哮喘中吸入性糖皮质激素的剂量反应：我们应该测量炎症吗？

Inhaled corticosteroid dose response in asthma: Should we measure inflammation?

作者信息

Anderson William J, Short Philip M, Jabbal Sunny, Lipworth Brian J

机构信息

Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland.

出版信息

Ann Allergy Asthma Immunol. 2017 Feb;118(2):179-185. doi: 10.1016/j.anai.2016.11.018. Epub 2017 Jan 3.

DOI:10.1016/j.anai.2016.11.018

PMID:28065396

Abstract

BACKGROUND

Inhaled corticosteroid (ICS) titration in asthma is primarily based on symptoms and pulmonary function. ICSs may not be increased on this basis despite residual airway inflammation.

OBJECTIVE

To compare the dose-response relationships of ICSs on measures of pulmonary function, symptoms, and inflammation in patients with persistent asthma.

METHODS

We performed a pooled post hoc analysis of 121 patients with mild to moderate asthma from 4 randomized clinical trials that incorporated an ICS dose ramp. Dose ramps were 0 to 200, 0 to 800, and 200 to 800 μg/d (beclomethasone equivalents). Outcome measures included spirometry, fractional exhaled nitric oxide, airway hyperresponsiveness (AHR), symptoms, serum eosinophilic cationic protein, and blood eosinophils.

RESULTS

We found a plateau beyond a small improvement at 0 to 200 μg for forced expiratory volume in 1 second: 3.3% (95% confidence interval [CI], 2.0%-4.7%) at 0 to 200 μg vs 0.3% (95% CI, -0.8% to 1.4%) 200 to 800 μg (P = .001). A similar plateau was seen for symptom improvement beyond 0 to 200 μg. Inflammatory and AHR outcomes revealed further room for improvement beyond low-dose ICSs. There was dose-related suppression (P < .001) for fractional exhaled nitric oxide: 40.4 ppb (95% CI, 34.7-46.9 ppb) for ICS free, 26.8 ppb (95% CI, 23.4-30.2 ppb) for 200 μg, and 20.8 ppb (95% CI, 18.8-23.1 ppb) for 800 μg. Eosinophilic cationic protein concentration was significantly reduced with both higher dose ramps. Eosinophil counts also improved across all 3 dose ramps, with dose separation of 370/μL (95% CI, 280-450/μL) for ICS free vs 250/μL (95% CI, 200-300/μL) 800 μg (P = .03). AHR improved with all 3 dose ramps, with greater improvement at lower doses for indirect vs direct challenges.

CONCLUSION

ICS dose response may extend beyond low dose for inflammation and AHR but not symptoms or spirometry. Further study is required to identify whether this correlates with suboptimal longitudinal asthma control.

TRIAL REGISTRATION

ClinicalTrials.gov Identifiers: NCT00667992, NCT00995657, NCT01216579, NCT01544634.

摘要

背景

哮喘患者吸入糖皮质激素（ICS）的滴定主要基于症状和肺功能。尽管存在残余气道炎症，但在此基础上ICS剂量可能不会增加。

目的

比较ICS剂量与持续性哮喘患者肺功能、症状及炎症指标之间的剂量反应关系。

方法

我们对4项纳入ICS剂量递增试验的随机临床试验中的121例轻度至中度哮喘患者进行了汇总事后分析。剂量递增幅度分别为0至200、0至800和200至800μg/d（倍氯米松等效剂量）。观察指标包括肺量计、呼出一氧化氮分数、气道高反应性（AHR）、症状、血清嗜酸性阳离子蛋白和血液嗜酸性粒细胞。

结果

我们发现，对于1秒用力呼气量，在0至200μg时仅有小幅改善，之后出现平台期：0至200μg时为3.3%（95%置信区间[CI]，2.0%-4.7%），200至800μg时为0.3%（95%CI，-0.8%至1.4%）（P = 0.001）。在0至200μg以上，症状改善也出现了类似的平台期。炎症和AHR指标显示，低剂量ICS之外仍有进一步改善的空间。呼出一氧化氮分数存在剂量相关的抑制作用（P < 0.001）：未使用ICS时为40.4 ppb（95%CI，34.7-46.9 ppb），200μg时为26.8 ppb（95%CI，23.4-30.2 ppb），800μg时为20.8 ppb（95%CI，18.8-23.1 ppb）。较高剂量递增幅度均显著降低了嗜酸性阳离子蛋白浓度。在所有3个剂量递增幅度中嗜酸性粒细胞计数均有所改善，未使用ICS时与800μg时的剂量差异为370/μL（95%CI，280-450/μL）对250/μL（95%CI，200-300/μL）（P = 0.03）。所有3个剂量递增幅度均使AHR得到改善，间接激发试验与直接激发试验相比，低剂量时改善更明显。