Ciofu Oana, Smith Sherie, Lykkesfeldt Jens
Department of International Health, Immunology and Microbiology, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark, 2200.
Cochrane Database Syst Rev. 2019 Oct 3;10(10):CD007020. doi: 10.1002/14651858.CD007020.pub4.
Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review.
To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF.
The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019.
Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF.
Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE.
One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups.
AUTHORS' CONCLUSIONS: With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.
气道感染会导致囊性纤维化（CF）患者的肺部逐渐受损，氧化应激被认为与该病的病因有关。因此，补充抗氧化微量营养素（维生素E、维生素C、β-胡萝卜素和硒）或作为谷胱甘肽来源的N-乙酰半胱氨酸（NAC）可能有助于维持氧化还原平衡。谷胱甘肽或NAC也可以吸入，以这种方式给药除了具有抗氧化作用外，还可能具有黏液溶解作用。目前的文献表明氧化状态与肺功能之间存在关联。这是对先前发表的一篇综述的更新。
综合现有关于抗氧化剂（如维生素C、维生素E、β-胡萝卜素、硒和谷胱甘肽（或作为谷胱甘肽前体的NAC））通过CF患者的炎症和氧化应激标志物对肺功能影响的知识。
使用详细的检索策略检索Cochrane囊性纤维化和遗传疾病小组的囊性纤维化试验注册库以及PubMed。我们联系了纳入研究的作者，并检查了这些研究的参考文献列表以寻找其他可能相关的研究。我们还检索了在线试验注册库。囊性纤维化试验注册库的最后一次检索时间：2019年1月8日。
随机和半随机对照研究，比较上述抗氧化剂（单独或联合使用）单次以上给药与CF患者的安慰剂或标准治疗。
两位作者独立选择研究、提取数据并评估纳入研究的偏倚风险。我们联系研究调查人员以获取缺失信息。如果进行荟萃分析，研究将根据补充剂、给药方法和补充持续时间进行亚组分析。我们使用GRADE评估证据质量。
纳入了1项半随机和19项随机对照研究（924名儿童和成人）；16项研究（n = 639）分析了口服抗氧化剂补充剂，4项研究分析了吸入补充剂（n = 285）。纳入的20项研究中只有1项被判定无偏倚。
口服补充剂与对照
仅在将NAC与对照进行比较时报告了三个月和六个月时预测的一秒用力呼气量（FEV）%相对于基线的变化。四项研究（125名参与者）在三个月时报告；由于证据质量非常低，我们不确定NAC是否改善了预测的FEV%，平均差异（MD）为2.83%（95%置信区间（CI）为-2.16至7.83）。然而，在六个月时，两项研究（109名参与者）表明NAC可能增加了相对于基线预测的FEV%（中等质量证据），MD为4.38%（95%CI为0.89至7.87）。一项关于维生素和硒联合补充剂的研究（46名参与者）报告，对照组在两个月时预测的FEV%相对于基线的变化更大，MD为-4.30%（95%CI为-5.64至-2.96）。一项研究（61名参与者）发现，NAC在六个月时可能对生活质量（QoL）相对于基线的变化几乎没有影响（中等质量证据）归一化平均差异（SMD）为-0.03（95%CI为-0.53至0.47），但为期两个月的维生素和硒联合研究报告称，QoL对对照组有微小差异，SMD为-0.66（95%CI为-1.26至-0.07）。NAC研究报告了体重指数（BMI）相对于基线的变化（62名参与者），同样发现NAC在组间可能没有差异（中等质量证据）。一项研究（69名参与者）发现，混合维生素和矿物质补充剂在六个月时导致肺部恶化的风险可能略低于多种维生素补充剂（低质量证据）。九项研究（366名参与者）提供了不良事件信息，但未发现治疗组或对照组之间存在任何明确且一致的差异证据，证据质量从低到中等不等。关于β-胡萝卜素和维生素E的研究一致报告了各自抗氧化剂的血浆水平更高。
吸入补充剂与对照
两项研究（258名参与者）表明，吸入谷胱甘肽可能在三个月时改善预测中的FEV%，MD为3.50%（95%CI为1.38至5.62），但与安慰剂相比，六个月时没有改善，MD为2.30%（95%CI为-0.12至4.71）（中等质量证据）。相同的研究还报告，与安慰剂相比，治疗组在三个月和六个月时的FEV L均有所改善。一项研究（1）参与者）报告，吸入谷胱甘肽可能对QoL相对于基线的变化几乎没有影响，MD为0.80（95%CI为-1.63至3.23）（中等质量证据）。没有研究报告六个月时BMI相对于基线的变化，但一项研究（16名参与者）在两个月时报告，另一项研究（105名参与者）在12个月时报告；两项研究在两个时间点均未发现任何差异。一项研究（153名参与者）报告，六个月时首次肺部恶化的时间没有差异。两项研究（223名参与者）报告，治疗可能对不良事件几乎没有影响（低质量证据），另一项研究（153名参与者）报告，各组严重不良事件的数量相似。
关于微量营养素，抗氧化微量营养素似乎对临床终点没有积极的治疗效果；然而，口服补充谷胱甘肽对肺功能和营养状况显示出一些益处。根据现有证据，吸入和口服谷胱甘肽似乎可改善肺功能，而口服给药可降低氧化应激；然而，由于CF患者接受非常强化的抗生素治疗和其他同时进行的治疗，在没有非常大的人群样本和长期研究期的情况下，抗氧化剂的有益效果在慢性感染患者中仍然难以评估。在得出关于抗氧化剂补充效果的明确结论之前，有必要进行进一步的研究，特别是针对非常年幼的儿童，使用诸如肺清除指数和胸部扫描得出的支气管扩张评分等结局指标，更加关注研究设计变量（如剂量水平和时间），并阐明氧化应激参与CF的明确生物学途径。未来还应评估抗氧化剂对接受CFTR调节剂治疗的CF患者的益处。
