Channing Division of Network Medicine and.
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Am J Respir Crit Care Med. 2023 Aug 1;208(3):247-255. doi: 10.1164/rccm.202301-0085OC.
Acute exacerbations of chronic obstructive pulmonary disease (AE-COPDs) are associated with a significant disease burden. Blood immune phenotyping may improve our understanding of a COPD endotype at increased risk of exacerbations. To determine the relationship between the transcriptome of circulating leukocytes and COPD exacerbations. Blood RNA sequencing data ( = 3,618) from the COPDGene (Genetic Epidemiology of COPD) study were analyzed. Blood microarray data ( = 646) from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study were used for validation. We tested the association between blood gene expression and AE-COPDs. We imputed the abundance of leukocyte subtypes and tested their association with prospective AE-COPDs. Flow cytometry was performed on blood in SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) ( = 127), and activation markers for T cells were tested for association with prospective AE-COPDs. Exacerbations were reported 4,030 and 2,368 times during follow-up in COPDGene (5.3 ± 1.7 yr) and ECLIPSE (3 yr), respectively. We identified 890, 675, and 3,217 genes associated with a history of AE-COPDs, persistent exacerbations (at least one exacerbation per year), and prospective exacerbation rate, respectively. In COPDGene, the number of prospective exacerbations in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage ⩾2) was negatively associated with circulating CD8 T cells, CD4 T cells, and resting natural killer cells. The negative association with naive CD4 T cells was replicated in ECLIPSE. In the flow-cytometry study, an increase in CTLA4 on CD4 T cells was positively associated with AE-COPDs. Individuals with COPD with lower circulating lymphocyte counts, particularly decreased CD4 T cells, are more susceptible to AE-COPDs, including persistent exacerbations.
慢性阻塞性肺疾病（COPD）的急性加重（AE-COPDs）与显著的疾病负担相关。血液免疫表型分析可能有助于我们深入了解 COPD 中易发生加重的表型。本研究旨在确定循环白细胞转录组与 COPD 加重的关系。对 COPDGene（COPD 的遗传流行病学）研究的血液 RNA 测序数据（ = 3618）进行分析。对 ECLIPSE（评估 COPD 纵向以确定预测替代终点）研究的血液微阵列数据（ = 646）进行验证。我们测试了血液基因表达与 AE-COPD 的相关性。我们推断了白细胞亚型的丰度，并测试了它们与前瞻性 AE-COPD 的相关性。在 SPIROMICS（COPD 研究的亚群和中间结果）（ = 127）中对血液进行流式细胞术检测，并测试了 T 细胞的激活标志物与前瞻性 AE-COPD 的相关性。在 COPDGene 中，随访期间报告了 4030 次和 2368 次 AE-COPD （5.3 ± 1.7 年）和 ECLIPSE（3 年），分别。我们确定了 890、675 和 3217 个基因与 AE-COPD 病史、持续性加重（每年至少一次加重）和前瞻性加重率相关。在 COPDGene 中，COPD 患者（慢性阻塞性肺疾病全球倡议阶段 ⩾2）的前瞻性加重次数与循环 CD8 T 细胞、CD4 T 细胞和静止自然杀伤细胞呈负相关。在 ECLIPSE 中复制了与幼稚 CD4 T 细胞的负相关。在流式细胞术研究中，CD4 T 细胞上 CTLA4 的增加与 AE-COPD 呈正相关。循环淋巴细胞计数较低的 COPD 患者，特别是 CD4 T 细胞减少，更容易发生 AE-COPD，包括持续性加重。
