Teo Edward, Lockhart Kathleen, Purchuri Sai Navya, Pushparajah Jennifer, Cripps Allan W, van Driel Mieke L
Emergency Department, Concord Repatriation General Hospital, Hospital Road, Concord, Sydney, New South Wales, Australia, 2137.
Cochrane Database Syst Rev. 2017 Jun 19;6(6):CD010010. doi: 10.1002/14651858.CD010010.pub3.
Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. Chronic obstructive pulmonary disease is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non-typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis.
To assess the effectiveness of an oral, whole-cell NTHi vaccine in protecting against recurrent episodes of acute exacerbations of chronic bronchitis and COPD in adults. To assess the effectiveness of NTHi vaccine in reducing NTHi colonising the respiratory tract during recurrent episodes of acute exacerbations of COPD.
We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), CINAHL (1981 to January 2017), LILACS (1985 to January 2017), and Web of Science (1955 to January 2017). We also searched trials registries and contacted authors of trials requesting unpublished data.
We included randomised controlled trials comparing the effects of an oral monobacterial NTHi vaccine in adults with recurrent acute exacerbations of chronic bronchitis or COPD when there was overt matching of the vaccine and placebo groups on clinical grounds. The selection criteria considered populations aged less than 65 years and those older than 65 years.
Two review authors independently assessed trial quality and extracted data from original records and publications for incidence and severity of bronchitis episodes and carriage rate of NTHi measured in the upper respiratory tract, as well as data relevant to other primary and secondary outcomes.
We identified six placebo-controlled randomised controlled trials with a total of 557 participants. These trials investigated the efficacy of enteric-coated, killed preparations of H influenzae in populations prone to recurrent acute exacerbations of chronic bronchitis or COPD. The vaccine preparation and immunisation regimen in all trials consisted of at least three courses of formalin-killed H influenzae in enteric-coated tablets taken at intervals (e.g. days 0, 28, and 56). Each course generally consisted of two tablets taken after breakfast over three consecutive days. In all cases the placebo groups took enteric-coated tablets containing glucose. Risk of bias was moderate across the studies, namely due to the lack of information provided about methods and inadequate presentation of results.Meta-analysis of the oral NTHi vaccine showed a small, non-statistically significant reduction in the incidence of acute exacerbations of chronic bronchitis or COPD (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.57 to 1.10; P = 0.16). There was no significant difference in mortality rate between the vaccine and placebo groups (odds ratio (OR) 1.62, 95% CI 0.63 to 4.12; P = 0.31).We were unable to meta-analyse the carriage levels of NTHi in participants as each trial reported this result using different units and tools of measurement. Four trials showed no significant difference in carriage levels, while two trials showed a significant decrease in carriage levels in the vaccinated group compared with the placebo group.Four trials assessed severity of exacerbations measured by requirement for antibiotics. Three of these trials were comparable and when meta-analysed showed a statistically significant 80% increase in antibiotic courses per person in the placebo group (RR 1.81, 95% CI 1.35 to 2.44; P < 0.001). There was no significant difference between the groups with regard to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04; P = 0.97). Adverse events were reported in five trials but were not necessarily related to the vaccine; a point estimate is suggestive that they occurred more frequently in the vaccine group, however this result was not statistically significant (RR 1.43, 95% CI 0.70 to 2.92; P = 0.87). Quality of life was not meta-analysed but was reported in two trials, with results at six months showing an improvement in quality of life in the vaccinated group (scoring at least two points better than placebo).
AUTHORS' CONCLUSIONS: Analyses demonstrate that NTHi oral vaccination of people with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence was mixed, and the individual trials that showed a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD.
慢性支气管炎和慢性阻塞性肺疾病（COPD）是严重的疾病，患者易发生病毒和细菌感染，从而导致可能致命的急性加重。慢性阻塞性肺疾病被定义为一种以肺气流受阻为特征的肺部疾病，会干扰正常呼吸。抗生素疗法在根除诸如不可分型流感嗜血杆菌（NTHi）等细菌方面并非特别有效，因为它们是许多人上呼吸道的自然菌群。然而，它们可引起机会性感染。已研发出一种口服NTHi疫苗，以预防慢性支气管炎反复发生的感染性急性加重。
评估口服全细胞NTHi疫苗对预防成人慢性支气管炎和COPD急性加重复发的有效性。评估NTHi疫苗在减少COPD急性加重复发期间NTHi在呼吸道定植方面的有效性。
我们检索了以下数据库：Cochrane对照试验中心注册库（CENTRAL）（2017年第1期）、医学期刊数据库（MEDLINE，1946年至2017年1月）、荷兰医学文摘数据库（Embase，1974年至2017年1月）、护理学与健康领域数据库（CINAHL，1981年至2017年1月）、拉丁美洲及加勒比地区健康科学数据库（LILACS，1985年至2017年1月）以及科学引文索引数据库（Web of Science，1955年至2017年1月）。我们还检索了试验注册库，并联系试验作者索要未发表的数据。
我们纳入了随机对照试验，这些试验比较了口服单一细菌NTHi疫苗对患有慢性支气管炎或COPD反复急性加重的成人的影响，且疫苗组和安慰剂组在临床方面有明显匹配。入选标准考虑了年龄小于65岁和大于65岁的人群。
两位综述作者独立评估试验质量，并从原始记录和出版物中提取数据，包括支气管炎发作的发生率和严重程度、上呼吸道中NTHi的携带率，以及与其他主要和次要结局相关的数据。
我们确定了6项安慰剂对照随机对照试验，共有557名参与者。这些试验研究了肠溶包衣的灭活流感嗜血杆菌制剂对易发生慢性支气管炎或COPD反复急性加重人群的疗效。所有试验中的疫苗制剂和免疫方案至少包括三个疗程的肠溶包衣片剂，其中含有经福尔马林灭活的流感嗜血杆菌，需间隔服用（如第0、28和56天）。每个疗程通常包括连续三天早餐后服用两片。在所有情况下，安慰剂组服用含葡萄糖的肠溶包衣片剂。各研究的偏倚风险为中等，原因是缺乏关于方法的信息且结果呈现不充分。对口服NTHi疫苗的荟萃分析显示，慢性支气管炎或COPD急性加重的发生率有小幅降低，但无统计学意义（风险比（RR）0.79，95%置信区间（CI）0.57至1.10；P = 0.16）。疫苗组和安慰剂组的死亡率无显著差异（比值比（OR）1.62，95% CI 0.63至4.12；P = 0.31）。我们无法对参与者中NTHi的携带水平进行荟萃分析，因为每个试验报告该结果时使用的测量单位和工具不同。四项试验显示携带水平无显著差异，而两项试验显示与安慰剂组相比，接种疫苗组的携带水平显著降低。四项试验评估了根据抗生素使用需求衡量的加重严重程度。其中三项试验具有可比性，荟萃分析显示安慰剂组每人使用抗生素疗程的数量在统计学上显著增加80%（RR 1.81，95% CI 1.35至2.44；P < 0.001）。两组在住院率方面无显著差异（OR 0.96，95% CI 0.13至7.04；P = 0.97）。五项试验报告了不良事件，但不一定与疫苗有关；点估计表明不良事件在疫苗组中更频繁发生，然而该结果无统计学意义（RR 1.43，95% CI 0.70至2.92；P = 0.87）。未对生活质量进行荟萃分析，但两项试验报告了相关结果，六个月时的结果显示接种疫苗组的生活质量有所改善（得分比安慰剂组至少高两分）。
分析表明，对慢性支气管炎或COPD反复加重的患者进行NTHi口服疫苗接种，在减少加重的数量和严重程度方面并无显著效果。证据不一，且显示疫苗有显著益处的个别试验规模太小，无法主张对COPD患者广泛进行口服疫苗接种。
