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Flowchart of the 631 entries in the STEC-HUS registry. 

Flowchart of the 631 entries in the STEC-HUS registry. 

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Background May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases.Methods To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exch...

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... May 22nd marks the beginning of a Shiga- toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 con fi rmed haemolytic – uraemic syndrome (HUS) cases. Methods. To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web- based registry of the DGfN (online since 27 May). Results. Of 631 entries, 491 ful fi lled the de fi nition of HUS (median age 46 years; 71% females). The median (inter- quartile range) hospital stay was 22 (14 – 31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strat- egy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9 – 1.3)] than in TPE [1.2 mg/dL (1.0 – 1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0 – 2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% ( n = 20) and did not differ signi fi cantly between the TPE and TPE-Ecu groups. Conclusions. Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short- term outcome was better than expected when compared with previous reports. Within the limitations of a retrospec- tive registry analysis, our data do not support the notion of a short-term bene fi t of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS. In early May 2011, an outbreak of haemorrhagic colitis associated with haemolytic – uraemic syndrome (HUS) fi rst developed in Hamburg but soon spread to Northern Germany and 15 other countries in Europe [1]. As of 27 July 2011, 2987 cases of Shiga-toxin-producing Escherichia coli (STEC) colitis (18 deaths) and 855 reported cases of HUS (35 deaths) had been reported to the Robert-Koch-Institute (RKI), Germany ’ s national centre for communicable disease prevention and control [2]. Sprouts were identi fi ed as the most likely outbreak vehicle [3]. The outbreak-strain O104:H4 combined virulence factors of typical enteroaggregative and Shiga-toxin-producing E. coli [4, 5], which may have contributed to the 24% occurrence rate of HUS, whereas in STEC-infected children, the HUS rate usually ranges between 2 and 16% [6, 7]. The increased virulence was also considered responsible for the high rate of seizures and coma leading to mechanical ventilation and intensive care unit treatment. The unexpected clinical severity prompted an urgent quest for therapeutic options and guidance; yet, evidence and recommendations for the treatment of STEC-HUS are based on case series and uncontrolled studies. Thus, the German Society of Nephrology (DGfN) published treatment suggestions on its homepage (www. dgfn.eu). These included best supportive care (BSC), the use of therapeutic plasma exchange (TPE) and the appli- cation of eculizumab (Ecu), a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, with reference to contraindications, dose and duration of Ecu treatment. In 1999, Dundas et al. [8] published a paper on 22 adult HUS patients urging to establish a national registry in the case of a large STEC-HUS outbreak. On 27 May 2011, 5 days after the outbreak had been of fi cially reported, the DGfN set up a web-based STEC-HUS registry, which was continuously updated in the following weeks [9]. Up to now, this registry presents the largest population of HUS patients and provides analysis of essential epidemiological and laboratory data, as well as clinical information from hospital admission to discharge. We compared the effectiveness of BSC, TPE and TPE combined with Ecu (TPE-Ecu) with regard to renal, neurological and survival outcome. To adjust imbalances in disease severity of treatment groups, statistical models using a propensity score-based method were applied. A total of 631 entries into the registry were made by a total of 84 centres. Out of these 631, 10 double entries, 58 patients lacking baseline parameter and 72 patients who did not ful fi l the RKI criteria for HUS were excluded (Figure 1). The 491 patients ful fi lling the HUS de fi nition were selected for further analysis. Four hundred ...

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... 43 In adults, the efficacy of eculizumab in STEC-HUS patients is not well established. 44 Eculizumab has also been evaluated in TMA in hematopoietic stem cell transplant patients (HSCT-TMA). Recent reports suggest that optimizing eculizumab doses improved one-year survival from 16.7% to 66% in patients affected by multiorgan injury, 45,46 indicating that better understanding of pharmacokinetics and pharmacodynamics may improve clinical outcomes. ...
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Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life‐threatening disease. Patients with TMA who do not exhibit a severe ADAMTS‐13 deficiency (defined as a disintegrin‐like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA‐13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA‐13n patients. We included 42 TMA‐13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9‐patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0–19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02–0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12–39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18–46.11). In conclusion, TMA‐13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor.
... C5 inhibition is ineffective in patients with DGKe variants or cyanocobalamin C deficiency in the absence of complement variants. There is also no proof that complement inhibition is beneficial in moderate or severe forms of Shiga toxin-producing Escherichia coliassociated (STEC)-HUS, 140 although some in vitro and ex/in vivo data document complement activated in STEC-HUS. Some case reports have claimed improvement of severe STEC-HUS after C5 blockade; however, it should be noted that STEC-HUS is a self-limiting condition in most cases. ...
... This may also explain the lack of benefit reported by Kielstein et al. and Loos et al. where eculizumab initiation was delayed with a mean of 11 days in the adult and a median of 22 days in the pediatric cohorts [11,12]. Three of five patient deaths reported in Table S2 be explained by elevated sC5b-9 levels, which have been described to occur with neurologic changes in severe multi-visceral TMA [8,14]. ...
Article
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The role of eculizumab in treating Shiga‐toxin‐producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC‐HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC‐HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC‐HUS.
... Recovery after PE has been demonstrated in some studies and case reports 32 , but extensive research has not been done to demonstrate the effectiveness of plasma-based therapy. 33,34 Eculizumab was administered to STEC-HUS patients with CNS involvement in the 2011 German epidemic; however, detailed analyses did not show a clear benefit. 17 Similarly, Ağbaş et al. 35 reported 21 STEC-HUS; no difference in kidney prognosis was found between patients treated with and without eculizumab. ...
Article
Classical clinical triad of hemolytic uremic syndrome (HUS) is microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell injury. Several situations, including infections, medications, malignancies, and transplantation can trigger endothelial damage. On the HUS spectrum, atypical hemolytic uremic syndrome (aHUS) deserves special attention in pediatric patients, as it can cause end-stage kidney disease and mortality. A dysfunction in the alternative complement pathway, either acquired or genetic, has been shown to be the main underlying cause. In the last decades, breathtaking advances have been made in understanding the pathophysiology of this rare disease, which has led to more efficient treatment. Recent studies have implicated genes in pathways beyond the alternative complement system, such as DGKE, TSEN2, and INF2 highlighting the importance of personalized management. Eculizumab has brought about dramatic improvements in the treatment of aHUS. Beyond eculizumab, there are many alternative therapeutics in the pipeline that target the complement system. Because of the rarity of aHUS, data from multiple patient registries are very important. The present report aimed to summarize the most important aspects of diagnosing and treating aHUS based on the Turkish national registry and the literature so as to improve clinical practice.
... The 2011 German outbreak of Shiga-toxin (ST) producing E. coli (STEC) associated HUS was caused by serotype 0104:H4 which shared the genetic elements with enterohemorrhagic and enteroaggregative E. coli (EAEC) [3]. EAEC comprises a variety of serotypes that possess enterotoxins, hemolysins, fimbriae, and outer membrane proteins involved in the adhesion process [4]. ...
... With regards to the usage of eculizumab in EAEC colitis, not much data is available. A retrospective registry analysis showed no beneficial effects of eculizumab as compared to plasmapheresis alone in the treatment of the 2011 German outbreak of EAEC HUS [3]. In contrast, the efficacy of eculizumab was demonstrated in 9 patients with STEC 0104:H4, 0-4 days after HUS diagnosis [25]. ...
Article
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Background. Hemolytic uremic syndrome (HUS) may present atypically without the full triad of classical HUS. Eculizumab has been shown to be efficacious in complement-mediated atypical HUS and some cases of Shiga-toxin (ST) associated HUS. We report the utility of eculizumab in enteroaggregative E. coli (EAEC) associated HUS. Case summary. A female toddler presented with hemolytic anemia, oliguric acute kidney injury (AKI) without thrombocytopenia, and peripheral schistocytes. The stool examination for ST was negative but positive for EAEC. She required several hemodialysis sessions and received one dosage of eculizumab with rapid reversal of AKI and hemolytic markers. A kidney biopsy revealed acute tubular injury and segmental glomerular basement membrane splitting. Genetic testing was negative for complement mutations or deficiencies. A follow-up six months later showed persistently normal renal function and hematological markers. Conclusion. The clinical and histological manifestations of non-ST-associated diarrheal HUS and the role of eculizumab in this condition warrant future larger studies.
... After screening based on title and abstract, 107 studies remained, of which 2 were not retrievable; therefore, 105 underwent full-text eligibility assessment. Fourteen met the inclusion criteria [22,[27][28][29][30][31][32][33][34][35][36][37][38][39]. One study was only reported as a conference abstract [39]. ...
... The timing of first eculizumab administration was variably described, either relative to symptom onset [34,36], time of diagnosis of HUS [29,32,33,37], or development of indication for eculizumab treatment [27,30,35], and was therefore not comparable across studies. In 4 studies, the median or average time from development of first symptoms or diagnosis of HUS to eculizumab administration was more than 10 days [33,34,36,37]. ...
... The timing of first eculizumab administration was variably described, either relative to symptom onset [34,36], time of diagnosis of HUS [29,32,33,37], or development of indication for eculizumab treatment [27,30,35], and was therefore not comparable across studies. In 4 studies, the median or average time from development of first symptoms or diagnosis of HUS to eculizumab administration was more than 10 days [33,34,36,37]. In 2 studies, eculizumab was administered within 24 h after developing an indication [27,30]. ...
Article
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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 .
... The O104:H4 outbreak provided an unprecedented basis for clinical investigation, and many patients were treated with complement blockade therapy. If the analysis of the German registry [59] did not support the use of eculizumab in adult STEC-HUS cases, early treatment was associated with rapid and efficient recovery in French patients [60] and children with central nervous system involvement. A concern with eculizumab treatment is the risk of infection with encapsulated bacterial organisms, particularly Neisseria meningitis, as a result of terminal complement blockade Therefore, patients must receive meningococcal vaccination before being treated with Eculizumab at least 1 week before treatment. ...
Article
Shiga toxin-producing Escherichia coli (STEC)-associated hemolytic uremic syndrome (STEC-HUS) is a clinical syndrome involving hemolytic anemia (with fragmented red blood cells), low levels of platelets in the blood (thrombocytopenia), and acute kidney injury (AKI). It is the major infectious cause of AKI in children. Severe forms can be associated with multiorgan involvement during the acute stage of the disease. Endothelial injury is the trigger event in the microangiopathic process. The host inflammatory response to toxin and E. coli lipopolysaccharide (LPS) is involved in disease pathophysiology. Early diagnosis and identification of underlying pathogenic mechanisms are of great significance for improving prognosis and reducing sequelae and mortality. Typical management of STEC-HUS patients relies on supportive care for electrolyte and water imbalance, anemia, hypertension, and renal failure. At present there is no specific therapy to ameliorate the prognosis. The Immediate outcome is most often favorable but long-term renal sequelae are frequent due to nephron loss. This review summarizes current knowledge regarding the epidemiological findings, the pathophysiological and clinical aspects, and its diagnosis and management.
... 13 Afterward, eculizumab has only been used in uncontrolled studies, mostly during the 2011 German outbreak, with conflicting results. 14 In 2018, Percheron et al. retrospectively studied the impact of eculizumab treatment in 33 children with severe STEC-HUS. In patients with favorable outcome, there was a trend toward more sustained complement blockade. ...
Article
Background: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring renal replacement therapy (RRT). Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority. Methods: We conducted a phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. Primary endpoint was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement. Results: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the 2 groups (48% in the placebo versus 38% in the eculizumab group; P=0.31) or in the course of acute renal failure. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P=0.04). No safety concern was reported. Conclusions: In pediatric STEC-HUS patients, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae.
... However, analysis of the German STEC-HUS registry did not show a benefit of eculizumab in adults. 179 Although one report did suggest benefit in three children with neurological involvement, 180 the overall evidence of efficacy and safety of eculizumab in STEC-HUS is unclear. 181 ...
Article
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Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.
... Plasma samples of patients with STEC-HUS (n = 27, median age 47, 24 female) were provided by the German STEC-HUS Registry (42). These samples were taken within 10 d after admission to the hospital (HUS acute stage) and at the day of the last plasmapheresis (HUS pre-discharge). ...
Article
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Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.