0.026) after lys-ASA. A trend toward higher nNO concentrations was observed after lys-ASA challenge at the 2-hour (p = 0.018) and 4-hour (p = 0.018) time points compared with baseline in subjects with AERD and a clinically negative result to the challenge. No significant changes in nNO levels after the challenge were observed in control groups. The combined increase and decrease in nNO levels gave the sensitivity as 0.94 and specificity 1.00 at best. nNO levels decrease after lys-ASA nasal challenge in subjects with AERD and a clinically positive result of the challenge. An unexpected trend toward an increase in nNO levels is observed in subjects with AERD and a clinically negative result of the challenge.

Aspirin Exacerbated Respiratory Disease

Aspirin Exacerbated Respiratory Disease

Effect of Genetic Polymorphism of ALOX15 on Aspirin-Exacerbated Respiratory Disease

Background: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD. Methods: We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (–427G/A, –272C/A, –217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay. Result: No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the –427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of –427G/A, –272C/A and –217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001). Conclusion: These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients.

Potential Association of DDR1 Genetic Variant with FEV1 Decline by Aspirin Provocation in Asthmatics

Background. The discoidin domain receptor tyrosine kinase 1 (DDR1) is positioned within the major histocompatibility complex (MHC) region which plays an important role in the immune system. In addition, DDR1 has been elucidated to be downregulated during the epithelial–mesenchymal transition of bronchial epithelium. Objective. To investigate the potential genetic associations between DDR1 and aspirin-exacerbated respiratory disease (AERD), this study conducted association studies of DDR1 single nucleotide polymorphisms (SNPs) with AERD and the obstructive symptom of forced expiratory volume in 1 s (FEV1) decline after aspirin provocation. Methods. Nine common SNPs were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) controls. The genotype distributions of all loci were in Hardy–Weinberg equilibrium (HWE; p > .05). Results. In the results of logistic analyses using age, sex, smoking status, and atopy as covariates, DDR1 rs1264320 in the intronic region showed a potent association signal with FEV1 decline by aspirin provocation in asthmatics of this study even after corrections for multiple testing (p = .003 and corrected p = .01). However, the variants of DDR1 were not significantly associated with the AERD development (corrected p > .05). On further comparison of FEV1 decline by aspirin provocation between AERD and ATA, the variant rs1264320 was found to be associated with the FEV1 decline of ATA rather than AERD. Conclusion. Despite the need for further functional evaluations and replications, we conclude that DDR1 polymorphisms are not likely to contribute to predispositions of AERD, but may be potentially associated with FEV1 decline by aspirin provocation in asthmatics.

Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization

Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.

Potential Association ofDCBLD2Polymorphisms with Fall Rates of FEV1by Aspirin Provocation in Korean Asthmatics

Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyposis and aspirin hypersensitivity. The aspirin-induced bronchospasm is mediated by mast cell and eosinophilic inflammation. Recently, it has been reported that the expression of discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is up-regulated in lung cancers and is regulated by transcription factor AP-2 alpha (TFAP2A), a component of activator protein-2 (AP-2) that is known to regulate IL-8 production in human lung fibroblasts and epithelial cells. To investigate the associations between AERD and DCBLD2 polymorphisms, 12 common variants were genotyped in 163 AERD subjects and 429 aspirin tolerant asthma (ATA) controls. Among these variants, seven SNPs (rs1371687, rs7615856, rs828621, rs828618, rs828616, rs1062196, and rs8833) and one haplotype (DCBLD2-ht1) show associations with susceptibility to AERD. In further analysis, this study reveals significant associations between the SNPs or haplotypes and the percentage of forced expiratory volume in one second (FEV1) decline following aspirin challenge using multiple linear regression analysis. Furthermore, a non-synonymous SNP rs16840208 (Asp723Asn) shows a strong association with FEV1 decline in AERD patients. Although further studies for the non-synonymous Asp723Asn variation are needed, our findings suggest that DCBLD2 could be related to FEV1-related phenotypes in asthmatics.