Update on the Management of Aspirin-Exacerbated Respiratory Disease

Kathleen M. Buchheit,Tanya M. Laidlaw 대한천식알레르기학회 2016 Allergy, Asthma & Immunology Research Vol.8 No.4

Aspirin-exacerbated respiratory disease (AERD) is an adult-onset upper and lower airway disease consisting of eosinophilic nasal polyps, asthma, and respiratory reactions to cyclooxygenase 1 (COX-1) inhibitors. Management includes guideline-based treatment of asthma and sinus disease, avoidance of COX-1 inhibitors, and for some patients aspirin desensitization followed by high-dose aspirin therapy. Despite this, many patients have inadequately controlled symptoms and require multiple sinus surgeries. In this review, we discuss the current standard approaches to the management of AERD, and we introduce several therapeutics under development that may hold promise for the treatment of AERD.

Diagnostic Value of Clinical Parameters in the Prediction of Aspirin-Exacerbated Respiratory Disease in Asthma

장헌수,박종숙,장안수,박성우,우수택,김영훈,박춘식 대한천식알레르기학회 2011 Allergy, Asthma & Immunology Research Vol.3 No.4

Purpose: Aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with increased asthma severity. However, oral aspirin challenge (OAC) to diagnose AERD is a time-consuming procedure, and some patients experience serious complications. Thus, we evaluated diagnostic values of non-invasive clinical parameters to predict AERD in asthmatic patients. Methods: A total of 836 Korean subjects were recruited from an asthma cohort. They underwent OAC, and clinical parameters including the history of aspirin hypersensitivity,nasal polyposis, and chronic sinusitis of aspirin-tolerant asthma (ATA) and AERD asthmatic patients were compared. Results: Significant differences (P<0.01) were found in eight parameters: age at diagnosis, body mass index, FEV1%, PC20, history of urticaria, nasal polyps, chronic sinusitis,and history of aspirin hypersensitivity. After logistic regression analysis based on the eight clinical parameters, nasal polyps, history of aspirin intolerance, sinusitis, and log [PC20 methacholine] remained significantly associated with AERD (P<0.05). The sensitivity and specificity of the history of aspirin hypersensitivity to predict AERD were 64.7% and 92.0%, respectively, and the positive and negative predictive values were 56.9% and 94.1%, respectively. Overall, the accuracy of the test was 88.2%. The accuracy of the tests for nasal polyps and chronic sinusitis were 67.3% and 60.4%, respectively. Conclusions: Among clinical parameters associated with AERD, the history of aspirin hypersensitivity has the best positive and negative predictive values for the oral aspirin challenge test. Because the false-positive and -negative rates were still high, additional non-invasive methods are needed to reduce the rate of false outcomes.

WDR46 is a Genetic Risk Factor for Aspirin-Exacerbated Respiratory Disease in a Korean Population

Charisse Flerida A. Pasaje,배준설,Byung-Lae Park,정현섭,Jeong-Hyun Kim,어수택,박춘식,신형두 대한천식알레르기학회 2012 Allergy, Asthma & Immunology Research Vol.4 No.4

Purpose: The human WD repeat-containing protein 46 (WDR46; also known as C6orf11), located at the disease-relevant centromere side of the class II major histocompatibility complex region, is hypothesized to be associated with risk of aspirin-exacerbated respiratory disease (AERD) as well as a decline in forced expiratory volume in the first second (FEV1), an important diagnostic marker of asthma. Methods: To investigate the association between WDR46 and AERD, five single-nucleotide polymorphisms (SNPs) were genotyped in 93 AERD cases and 96 aspirin-tolerant asthma controls of Korean ethnicity. Three major haplotypes were inferred from pairwise comparison of the SNPs, and one was included in the association analysis. Differences in the frequency distribution of WDR46 SNPs and haplotype were analyzed using logistic and regression models via various modes of genetic inheritance. Results: Depending on the genetic model, the logistic and regression analyses revealed significant associations between rs463260, rs446735, rs455567, rs469064, and WDR46_ht2 and the risk of AERD (P=0.007-0.04, Pcorr =0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, Pcorr =0.01-0.03). Furthermore, functional analysis in silico showed that the G>A allele of rs463260 located in the 5’untranslated region potentially matched a nucleotide sequence within an upstream open reading frame of WDR46. Conclusions: These findings show for the first time that WDR46 is an important genetic marker of aspirin-induced airway inflammation and may be useful for formulating new disease-management strategies.

Association of the <i>CCR3</i> gene polymorphism with aspirin exacerbated respiratory disease

Kim, Seung-Hyun,Yang, Eun-Mi,Lee, Haet-Nim,Choi, Gil-Soon,Ye, Young-Min,Park, Hae-Sim Elsevier 2010 Respiratory medicine Vol.104 No.5

<P><B>Summary</B></P><P><B>Introduction</B></P><P>Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway.</P><P><B>Objectives</B></P><P>The main objective of this study is to investigate the association between <I>CCR3</I> gene polymorphisms and aspirin hypersensitivity, including AERD and AICU.</P><P><B>Methods</B></P><P><I>CCR3</I> mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two <I>CCR3</I> promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay.</P><P><B>Results</B></P><P><I>CCR3</I> mRNA expression was significantly increased after aspirin provocation in AERD patients (<I>P</I>=<I>0.002</I>) but not in AICU patients. An <I>in vitro</I> functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (<I>P</I><I><</I>0.001). We found -520G and -174T specific bands on EMSA.</P><P><B>Conclusion</B></P><P>This result suggests that the <I>CCR3</I> genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes.</P>

Aspirin-Exacerbated Respiratory Disease: Evaluation and Management

Rachel U. Lee,Donald D. Stevenson 대한천식알레르기학회 2011 Allergy, Asthma & Immunology Research Vol.3 No.1

The clinical syndrome of aspirin-exacerbated respiratory disease (AERD) is a condition where inhibition of cyclooxygenase-1 (COX-1) induces attacks of upper and lower airway reactions, including rhinorrhea and varying degrees of bronchospasm and laryngospasm. Although the reaction is not IgEmediated,patients can also present with anaphylactic hypersensitivity reactions, including hypotension, after exposure to COX-1 inhibiting drugs. All patients with AERD have underlying nasal polyps and intractable sinus disease which may be difficult to treat with standard medical and surgical interventions. This review article focuses on the management of AERD patients with a particular emphasis on aspirin desensitization and continuous treatment with aspirin.

Lack of Association between <i>CD58</i> Genetic Variations and Aspirin-Exacerbated Respiratory Disease in a Korean Population

Pasaje, Charisse Flerida A.,Bae, Joon Seol,Park, Byung-Lae,Cheong, Hyun Sub,Jang, An-Soo,Uh, Soo-Taek,Kim, Mi-Kyeong,Kim, Jeong-Hyun,Park, Tae-Joon,Lee, Jin-Sol,Kim, Yongha,Park, Choon-Sik,Shin, Hyoun Informa Healthcare 2011 The Journal of asthma Vol.48 No.6

<P><I>Background</I>. Exacerbation of asthma symptoms due to aspirin ingestion may lead to life-threatening lung failure. The adhesion molecule <I>CD58</I> gene may play a crucial role in aspirin-exacerbated respiratory disease (AERD) pathogenesis by mediating the biological functions of asthma-inducing mechanisms including T helper cells, proinflammatory cytokines, and natural killer T cells. <I>Objective</I>. This study aimed to investigate the association of <I>CD58</I> variations with aspirin-induced bronchospasm in Korean asthma patients. <I>Methods</I>. Seven single-nucleotide polymorphisms were selected for genotyping based on previously reported polymorphisms in the International HapMap database. Genotyping was carried out using TaqMan assay and 2 major haplotypes were obtained in 163 AERD cases and 429 aspirin-tolerant asthma controls. Frequency distributions of <I>CD58</I> variations were analyzed using logistic and regression models. <I>Results</I>. Results showed that none of the analyzed <I>CD58</I> single-nucleotide polymorphisms and haplotypes was significantly associated with AERD development and fall rate of FEV<SUB>1</SUB> by aspirin provocation, an important diagnostic marker of aspirin hypersensitivity. <I>Conclusions</I>. This preliminary study suggests that <I>CD58</I> does not affect AERD susceptibility in a Korean population, and may provide a new direction for future disease etiology.</P>

Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population

Lee, Jin Sol,Bae, Joon Seol,Park, Byung-Lae,Cheong, Hyun Sub,Kim, Jeong-Hyun,Kim, Jason Yongha,Namgoong, Suhg,Kim, Ji-On,Park, Choon-Sik,Shin, Hyoung Doo Korea Genome Organization 2014 Genomics & informatics Vol.12 No.2

The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signaling transmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses, such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbated respiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects, which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed to examine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed that TEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for the fall rate of forced expiratory volume in 1 second ($FEV_1$) by aspirin provocation, two variations (rs7664091 and rs12500534) and one haplotype (TEC_BL2_ht4) showed nominal associations with $FEV_1$ decline (p=0.03-0.04). However, the association signals were not retained after performing corrections for multiple testing. Despite TEC playing an important role in immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.

Lack of association of HLA-DRA polymorphisms with aspirin exacerbated respiratory disease in a Korean population

Jin Sol Lee,배준설,Byung-Lae Park,정현섭,김정현,Charisse Flerida A. Pasaje,Jason Yongha Kim,Tae Joon Park,어수택,박춘식,신형두 한국유전학회 2011 Genes & Genomics Vol.33 No.6

The human HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA) is a member of the MHC class II gene family that activates T cells allowing secretion in various cytokines to immune responses. Thus, we explored whether the genetic variations in HLA-DRA gene can influence susceptibility for aspirin exacerbated respiratory disease (AERD). To carry out the investigation, 22 single nucleotide polymorphisms (SNPs)in HLA-DRA were genotyped in 592 Korean asthma patients. Logistic and regression analyseis wereas used to evaluate the P-values for associations of HLA-DRA polymorphisms with AERD and a relevant phenotype, the fall rate of forced expiratory volume in the 1^(st) second (FEV_1). Logistic analyses revealed that two variants, rs6911777 and HLA_DRA_BL1_ht3were initially associated with AERD via dominant and recessive models (P = 0.05 and 0.01, respectively), however, the signals did not reach the threshold of significance after multiple corrections. Furthermore, we observed that fall rate of FEV_1by aspirin provocation was marginally different between AERD cases and aspirin-tolerant asthma (ATA) controls (mean = 24.63vs 3.54, respectively). This study provides result of first association analysis between the variants of HLA-DRA and the risk of AERD, and conclusions derived from the study do not support significant roles of polymorphisms in HLA-DRA with AERD.

Association Analysis of TEC Polymorphisms with Aspirin-Exacerbated Respiratory Disease in a Korean Population

이진솔,배준설,박병래,정현섭,김정현,Jason Yongha Kim,남궁석,김지온,박춘식,신형두 한국유전체학회 2014 Genomics & informatics Vol.12 No.2

The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signalingtransmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses,such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbatedrespiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects,which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed toexamine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed thatTEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for thefall rate of forced expiratory volume in 1 second (FEV1) by aspirin provocation, two variations (rs7664091 and rs12500534)and one haplotype (TEC_BL2_ht4) showed nominal associations with FEV1 decline (p = 0.03-0.04). However, theassociation signals were not retained after performing corrections for multiple testing. Despite TEC playing an important rolein immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.

Genetic analysis between FGD6 and aspirin exacerbated respiratory disease in a Korean population

Charisse Flerida A. Pasaje,배준설,박병래,정현섭,장안수,어수택,김미경,김정현,박태준,이진솔,Yongha Kim,박춘식,신형두 한국유전학회 2011 Genes & Genomics Vol.33 No.5

The human FYVE, RhoGEF and PH domain containing 6(FGD6) gene regulates mechanisms that are implicated in airway bronchospasm, and therefore, may be a risk factor for aspirin exacerbated respiratory disease (AERD). This study aims to investigate the association between FGD6 variations and AERD in a Korean asthma cohort. A total of 34 single nucleotide polymorphisms (SNPs) were selected for genotyping based on previously reported polymorphisms in the HapMap database. Genotyping was carried out using TaqMan assay and nine major haplotypes from two haplotype blocks were obtained in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. Genotype frequency distributions ofFGD6 polymorphisms and haplotypes were analyzed using logistic and regression models. Findings from logistic and regression analyses revealed a lack of association of FGD6genetic variations with AERD and fall rate of FEV_1 (P >0.05 in co-dominant, dominant and recessive models). This preliminary report provides evidences that variations in the FGD6 gene do not influence the risk of AERD and its relevant phenotype in a Korean population. This report may contribute to the etiology of aspirin hypersensitivity in Korean asthma patients.