Background

Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces.

Objective

We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns.

Methods

Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay.

Results

Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n = 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for T_h17 (IL-17, IL-6, G-CSF) and T_h1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression.

Conclusions

The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed T_h17/T_h1/T_h2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.

中文翻译：

---

重度中性粒细胞和少粒细胞哮喘患儿支气管肺泡灌洗细胞因子模式

背景

哮喘是一种复杂的异质性疾病，发生在成人和儿童中，以不同的炎症模式为特征。虽然已经在成人中进行了大量研究，但对于儿童严重哮喘的异质性知之甚少，特别是涉及气隙的炎症特征。

客观的

我们试图确定根据嗜中性粒细胞与非嗜中性粒细胞 BAL 炎症细胞模式分层的严重难治性哮喘儿童支气管肺泡灌洗 (BAL) 细胞因子/趋化因子表达模式的关系。

方法

接受了诊断性支气管镜检查和 BAL 治疗但症状控制不充分的重度哮喘儿童。使用多重蛋白珠测定法测定炎症细胞因子/趋化因子浓度。

结果

使用无偏聚类方法分析 BAL 成分揭示了不同的细胞因子/趋化因子模式，这些模式与与 2 型先天淋巴细胞、单核细胞、中性粒细胞运输和 T 效应细胞相关的途径一致。与非中性粒细胞哮喘相比，所有检查的细胞因子 (n = 27) 与 1 个例外（血管内皮生长因子）均在 BAL 中性粒细胞增多症中过度表达，这在交叉验证分析中得到证实。专门负责 T _h 17 (IL-17、IL-6、G-CSF) 和 T _{h的细胞因子}中性粒细胞队列中的 1 分化和表达（IL-12、TNF-α、IFN-γ）增强。中性粒细胞组的特征还在于细菌和病毒病原体的患病率较高；然而，细胞因子表达模式的表现独立于病原体表达。

结论

结果表明，患有难治性哮喘和中性粒细胞炎症的儿童具有与混合 T _h 17/T _h 1/T _h 2 反应一致的 BAL 细胞因子模式。相反，非中性粒细胞哮喘独立于细胞因子过度表达。