第二军医大学学报  2016, Vol. 37 Issue (10): 1250-1255   PDF    
呼出气一氧化氮检测在哮喘-慢阻肺重叠综合征治疗中的应用价值
吉泽1, 潘星2, 姬峰3, 倪殿涛1, 商艳4, 白冲4     
1. 上海交通大学医学院附属苏州九龙医院呼吸内科, 苏州 215028;
2. 上海交通大学医学院附属苏州九龙医院护理部, 苏州 215028;
3. 武警山东总队医院呼吸内科, 济南 250014;
4. 第二军医大学长海医院呼吸及危重症医学科, 上海 200433
摘要: 目的 探讨呼出气一氧化氮(FeNO)测定在哮喘-慢阻肺重叠综合征(ACOS)治疗中的应用价值。 方法 收集2015年5月至2015年10月在苏州九龙医院确诊但未规范使用药物治疗的ACOS患者28例,给予为期12周的吸入性糖皮质激素/长效β受体激动剂(ICS/LABA)吸入治疗,检测治疗前后患者的FeNO值、FEV1% pred、诱导痰嗜酸粒细胞(EOS)、血清总IgE、超敏C反应蛋白(hs-CRP)的水平;Pearson相关系数法分析FeNO值与其他指标的相关性。将患者按不同年龄和吸烟状况进行分组,比较各组患者在治疗前后各项指标的变化。同时选取28例健康受试者作为对照,检测其FeNO水平。 结果 治疗前、后ACOS患者的FeNO水平[(32.04±8.34)×10-9 mol/L vs(25.56±4.13)×10-9 mol/L,P<0.05]、诱导痰EOS[(18.51±5.36)% vs(13.18±1.56)%,P<0.05]、血清总IgE[(251.91±42.24)ng/mL vs(204.65±28.52)ng/mL,P<0.05]差异有统计学意义;而FEV1% pred[(52.03±7.03)% vs(55.16±8.20)%,P=0.391]、hs-CRP水平[(10.86±4.92)mg/L vs(9.16±1.82)mg/L,P=0.077]差异无统计学意义。治疗前、后ACOS组患者的FeNO水平均高于健康对照组[(32.04±8.34)×10-9 mol/L、(25.56±4.13)×10-9 mol/L vs(17.04±0.97)×10-9 mol/L,P<0.05]。不同年龄和吸烟状况的患者在ICS/LABA治疗前、后的FeNO值、诱导痰EOS、血清总IgE差异也均有统计学意义。ICS/LABA吸入治疗前、后ACOS组患者的FeNO水平与诱导痰EOS、血清总IgE均呈正相关(治疗前:r=0.924,P<0.01;r=0.945,P<0.01。治疗后:r=0.247,P<0.01;r=0.443,P<0.01),而与血清hs-CRP、FEV1% pred则无相关性。 结论 ACOS患者气道存在EOS性炎症,可使用ICS/LABA吸入治疗,其疗效不受年龄及吸烟状况的影响。FeNO检测可作为检测和评估ACOS使用ICS/LABA治疗疗效的有效手段,且其与诱导痰EOS、血清总IgE相关。
关键词: 呼出气一氧化氮     IgE     诱导痰     嗜酸粒细胞     哮喘-慢阻肺重叠综合征    
Fractional exhaled nitric oxide detection in treatment of asthma-chronic obstructive pulmonary disease overlap syndrome
JI Ze1, PAN Xing2, JI Feng3, NI Dian-tao1, SHANG Yan4, BAI Chong4     
1. Department of Respiratory Medicine, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215028, Jiangsu, China;
2. Department of Nursing, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215028, Jiangsu, China;
3. Department of Respiratory Medicine, Shandong Provincial Corps Hospital of Chinese People's Armed Police Forces, Jinan 250014, Shandong, China;
4. Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Supported by National Natural Science Foudation of China (81570020), Shanghai Pujiang Talent Program (14PJ1411000), Scientific Research Foundation of Ministry of Education for the Returned Overseas Chinese Scholars, Public Welfare Technology Application Research Project of Zhejiang Province (2016C33216), and Suzhou Industrial Park Incubator Project.
Abstract: Objective To investigate the value of fractional exhaled nitric oxide (FeNO) in the treatment of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS). Methods The twenty-eight ACOS patients receiving no standard medication treatment were recruited from May 2015 to Oct. 2015 in Suzhou Kowloon Hospital; the patients inhaled corticosteroids/long-acting beta agonist (ICS/LABA) for 12 weeks and the changes of FeNO levels, FEV1%pred, induced sputum eosinophil (EOS), blood total IgE, and high sensitivity C-reactive protein (hs-CRP) were examined before and after treatment. The correlations between FeNO and other indices were analyzed by Pearson correlation coefficient method. The patients were divided into different groups according to different age and smoking statuses, and the changes of the indices before and after treatment were compared between different groups. Twenty-eight healthy participants were recruited as control group and their FeNO levels were also tested. Results After treatment, the FeNO levels ([32.04±8.34]×10-9 mol/L vs[25.56±4.13]×10-9 mol/L, P<0.05), induced sputum EOS ([18.51±5.36]% vs[13.18±1.56]%, P<0.05), and blood total IgE ([251.91±42.24] ng/mL vs[204.65±28.52] ng/mL, P<0.05) of ACOS patients were significantly lower than those before treatment. There was no significant difference in FEV1%pred ([52.03±7.03]% vs[55.16±8.20]%, P=0.391) or hs-CRP ([10.86±4.92] mg/L vs[9.16±1.82) mg/L, P=0.077) before and after treatment in ACOS patients. Meanwhile, the levels of FeNO in ACOS group were significantly higher than those in the healthy control group before and after treatment([32.04±8.34]×10-9 mol/L,[25.56±4.13]×10-9 mol/L vs[17.04±0.97]×10-9 mol/L,P<0.05). The levels of FeNO, induced sputum EOS and serum total IgE were significantly different among different ages and smoking status before and after ICS/LABA treatment. The pre- and post-treatment FeNO levels were positively correlated with induced sputum EOS and serum total IgE (pre-treatment:r=0.924, P<0.01 and r=0.945, P<0.01; post-treatment:r=0.247, P<0.01 and r=0.443, P<0.01); while it was not correlated with serum hs-CRP or FEV1%pred. Conclusion Our findings indicate that eosinophilic inflammation is present in the airways of ACOS patients, which can be treated with ICS/LABA inhalation. The curative effect is not affected by age or smoking status. FeNO detection can be used to evaluate the efficacy of ICS/LABA for ACOS, which is associated with induced sputum EOS and serum total IgE.
Key words: fractional exhaled nitric oxide     IgE     induced sputum     eosinophil     asthma-chronic obstructive pulmonary disease overlap syndrome    

2014年、2015年慢性阻塞性肺疾病全球防治策略(global initiative for chronic obstructive lung disease,GOLD)以及全球哮喘防治创议(global initiative for asthma,GINA)相继增加了哮喘-慢阻肺重叠综合征(asthma-chronic obstructive pulmonary disease overlap syndrome,ACOS)[1-3],指出ACOS的特征是持续性气流受限,同时具有哮喘和慢性阻塞性肺疾病(COPD)的特征。ACOS应给予吸入性糖皮质激素/长效β受体激动剂(inhaled corticosteroids/long-acting β agonist,ICS/LABA)治疗,但目前指南中关于ACOS的药物选择以及疗程并没有明确规定。

呼出气一氧化氮(fractional exhaled nitric oxide,FeNO)检测能很好地反映气道嗜酸粒细胞(eosinophil,EOS)炎症程度,判断激素治疗反应性。国内已有研究证实FeNO联合肺功能检测有助于ACOS的鉴别诊断[4],但有关其在ACOS治疗效果评估中的作用研究较少。本研究通过观察ACOS患者为期12周的ICS/LABA吸入治疗前、后的FeNO值、肺功能、诱导痰EOS、血清总IgE、超敏C反应蛋白(high sensitivity C-reactive protein,hs-CRP)的变化,分析上述指标和患者的临床特征可否作为判断ACOS患者吸入治疗效果的有效预测指标,现报告如下。

1 对象和方法 1.1 研究对象

选取2015年5月至2015年10月期间在苏州九龙医院门诊或病房确诊为ACOS且未规范使用药物治疗的患者28例,设为ACOS组。纳入标准:(1)年龄20~65岁,男女不限;(2)依据2015年GOLD指南ACOS(5步法)诊断标准诊断为ACOS;(3)未规范使用过包括ICS/LABA在内的控制药物;(4)受试者签署知情同意书。排除标准:(1)入组前1个月内有急性上呼吸道感染和(或)肺部感染病史者;(2)合并其他脏器严重疾病史;(3)依从性差。同时从本院同期健康体检人群中选取28位受试者设为健康对照组。健康受试者入组前1个月内无急性上呼吸道感染和(或)肺部感染病史,无过敏性疾病史及哮喘、COPD家族史。对诊断为ACOS的患者给予为期12周的ICS/LABA吸入治疗,并检测治疗前后患者的FeNO值、肺功能、诱导痰EOS、血清总IgE和hs-CRP水平;检测28例健康受试者FeNO水平。

1.2 研究方法

ACOS组患者入组当日即进行FeNO值、肺功能、诱导痰EOS、血清总IgE、hs-CRP检查,随后给予为期12周的布地奈德福莫特罗粉吸入剂(阿斯利康制药有限公司,160 μg/4.5 μg,2吸/bid;生产批号:XCPL)或者福莫特罗替卡松粉吸入剂(葛兰素史克制药有限公司,50 μg/500 μg,1吸/bid;生产批号:R701415)规范治疗。健康对照组则只进行FeNO值检测。比较FeNO值等指标在ICS/LABA治疗前、后的变化,分析FeNO值与其他指标间的相关性,进而评估FeNO检查在ACOS治疗中的作用。

FeNO测定采用瑞典尼尔斯(NIOX)呼出气一氧化氮测定系统(NIOX MINO,瑞典Aerocrine AB公司),测量方法根据2005年ATS/ERS测定技术标准方法[5]和使用说明书进行操作测量。肺功能检测采用德国耶格生产的MS-PFT肺功能检测仪测定,选取一秒用力呼气容积占预计值百分比(the percent of forced expiratory volume in one second to predicted value,FEV1%pred)为评价指标。诱导痰EOS计数参照文献[6],患者吸入沙丁胺醇10 min,用清水漱口、擤鼻后用高渗盐水超声雾化吸入,嘱患者深咳出痰至培养皿;再从收集到的痰液中选取黏稠度高的分泌物,加入0.1%二硫苏糖醇(dithiothreitol,DTT)裂解后过滤杂质,离心沉淀用PBS悬浮;用锥虫蓝鉴定细胞活力;制作细胞涂片,风干后多聚甲醛固定、染色,烘干后用中性树胶封片,使用普通光学显微镜计数400个白细胞进行细胞分类(EOS、中性粒细胞、巨噬细胞和淋巴细胞等)。抽取外周静脉血,采用全自动血细胞分析仪测定外周静脉血hs-CRP,采用酶联免疫法测定血清总IgE。

1.3 统计学处理

采用SPSS 17.0软件进行分析。结果以x±s表示。ACOS组与健康对照组组间比较采用独立样本t检验。ACOS组治疗前与治疗后数据比较采用配对样本t检验和Wilcoxon秩和检验。分类变量资料采用Pearson χ2检验。两变量之间的相关性采用Pearson相关系数分析。检验水准(α)为0.05。

2 结果 2.1 基本资料

ACOS组和健康对照组患者在年龄、性别、体质量指数、吸烟史方面的差异均无统计学意义(表 1)。

表 1 ACOS组与健康对照组一般资料 Tab 1 Characteristics of participants in ACOS and healthy control groups

2.2 ICS/LABA治疗前后ACOS组患者FeNO、肺功能、诱导痰EOS、血清总IgE和hs-CRP水平的变化

ACOS组患者在接受ICS/LABA治疗后FeNO的水平较治疗前降低(P <0.05,表 2);但治疗前、后ACOS组患者的FeNO水平均高于健康对照组[(32.04±8.34) ×10-9 mol/L、(25.56±4.13) ×10-9 mol/L vs (17.04±0.97) ×10-9 mol/L;P<0.01,P<0.05]。使用ICS/LABA治疗后,ACOS组患者诱导痰EOS、血清总IgE较治疗前也均降低(P<0.01,表 2),而FEV1%pred、血清hs-CRP水平差异无统计学意义(表 2)。同时,不同年龄和吸烟状况人群ACOS患者在使用ICS/LABA治疗后的FeNO、诱导痰EOS、血清总IgE较治疗前均有改善(P<0.01,表 3)。

表 2 ICS/LABA治疗前后ACOS组患者各项指标的比较 Tab 2 Comparison of parameters in ACOS group before and after ICS/LABA treatment

表 3 ICS/LABA治疗前后ACOS组不同年龄和吸烟状况的患者各项指标的比较 Tab 3 Comparison of indicators in ACOS group with different ages and smoking status before and after ICS/LABA treatment

2.3 ICS/LABA治疗前、后FeNO水平与血清总IgE、诱导痰EOS、血清hs-CRP以及FEV1%pred的相关性分析

结果(图 1)显示,在ICS/LABA吸入治疗前,ACOS组患者的FeNO水平与诱导痰EOS、血清总IgE均呈正相关(r=0.924,P<0.01;r=0.945,P<0.01);在ICS/LABA吸入治疗后,ACOS组患者的FeNO水平与诱导痰EOS、血清总IgE呈正相关(r=0.247,P<0.01;r=0.443,P<0.01),而与血清hs-CRP、FEV1%pred则无相关性。

图 1 ICS/LABA治疗前后FeNO水平与血清总IgE、诱导痰EOS、hs-CRP以及FEV1%pred的相关性 Fig 1 Correlation analysis of FeNO level and total IgE,induced sputum EOS, hs-CRP,FEV1%pred before and after ICS/LABA treatment

3 讨论

2015年GOLD指南[2]指出,当患者所具有的支持哮喘和COPD特征的条目各为3条以上时,就应当考虑为ACOS。如果其吸入支气管扩张剂后FEV1/FVC <0.7,并伴有可逆性或不完全可逆性的持续气流受限,即符合ACOS诊断,应给予ICS/LABA吸入的治疗方案。因此若能筛选出可以预测ACOS患者使用ICS/LABA治疗效果的检测项目,将对临床ACOS的治疗有很好的指导价值。

近年来FeNO检测在临床工作中的应用越来越广泛,一氧化氮能通过转导细胞内信号影响EOS等多种炎症反应进程,在气道炎症反应中起关键的调控作用。在GINA和GOLD关于ACOS的定义中,均提出FeNO是区分哮喘与COPD的有效炎症标记物[2-3]。目前多篇文献报道FeNO检测在哮喘(咳嗽变异性哮喘、典型哮喘)、COPD等疾病诊治方面有较好的指导意义[6-11],但FeNO检测在指导ACOS治疗中的价值鲜有报道。Tamada等[12]报道,进行FeNO检测时以35×10-9为界有助于从COPD患者中筛选出ACOS,史菲[4] 研究证实FeNO与肺通气功能联合应用有助于ACOS与其他慢性阻塞性气道疾病的鉴别诊断。

本研究比较了ACOS患者在使用ICS/LABA吸入治疗前及治疗12周后FeNO值、肺功能、诱导痰EOS、血清总IgE和hs-CRP的变化,同时也比较了不同临床特征的患者在治疗前、后上述指标的变化。结果显示ACOS组患者在使用ICS/LABA治疗后FeNO值、诱导痰EOS、血清总IgE均降低,而FEV1%pred、血清hs-CRP在治疗前、后差异无统计学意义,提示ACOS患者的肺功能改善可能相对滞后,需要延长治疗时间或根据西班牙指南建议加用LAMA治疗[8]。此外,无论年龄>40岁或≤40岁的患者,还是吸烟或不吸烟的患者,其在使用ICS/LABA治疗前后的FeNO、诱导痰EOS、血清总IgE差异均有统计学意义,这与目前研究结果[3, 12]相似,表明ACOS患者气道以EOS性炎症为主,这可能也是ACOS患者气喘症状反复发作的原因,不能将年龄、吸烟等临床特征作为筛选ICS/LABA治疗是否有效的依据。本研究结果显示FeNO与诱导痰EOS、血清总IgE呈线性正相关,提示FeNO、诱导痰EOS、血清总IgE可能是评估ACOS治疗效果的有效指标,这与Tamada等[12]研究结果相似,提示在临床工作中FeNO值较高的ACOS患者可能从ICS/LABA治疗中获益更多。本研究团队目前正在募集已确诊为COPD、支气管哮喘的患者,检测患者的FeNO值,分析根据FeNO检测结果是否可以有助于从COPD、哮喘患者中筛选出ACOS患者,目前尚处于数据收集阶段。如果能够通过FeNO检测有效筛选出ACOS患者的检测临界值,并根据检测结果预测吸入治疗药物的疗效,可以为FeNO检测在二级医院的推广以及评估吸入治疗疗效提供很好的指导。

综上所述,在临床工作中对于临床诊断或者确诊为ACOS的患者,检测FeNO可反映患者的气道EOS炎症水平,FeNO水平较高的患者可能从ICS/LABA治疗中获益更多。

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