Abstract
Aspirin-exacerbated respiratory disease (AERD) remains widely underdiagnosed in asthmatics, primarily due to insufficient awareness of the relationship between aspirin ingestion and asthma exacerbation. The identification of aspirin hypersensitivity is therefore essential to avoid serious aspirin complications. The goal of the study was to develop plasma biomarkers to predict AERD. We identified differentially expressed genes in peripheral blood mononuclear cells (PBMC) between subjects with AERD and those with aspirin-tolerant asthma (ATA). The genes were matched with the secreted protein database (http://spd.cbi.pku.edu.cn/) to select candidate proteins in the plasma. Plasma levels of the candidate proteins were then measured in AERD (n = 40) and ATA (n = 40) subjects using an enzyme-linked immunosorbent assay (ELISA). Target genes were validated as AERD biomarkers using an ROC curve analysis. From 175 differentially expressed genes (p-value <0.0001) that were queried to the secreted protein database, 11 secreted proteins were retrieved. The gene expression patterns were predicted as elevated for 7 genes and decreased for 4 genes in AERD as compared with ATA subjects. Among these genes, significantly higher levels of plasma eosinophil-derived neurotoxin (RNASE2) were observed in AERD as compared with ATA subjects (70(14.62∼311.92) µg/ml vs. 12(2.55∼272.84) µg/ml, p-value <0.0003). Based on the ROC curve analysis, the AUC was 0.74 (p-value = 0.0001, asymptotic 95% confidence interval [lower bound: 0.62, upper bound: 0.83]) with 95% sensitivity, 60% specificity, and a cut-off value of 27.15 µg/ml. Eosinophil-derived neurotoxin represents a novel biomarker to distinguish AERD from ATA.
Highlights
Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction and nasal manifestations in asthmatic individuals following the ingestion of aspirin and/or other nonsteroidal anti-inflammatory drugs (NSAIDs) [1,2]
Candidate Genes for AERD Among the 318 differentially expressed genes between the AERD and ATA groups using our gene-chip data analysis [12], we selected a total of 175 genes with a p-value less than 0.0001 and queried them with the secreted protein database (SPD)
Since eosinophils may be associated with severe asthma, and a marker associated with eosinophils may be related with severity rather than aspirin sensitivity, FEV1 and PC20 methacholine, blood eosinophil %, age, sex, smoking, BMI were matched between the AERD and ATA subjects
Summary
Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction and nasal manifestations in asthmatic individuals following the ingestion of aspirin and/or other nonsteroidal anti-inflammatory drugs (NSAIDs) [1,2]. Aspirin hypersensitivity has attracted a great deal of attention due to its association with increased asthma severity, including life threatening asthma attacks and the possible remodeling of both the upper and lower airways [4]. In patients requiring emergency mechanical ventilation, the prevalence of aspirin intolerance was reported to be 24.3% [5]. Picado et al reported the occurrence of life-threatening asthma attacks requiring mechanical ventilation in 14% of adults with aspirin intolerance [6]. The high incidence of severe asthma attacks may originate from underdiagnosis in asthmatics, due to insufficient awareness of the relationship between aspirin ingestion and asthma exacerbation. It is of note that a reported 15–30% of patients are entirely unaware that they suffer from aspirin intolerance, with only provocation tests revealing their hypersensitivity [7,8]. The identification of aspirin hypersensitivity is essential to avoid serious aspirin complications
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