肠出血性大肠杆菌发病机制解读---HUS

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Complement Blockade Severe Shiga-Toxin–Associated HUS
The hemolytic–uremic syndrome (HUS), a thrombotic microangiopathy（血栓形成性微血管病）, most commonly occurs secondary to infection with Shiga-toxin–producing Escherichia coli (STEC-HUS), although rare, atypical（非典型） forms are associated with abnormalities in complement-regulating proteins（补体调节蛋白）. The inhibition of terminal complement complex formation by the monoclonal C5 antibody（单克隆C5抗体） eculizumab has recently been reported as a treatment for atypical HUS.1

We report on three 3-year-old patients with severe STEC-HUS that required hemodialysis（血液透析）. In Patient 1, plasma exchanges were performed because of low C3 and elevated C3d serum concentrations, which suggested complement activation. Plasma exchange（血浆交换） was also performed in Patient 2 because of severe central nervous system involvement, a rare complication that often leads to death or permanent neurologic damage.2 Progressive involvement of the central nervous system developed in both patients despite 5 consecutive days of plasma exchange.

Given the devastating prognosis, we administered eculizumab to these two patients, as well as to a third patient with a similar disease course, at 7-day intervals, twice in Patients 1 and 3 and four times in Patient 2. The neurologic status in all three patients improved dramatically within 24 hours after the first eculizumab infusion. Clinical improvement was associated with rapid normalization of markers of disease activity: platelet counts（血小板计数） normalized, and lactate dehydrogenase （乳酸脱氢酶）levels decreased within 5 days in all patients 。

Dialysis （透析）was discontinued after 3 days in Patient 1, after 16 days in Patient 2, and after 13 days in Patient 3, and the patients were discharged with apparently normal neurologic status 9, 35, and 20 days, respectively, after the administration of the first dose of eculizumab. Renal function fully recovered, with mild residual proteinuria （残余蛋白尿）and hypertension in Patients 1 and 3. All patients have remained in full remission for the past 6 months. Screening for mutations in the genes encoding complement regulatory proteins (CFH, CFI, MCP, C3, CFB, and THBD) and testing for anti-CFH antibodies were negative in all patients.

In the cases reported here, spontaneous recovery seemed unlikely, given the rapidly progressive course of the disease. The rapid clinical response to eculizumab in all three children supports the concept that Shiga toxin may activate complement directly,3 providing a rationale for therapeutic complement blockade in STEC-HUS with severe complications. Complement hyperactivation was recently demonstrated in STEC-HUS,4 and a mutation in the complement-regulating gene MCP was reported in a fatal case of STEC-HUS.5 The dramatic resolution of symptoms after eculizumab administration in the cases reported here suggests that STEC-HUS is an area deserving further careful investigation of the risk–benefit ratio of therapeutic complement blockade in this toxin-mediated vasculopathy.

1、其发病机制：————目前认为主要是在某些致病因素(如细菌、病毒等)的作用下，通过各种途径导致毛细血管内皮细胞损伤，血小板激活，在受损部位的内皮细胞表面黏附聚集，同时纤维蛋白在损伤部位沉积，形成微血栓，阻塞微血管，继发红细胞和血小板机械性损害，红细胞碎裂溶血，出现微血管病性溶血性贫血和血小板减少。

结合文章认为可能跟大肠杆菌的毒素激活补体途径导致毛细血管内皮细胞损伤有关，所以这篇文章介绍可以采用Complement Blockade 治疗HUS。

2、O104:H4血清型，Husec41亚型/变种，网上的报道是这么写的，其实是同一个东西。

3、关于抗生素为何没有用反而加重，b]其一是：该细菌有较强的抗药性；其二是：不是这种细菌直接致病，而是通过细菌产生的毒素致病，类似于以前的霍乱。服用抗生素只是缩短了病程，而对细菌产生的毒素，抗生素没有作用。目前还没有特效的治疗方法，大部分病人能自限。血浆置换（俗称：洗血疗法）有一定效果。不知各位大侠怎么看？

4、进一步解读新英格兰医学杂志上这篇文章所提到Eculizumab的机制：

Eculizumab，即人源型抗C5单克隆抗体，是一种用于治疗肾衰竭的特殊药物，这种抑制末端补体成分活化的重组人源型单克隆抗体能特异性地键合到人末端补体蛋白C5，通过抑制人补体C5向C5a和C5b的裂解以阻断炎症因子C5a的释放及C5b-9的形成。临床前研究表明该抗体对c5有高度亲和力，能阻断C5a和C5b-9的形成，并保护哺乳动物细胞不受C5b-9介导的损伤。这一抗体之前曾有报道能用于安全地治疗阵发性睡眠性血红蛋白尿症（PNH，引起溶血，因此需要输血）。

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