Meta-analysis of Anti-TNF Therapies in Clinical Sepsis Trials

尽管采用传统的治疗方法，但感染导致败血症和感染性休克与高死亡率有关。脓毒症的发病率也在上升，这与几个因素有关。尽管20世纪90年代应用介体选择性抗炎药辅助治疗脓毒症的临床经验令人失望，但过度的宿主炎症仍被认为是脓毒症的重要致病机制。正在进行的和拟议的针对这一反应中的成分(例如皮质类固醇、厄立特里亚四钠、重组人活化蛋白C5)的脓毒症治疗的临床试验突出了这一点。其中一种药物是AZD9773(阿斯利康)，一种针对人肿瘤坏死因子(TNF)的多克隆抗体(ClinicalTrials.gov，识别码：NCT01145560和NCT01144624)。 业界对选择性肿瘤坏死因子抑制剂治疗脓毒症的持续兴趣可能是意想不到的。在20世纪90年代，当业界对脓毒症的介体选择性抗炎疗法的开发热情高涨时，抗肿瘤坏死因子药物是研究最多的。然而，尽管临床前发现前景看好，但在10多个随机对照试验(RCT)中，选择性肿瘤坏死因子抑制剂表现出的益处很小。然而，从整体上看，这种方法似乎确实有潜在的好处。然而，目前还没有对整个经验进行系统分析，目前包括15项试验。 鉴于抗炎药在脓毒症中应用的持续兴趣，以及针对肿瘤坏死因子的AZD9773正在进行的研究，有必要全面系统地回顾以往在脓毒症中应用抗肿瘤坏死因子药物的经验。本项目的目的是进行这样的分析，不仅检查这类药物对存活率的总体影响，而且检查其他结果，如逆转休克、预防器官损伤和潜在的不良影响。此外，还进行了系统的分析，以确定是否存在可识别的患者亚组，这些亚组更容易受到这种治疗的潜在益处的影响。 这一分析表明，在所检查的试验中，抗肿瘤坏死因子药物总体上表现出高度一致和显著的益处。然而，尽管在大多数研究中，抗肿瘤坏死因子治疗确实导致了肿瘤坏死因子水平的降低，但无法检测到其他变化，如休克或器官损伤的逆转，从而为这种对生存的有益影响提供基础。这项研究的结果已在2012年ATS国际会议上公布，并已出版了一份手稿。

Despite conventional therapy, infection causing sepsis and septic shock is associated with a high mortality rate. The incidence of sepsis is also rising related to several factors. Despite a disappointing clinical experience with mediator-selective anti-inflammatory agents as adjunctive treatments for sepsis during the 1990s, excessive host inflammation is still considered an important pathogenic mechanism underlying sepsis. This point is highlighted by ongoing and proposed clinical sepsis trials of therapies targeting components in this response (e.g. corticosteroids, Eritoran tetrasodium, recombinant human activated protein C5). One of these agents is AZD9773 (AstraZeneca), a polyclonal antibody directed against human tumor necrosis factor- (TNF) (ClinicalTrials.gov identifier: NCT01145560 and NCT01144624). Continued industry interest in selective TNF inhibitors for sepsis might be unexpected. During the 1990s when there was high industry enthusiasm for the development of mediator-selective anti-inflammatory therapies for sepsis, anti-TNF agents were the most studied. Despite promising preclinical findings however, selective TNF inhibitors showed little benefit in more than 10 randomized controlled trials (RCT). However, when examined overall, there does appear to be potential benefit with this approach. At this time however, a systematic analysis of this entire experience, which now includes 15 trials, has not been undertaken. In light of continued interest in the application of anti-inflammatory agents for sepsis and with the ongoing studies of AZD9773, which is directed specifically at TNF, it is relevant to systematically review the prior experience with anti-TNF agents in sepsis in its entirety. The purpose of the present project has been to do such an analysis, examining not only the overall effect of this type of agent on survival, but on other outcomes such as reversal of shock, prevention of organ injury and potential adverse effects. In addition, systematic analysis has been performed to determine whether there are identifiable patient subgroups, which are more amenable to the potential beneficial effects of this type of therapy. This analysis shows that overall anti-TNF agents showed highly consistent and significant benefit across the trials examined. However, while anti-TNF therapies did result in reductions in TNF levels in most studies in which this was examined, other changes such as reversal of shock or organ injury, could not be detected to provide a basis for this beneficial effect on survival. Findings from this study were presented at the 2012 ATS International Conference and a manuscript has been published.