1、慢阻肺诊断、治疗与预防全球倡议（GOLD）2018版 解读,要点概述,1. GOLD 2018沿用了GOLD 2017对慢阻肺和AECOPD的定义，维持了慢阻肺综合评估以及稳定期药物治疗推荐，主要对各章节的循证证据进行了更新。2. 支气管扩张剂仍是慢阻肺稳定期治疗的基石用药：唯有LAMA是所有分组患者的首选单药治疗药物；LAMA预防急性加重优于LABA；LAMA/LABA联用是B-D组患者的推荐用药。3. 适合以ICS/LABA作为起始治疗药物的患者限于某些特定亚型的患者人群。,第一章：定义和概述,GOLD 2018维持了GOLD 2017对慢阻肺的定义：“慢阻肺是可防可治的常见病，以持续性呼
2、吸道症状和气流受限为特点，常与有毒颗粒或气体的显著暴露引起的气道和/或肺泡异常有关”。,慢阻肺的病理生理学,1、医学研究委员会国家卫生与发展调查发现，在43岁时，肺功能受吸烟和婴幼儿呼吸道感染以及童年家庭过度拥挤的协同交互作用影响。The Medical Research Council National Survey of Health and Development recently documented a synergistic interaction between smoking and infant respiratory infection as well as early l
3、ife home overcrowding with lung function at age 43. (Allinson et al., 2017)2、来自我国的一项横断面研究显示，周围环境的PM 2.5/10 水平与慢阻肺患病率相关。A recent cross-sectional analysis from China showed an association between ambient levels of particulate matter (PM2.5/10) and COPD prevalence. (Liu et al., 2017).3、局部 IgA 缺乏与细菌移位、小
4、气道炎症以及气道重塑相关。A recent study suggests that local IgA deficiency is associated with bacterial translocation, small airway inflammation and airway remodeling. (Polosukhin et al., 2017)4、即使在轻度慢阻肺，或易发生肺气肿的吸烟人群，其肺部微血管血流存在显著异常，并随疾病进展而恶化。Even in mild COPD, or in smokers susceptible to emphysema, (Alford, va
5、n Beek, McLennan, Iyer et al., 2016) there are significant abnormalities in pulmonary microvascular blood flow that worsen with disease progression. (Peinado, Pizarro, & Barbera, 2008).,第二章：诊断和起始评估 慢阻肺的诊断,在利用肺功能检查评价气流受限时，考虑到某些患者在下一次测量时FEV1/FVC会随生理性变化而改变，若使用支扩剂后FEV1/FVC介于0.6-0.8，应在另一场合再次测量以确诊。Assessm
6、ent of the presence or absence of airflow obstruction based on a single measurement of the post-bronchodilator FEV1/FVC ratio should be confirmed by repeat spirometry on a separate occasion if the value is between 0.6 and 0.8, as in some cases the ratio may change as a result of biological variation
7、 when measured at a later interval (Aaron et al., 2017; Schermer et al., 2016) If the initial post-bronchodilator FEV1/FVC ratio is less than 0.6 it is very unlikely to rise above 0.7 spontaneously.(Aaron et al., 2017)ABCD评估工具 GOLD 2018维持了慢阻肺综合评估的临床路径，在ABCD分组的急性加重史中注明了是 “中到重度急性加重史” (图1)。,2018版慢阻肺综合评
8、估流程,急性加重风险的评估 。,目前已开展多项采用GOLD肺功能标准对患者进行分级的大型临床研究，这些研究显示急性加重率在患者个体间和随访期间存在非常大的变异率。 A number of large studies that classified patients using the GOLD spirometric grading systems have been conducted. (Decramer et al., 2009; Hurst et al., 2010; Jenkins et al., 2009) These studies demonstrate that exacer
9、bation rates vary greatly between patients (Hurst et al., 2010) and during follow-up. (Han et al., 2017) 注： GOLD 2018维持了2017版对AECOPD的定义和分级。AECOPD的定义为呼吸道症状的急性恶化，导致需要额外治疗。急性加重史是预测频繁急性加重 (年AECOPD2) 的最佳预测因子。,AECOPD的分级包括：,轻度：仅需要短效支扩剂治疗； 中度：需要短效支扩剂联合抗生素和/或口服糖皮质激素治疗； 重度：患者需要住院或者至急诊就诊；重度急性加重还可能伴随急性呼吸衰竭。,第三章
10、：基于证据支持的预防及维持治疗 戒烟与电子烟,1、除了个人主动戒烟，通过立法禁烟能够有效提高戒烟率、降低二手烟暴露导致的危害。 Besides individual approaches to smoking cessation, legislative smoking bans are effective in increasing quit rates and reducing harm from second-hand smoke exposure. (Frazer et al., 2016) 2、吸入电子烟会改变吸烟者的肺部宿主反应。 Recent data suggest that
11、e-cigarette inhalation alters the lung host response in smokers. (Reidel et al., 2017) 注： 这篇发表在Am J Respir Crit Care Med(IF = 13.2) 的最新研究显示，吸入电子烟会改变气道分泌和固有免疫相关的蛋白表达，进而引起中性粒细胞激活和黏液分泌功能改变，这些效应与传统吸烟部分重叠。该研究挑战了“电子烟比传统卷烟更为健康”的观点。,药物治疗-支扩剂,1、患者基线症状越重，联用双支扩剂 (LAMA/LABA) 相比安慰剂或对应单药对生活质量带来的改善越显著。 2、一项双盲平行组的R
12、CT显示,与常规噻托溴铵相比，使用外固定三联疗法治疗症状性COPD的患者有临床益处。 3、另一项双盲RCT表明三联FDC治疗晚期慢阻肺效果优于ICS/LABA。,药物治疗-PDE4抑制剂,对于有既往急性加重住院史的患者，罗氟司特能带来更多的临床获益。 The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute exacerbation. (Han et al., 2014; Rabe,
13、 Calverley, Martinez, & Fabbri, 2017),药物治疗-抗生素,1、相比常规治疗，高风险患者接受阿奇霉素 (250mg/天, 或500mg 一周三次) 或红霉素 (500mg BID) 治疗1年降低急性加重风险。2、应用阿奇霉素与细菌耐药和听力受损相关。3、一项事后分析表明现吸烟者从阿奇霉素中得到的治疗获益较少。4、目前没有研究评价阿奇霉素长期治疗1年以上时预防急性加重的有效性或安全性。Azithromycin (250 mg/day or 500 mg three times per week) or erythromycin (500 mg two times
14、 per day) for one year in patients prone to exacerbations reduced the risk of exacerbations compared to usual care. (Albert et al., 2011; Seemungal et al., 2008; Uzun et al., 2014) Azithromycin use was associated with an increased incidence of bacterial resistance and impaired hearing tests. (Albert
15、 et al., 2011) A post-hoc analysis suggests lesser benefit in active smokers. (Han et al., 2014) There are no data beyond one-year of chronic azithromycin treatment showing the efficacy or safety of its use to prevent COPD exacerbations.,肺康复,1、肺康复可以在多种场所开展。家庭肺康复对资源需求小，是门诊肺康复的等效替代方案，也利于住所远离康复场所的患者开展治
16、疗。 Pulmonary rehabilitation can be conducted at a range of sites. (Spruit et al., 2013) Home rehabilitation delivered with minimal resources in patients with COPD may be an equivalent alternative to facility located outpatient rehabilitation. (Holland et al., 2017) Home rehabilitation may be a solut
17、ion for many patients who live outside the reach of facility-based programs.2、肺康复的获益似乎随时间推移逐渐减少。长期肺康复治疗可以维持初次康复治疗后的获益，但也有一项研究指出获益在随访期间减少。 Another challenge is that the benefits of rehabilitation tend to wane over time. Long-term maintenance pulmonary rehabilitation may sustain the benefits achieved
18、after completion of the initial pulmonary rehabilitation program, although one study reported attenuation during follow-up. (Guell et al., 2017),氧疗和通气支持,1、对于存在轻度低氧血症或非低氧血症而无需家庭氧疗的患者，在运动期间给予氧疗可以缓解呼吸困难，但有研究显示此类患者开展家庭氧疗对日常生活呼吸困难或健康相关生活质量的改善均无获益。 Breathlessness may be relieved in COPD patients who are e
19、ither mildly hypoxemic, or non-hypoxemic but do not otherwise qualify for home oxygen therapy, when oxygen is given during exercise training; however, studies have shown no improvement of breathlessness in daily life and no benefit on health related quality of life (Table 3.10). (Ekstrom, Ahmadi, Bo
20、rnefalk-Hermansson, Abernethy, Long-term Oxygen Treatment Trial Research Group, 2016) 2、对于合并阻塞性睡眠呼吸暂停的慢阻肺患者，持续气道正压通气 (CPAP) 显著改善生存、降低住院风险。 In patients with both COPD and obstructive sleep apnea there are clear benefits associated with the use of continuous positive airway pressure (CPAP) to improve
21、both survival and the risk of hospital admissions. (Marin, Soriano, Carrizo, Boldova, & Celli, 2010),3、目前对于住院后发生慢性呼吸衰竭急性发作的患者是否可以在家长期应用无创正压通气 (NPPV) 存在争议。近期一项前瞻性RCT研究纳入了116例出院2-4周后因急性加重出现持续高碳酸血症 (PaCO2 53 mmHg) 的慢阻肺患者，比较家庭无创通气 (NIV) 联合氧疗与仅家庭氧疗对再次入院或死亡的影响。在排除BMI 35 kg/m2、阻塞性睡眠呼吸暂停综合征或其他呼吸衰竭诱因之后，2,021
22、 例患者中仅 124 例 (6%) 符合条件。研究结果显示家庭NIV 联合氧疗显著延长12 个月内再次入院或死亡的发生时间。Whether to use NPPV chronically at home to treat COPD patients with acute on chronic respiratory failure following hospitalization remains controversial. A recent multicenter (13 sites) prospective RCT of COPD patients (n=116) with persis
23、tent hypercapnia (PaCO2 53 mmHg) after 2-4 weeks of hospital discharge because an acute episode of exacerbation, compared the effects of home noninvasive ventilation (NIV) plus oxygen compared to home oxygen alone on time to readmission or death. (Murphy et al., 2017) Patients with body mass index 3
24、5 Kg/m2, obstructive sleep apnea syndrome, or other causes of respiratory failure were excluded. Of 2,021 patients screened, only 124 (6%) were eligible. Results showed that adding home NIV to oxygen therapy significantly prolonged the time to readmission or death within 12 months. (Murphy et al., 2
25、017)4、两项回顾性研究和三项RCT中的两项研究发现，出院后使用NPPV 可降低再次住院率并提高生存率。不同研究间结论的差异可能与患者选择不同、研究效能不足、NPPV设置不足以实现充分通气、以及NPPV依从性差相关。在应用NPPV时，应由熟悉设备和操作的人员进行指导和监测。 Two previous retrospective studies (Coughlin, Liang, Lightowler, Wedzicha, Elliott, & Ram, 2003),第四章：稳定期慢阻肺的管理,GOLD 2018维持了GOLD 2017对稳定期ABCD组患者的药物治疗推荐 稳定期慢阻肺的药物治
26、疗策略,A组患者 所有A组患者均需要使用支气管扩张剂（短效或者长效），评估疗效后可继续、停用或者更换其他支气管扩张剂 B组患者 B组患者的起始用药是长效支气管扩张剂（LAMA或LABA）：长效支扩剂效果优于按需使用的短效支扩剂。 目前无证据支持在B组患者中哪类长效支扩剂作为初始治疗药物能够更好的缓解症状，具体药物选择应根据患者对症状缓解程度的感受； 若单药治疗下呼吸困难未缓解，推荐LAMA/LABA联合治疗； 若患者存在重度呼吸困难， LAMA/LABA可作为初始用药； 若加用另外一种支气管扩张剂没有改善症状，建议降级治疗至使用一种支气管扩张剂； 需要综合考虑B组患者可能存在的、对症状和预后有
27、影响的合并症。 C组患者 C组患者的起始用药是长效支气管扩张剂单药治疗，推荐LAMA：在两项头对头研究中， LAMA在预防急性加重方面优于LABA； 若患者存在持续的急性加重，可联合应用LAMA/LABA，或者ICS/LABA。但ICS增加部分患者的肺炎风险，因此首选是LAMA/LABA。,D组患者 对于D组患者，首选LAMA/LABA联合治疗，原因如下： 研究证明LAMA/LABA联用在改善患者报告的临床结局方面优于单药。若起始采用单药治疗，首选LAMA：LAMA预防急性加重效果优于LABA； 在D组患者中LAMA/LABA在预防急性加重和改善其他患者报告的临床结局方面优于ICS/LABA；
28、 D组患者接受ICS治疗发生肺炎风险更高。 某些患者（既往诊断/目前怀疑为ACOS，或血嗜酸性粒细胞增多的患者）可能从首选ICS/LABA中获益； 对于LAMA/LABA无法控制急性加重的患者，两条推荐路线如下： 升级为LAMA/LABA/ICS：比较LAMA/LABA和LAMA/LABA/ICS预防急性加重差异的研究正在进行中； 转换为ICS/LABA，但目前没有证据证明从LAMA/LABA转换为ICS/LABA能更好地预防急性加重。若ICS/LABA未改善急性加重或症状，可加用LAMA； 6. 若LAMA/LABA/ICS仍无法控制急性加重，可考虑： 加用罗氟司特：针对FEV1%预计值 加
29、用大环内酯类抗生素：阿奇霉素的证据最足； 降级治疗、停用ICS：研究表明在治疗无效且增加不良反应时撤除ICS不会带来额外风险。,第五章：AECOPD的管理,1、我国研究者发现短期暴露于PM2.5与增加急性加重住院和慢阻肺死亡率相关。 Short-term exposure to fine particulate matter (PM2.5) is associated with increased hospitalizations for acute exacerbations and increased mortality of COPD. (Li et al., 2016; Liu et
30、al., 2017)2、个体患者对急性加重易感性增加的确切原因尚不明确。但与无频繁急性加重的患者相比，频繁急性加重的患者对呼吸困难的感知度更强，提示除了生理或诱发因素，对呼吸困难的感知也可能促进急性加重时的呼吸症状的发生。 The exact reason for an individuals increased susceptibility to exacerbation symptoms remains largely unknown. However, the perception of breathlessness is greater in frequent exacerbators
31、 than infrequent exacerbators, (Scioscia et al., 2017) suggesting that a perception of breathing difficulty may contribute to precipitating the respiratory symptoms of an exacerbation rather than solely physiological or causative factors.3、新版指南中过去1年内的急性加重次数仍是预测未来急性加重频率的最佳预测因子。普遍认为这些患者是一群相对稳定的表型，但有一些
32、研究显示相当比例患者的急性加重频率会随着FEV1的恶化发生改变。 The strongest predictor of a patients future exacerbation frequency remains the number of exacerbations they have had in the prior year. (Hurst et al., 2010) It is recognized that these patients form a moderately stable phenotype, although some studies have shown tha
33、t a significant proportion of patients change their exacerbation frequency especially with worsening FEV1. (Donaldson et al., 2013),4、一篇近期更新的考克兰系统综述显示，包含单次简短教育项目和持续支持的慢阻肺急性加重行动计划可以减少院内医疗资源的使用。该教育项目同时也能够提高急性加重期治疗时激素和抗生素的使用。 A recent updated Cochrane review concluded that the use of COPD exacerbation
34、action plans with a single short educational component, in conjunction with ongoing support, reduced in-hospital healthcare utilisation. Such educational interventions were also found to increase the treatment of COPD exacerbations with corticosteroids and antibiotics. (Howcroft, Walters, Wood-Baker
35、, a randomized cross-over trial demonstrated that HFNC improved ventilation and decreased hypercarbia. (Fraser, Spooner, Dunster, Anstey, & Corley, 2016) A systematic review of RCTs in patients with acute hypoxemic respiratory failure suggests that HFNC trends to reduce intubation rate, but did not
36、meet statistical significance compared with conventional oxygen therapy or NIV, and had no effect on mortality. (Lin, Liu, Lin, & Lin, 2017) However, the meta-analysis included no studies of patients with acute respiratory failure due to a COPD exacerbation. There is a need for well-designed, randomized, multicenter trials to study the effects of HFNC in acute hypoxemic respiratory failure in COPD patients.,
