Aspirin-tolerant Asthma Patients Research Articles

Long-term clinical outcomes of aspirin-exacerbated respiratory disease: Real-world data from an adult asthma cohort.

Aspirin-exacerbated respiratory disease (AERD) is a phenotype of severe asthma, but its disease course has not been well documented compared with that of aspirin-tolerant asthma (ATA). This study aimed to investigate the long-term clinical outcomes between AERD and ATA. AERD patients were identified by the diagnostic code and positive bronchoprovocation test in a real-world database. Longitudinal changes in lung function, blood eosinophil/neutrophil counts, and annual numbers of severe asthma exacerbations (AEx) were compared between the AERD and the ATA groups. Within a year after baseline, two or more severe AEx events indicated severe AERD, whereas less than two AEx events indicated nonsevere AERD. Among asthmatics, 353 had AERD in which 166 and 187 patients had severe and nonsevere AERD, respectively, and 717 had ATA. AERD patients had significantly lower FEV1%, higher blood neutrophil counts, and higher sputum eosinophils (%) (all p < .05) as well as higher levels of urinary LTE4 and serum periostin, and lower levels of serum myeloperoxidase and surfactant protein D (all p < .01) than those with ATA. In a 10-year follow-up, the severe AERD group maintained lower FEV1% with more severe AEs than the nonsevere AERD group. We demonstrated that AERD patients presented poorer long-term clinical outcomes than ATA patients in real-world data analyses.

Associations between TMEM196 polymorphisms and NSAID-exacerbated respiratory disease in asthma.

We previously found differences in the minor allele frequency (MAF) of single-nucleotide polymorphisms (SNPs) in transmembrane protein 196 (TMEM196) between 995 patients with aspirin-tolerant asthma (ATA) and 141 asthmatic patients with NSAID-exacerbated respiratory disease (NERD). In this study, we statistically analyzed the distributions of the genotypes and haplotypes of these SNPs to determine the exact association between TMEM196 genetic variants and the risk for NERD. Lewontin's D' and r values were used to measure linkage disequilibrium between the biallelic loci having MAFs more than 0.05, and haplotypes were inferred using the PHASE algorithm (version 2.0). The genotype distribution was analyzed by logistic regression models using age of onset, smoking status (nonsmoker=0, ex-smoker=1, smoker=2), and BMI as covariates. Regression analysis of the association between SNPs and the risk of NERD was analyzed using SPSS version 12.0 and PLINK version 1.9. The MAF of rs9886152 C>T was significantly lower in NERD than in ATA [24.8 vs. 34.0%, odds ratio=0.64 (0.48-0.85), P=2.07×10, Pcorr=0.048]. The rate of the rs9886152 C>T minor allele was significantly lower in NERD than in ATA [44.0 vs. 56.4% in the codominant model, P=0.002, Pcorr=0.049, odds ratio=0.64 (0.48-0.85)]. An additional three SNPs (rs9639334 A>G, rs9638765 A>G, and rs2097811 G>A) showed similar associations with the risk of NERD. NERD patients had lower frequencies of the rs9639334 A>G minor allele (51.1 vs. 64.4%, P=0.002, Pcorr=0.043), rs9638765 A>G (49.7 vs. 64.2%, P=0.001, Pcorr=0.017), and rs2097811 G>A (51.1 vs. 64.5%, P=0.002, Pcorr=0.04) compared with ATA patients. Patients homozygous for the minor alleles of the four SNPs showed significantly less of an aspirin-induced decrease in forced expiratory volume in one second compared with those homozygous for the common alleles (P=0.003-0.012). The minor alleles of the four SNPs in TMEM196 may exert a protective effect against the development of NERD and may be useful genetic markers to predict the risk of NERD.

Solute Carrier Family 6 Member 12 Gene Polymorphisms in Japanese Patients with Aspirin-Exacerbated Respiratory Disease

Background: Betaine/gamma-aminobutyric acid (GABA) signaling pathway in the airway epithelium has been revealed to play a critical role in bronchial asthma. To elucidate any genetic influence of the GABAergic in aspirinexacerbated respiratory disease (AERD), we investigated the association of solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in Japanese patients with AERD. Methods: DNA specimens were obtained from 103 AERD patients, 300 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. Allelic discrimination assay for two single nucleotides polymorphisms in SLC6A12 gene (rs499368 and rs557881) was carried out. Results: The minor allele frequencies in SLC6A12 intron 2 A>T genotype (rs49936) were higher in AERD patients than in normal controls, and that in SLC6A12 exon 4 T>C genotype (rs557881) were higher in AERD patients than in ATA patients and normal controls. The frequencies of the combined TC/CC genotype group of SLC6A12 exon 4 T>C were higher than those of the TT genotype in AERD patients compared with those in ATA patients (P=0.021; odds ratio, 1.724; 95% confidence interval, 1.087-2.732). In male patients with AERD, frequencies of the TC/CC genotype group were higher than those of the TT genotype compared with male patients with ATA (P = 0.010; odds ratio, 3.177; 95% confidence interval, 1.311-7.699). Forced expiratory volume in one second (percentage predicted) in AERD patients with the TC/CC genotype group of the SLC6A12 exon 4 T>C gene was lower than that in the patients with the TT genotype (P=0.039). Conclusion: This is the first Japanese study to investigate the SLC6A12 intron 2 A>T and SLC6A12 exon 4 T>C genotype polymorphisms in patients with AERD. Our findings suggest that the association between SLC6A12 intron 2 A>T and exon 4 T>C gene sequence variations might be implicated in the development of AERD in a Japanese population.

Single Nucleotide Polymorphisms in Thymic Stromal Lymphopoietin Gene are not Associated with Aspirin-Exacerbated Respiratory Disease Susceptibility - A Pilot Study in a Japanese Population

Background: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine, implicated in the development and progression of allergic diseases. Several studies indicated polymorphisms in TSLP gene were associated asthma, and two single nucleotides polymorphisms (SNPs) in TSLP (rs1837253 and rs2289276) were shown to be associated with asthma in a sex-specific fashion. However, there has been no report that investigated TSLP gene polymorphisms in patients with aspirin-exacerbated respiratory disease (AERD). Methods: DNA specimens were obtained from the following three groups: 105 patients with AERD, 270 patients with aspirin-tolerant asthma (ATA) and 90 normal controls. The target DNA sequence of the TSLP gene was amplified using a set of primers. Allelic discrimination assay for the two SNPs in TSLP gene (rs1837253 and rs2289276) was carried out. All patients were Japanese, and they were in a stable condition. Results: The frequency of the T minor allele of TSLP -5717C>T in patients with AERD and those with ATA was significantly higher than that in normal controls. There were no significant difference of the T minor allele frequency of TSLP -82C>T among the three groups. Analysis of genotype frequencies of the CT/TT genotype group and CC genotype both in TSLP -5717C>T and in TSLP -82C>T showed no differences between AERD and ATA patients. In addition, subgroup analysis of the genotype frequencies with gender did not differ between AERD and ATA patients. Conclusion: This is the first pilot study to investigate TSLP gene polymorphisms in AERD, which didn’t find an association between the TSLP gene polymorphisms and AERD susceptibility in a Japanese population, suggesting polymorphisms in TSLP gene may contribute to asthma, but not to aspirin hypersensitivity.

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.

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.

Mediator release after nasal aspirin provocation supports different phenotypes in subjects with hypersensitivity reactions to NSAIDs

Multiple NSAID-induced urticaria/angioedema (MNSAID-UA) is an entity well differentiated from aspirin-exacerbated respiratory disease (AERD), although no detailed phenotype analysis has yet been performed. The objective was to evaluate the functional characteristics of MNSAID-UA subjects by analyzing the response to nasal lysine-aspirin challenge and measurement of nasal inflammatory mediator release compared with AERD subjects and controls. The study included 85 subjects with confirmed hypersensitivity to NSAIDs (≥3 episodes with >2 different NSAIDs or positive drug provocation) with either cutaneous (MNSAID-UA, n = 25) or respiratory manifestations (AERD, n = 60) and 30 tolerant controls (15 aspirin-tolerant asthmatic patients and 15 healthy controls). Nasal lavages at 0, 15, 60, and 120 min after lysine-aspirin challenge were analyzed for ECP, tryptase, PGE2 , PGD2 , LTD4 , and LTE4 . Lysine nasal challenge was positive in 80% of the AERD cases but positive only in 12% of the MNSAID-UA group. MNSAID-UA subjects showed no changes in nasal ECP, whereas subjects with AERD had increased levels of ECP, with the highest peak at 15 min after challenge (P < 0.05). Tryptase levels were higher in AERD compared with MNSAID-UA and controls with the highest release of tryptase at 60 min (P < 0.05). Significant increases in PGD2 , LTD4 , and LTE4 were observed in AERD (at 60 min for PGD2 , LTD4 , and LTE4 ) but not in MNSAID-UA or control subjects (P < 0.05). Data support the observation that MNSAID-UA, although sharing a common response with AERD to COX inhibitors, seems to have a distinctive phenotype, based on the response to nasal challenge and the release of inflammatory mediators.

Aspirin-intolerant asthma in the Korean population: Prevalence and characteristics based on a questionnaire survey

Aspirin-intolerant asthma is a unique clinical syndrome characterized by acute bronchoconstriction following the administration of aspirin and/or non-steroidal anti-inflammatory drugs. We assessed the prevalence and investigated the demographic and clinical characteristics of adult patients with aspirin-intolerant asthma in Korea. Using an adult asthma cohort (COREA) from 11 university hospitals in Korea, we analyzed the prevalence of aspirin-intolerant asthma, defined as a positive response to the question: "Have you ever experienced dyspnea and cough after taking an aspirin or any NSAID (cold medicine)?" Demographic and clinical characteristics were compared between patients with aspirin-intolerant asthma and aspirin-tolerant asthma. Aspirin-intolerant asthma was reported in 68 (5.8%) of 1173 adult asthmatics (age 15-84). Patients with aspirin-intolerant asthma had a lower mean age (43.9±13.4 vs. 49.0±15.6, P=0.003) and a higher prevalence of rhinosinusitis (77.9% vs. 61.7%, P=0.012) and atopic dermatitis (16.2% vs. 5.7%, P=0.001) than aspirin-tolerant asthma patients. There were no significant differences in lung function, asthma severity or the use of asthma controllers. However, aspirin-intolerant asthma was associated with greater use of healthcare services over a lifetime and over the past 12 months. Aspirin-intolerant asthma was significantly associated with emergency room visits over the past 12 months (P=0.029, OR 2.19, 95% CI 1.08-4.42). Based on histories, the prevalence of aspirin-intolerant asthma is 5.8% among adult asthma patients in Korea. Aspirin-intolerant asthma is associated with lower age, higher prevalence of rhinosinusitis and atopic dermatitis, and more frequent exacerbations.

Thromboxane A2 receptor +795T&gt;C and chemoattractant receptor-homologous molecule expressed on Th2 cells -466T&gt;C gene polymorphisms in patients with aspirin-exacerbated respiratory disease

It is well known that aspirin-exacerbated respiratory disease (AERD) is more common in women than in men, however, whether gene polymorphisms of the thromboxane A2 receptor (TBXA2R) and chemoattractant receptor-homologous molecules expressed on Th2 cells (CRTH2) are associated with the susceptibility of AERD remains unknown. In this study, we examined the gene polymorphisms in a Japanese population. DNA specimens were obtained from the following three groups: 96 patients with AERD, 500 patients with aspirin-tolerant asthma (ATA) and 100 normal controls. The target DNA sequence of each gene was amplified, and an allelic discrimination assay for single nucleotide polymorphisms relating to expression of each gene was carried out. The frequencies of the CC/CT genotype of TBXA2R +795T>C were higher than those of the TT genotype in AERD patients compared to ATA patients (P=0.015). In female AERD patients, but not in males, frequencies of the CC/CT genotype were higher than those of the TT genotype of TBXA2R +795T>C compared to female ATA patients (P=0.013). Also, frequencies of the TT genotype of CRTH2 -466T>C were higher than those of the CC/CT genotype in AERD patients compared to ATA patients (P=0.034). In female AERD patients, but not in male, frequencies of the TT genotype were higher than those of the CC/CT genotype of CRTH2 -466T>C in AERD patients compared to female ATA patients (P=0.046). Based on our investigations, no significant relationship was found between the genotype and the clinical characteristics according to these gene polymorphisms in AERD patients. Our results suggest that an association between the TBXA2R and CRTH2 gene polymorphisms with AERD may exist in the Japanese population.

IL-13 and IL-17A gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease

The role of interleukin (IL) 13 and IL-17A in aspirin-exacerbated respiratory disease (AERD) remains unknown. To analyze the IL-13 and IL-17A gene polymorphisms in Japanese patients with AERD. The single-nucleotide polymorphisms in each gene were examined in patients with AERD, patients with aspirin-tolerant asthma (ATA), and healthy controls. Frequencies of the TT/CT genotype of the IL-13 -1111C>T gene were higher than frequencies of the CC genotype in AERD patients compared with ATA patients (P < .001). In female patients with AERD, frequencies of the TT/CT genotype were higher than those of the CC genotype compared with female patients with ATA (P < .001). However, genotype frequencies of IL-13 Arg110Gln did not differ between AERD and ATA patients. Frequencies of the CC genotype of the IL-17A -737C>T gene were higher than those of the TT/CT genotype in AERD patients compared with ATA patients (P = .02). In female patients with AERD, frequencies of the CC genotype were higher than those of the TT/CT genotype compared with female patients with ATA (P = .03). Forced expiratory volume in 1 second (percentage predicted) in AERD patients with the CC genotype of the IL-13 -1111C>T gene was lower than that in the patients with the TT/CT genotype. AERD patients with the TT/CT genotype of the IL-17A -737C>T gene had a higher peripheral total eosinophil count compared with the patients with the CC genotype. The comparison of the clinical characteristics according to the IL-13 Arg110Gln gene polymorphism showed no difference. These findings suggest that the IL-13 -1111C>T and IL-17A -737C>T gene sequence variations might have a role in the development of AERD.

The Nose as a Target Organ in the Diagnosis of Severe Aspirin-exacerbated Respiratory Disease

The nasal provocation test (NPT) with lysine aspirin is a useful tool in the diagnosis of aspirin-exacerbated respiratory disease (AERD), previously reffered to as Samter's disease. The aim of the present study focuses on methodological interventions to show the usefulness of the NPT with lysine aspirin in differentiating AERD patients from aspirin-tolerant asthma (ATA) patients to improve the diagnostic efficacy and minimize the risk for adverse reactions compared with the gold standard. Thirty AERD patients comprised the active study group while the control group consisted of 25 ATA patients. A combination of objective nasal aerodynamic response (i.e., nasal inspiratory flow and nasal inspiratory resistance) was evaluated by active anterior rhinomanometry and the subjective clinical nasal and extranasal symptoms (including forced expiratory volume) were monitored throughout the challenge. Fifty-five NPTs were successfully completed: sensitivity, 87%; specificity, 100%; positive predictive value, 100%; negative predictive value, 86%; global efficacy, 92.72%. No severe adverse reactions were recorded. The present NPT with lysine aspirin proved to be a safe, efficient, and a timesaving method in the diagnosis of patients with AERD, even in those with severe rhinitis-rhinosinusitis and/or recurrent nasal polyposis.

Genetic variability in CRTH2 polymorphism increases eotaxin‐2 levels in patients with aspirin exacerbated respiratory disease

CRTH2 is expressed on the surface of eosinophils and has been shown to mediate PGD2-induced eosinophil migration in vitro. Eosinophilic infiltration in the upper and lower airways is the key feature of asthma. Considering the fact that eosinophil infiltration is prominent in the upper and lower airways of aspirin exacerbated respiratory disease (AERD) compared to aspirin-tolerant asthma (ATA) patients, we hypothesized that activation of eosinophils via dysregulation of the CRTH2 gene may play an important role and be an important marker for AERD. The three study groups - 107 with AERD, 115 with ATA and 133 normal healthy controls (NC) - were recruited from Ajou University Hospital, South Korea. Two polymorphisms of the CRTH2 gene at -466T>C and -129C>A were genotyped using primer extension methods. AERD patients had significantly higher serum eotaxin-2 levels than did those with ATA (P = 0.034). A significant difference in the genotype frequencies of CRTH2 -466T>C was detected between AERD and ATA patients (P < 0.05). The serum eotaxin-2 level was significantly higher in AERD patients carrying the TT genotype of CRTH2 -466T>C than those with the CT and CC (P < 0.05). In vitro functional study demonstrated that the -466T allele had lower luciferase activity (P < 0.001) and lower mRNA expression with higher production of eotaxin-2 (P = 0.003) in human lung epithelial cells. EMSA showed that CRTH2 -466T produced a specific band with a higher affinity than CRTH2 -466C had. The CRTH2 -466T>C polymorphism increases serum and cellular eotaxin-2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients.

Association of three sets of high-affinity IgE receptor (FcepsilonR1) polymorphisms with aspirin-intolerant asthma

The high-affinity IgE receptor comprises a tetramer of the ligand-binding alpha chain, a signal-augmenting beta chain, and a signal-transducing gamma chain dimer on mast cells. We hypothesized that the three subsets of the FCER1 gene may play a role in the development of the aspirin-intolerant asthma (AIA) phenotype and analyzed these genetic polymorphisms in association with clinical parameters in AIA patients. Six polymorphisms of FCER1 (FCERIA-344C>T, FCER1A-95T>C, MS4A2-109T>C, MS4A2 E237G, FCER1G-237A>G, FCER1G-54G>T) were genotyped in 126 AIA patients compared to 177 patients with aspirin-tolerant asthma (ATA) and 222 normal health controls (NC). A significant difference in the genotype frequencies of FCER1G-237A>G was detected between AIA and ATA patients (p<0.05) both in co-dominant and recessive analysis models, whereas no significant relationships were identified between the frequencies of the other five single-nucleotide polymorphisms and AIA, ATA, and NC subjects. In addition, AIA patients carrying the homozygous AA genotype of FCER1G-237A>G exhibited significantly higher total serum IgE levels than did those with the GG/AG genotype (p=0.012). AIA patients expressing the CT/TT genotype at FCERIA-344C>T showed a higher prevalence of serum IgE specific to Staphylococcal enterotoxin A than did those with the CC genotype (p=0.008). The FCER1G-237A>G and FCERIA-344C>T polymorphisms may contribute to the development of AIA in a Korean population.

Asthma Outcomes after Endoscopic Sinus Surgery in Aspirin-Tolerant versus Aspirin-Induced Asthmatic Patients

Certain diseases affect both upper and lower airways. Aspirin-induced asthma (AIA) is a clinical entity characterized by asthma, nasal polyposis, and aspirin intolerance. To understand the response of the lower airway to surgical treatment of the sinuses, we examined asthma outcomes in AIA compared with a second group of aspirin-tolerant asthmatic (ATA) patients to establish if there were any differences between the two groups after endoscopic sinus surgery (ESS). A retrospective record review was performed of 91 asthmatic subjects with chronic rhinosinusitis. Forty-one subjects had AIA and 50 subjects had ATA. Subjective and objective asthma outcome parameters were used to compare between the two groups at three time points: immediately before ESS and 6 and 12 months after ESS. Preoperatively, AIA patients had significantly higher asthma severity (p<0.0001) and lower forced expiratory volume in 1 second values (p=0.04). At 12 months after ESS, a statistically significant difference between the two groups with better results in AIA patients was seen in asthma severity improvement (p=0.010) and in the decrease of ICS doses (p<0.0001), without significant differences between the two groups in other asthma outcome parameters. AIA patients usually present with more severe asthma. The asthmatic complaints of AIA and ATA patients continue to improve significantly over 6 and 12 month after ESS. Although ESS helped both groups of patients, AIA had statistically significant better results compared with ATA patients in asthma severity scores and decreased need for ICS.

PGE2 suppresses excessive anti‐IgE induced cysteinyl leucotrienes production in mast cells of patients with aspirin exacerbated respiratory disease

Aspirin causes bronchospasm in patients with aspirin exacerbated respiratory disease (AERD). The contribution of mast cells to the increased cysteinyl-leucotrienes (cys-LTs) detected in AERD patients is however not defined. Effects of prostaglandin (PG) E(2) and inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) pathways on mediator release from cultured mast cells of normal subjects, aspirin tolerant asthma (ATA) and AERD patients were compared to better define the role of mast cells in AERD. Mast cells were cultured from peripheral blood progenitors and were activated by anti-IgE. Histamine, PGD(2) and cys-LTs released were then determined. Basal release of all three mediators was similar in all subjects. Although the release of all three mediators was increased by anti-IgE, mast cells from AERD patients produced significantly more cys-LTs (6.9 +/- 2.0 ng/10(6) cells) than normal and ATA subjects (2.3 +/- 0.8 and 1.7 +/- 0.5 ng/10(6) cells, respectively). While COX and LO pathway inhibitors did not affect anti-IgE induced histamine release, they significantly suppressed the production of PGD(2) and cys-LTs, respectively, in all patients. PGE(2) significantly enhanced anti-IgE induced histamine and PGD(2) release from mast cells of normal subjects but not those of ATA and AERD patients. In contrast, PGE(2) suppressed only anti-IgE induced cys-LTs release from mast cells of AERD patients. We speculate that overproduction of cys-LTs is unique to mast cells of AERD patients and is particularly sensitive to suppression by PGE(2). Consequently reduction of PGE(2) production by aspirin removes this endogenous control of cys-LTs overproduction, resulting in asthma attack.

Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma

Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype. We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls). Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: -616C>G (P=0.038) and -166G>A (P=0.023) in PTGER2; -1709T>A (P=0.043) in PTGER3; -1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and -4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015). These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.

Role of staphylococcal superantigen-specific IgE antibodies in aspirin-intolerant asthma

IgE antibodies specific for staphylococcal superantigens (SAg) have been implicated in the pathology of several allergic diseases such as rhinosinusitis, nasal polyposis, asthma, and aspirin intolerance. We sought to determine whether SAg-specific IgE levels associate with clinical parameters in patients with aspirin-intolerant asthma (AIA), as compared with patients with aspirin-tolerant asthma (ATA) and nonatopic controls. Eighty patients with AIA, 62 patients with ATA, and 52 normal controls were enrolled in this study. Total serum IgE and IgE specific for staphylococcal enterotoxin A, staphylococcal enterotoxin B, and staphylococcal toxic shock syndrome toxin 1 (TSST-1) were measured using the CAP system (Pharmacia, Uppsala, Sweden). The prevalence of staphylococcal enterotoxin B-specific IgE and TSST-1-specific IgE was significantly higher in the asthma patients than in the healthy controls. The prevalence of SEB-specific IgE was slightly higher in patients with AIA than in those with ATA (22.5% versus 14.5%), although this difference was not statistically significant. No significant difference in staphylococcal enterotoxin A-specific or TSST-1-specific IgE was found between AIA and ATA subjects. Total serum IgE levels were higher in asthma patients with detectable SAg-specific serum IgE than in those without. Airway hyperresponsiveness, as measured by PC20 methacholine, was significantly increased in asthma patients with detectable SAg-specific IgE than in asthma patients without (p = 0.038). There were no significant differences in other clinical parameters between AIA and ATA patients with and without detectable SAg-specific antibody responses. These findings suggest that the staphylococcal SAg may contribute to airway inflammation and the development of airway hyperresponsiveness in asthma.

Expression of 5‐lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin‐intolerant asthma

In aspirin-intolerant subjects, adverse bronchial and nasal reactions to cyclooxygenase (COX) inhibitors are associated with over-production of cysteinyl-leukotrienes (cys-LTs) generated by the 5-lipoxygenase (5-LO) pathway. In the bronchi of patients with aspirin-intolerant asthma, we previously linked cys-LT over-production and aspirin hyper-reactivity with elevated immunoexpression in eosinophils of the terminal enzyme for cys-LT production, LTC4 synthase. We investigated whether this anomaly also occurs in the nasal airways of these patients. Immunohistochemical expression of 5-LO and COX pathway proteins was quantified in nasal polyps from 12 patients with aspirin-intolerant asthma and 13 with aspirin-tolerant asthma. In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04). There were also three-fold more cells expressing 5-LO (p=0.037), with no differences in 5-LO activating protein (FLAP), COX-1 or COX-2. LTC4 synthase-positive cell counts correlated exclusively with mucosal eosinophils (r=0.94, p<0.001, n=25). Co-localisation confirmed that five-fold higher eosinophil counts (p=0.007) accounted for the increased LTC4 synthase expression in polyps from aspirin-intolerant asthmatic patients, with no alterations in mast cells or macrophages. Within the epithelium, increased counts of eosinophils (p=0.006), macrophages (p=0.097), and mast cells (p=0.034) in aspirin-intolerant asthmatic polyps were associated only with 2.5-fold increased 5-LO-positive cells (p<0.05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways.

Comparison of Plasma Eotaxin Family Level in Aspirin-Induced and Aspirin-Tolerant Asthma Patients

Eosinophilic infiltration of airway tissue is a central feature of aspirin-induced asthma (AIA). Eotaxins belong to the family of CC chemokines, which coordinate the recruitment of inflammatory cells bearing chemokine (C-C motif) receptor-3 to sites of allergic inflammation. In the present study, the levels of eotaxin-1, eotaxin-2, and eotaxin-3 following an oral aspirin provocation test (APT) were measured, and the relationship between the eotaxin level and clinical parameters in patients with asthma was evaluated. An APT was performed in patients with asthma. Twenty AIA patients and 23 aspirin-tolerant asthma (ATA) patients were identified. Plasma levels of eotaxin-1, eotaxin-2, and eotaxin-3 levels were measured by enzyme-linked immunosorbent assay in the 43 patients with asthma and in 39 control subjects. The proportion of blood eosinophils was significantly higher in asthmatic patients than in control subjects. Nasal polyps were more common in AIA patients than in ATA patients (p < 0.05). In addition, the eotaxin-1 level was higher in AIA and ATA patients than in control subjects (p < 0.01 for each). The eotaxin-2 level was higher in ATA patients than in either the AIA patients (p < 0.05) or control subjects (p < 0.01). Similarly, the eotaxin-3 level was higher in ATA patients than in control subjects. A trend toward higher plasma levels of eotaxin-1 and eotaxin-3 at baseline and at 4 h after APT administration in the ATA group was noted but was not significant. Eotaxin-2 was also higher in ATA patients than in AIA patients at baseline and at 4 h after the APT. This study shows that eotaxin-2 is differentially secreted in patients with asthma according to aspirin intolerance, and that secretion is not time-dependent in response to the APT in AIA and ATA patients. It therefore appears that eotaxin-2 may be up-regulated and may act differentially in patients with ATA.

Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.