轻度支气管哮喘治疗策略的商榷
2018年7期
中华泌尿外科杂志，第41卷第7期 第572页-第576页
王刚,张欣,王蕾,王刚
参考文献
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支气管哮喘(哮喘)作为慢性气道炎症性疾病[1]，目前全球至少有3亿，中国大陆地区至少有3 000万哮喘患者[2]。虽然在发达国家和地区哮喘发病似乎已进入平台期[3]，但是我国的发病率仍呈上升趋势[4]。在既往哮喘指南和临床实践中，根据哮喘症状及所需治疗级别，哮喘可分为轻度间歇(intermittent asthma)、轻度持续(mild persistent asthma)、中度持续和重度持续[5,6]。尽管近年全球哮喘防治创议(the global initiative for asthma，GINA)[7]逐渐淡化了轻度间歇和轻度续性哮喘的严重程度分级，将其统一为轻度哮喘，但此分级在临床研究工作中仍有重要意义[8]。
目前各国哮喘防治指南均推荐根据治疗后哮喘控制水平，对治疗方案进行动态调整，即所谓升降级治疗(stepwise)，升降级的维持疗程一般为3～6个月。哮喘分级治疗对改善哮喘病情、保护肺功能、提高生活质量，同时减少药物不良反应产生了积极影响。绝大多数哮喘患者从中受益，病情得到良好甚至完全控制。轻度哮喘接受第1级(Step 1)或者第2级(Step 2)治疗方案，便能获得良好控制[8,9]。基于人群的流行病学研究结果显示，50%以上的哮喘患者为轻度哮喘[10,11]，然而此类患者目前未受到足够重视[12,13]。多个哮喘防治指南(表1)均推荐轻度间歇哮喘按需使用短效β2-受体激动剂(short-acting β2-agonists，SABA)，轻度持续哮喘规律使用低剂量吸入糖皮质激素(inhaled corticosteroids，ICS)且按需使用SABA。这些指南性推荐意见，为全球轻度哮喘的整体控制发挥了重要作用，但是亦有部分不足和矛盾之处，临床证据质量亦不高，且这些推荐治疗策略可能在真实世界难以奏效。
β2肾上腺素受体激动剂(β2 adrenergic receptor agonists)是一类作用于β2肾上腺素受体的药物，其良好的舒张支气管平滑肌作用，常用于气道阻塞性疾病的治疗，如哮喘和慢性阻塞性肺疾病(慢阻肺)等。按作用时间长短，可分为短效β2-受体激动剂，长效β2-受体激动剂(long-acting β2-agonists，LABA)和超长效β2-受体激动剂(ultra-long-acting β2 agonists)。尽管指南推荐SABA为轻度哮喘按需治疗方案(表1)，但亦存在矛盾之处。
首先，就第1级治疗方案而言，按需使用SABA与哮喘的病理矛盾[14]。哮喘作为慢性气道炎症性疾病[1,7]，轻度哮喘患者气道炎症仍然持续存在[15,16]，但是该推荐意见并无针对气道炎症的药物[17]。相反，体外实验结果证实，SABA可诱导2型T细胞产生促炎因子[18]，这与以抗炎为中心的哮喘治疗理念相悖。此外，把按需使用SABA作为优先推荐的治疗方案，可能让患者误将SABA而不是ICS视为哮喘治疗的核心药物，这可能会影响后续的升级治疗[14]。
其次，在接受第2级治疗方案中，推荐按需使用SABA亦存在不足。哮喘的临床表现为喘息、气急、胸闷或咳嗽等症状，哮喘病程中常伴随着这些症状的波动。当哮喘症状出现或加重时，通常伴随气道炎症的增加[19,20]。按需使用SABA可以快速缓解临床症状[21]，却不能控制炎症[17]。此外，由于SABA带给患者的直观感受，可能使患者错误地认为SABA是一种"快速、有效、方便且经济"的治疗药物[22]，使患者产生对SABA的依赖和对规律维持治疗药物(如ICS等)的抵制。患者长期过度依赖SABA会导致肾上腺素受体耐受，进而增加哮喘急性发作和住院的风险[23,24]，甚至轻度哮喘相关的死亡[25,26]。
轻度持续哮喘患者规律使用低剂量ICS可以减少哮喘相关症状，增加患者肺功能，改善患者生活质量，并且可有效减少哮喘急性发作和哮喘相关住院和死亡[27,28,29,30]。虽然规律使用低剂量ICS具有众多优点，但是指南关于推荐规律使用低剂量ICS仍有一些问题需要思考。
首先，轻度哮喘患者按需使用SABA>2次/周[31,32]或者2次/月[1,7]，指南推荐应规律使用低剂量ICS治疗，而具体推荐剂量却很模糊。研究结果证实，轻度哮喘患者使用双倍剂量的ICS并不能减少哮喘急性发作[33,34]，但是完全不使用ICS却会增加哮喘急性发作的风险[35]。这就导致轻度哮喘的激素推荐剂量成为一个悬而未决的问题。此外，由于糖皮质激素的敏感性存在个体差异[36]，寻找一个适合所有人的激素推荐用量非常困难。
其次，依从性是规律使用低剂量ICS临床疗效的保证。哮喘患者用药依从性差和哮喘急性发作相关[37]，但是多数患者(特别是轻度哮喘)仍倾向于间歇或者按需使用药物[30,38]。我们在PubMed上以"asthma"、"ICS"、"real-world"、"real-life"、"pragmatic"和"naturalist"为关键词检索，探索真实世界规律使用ICS的依从性。截止至2017年5月，共检索到59项研究，11项研究被纳入分析，其中有8个队列研究，3个随机对照试验[39]。我们使用天数占比(proportion of days covered，PDC)判断规律使用ICS的依从性，定义为总的使用药物天数除以总观察天数。结果发现，真实世界哮喘患者"规律"使用ICS的依从性仅37.6%(95% CI为33.1～ 42.2，表2)，较低的依从性可明显降低ICS的疗效[40]。同样，亚太地区的流行病学调查结果显示，轻度持续哮喘患者中有54.3%使用速效支气管舒张药物(如SABA)，而仅有14%使用控制药物(如ICS)[41]。此外，为防止12周[40]甚至更长时间出现一次哮喘急性发作，推荐每天规律使用ICS，并未尊重患者治疗偏好，这样的治疗决策可能会降低患者用药依从性[42]。
基于以上指南推荐中的不足，迫切需要其他可行的针对轻度哮喘的管理方案。按需使用吸入激素联合速效β2-受体激动剂(the combination corticosteroid/fast-onset-acting β2-agonist，ICS/FABA)似乎是一个可行的管理方案[39,40,41,42,43]。该方案源于使用单一吸入装置以维持缓解治疗(single inhaler for maintenance and reliever therapy，SMART)策略，是SMART的发展和延伸。在中～重度哮喘患者中，相对于指南推荐的其他治疗方案，SMART能明显减少重度哮喘急性发作和全身激素使用[1,7]。基于相关证据源于中～重度哮喘患者的临床试验，导致该方案无可靠证据(外在真实性)向轻度间歇和轻度持续哮喘患者推广。近年，已有相关研究探讨了轻度哮喘患者按需使用ICS/FABA的可行性[43]，新近我们的概念验证性荟萃分析(proof-of-concept meta-analysis)[39]结果为轻度哮喘按需使用ICS/FABA提供了前期定量数据。
按需使用ICS/FABA治疗策略具有以下一些优点。第一，该方案同时包含缓解临床症状的成分(FABA)和控制气道炎症的成分(ICS)。指南推荐的轻度哮喘患者治疗方案中，按需使用ICS/FABA较按需使用SABA更加符合哮喘的炎症病理过程。我们的研究结果[39]显示，按需使用ICS/FABA较按需使用SABA可明显减少中～重度哮喘急性发作[5]和重度哮喘急性发作[5]风险，且能延长自入组至第1次哮喘急性发作的时间(图1，图2)。此外，联合使用ICS可逆转FABA可能导致的β2肾上腺素受体耐受和促炎因子释放[18,44]。
注：ICS：吸入糖皮质激素；FABA：速效β2-受体激动剂；ICS/LABA：吸入糖皮质激素联合速效β2-受体激动剂；HR：风险比
第二，按需使用ICS/FABA可以根据患者的症状变化有效调节ICS用量，做到"精准"用药。规律使用低剂量ICS的激素用量是按需使用ICS/FABA的2～5倍[39]，激素暴露的增加常伴随其相关不良反应的增加。一项为期44周的临床研究[45]结果显示，与按需使用SABA组比较，规律使用ICS组的小孩身高增长减少1.1 cm(SD＝0.3)，而按需使用ICS/FABA组的小孩身高增长差异无统计学意义(0.3 cm，SD＝0.2)。另一项研究结果亦显示，经16周治疗，按需使用ICS/FABA组较规律使用ICS组的小孩身高多增加0.2 cm[46]。
第三，按需使用ICS/FABA较规律使用ICS在依从性方面更有优势。真实世界数据显示，哮喘患者规律使用ICS的依从性仅37.6%。虽然已有多项研究探索提高患者规律使用ICS依从性的策略，如视听装置(audiovisual reminders)[47,48]、电子监督装置(electronic monitoring)[48]、基于电话的自动应答系统(interactive voice response system via mobile phone)[49]、短信提醒(text message reminders)[50]和患者教育(patient education)[51]等，但这些方法提高依从性有限(4%～20%)[52]。基于具有高依从性哮喘人群的随机对照临床研究结果表明[39]，与规律使用ICS(依从性>75%)比较，按需使用ICS/FABA存在偏高的中～重度哮喘急性发作(RR＝1.39, 95% CI为1.08～1.79)和重度哮喘急性发作(RR＝1.34, 95% CI为1.02～1.75)风险，但是自入组至第1次哮喘急性发作的时间差异无统计学意义(HR＝1.30, 95% CI为0.81～2.08)。鉴于真实世界较低的依从性，规律使用ICS极可能难以在真实世界奏效。此外，与上述被动提升患者依从性策略比较，按需使用ICS/FABA在提升依从性方面更为主动，且按需使用的用药方式在医患沟通上亦更容易获得患者的理解。
基于以患者为中心的共同决策(shared decision-making)模式[53]，尊重和回应患者个人偏好、需求和价值观，我们认为轻度间歇和轻度持续哮喘患者按需使用ICS/FABA是一可行的治疗策略。尽管有两项涉及轻度哮喘患者按需使用ICS/FABA的随机对照试验(randomized controlled trials，RCT)正在进行[54,55]，但并非是真实世界研究，未来真实世界高质量观察性数据库研究(observational database studies)[56]或真实世界的RCT有望能解决这些疑问。
总之，现有哮喘指南关于轻度哮喘第1级治疗方案，推荐按需使用SABA与以抗炎为中心的哮喘治疗理念相悖，第2级治疗方案不能及时缓解气道炎症，而且规律使用低剂量ICS在激素推荐剂量和依从性方面同样存在诸多疑问或不足。按需使用ICS/FABA可能是一种切实可行的治疗选择，它符合哮喘的病理过程，能减少激素的暴露且不依赖用药依从性，有益于轻度哮喘患者的管理和总体控制。