From the Department of Neurology (B.J.M., S.A.G., E.L.F.), and Department of Biostatistics (J.B., S.K.), School of Public Health, University of Michigan, Ann Arbor.
Neurol Neuroimmunol Neuroinflamm. 2021 Feb 2;8(2). doi: 10.1212/NXI.0000000000000953. Print 2021 Mar.
To determine whether neutrophils contribute to amyotrophic lateral sclerosis (ALS) progression, we tested the association of baseline neutrophil count on ALS survival, whether the effect was sex specific, and whether neutrophils accumulate in the spinal cord.
A prospective cohort study was conducted between June 22, 2011, and October 30, 2019. Blood leukocytes were isolated from ALS participants and neutrophil levels assessed by flow cytometry. Participant survival outcomes were analyzed by groups (<2 × 10, 2-4 × 10, and >4 × 10 neutrophils/mL) with adjustments for relevant ALS covariates and by sex. Neutrophil levels were assessed from CNS tissue from a subset of participants.
A total of 269 participants with ALS within 2 years of an ALS diagnosis were included. Participants with baseline neutrophil counts over 4 × 10/mL had a 2.1 times higher mortality rate than those with a neutrophil count lower than 2 × 10/mL (95% CI: 1.3-3.5, = 0.004) when adjusting for age, sex, and other covariates. This effect was more pronounced in females, with a hazard ratio of 3.8 (95% CI: 1.8-8.2, = 0.001) in the >4 × 10/mL vs <2 × 10/mL group. Furthermore, ALS participants (n = 8) had increased neutrophils in cervical ( = 0.049) and thoracic ( = 0.022) spinal cord segments compared with control participants (n = 8).
Higher neutrophil counts early in ALS associate with a shorter survival in female participants. Furthermore, neutrophils accumulate in ALS spinal cord supporting a pathophysiologic correlate. These data justify the consideration of immunity and sex for personalized therapeutic development in ALS.
This study provides Class III evidence that in female participants with ALS, higher baseline neutrophil counts are associated with shorter survival.
为了确定中性粒细胞是否会导致肌萎缩侧索硬化症（ALS）进展，我们检验了基线中性粒细胞计数与 ALS 生存之间的关联，以及这种效应是否具有性别特异性，同时还检测了中性粒细胞是否在脊髓中聚集。
这是一项前瞻性队列研究，于 2011 年 6 月 22 日至 2019 年 10 月 30 日进行。从 ALS 参与者中分离血液白细胞，并通过流式细胞术评估中性粒细胞水平。根据参与者的相关 ALS 协变量和性别，将生存结果分为以下几组进行分析：<2×10、2-4×10 和>4×10 个中性粒细胞/mL。还评估了一组参与者的中枢神经系统组织中的中性粒细胞水平。
共纳入了 269 名在 ALS 诊断后 2 年内的 ALS 参与者。在校正年龄、性别和其他协变量后，基线中性粒细胞计数超过 4×10/mL 的参与者的死亡率比计数低于 2×10/mL 的参与者高 2.1 倍（95%CI：1.3-3.5， = 0.004）。在女性中，这种影响更为明显，在计数>4×10/mL 与计数<2×10/mL 的组中，风险比为 3.8（95%CI：1.8-8.2， = 0.001）。此外，与对照组参与者（n=8）相比，ALS 参与者（n=8）的颈段（ = 0.049）和胸段（ = 0.022）脊髓中的中性粒细胞增多。
ALS 早期较高的中性粒细胞计数与女性参与者的生存时间较短相关。此外，中性粒细胞在 ALS 脊髓中聚集，支持其存在病理生理相关性。这些数据证明免疫和性别因素在 ALS 的个体化治疗开发中值得考虑。
本研究提供了 III 级证据，表明在女性 ALS 参与者中，基线较高的中性粒细胞计数与较短的生存时间相关。
