Background

Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS.

Methods

PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively.

Results

A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations.

Discussion

Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients.

Systematic review registration number

OSF Registries, MSZY4, Registration DOI https://doi.org/10.17605/OSF.IO/MSZY4.

中文翻译：

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依库珠单抗在产志贺毒素大肠杆菌溶血性尿毒症综合征中的应用：系统评价

背景

感染相关溶血性尿毒症综合征（IA-HUS）最常见是由于产生志贺毒素的细菌感染，主要影响幼儿。它可能严重危及生命，并导致长期的肾脏和神经系统疾病。缺乏已证实有效的特异性治疗方法。由于补体旁路途径的激活发生在 HUS 中，因此一旦发生癫痫等并发症，单克隆 C5 抗体依库丽单抗通常会在标签外使用。依库珠单抗价格昂贵且存在感染风险。其在 IA-HUS 中的效用尚未得到系统研究。本系统评价旨在呈现、总结和评估有关依库丽单抗给药对 IA-HUS 中长期结局（即急性期后具有永久性特征的结局）影响的所有现有数据。

方法

系统地检索了 PubMed、Embase 和 Web of Science，寻找报告依库丽单抗对 IA-HUS 中长期结果影响的研究。最终检索于 2022 年 3 月 2 日进行。研究提供了至少 5 名 IA-HUS 患者的中长期结果的原始数据，这些患者在急性疾病期间接受了至少一剂依库丽单抗治疗。对于患者群体没有其他限制。如果数据与其他研究有很大重叠，或者 IA-HUS 患者的结果没有单独报告，则研究被排除。研究质量使用 ROBINS-I 工具评估非随机干预研究中的偏倚风险。对数据进行描述性分析。

结果

总共确定了 2944 项研究。其中，14 项研究（包括 386 名接受依库珠单抗治疗的患者）符合纳入标准。所有研究都是观察性的。产志贺毒素大肠杆菌(STEC) 被确定为 386 名患者中的 381 名 (98.7%) 的传染源，这有效地限制了对 STEC-HUS 患者数据的解释。跨研究的数据汇集是不可能的。没有研究报告依库丽单抗对任何中长期结果具有统计学上显着的积极作用。然而，大多数研究由于混杂因素而存在严重的偏倚风险，因为更多的重症患者接受了依库珠单抗治疗。三项研究试图通过患者匹配来控制混杂因素，尽管由于匹配限制仍然存在残余偏倚。

讨论

鉴于严重的偏倚风险，目前的观察证据不允许就依库丽单抗对 IA-HUS 的影响得出任何结论。人们迫切等待随机临床试验的结果，因为迫切需要新的治疗策略来预防这些重症患者的长期发病。

系统评审注册号

OSF 注册机构，MSZY4，注册 DOI https://doi.org/10.17605/OSF.IO/MSZY4。