Background

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) asthma is characterized by chronic rhinosinusitis and intolerance of aspirin and other COX1 inhibitors. Clinical data point to a heterogeneity within the N-ERD phenotype.

Objective

Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD.

Methods

Levels of cytokines (determined by using Luminex assay) and eicosanoids (determined by using mass spectrometry) were measured in bronchoalveolar lavage fluid (BALF) from patients with N-ERD (n = 22), patients with NSAID-tolerant asthma (n = 21), and control subjects (n = 11). mRNA expression in BALF cells was quantified by using TaqMan low-density arrays.

Results

Lower airway eosinophilia was more frequent in N-ERD (54.5%) than in NSAID-tolerant asthma (9.5% [P = .009]). The type-2 (T2) immune signature of BALF cells was more pronounced in the eosinophilic subphenotype of N-ERD. Similarly, BALF concentrations of periostin and CCL26 were significantly increased in eosinophilic N-ERD and correlated with T2 signature in BALF cells. Multiparameter analysis of BALF mediators of all patients with asthma revealed the presence of 2 immune endotypes: T2-like (with an elevated level of periostin in BALF) and non-T2/proinflammatory (with higher levels of matrix metalloproteinases and inflammatory cytokines). Patients with N-ERD were classified mostly as having the T2 endotype (68%). Changes in eicosanoid profile (eg, increased leukotriene E₄ level) were limited to patients with N-ERD with airway eosinophilia. Blood eosinophilia appeared to be a useful predictor of airway T2 signature (area under the curve [AUC] = 0.83); however, surrogate biomarkers had moderate performance in distinguishing eosinophilic N-ERD (for blood eosinophils, AUC = 0.72; for periostin, AUC = 0.75).

Conclusions

Lower airway immune profiles show considerable heterogeneity of N-ERD, with skewing toward T2 response and eosinophilic inflammation. Increased production of leukotriene E₄ was restricted to a subgroup of patients with eosinophilia in the lower airway.

中文翻译：

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NSAID加重呼吸系统疾病患者下呼吸道炎症的异质性

背景

非甾体抗炎药 (NSAID) 加重性呼吸系统疾病 (N-ER​​D) 哮喘的特点是慢性鼻窦炎和对阿司匹林和其他 COX1 抑制剂的不耐受。临床数据表明 N-ERD 表型存在异质性。

客观的

我们的目的是调查 N-ERD 患者下呼吸道的免疫介质分布。

方法

在来自 N-ERD 患者（n = 22）、NSAID 耐受性哮喘患者（n = 21）的支气管肺泡灌洗液 (BALF) 中测量细胞因子（通过使用 Luminex 测定法确定）和类二十烷酸（通过使用质谱法确定）的水平) 和对照受试者 (n = 11)。使用 TaqMan 低密度阵列定量 BALF 细胞中的 mRNA 表达。

结果

N-ERD 患者的下呼吸道嗜酸性粒细胞增多 (54.5%) 比耐受 NSAID 的哮喘患者 (9.5% [ P  = .009])更常见。BALF 细胞的 2 型 (T2) 免疫特征在 N-ERD 的嗜酸性亚表型中更为明显。类似地，嗜酸性 N-ERD 中骨膜蛋白和 CCL26 的 BALF 浓度显着增加，并与 BALF 细胞中的 T2 特征相关。对所有哮喘患者 BALF 介质的多参数分析显示存在 2 种免疫内型：T2 样（BALF 中骨膜蛋白水平升高）和非 T2/促炎（基质金属蛋白酶和炎性细胞因子水平较高）。N-ERD 患者大多被归类为 T2 内型 (68%)。类二十烷酸谱的变化（例如，增加的白三烯 E ₄水平）仅限于气道嗜酸性粒细胞增多的 N-ERD 患者。血液嗜酸性粒细胞增多似乎是气道 T2 特征的有用预测指标（曲线下面积 [AUC] = 0.83）；然而，替代生物标志物在区分嗜酸性粒细胞 N-ERD 方面表现中等（对于血液嗜酸性粒细胞，AUC = 0.72；对于骨膜蛋白，AUC = 0.75）。

结论

下呼吸道免疫特征显示 N-ERD 具有相当大的异质性，倾向于 T2 反应和嗜酸性粒细胞炎症。白三烯 E ₄产生的增加仅限于下呼吸道嗜酸性粒细胞增多的患者亚组。