Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Outcome of children with Shiga toxin–associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study

Outcome of children with Shiga toxin–associated haemolytic uraemic syndrome treated with... Abstract Background Treatment with eculizumab in Shiga toxin–associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study. Methods Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme. Results Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS. Conclusion The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication. children, eculizumab, haemolytic uraemic syndrome, outcome INTRODUCTION Haemolytic and uraemic syndrome (HUS) is a thrombotic microangiopathy syndrome defined by the triad of haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the typical form, HUS is preceded by bloody diarrhoea induced by a Shiga toxin (STX)-producing Escherichia coli (STEC) and transmitted by contaminated food. The acute phase of STEC-HUS is severe, with a mortality rate of 1–5% and 20% presenting neurological involvement [2]. Moreover, at least 40% of affected children require acute dialysis [2]. There is currently no specific treatment for STEC-HUS, and even if almost all patients recover from the acute episode with supportive treatment only, they can develop long-term sequelae such as chronic kidney disease (CKD), proteinuria and hypertension [3–5]. Typical or STEC-HUS must be differentiated from atypical HUS, induced by gene mutations of complement regulatory proteins or anti-factor H autoantibodies, leading to dysregulation of the complement alternative pathway, and from cobalamin C deficiency–related HUS and various causes of secondary HUS [1]. In 2011, eculizumab, a monoclonal humanized anti-C5 antibody, was approved for the treatment of atypical HUS [6], showing that an effective terminal complement blockade can improve renal function, reduce the duration of thrombocytopenia and prevent progression to end-stage renal disease [7]. A hyperactivation of complement by Shiga toxin has been shown in STEC-HUS [8–11], suggesting that eculizumab may be helpful in STEC-HUS. In 2011, Lapeyraque et al. [12] reported the use of eculizumab in three paediatric cases of severe STEC-HUS with neurological symptoms resistant to every supportive treatment and plasmapheresis that was tried. During the German STEC-HUS outbreak due to E. coli O104:H4 in 2011, 328 patients among the 845 HUS cases were treated with eculizumab (with or without plasmapheresis), including 13 of 90 contaminated children. In the following reports, short and intermediate outcomes of patients treated with eculizumab did not differ from those treated with supportive treatment, suggesting a potential lack of efficacy of this therapy [13–16]. Conversely, during a French outbreak in the same year, all nine STEC-HUS patients (including one child) treated with eculizumab (regardless of the initial severity) showed a favourable outcome without serious renal or extrarenal sequelae at 10 weeks [17]. The efficacy of eculizumab in STEC-HUS still remains largely unknown [18]. These controversial data and the limited evidence about eculizumab in STEC-HUS led us to evaluate the short- and intermediate-term outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study. MATERIALS AND METHODS Study design The study consisted of a retrospective chart review of all children <15 years of age with a diagnosis of STEC-HUS, hospitalized in Bordeaux Children’s University Hospital, who received treatment with eculizumab between 2011 and 2017. A historical group of untreated patients diagnosed between 1995 and 2015, matched for age, sex and severity of renal impairment (presence of anuric acute kidney injury) at disease onset, served as controls with a 1:2 matching scheme. A computer-generated matching of controls to cases was performed using an SAS macro (SAS Institute, Cary, NC, USA). Patients were identified through the hospital discharge data system and from the French Institute for Public Health Surveillance (Santé Publique France), which has collected all cases of HUS in France since 1996. Case definition STEC-HUS cases were defined by prodromal diarrhoea; the triad of acute haemolytic anaemia (haemoglobin level <10 g/dL) with evidence of red cell fragmentation (schistocytes >1%), thrombocytopenia (platelet count <150 × 109/L) and acute kidney injury, including proteinuria and/or renal failure (serum creatinine level >60 µmol/L if age <2 years or >70 µmol/L if age >2 years); and exclusion of atypical HUS, secondary HUS and post-infectious HUS without diarrhoea. Patients participating in ongoing clinical trials were not included in this study. Renal injury was defined by the presence of hypertension requiring an antihypertensive medication or abnormal proteinuria (proteinuria >0.15 g/L or urinary protein:creatinine ratio >20 mg/mmol in children >2 years or albuminuria >30 mg/L) or CKD Stage 2 or higher with an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 using the bedside Schwartz formula [19, 20]. Extrarenal sequelae were defined by any clinical or biological symptom that appeared after HUS onset and required specific follow-up or treatment. Data collection All data were collected from computerized medical records and included demographic and anthropometric data, clinical features, treatment and outcomes. Short-term outcome was compared between the eculizumab and control groups based on the evolution of creatinine, haemoglobin and platelets in the acute phase until 1 month after HUS onset. Intermediate-term outcome was evaluated by the presence of renal injury (decreased eGFR, abnormal proteinuria and high blood pressure) and extrarenal sequelae at 1 month, 12 months and the last follow-up. A subgroup analysis was carried out among patients with a follow-up <6 years. Eculizumab administration Eculizumab (Soliris, Alexion Pharmaceuticals, Boston, MA, USA) is a recombinant monoclonal humanized antibody targeting the complement component protein C5. According to the French Agency for the Safety of Health Products recommendations of 2011, eculizumab was administrated in STEC-HUS patients with severe neurological involvement (seizure, focal neurological deficit, coma or psychiatric disorder). In 2012, a modified local protocol expanded the use of eculizumab to STEC-HUS with neurological involvement, cardiac injury (elevated troponin, electrocardiogram or echocardiographic abnormalities), pulmonary oedema, severe pancreatitis (lipase >3 times the upper limit of normal) and severe enterocolitis associated with persistent renal failure despite 4 days of renal replacement therapy. All patients received an anti-meningococcal vaccination prior to the first injection of eculizumab (for protection against serogroups A, C, Y W, then against serogroup B since 2013). As per local protocol, and since azithromycin is believed to have an inhibitory effect on STX release, antibiotic prophylaxis consisted of azithromycin during 5 days followed by oracillin until 14 days after the last eculizumab injection. Complement activation monitoring Inhibition of the terminal complement complex was evaluated through an immunoenzymatic dosage of functional complement activity (in UCAE/mL) using an enzyme-linked immunosorbent assay kit (CAE DiaSorin kit, stillwater). The blockade of complement activity was considered as complete when the complement activity was <1 UCAE/mL (normal range 63–145 ) [21]. Complement activity was measured prior to every eculizumab injection to obtain residual functional activity and at Days 1–3 after every injection. Statistical and ethical aspects Quantitative data are presented as medians and interquartile ranges (IQRs) and qualitative data are expressed as percentages. The Kruskal–Wallis test and chi-squared test were used for comparisons of medians and proportions. Statistical analyses were performed using SAS software version 9.3 (SAS Institute). Patients and families were fully and clearly informed about off-label use of eculizumab and gave their consent to receive the drug. The study was approved by the South West France Research Ethics Committee. RESULTS Clinical and biological features Between 2011 and 2017, 18 children with STEC-HUS were treated with eculizumab in the Bordeaux University Hospital. Thirty-six patients diagnosed with HUS in the period 1995–2015 were included in the control group. The clinical findings and laboratory data of the study population are summarized in Table 1. Table 1 Clinical features and laboratory data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 a Lowest or highest value according to the parameter. View Large Table 1 Clinical features and laboratory data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 a Lowest or highest value according to the parameter. View Large The two groups were similar with respect to age, sex, anuric acute kidney injury, blood pressure and presence of extrarenal complications. However, neurological, cardiac and gastrointestinal complications were more frequently observed in the eculizumab group (statistically significant for neurological complications). At HUS onset, laboratory data were similar in the two groups. STEC confirmation was possible in 16 (89%) patients treated with eculizumab and in only 20 (56%) controls. Therapeutic management The two groups had statistically comparable transfusion rates, need for and duration of renal replacement therapy, length of hospitalization and length of paediatric intensive care unit stay (Table 2). The only difference was the use of antibiotic therapy (100% in the eculizumab group and 44% in controls; P = 0.01), which is explained by systematic antibiotic prophylaxis for patients receiving eculizumab. Table 2 Therapeutic data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 View Large Table 2 Therapeutic data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 View Large Indication for eculizumab treatment Criteria for eculizumab treatment were most frequently severe acute neurological involvement in 10 patients, with cardiac involvement in 4 of them. Five patients were treated several days after HUS onset because of increasing haemolysis requiring transfusions and the need for renal replacement therapy associated with severe pancolitis (including one rectal prolapse) or multiple organ involvement. Two patients received eculizumab treatment because of severe acute pancreatitis. Finally, one patient did not exhibit severe symptoms of HUS but was treated early in the course of the disease in the context of a STEC-HUS O104:H4 outbreak due to fenugreek sprouts in the Bordeaux area in 2011 [17]. Mechanical ventilation was required in three patients treated with eculizumab. Eculizumab administration and complement activity monitoring Patients received a median number of three eculizumab injections (range 2–5); five patients received two doses, seven patients received three doses and six patients received five doses (Supplementary data, Figure S1). The first, second and third eculizumab injections were given after a median time of 3 days (range 0–8), 11 days (range 5–20) and 20 days (range 12–37) after the diagnosis of HUS, respectively (Supplementary data, Figure S1). Blockade of complement activity (<1 UCAE/mL) was obtained after the first eculizumab injection in 10 of 18 patients (55%). Three patients received an additional injection between Days 3 and 8. Nine of 16 patients (56%) showed complete blockade of complement activity after the second injection and 6 of 10 (60%) after the third injection. The timing of complement activity monitoring and the values of CAE before and after eculizumab injections are shown in Figure 1. FIGURE 1 View largeDownload slide Complement activity kinetics during the first 3 weeks of treatment. Bars represent median and IQR. D: day; ECZ: eculizumab. FIGURE 1 View largeDownload slide Complement activity kinetics during the first 3 weeks of treatment. Bars represent median and IQR. D: day; ECZ: eculizumab. Comparison of outcomes between patients treated with eculizumab and controls There was no statistically significant difference between groups for haemoglobin level and platelet count kinetics over 1 month after HUS onset (Supplementary data, Figures S2 and S3). The increase in platelet count between Days 1 and 8 appeared more quickly in the eculizumab group than in controls, but this did not reach statistical significance. Similarly, the duration of initial renal replacement therapy (Table 2) and evolution of serum creatinine over 1 year (Figure 2) did not differ significantly between the eculizumab and control groups. FIGURE 2 View largeDownload slide Comparative changes of serum creatinine between patients treated with eculizumab (n = 18) and controls (n = 36). Bars are median and IQR. D: day; M: month; NS: non-significant. FIGURE 2 View largeDownload slide Comparative changes of serum creatinine between patients treated with eculizumab (n = 18) and controls (n = 36). Bars are median and IQR. D: day; M: month; NS: non-significant. At 1 and 12 months of follow-up there was no statistically significant difference between the two groups regarding the proportion of high blood pressure, proteinuria and decreased eGFR (Figure 3). Overall, the median follow-up after HUS onset was 2.5 years in treated patients and 5.0 years in controls. At the last follow-up, the prevalence of decreased eGFR was not statistically lower in the eculizumab group [5/18 (27%)] than in controls [14/36 (38%)] and the prevalence of proteinuria was not statistically lower in the eculizumab group [3/18 (17%)] than in controls [10/36 (27%)] (Figure 3). The prevalence of high blood pressure requiring treatment was 17% in the eculizumab group and 11% in controls. FIGURE 3 View largeDownload slide Proportion of patients with renal impairment over follow-up in children treated with eculizumab (n = 18) and in controls (n = 36). Low eGFR is defined as a GFR <90 mL/min/1.73 m2. Proteinuria is defined as a urine protein:creatinine ratio >20 mg/mmol or urinary protein >0.15 g/L. High blood pressure (BP) is defined as the need for a antihypertensive treatment. FIGURE 3 View largeDownload slide Proportion of patients with renal impairment over follow-up in children treated with eculizumab (n = 18) and in controls (n = 36). Low eGFR is defined as a GFR <90 mL/min/1.73 m2. Proteinuria is defined as a urine protein:creatinine ratio >20 mg/mmol or urinary protein >0.15 g/L. High blood pressure (BP) is defined as the need for a antihypertensive treatment. To make the two groups more comparable, we performed a subgroup analysis excluding the patients with the longest follow-up. After excluding those with a follow-up >6 years, the median follow-up duration was comparable between the two groups: 2.3 years (IQR 0.9–4.1) in the eculizumab group (n = 17) versus 3.6 years (IQR 1.6–5.1) in controls (n = 23). The prevalence of decreased eGFR, proteinuria and hypertension was again similar in the two groups. eGFR at the last follow-up was comparable between patients treated with eculizumab [median 108 mL/min/1.73 m2 (IQR 83–124)] and controls [median 110 mL/min/1.73 m2 (IQR 90–122)], as was urine protein:creatinine ratio [15 mg/mmol (IQR 13–20) versus 14 mg/mmol (IQR 10–27)]. Extrarenal outcome All patients survived in the two groups. Five patients from the eculizumab group (27%) and two from the control group (5%) had extrarenal sequelae after >1 year of follow-up (P = 0.02). Two patients treated with eculizumab presented psychomotor delay with language and walking acquisition delay, two had strabismus and one showed moderate motor impairment. Four of these patients had neurological involvement in the acute phase. Among patients with extrarenal sequelae from the control group, one presented pancreatic pseudocysts and the other had psychomotor delay and attention deficit disorder. Four of 10 patients with neurological involvement treated with eculizumab (40%) and 1 of 9 untreated patients (11%) kept long-term neurological sequelae. Safety No serious adverse events related to the drug have been reported among patients treated with eculizumab; in particular, no invasive meningococcal disease or other severe infection. Moderate late-onset alopecia occurred in two children (at 1 and 2 months after the last injection of eculizumab) and resolved without sequelae. DISCUSSION In this single-centre matched cohort study, we found no statistically significant difference at the acute phase of STEC-HUS for the recovery of serum creatinine, platelet count and haemoglobin level within 1 month between 18 patients treated with eculizumab and 36 untreated controls. In addition, intermediate-term renal outcome at 1 year and at 2–5 years of follow-up was comparable between the two groups. The proportion of extrarenal sequelae was higher among patients treated with eculizumab than in controls, likely reflecting the more severe neurological presentation in the eculizumab group at HUS onset. No deaths occurred. Finally, eculizumab was well tolerated, with only two transient moderate adverse drug events. Our findings suggest either a modest effect or a lack of efficacy of eculizumab in STEC-HUS. Reports by Loos et al. [15, 16] about the follow-up of children with STEC-HUS during the German outbreak of 2011 indicated that the 13 cases of HUS with neurological involvement treated with eculizumab (combined with plasmapheresis for 7 of them) have the same outcomes as those treated with supportive treatment only. Conclusions yielded by the study of Kielstein et al. [13] were similar in adult patients from the German STEC-HUS registry following the 2011 O104:H4 outbreak. In the study of Menne et al. [14], 67 adults treated with eculizumab were compared retrospectively with untreated controls with similar disease severity and hospitalized in another centre where eculizumab was unavailable. No significant difference was noted for platelet recovery and levels of lactate dehydrogenase, creatinine or haemoglobin, and the complications rate HUS was also similar between groups. Conversely, in the smaller French O104:H4 outbreak in Bordeaux during the same year, all nine individuals who developed STEC-HUS received eculizumab and recovered with rapid haematological improvement and without severe neurological or renal sequelae [17]. Differences between these studies conclusions may be explained by disparities in sample size and the fact that during the German outbreak, eculizumab was only used to treat the most severely affected patients, contrary to the French outbreak, and was often combined with plasma exchanges, which interferes with eculizumab pharmacokinetics. In a recently published review of the current evidence on eculizumab efficacy in STEC-HUS [18], it is suggested that the delay between HUS diagnosis and eculizumab administration may play a role in patient recovery. During the German HUS outbreak, adult patients received a first dose of eculizumab an average of 10 days after diagnosis [13] and children after a median of 22 days [15], as compared with a median of 1 day in the French outbreak [17]. In the initial case series from Lapeyraque et al. [12], eculizumab was given between 5 and 8 days after STEC-HUS diagnosis. In our study, the interval between STEC-HUS diagnosis and first eculizumab injection was 3 days, with complete complement activity blockade in a majority of cases and a few patients who required an additional injection between Days 3 and 8. All patients from our cohort survived, none showed severe disability, but 13% experienced mild to moderate neurological sequelae during follow-up. In our cohort study, a neurological complication occurred at HUS onset in 25% of patients from the control group, which is in line with the published literature [2], and in 55% of children treated with eculizumab. It has been suggested that eculizumab might improve neurological outcome [22]. In our study, among the 10 patients treated with eculizumab with neurological involvement at onset, 4 had residual neurological changes at the last follow-up. In the acute phase of HUS, two of them needed mechanical ventilation because of repeated seizures and coma. Magnetic resonance imaging (MRI) was abnormal in both cases and an electroencephalogram showed encephalopathy patterns. Improvement of both patients occurred 2–4 days after the first eculizumab injection. The MRI and electroencephalogram normalized during the year after HUS. Our results are somewhat consistent with the single-centre report by Pape et al. [22] where all 11 patients with severe neurological involvement were treated with eculizumab, of whom 1 (9%) died, 2 (18%) had mild or severe neurological sequelae and 8 (72%) had minor or no sequelae. These findings and ours raise the question of the efficacy of eculizumab in patients with neurological involvement. In an uncontrolled cohort of 33 children treated with eculizumab for severe STEC-HUS, including 28 with neurological symptoms, 19 (70%) had a complete neurological recovery, with 17 showing clinical improvement within days following the first eculizumab injection [23]. A review of eculizumab use in STEC-HUS [18] retrieved outcome data from a total of 31 children, including 29 (94%) with neurological involvement [12, 15, 17, 22, 24–26]. Complete recovery or minor sequelae was observed in 24 children (83%), a proportion significantly higher than the recovery rate (58%) reported in a previous French study of 52 children with STEC-HUS and neurological impairment [27]. Contrary to our findings, smaller reports describe dramatic improvement in the outcome of patients with severe neurological involvement treated with eculizumab, including Lapeyraque et al. (three out of three recovered) [12], Ekinci et al. (two out of two recovered) [26] or recently Giordano et al. (four out of five recovered) [28]. We found no statistically significant difference in renal outcome (prevalence of low eGFR, proteinuria or high blood pressure) between the two groups at an intermediate follow-up. When restricting the analysis to patients with a follow-up <6 years, allowing a more comparable follow-up between the two groups, we found similar GFRs and urine protein:creatinine ratios in patients treated with eculizumab and in controls. Our findings are consistent with the 3-year outcomes of 11 out of 13 children treated with eculizumab during the German outbreak [16]. Our study has several limitations, including the retrospective design of the study, missing data and variations over time in eculizumab indications and administration modalities. To limit these weaknesses, we constructed a control group well matched for age, sex and severity of acute kidney injury. However, a selection bias likely persisted with more severe disease among controls, especially regarding neurological complications. Moreover, in order to limit the bias by indication, we selected most patients of the control group [n = 25 (70%)] from the population of paediatric STEC-HUS patients diagnosed before eculizumab use in France (2011). As a consequence, the median follow-up of patients treated with eculizumab is shorter than in the controls (2.5 versus 5 years), inducing another possible bias for the interpretation of long-term outcome data. However, subgroup analysis restricted to patients followed for <6 years led to a comparable follow-up duration between groups and yielded similar results. In conclusion, eculizumab treatment does not seem to improve short- or intermediate-term renal outcome after STEC-HUS in children despite the methodological limitations of this study. However, whether eculizumab has a potential interest for extrarenal outcome remains unknown. Eculizumab appears to be safe in severe forms of STEC-HUS. Investigating eculizumab as a prophylactic therapy before the development of neurological or other severe symptoms associated with STEC-HUS is one of the goals of ongoing randomized placebo-controlled trials [29]. Results of these trials will provide some evidence about eculizumab treatment to improve clinical care of children with STEC-HUS [30]. AUTHORS’ CONTRIBUTIONS C.M.D. and A.C. drafted the manuscript. C.M.D., A.G.D., L.A., C.C.B., Y.D., O.B. and B.L. followed the patients and collected and analysed the data. J.H. designed the study, interpreted data and drafted the manuscript. All authors participated in critically reviewing the article for important intellectual content and approved the final version of the manuscript. CONFLICT OF INTEREST STATEMENT Y.D. has received lecture fees from Alexion Pharmaceuticals. J.H. has received consultancy fees from Alexion Pharmaceuticals. All other authors have no competing interests to declare. REFERENCES 1 Fakhouri F , Zuber J , Frémeaux-Bacchi V et al. . Haemolytic uraemic syndrome . Lancet 2017 ; 390 : 681 – 696 Google Scholar Crossref Search ADS PubMed WorldCat 2 Trachtman H , Austin C , Lewinski M et al. . Renal and neurological involvement in typical Shiga toxin-associated HUS . Nat Rev Nephrol 2012 ; 8 : 658 – 669 Google Scholar Crossref Search ADS PubMed WorldCat 3 Spinale JM , Ruebner RL , Copelovitch L et al. . Long-term outcomes of Shiga toxin hemolytic uremic syndrome . Pediatr Nephrol 2013 ; 28 : 2097 – 2105 Google Scholar Crossref Search ADS PubMed WorldCat 4 Rosales A , Hofer J , Zimmerhackl LB et al. . Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late emerging sequelae . Clin Infect Dis 2012 ; 54 : 1413 – 1421 Google Scholar Crossref Search ADS PubMed WorldCat 5 Monet-Didailler C , Godron-Dubrasquet A , Madden I et al. . Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort . Pediatr Nephrol 2019 ; 34 : 657 – 662 Google Scholar Crossref Search ADS PubMed WorldCat 6 Loirat C , Fakhouri F , Ariceta G et al. . An international consensus approach to the management of atypical hemolytic uremic syndrome in children . Pediatr Nephrol 2016 ; 31 : 15 – 39 Google Scholar Crossref Search ADS PubMed WorldCat 7 Legendre CM , Licht C , Muus P et al. . Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome . N Engl J Med 2013 ; 368 : 2169 – 2181 Google Scholar Crossref Search ADS PubMed WorldCat 8 Orth D , Khan AB , Naim A et al. . Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome . J Immunol 2009 ; 182 : 6394 – 6400 Google Scholar Crossref Search ADS PubMed WorldCat 9 Morigi M , Galbusera M , Gastoldi S et al. . Alternative pathway activation of complement by Shigatoxin promotes exuberant C3a formation that triggers microvascular thrombosis . J Immunol 2011 ; 187 : 172 – 180 Google Scholar Crossref Search ADS PubMed WorldCat 10 Noris M , Mescia F , Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation . Nat Rev Nephrol 2012 ; 8 : 622 – 633 Google Scholar Crossref Search ADS PubMed WorldCat 11 Karpman D , Tati R. Complement contributes to the pathogenesis of Shigatoxin-associated hemolytic uremic syndrome . Kidney Int 2016 ; 90 : 726 – 729 Google Scholar Crossref Search ADS PubMed WorldCat 12 Lapeyraque AL , Malina M , Fremeaux-Bacchi V et al. . Eculizumab in severe Shiga-toxin-associated HUS . N Engl J Med 2011 ; 364 : 2561 – 2563 Google Scholar Crossref Search ADS PubMed WorldCat 13 Kielstein JT , Beutel G , Fleig S et al. . Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry . Nephrol Dial Transplant 2012 ; 27 : 3807 – 3815 Google Scholar Crossref Search ADS PubMed WorldCat 14 Menne J , Nitschke M , Stingele R et al. . Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study . BMJ 2012 ; 345 : e4565 Google Scholar Crossref Search ADS PubMed WorldCat 15 Loos S , Ahlenstiel T , Kranz B et al. . An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children . Clin Infect Dis 2012 ; 55 : 753 – 759 Google Scholar Crossref Search ADS PubMed WorldCat 16 Loos S , Aulbert W , Hoppe B et al. . Intermediate follow-up of pediatric patients with hemolytic uremic syndrome during the 2011outbreak caused by E. coli O104:H4 . Clin Infect Dis 2017 ; 64 : 1637 – 1643 Google Scholar Crossref Search ADS PubMed WorldCat 17 Delmas Y , Vendrely B , Clouzeau B et al. . Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab . Nephrol Dial Transplant 2014 ; 29 : 565 – 572 Google Scholar Crossref Search ADS PubMed WorldCat 18 Keenswijk W , Raes A , Johan Vande Walle J. Is eculizumab efficacious in Shigatoxin-associated hemolytic uremic syndrome? A narrative review of current evidence . Eur J Pediatr 2018 ; 177 : 311 – 318 Google Scholar Crossref Search ADS PubMed WorldCat 19 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification . Am J Kidney 2002 ; 39 ( 2 Suppl 1 ): S1 – S266 WorldCat 20 Schwartz GJ , Muñoz A , Schneider MF et al. . New equations to estimate GFR in children with CKD . J Am Soc Nephrol 2009 ; 20 : 629 – 637 Google Scholar Crossref Search ADS PubMed WorldCat 21 Gatault P , Brachet G , Ternant D et al. . Therapeutic drug monitoring of eculizumab: rationale for an individualized dosing schedule . MAbs 2015 ; 7 : 1205 – 1211 Google Scholar Crossref Search ADS PubMed WorldCat 22 Pape L , Hartmann H , Bange FC et al. . Eculizumab in typical hemolytic uremic syndrome (HUS) with neurological involvement . Medicine (Baltimore) 2015 ; 94 : e1000 Google Scholar Crossref Search ADS PubMed WorldCat 23 Percheron L , Gramada R , Tellier S et al. . Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study . Pediatr Nephrol 2018 ; 33 : 1385 – 1394 Google Scholar Crossref Search ADS PubMed WorldCat 24 Saini A , Emke AR , Silva MC et al. . Response to eculizumab in Escherichia coli O157:H7-induced hemolytic uremic syndrome with severe neurological manifestations . Clin Pediatr (Phila) 2015 ; 54 : 387 – 389 Google Scholar Crossref Search ADS PubMed WorldCat 25 Gitiaux C , Krug P , Grevent D et al. . Brain magnetic resonance imaging pattern and outcome in children with haemolytic uraemic syndrome and neurological impairment treated with eculizumab . Dev Med Child Neurol 2013 ; 55 : 758 – 765 Google Scholar PubMed WorldCat 26 Ekinci Z , Candan C , Alpay H et al. . Hemolytic uremic syndrome outbreak in Turkey in 2011 . Turk J Pediatr 2013 ; 55 : 246 – 252 Google Scholar PubMed WorldCat 27 Nathanson S , Kwon T , Elmaleh M et al. . Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome . Clin J Am Soc Nephrol 2010 ; 5 : 1218 – 1228 Google Scholar Crossref Search ADS PubMed WorldCat 28 Giordano P , Netti GS , Santangelo L et al. . A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement . Pediatr Nephrol 2019 ; 34 : 517 – 527 Google Scholar Crossref Search ADS PubMed WorldCat 29 Walsh PR , Johnson S. Eculizumab in the treatment of Shiga toxin haemolytic uraemic syndrome . Pediatr Nephrol 2019 ; 34 : 1485 – 1492 Google Scholar Crossref Search ADS PubMed WorldCat 30 Loos S , Oh J , Kemper MJ. Eculizumab in STEC-HUS: need for a proper randomized controlled trial . Pediatr Nephrol 2018 ; 33 : 1277 – 1281 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Catherine Monet-Didailler and Audrey Chevallier contributed equally to this work. © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Outcome of children with Shiga toxin–associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study

Download PDF
7 pages

Loading next page...
 
/lp/oxford-university-press/outcome-of-children-with-shiga-toxin-associated-haemolytic-uraemic-uWQPAi8Fox

References (31)

Publisher
Oxford University Press
Copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
ISSN
0931-0509
eISSN
1460-2385
DOI
10.1093/ndt/gfz158
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Treatment with eculizumab in Shiga toxin–associated haemolytic and uraemic syndrome (STEC-HUS) remains controversial despite its increasing utilization. The aim of our study was to evaluate the outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study. Methods Data were retrospectively collected from medical records of children diagnosed with STEC-HUS. The outcomes of patients treated with eculizumab for STEC-HUS were compared with those of a control group of untreated patients matched for age, sex and severity of acute kidney injury with a 1:2 matching scheme. Results Eighteen children (median age 40.6 months) with STEC-HUS treated with eculizumab were compared with 36 matched control patients (median age 36.4 months) who did not receive eculizumab. All patients survived in the two groups. Within 1 month of HUS onset, the evolution of haematological and renal parameters did not differ between the two groups. At 12 months of follow-up, renal outcome was not significantly different between the two groups. At the last follow-up, the prevalence of decreased glomerular filtration rate in the eculizumab group (27%) was not statistically different from that in controls (38%), as was the prevalence of proteinuria and high blood pressure. Children who received eculizumab more often had extrarenal sequelae during follow-up. Eculizumab treatment appeared to be safe in children with STEC-HUS. Conclusion The benefit of eculizumab on renal and extrarenal outcomes in STEC-HUS could not be established based on our findings. However, efficacy and safety are not best assessed by the observational design and small sample size of our study. Randomized controlled trials are thus required to determine the efficacy of eculizumab in this indication. children, eculizumab, haemolytic uraemic syndrome, outcome INTRODUCTION Haemolytic and uraemic syndrome (HUS) is a thrombotic microangiopathy syndrome defined by the triad of haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the typical form, HUS is preceded by bloody diarrhoea induced by a Shiga toxin (STX)-producing Escherichia coli (STEC) and transmitted by contaminated food. The acute phase of STEC-HUS is severe, with a mortality rate of 1–5% and 20% presenting neurological involvement [2]. Moreover, at least 40% of affected children require acute dialysis [2]. There is currently no specific treatment for STEC-HUS, and even if almost all patients recover from the acute episode with supportive treatment only, they can develop long-term sequelae such as chronic kidney disease (CKD), proteinuria and hypertension [3–5]. Typical or STEC-HUS must be differentiated from atypical HUS, induced by gene mutations of complement regulatory proteins or anti-factor H autoantibodies, leading to dysregulation of the complement alternative pathway, and from cobalamin C deficiency–related HUS and various causes of secondary HUS [1]. In 2011, eculizumab, a monoclonal humanized anti-C5 antibody, was approved for the treatment of atypical HUS [6], showing that an effective terminal complement blockade can improve renal function, reduce the duration of thrombocytopenia and prevent progression to end-stage renal disease [7]. A hyperactivation of complement by Shiga toxin has been shown in STEC-HUS [8–11], suggesting that eculizumab may be helpful in STEC-HUS. In 2011, Lapeyraque et al. [12] reported the use of eculizumab in three paediatric cases of severe STEC-HUS with neurological symptoms resistant to every supportive treatment and plasmapheresis that was tried. During the German STEC-HUS outbreak due to E. coli O104:H4 in 2011, 328 patients among the 845 HUS cases were treated with eculizumab (with or without plasmapheresis), including 13 of 90 contaminated children. In the following reports, short and intermediate outcomes of patients treated with eculizumab did not differ from those treated with supportive treatment, suggesting a potential lack of efficacy of this therapy [13–16]. Conversely, during a French outbreak in the same year, all nine STEC-HUS patients (including one child) treated with eculizumab (regardless of the initial severity) showed a favourable outcome without serious renal or extrarenal sequelae at 10 weeks [17]. The efficacy of eculizumab in STEC-HUS still remains largely unknown [18]. These controversial data and the limited evidence about eculizumab in STEC-HUS led us to evaluate the short- and intermediate-term outcomes of children treated with eculizumab for STEC-HUS in a single-centre matched cohort study. MATERIALS AND METHODS Study design The study consisted of a retrospective chart review of all children <15 years of age with a diagnosis of STEC-HUS, hospitalized in Bordeaux Children’s University Hospital, who received treatment with eculizumab between 2011 and 2017. A historical group of untreated patients diagnosed between 1995 and 2015, matched for age, sex and severity of renal impairment (presence of anuric acute kidney injury) at disease onset, served as controls with a 1:2 matching scheme. A computer-generated matching of controls to cases was performed using an SAS macro (SAS Institute, Cary, NC, USA). Patients were identified through the hospital discharge data system and from the French Institute for Public Health Surveillance (Santé Publique France), which has collected all cases of HUS in France since 1996. Case definition STEC-HUS cases were defined by prodromal diarrhoea; the triad of acute haemolytic anaemia (haemoglobin level <10 g/dL) with evidence of red cell fragmentation (schistocytes >1%), thrombocytopenia (platelet count <150 × 109/L) and acute kidney injury, including proteinuria and/or renal failure (serum creatinine level >60 µmol/L if age <2 years or >70 µmol/L if age >2 years); and exclusion of atypical HUS, secondary HUS and post-infectious HUS without diarrhoea. Patients participating in ongoing clinical trials were not included in this study. Renal injury was defined by the presence of hypertension requiring an antihypertensive medication or abnormal proteinuria (proteinuria >0.15 g/L or urinary protein:creatinine ratio >20 mg/mmol in children >2 years or albuminuria >30 mg/L) or CKD Stage 2 or higher with an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 using the bedside Schwartz formula [19, 20]. Extrarenal sequelae were defined by any clinical or biological symptom that appeared after HUS onset and required specific follow-up or treatment. Data collection All data were collected from computerized medical records and included demographic and anthropometric data, clinical features, treatment and outcomes. Short-term outcome was compared between the eculizumab and control groups based on the evolution of creatinine, haemoglobin and platelets in the acute phase until 1 month after HUS onset. Intermediate-term outcome was evaluated by the presence of renal injury (decreased eGFR, abnormal proteinuria and high blood pressure) and extrarenal sequelae at 1 month, 12 months and the last follow-up. A subgroup analysis was carried out among patients with a follow-up <6 years. Eculizumab administration Eculizumab (Soliris, Alexion Pharmaceuticals, Boston, MA, USA) is a recombinant monoclonal humanized antibody targeting the complement component protein C5. According to the French Agency for the Safety of Health Products recommendations of 2011, eculizumab was administrated in STEC-HUS patients with severe neurological involvement (seizure, focal neurological deficit, coma or psychiatric disorder). In 2012, a modified local protocol expanded the use of eculizumab to STEC-HUS with neurological involvement, cardiac injury (elevated troponin, electrocardiogram or echocardiographic abnormalities), pulmonary oedema, severe pancreatitis (lipase >3 times the upper limit of normal) and severe enterocolitis associated with persistent renal failure despite 4 days of renal replacement therapy. All patients received an anti-meningococcal vaccination prior to the first injection of eculizumab (for protection against serogroups A, C, Y W, then against serogroup B since 2013). As per local protocol, and since azithromycin is believed to have an inhibitory effect on STX release, antibiotic prophylaxis consisted of azithromycin during 5 days followed by oracillin until 14 days after the last eculizumab injection. Complement activation monitoring Inhibition of the terminal complement complex was evaluated through an immunoenzymatic dosage of functional complement activity (in UCAE/mL) using an enzyme-linked immunosorbent assay kit (CAE DiaSorin kit, stillwater). The blockade of complement activity was considered as complete when the complement activity was <1 UCAE/mL (normal range 63–145 ) [21]. Complement activity was measured prior to every eculizumab injection to obtain residual functional activity and at Days 1–3 after every injection. Statistical and ethical aspects Quantitative data are presented as medians and interquartile ranges (IQRs) and qualitative data are expressed as percentages. The Kruskal–Wallis test and chi-squared test were used for comparisons of medians and proportions. Statistical analyses were performed using SAS software version 9.3 (SAS Institute). Patients and families were fully and clearly informed about off-label use of eculizumab and gave their consent to receive the drug. The study was approved by the South West France Research Ethics Committee. RESULTS Clinical and biological features Between 2011 and 2017, 18 children with STEC-HUS were treated with eculizumab in the Bordeaux University Hospital. Thirty-six patients diagnosed with HUS in the period 1995–2015 were included in the control group. The clinical findings and laboratory data of the study population are summarized in Table 1. Table 1 Clinical features and laboratory data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 a Lowest or highest value according to the parameter. View Large Table 1 Clinical features and laboratory data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 Eculizumab group (n = 18) Control group (n = 36) P-value Variablea Male sex, n (%) 7 (39) 12 (33) 0.68 Age at diagnosis (months), median (IQR) 40.6 (15.7–110.1) 36.4 (20.9–95.0) 0.92 STEC identification, n (%) 16 (89) 20 (56) 0.02 Anuria 9 (50) 18 (50) 1.00 High blood pressure 11 (61) 15 (42) 0.18 Extrarenal manifestations 16 (88) 27 (75) 0.35  Neurological 10 (55) 9 (25) 0.02  Cardiac 4 (22) 2 (6) 0.06  Gastrointestinal 16 (88) 26 (72) 0.16 Haemoglobin level (g/dL), median (IQR) 6.2 (5.4–6.6) 6.0 (5.6–6.9) 0.74 Platelet count (109/L), median (IQR) 19.5 (13.0–38.0) 27.5 (20.5–39.0) 0.10 Lactate dehydrogenase (UI/L), median (IQR) 2982 (2200–3249) 2584 (1847–5545) 0.82 Serum creatinine (µmol/L), median (IQR) 294 (142–353) 334 (219–408) 0.29 Urine protein:creatinine ratio (mg/mmol), median (IQR) 1452 (655–2430) 862 (390–1727) 0.08 a Lowest or highest value according to the parameter. View Large The two groups were similar with respect to age, sex, anuric acute kidney injury, blood pressure and presence of extrarenal complications. However, neurological, cardiac and gastrointestinal complications were more frequently observed in the eculizumab group (statistically significant for neurological complications). At HUS onset, laboratory data were similar in the two groups. STEC confirmation was possible in 16 (89%) patients treated with eculizumab and in only 20 (56%) controls. Therapeutic management The two groups had statistically comparable transfusion rates, need for and duration of renal replacement therapy, length of hospitalization and length of paediatric intensive care unit stay (Table 2). The only difference was the use of antibiotic therapy (100% in the eculizumab group and 44% in controls; P = 0.01), which is explained by systematic antibiotic prophylaxis for patients receiving eculizumab. Table 2 Therapeutic data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 View Large Table 2 Therapeutic data of the study population Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 Eculizumab group (n = 18) Control group (n = 36) P-value Variable Red blood cells transfusion, n (%) 17 (94) 32 (88) 0.62 Platelets transfusion, n (%) 10 (55) 18 (50) 0.69 Renal replacement therapy, n (%) 13 (72) 22 (61) 0.42 Duration of renal replacement therapy (days), median (IQR) 6 (4–12) 7 (4–15) 0.61 Plasma exchanges, n (%) 1 (6) 4 (11) 0.81 Antibiotic therapy, n (%) 18 (100) 16 (44) <0.01 View Large Indication for eculizumab treatment Criteria for eculizumab treatment were most frequently severe acute neurological involvement in 10 patients, with cardiac involvement in 4 of them. Five patients were treated several days after HUS onset because of increasing haemolysis requiring transfusions and the need for renal replacement therapy associated with severe pancolitis (including one rectal prolapse) or multiple organ involvement. Two patients received eculizumab treatment because of severe acute pancreatitis. Finally, one patient did not exhibit severe symptoms of HUS but was treated early in the course of the disease in the context of a STEC-HUS O104:H4 outbreak due to fenugreek sprouts in the Bordeaux area in 2011 [17]. Mechanical ventilation was required in three patients treated with eculizumab. Eculizumab administration and complement activity monitoring Patients received a median number of three eculizumab injections (range 2–5); five patients received two doses, seven patients received three doses and six patients received five doses (Supplementary data, Figure S1). The first, second and third eculizumab injections were given after a median time of 3 days (range 0–8), 11 days (range 5–20) and 20 days (range 12–37) after the diagnosis of HUS, respectively (Supplementary data, Figure S1). Blockade of complement activity (<1 UCAE/mL) was obtained after the first eculizumab injection in 10 of 18 patients (55%). Three patients received an additional injection between Days 3 and 8. Nine of 16 patients (56%) showed complete blockade of complement activity after the second injection and 6 of 10 (60%) after the third injection. The timing of complement activity monitoring and the values of CAE before and after eculizumab injections are shown in Figure 1. FIGURE 1 View largeDownload slide Complement activity kinetics during the first 3 weeks of treatment. Bars represent median and IQR. D: day; ECZ: eculizumab. FIGURE 1 View largeDownload slide Complement activity kinetics during the first 3 weeks of treatment. Bars represent median and IQR. D: day; ECZ: eculizumab. Comparison of outcomes between patients treated with eculizumab and controls There was no statistically significant difference between groups for haemoglobin level and platelet count kinetics over 1 month after HUS onset (Supplementary data, Figures S2 and S3). The increase in platelet count between Days 1 and 8 appeared more quickly in the eculizumab group than in controls, but this did not reach statistical significance. Similarly, the duration of initial renal replacement therapy (Table 2) and evolution of serum creatinine over 1 year (Figure 2) did not differ significantly between the eculizumab and control groups. FIGURE 2 View largeDownload slide Comparative changes of serum creatinine between patients treated with eculizumab (n = 18) and controls (n = 36). Bars are median and IQR. D: day; M: month; NS: non-significant. FIGURE 2 View largeDownload slide Comparative changes of serum creatinine between patients treated with eculizumab (n = 18) and controls (n = 36). Bars are median and IQR. D: day; M: month; NS: non-significant. At 1 and 12 months of follow-up there was no statistically significant difference between the two groups regarding the proportion of high blood pressure, proteinuria and decreased eGFR (Figure 3). Overall, the median follow-up after HUS onset was 2.5 years in treated patients and 5.0 years in controls. At the last follow-up, the prevalence of decreased eGFR was not statistically lower in the eculizumab group [5/18 (27%)] than in controls [14/36 (38%)] and the prevalence of proteinuria was not statistically lower in the eculizumab group [3/18 (17%)] than in controls [10/36 (27%)] (Figure 3). The prevalence of high blood pressure requiring treatment was 17% in the eculizumab group and 11% in controls. FIGURE 3 View largeDownload slide Proportion of patients with renal impairment over follow-up in children treated with eculizumab (n = 18) and in controls (n = 36). Low eGFR is defined as a GFR <90 mL/min/1.73 m2. Proteinuria is defined as a urine protein:creatinine ratio >20 mg/mmol or urinary protein >0.15 g/L. High blood pressure (BP) is defined as the need for a antihypertensive treatment. FIGURE 3 View largeDownload slide Proportion of patients with renal impairment over follow-up in children treated with eculizumab (n = 18) and in controls (n = 36). Low eGFR is defined as a GFR <90 mL/min/1.73 m2. Proteinuria is defined as a urine protein:creatinine ratio >20 mg/mmol or urinary protein >0.15 g/L. High blood pressure (BP) is defined as the need for a antihypertensive treatment. To make the two groups more comparable, we performed a subgroup analysis excluding the patients with the longest follow-up. After excluding those with a follow-up >6 years, the median follow-up duration was comparable between the two groups: 2.3 years (IQR 0.9–4.1) in the eculizumab group (n = 17) versus 3.6 years (IQR 1.6–5.1) in controls (n = 23). The prevalence of decreased eGFR, proteinuria and hypertension was again similar in the two groups. eGFR at the last follow-up was comparable between patients treated with eculizumab [median 108 mL/min/1.73 m2 (IQR 83–124)] and controls [median 110 mL/min/1.73 m2 (IQR 90–122)], as was urine protein:creatinine ratio [15 mg/mmol (IQR 13–20) versus 14 mg/mmol (IQR 10–27)]. Extrarenal outcome All patients survived in the two groups. Five patients from the eculizumab group (27%) and two from the control group (5%) had extrarenal sequelae after >1 year of follow-up (P = 0.02). Two patients treated with eculizumab presented psychomotor delay with language and walking acquisition delay, two had strabismus and one showed moderate motor impairment. Four of these patients had neurological involvement in the acute phase. Among patients with extrarenal sequelae from the control group, one presented pancreatic pseudocysts and the other had psychomotor delay and attention deficit disorder. Four of 10 patients with neurological involvement treated with eculizumab (40%) and 1 of 9 untreated patients (11%) kept long-term neurological sequelae. Safety No serious adverse events related to the drug have been reported among patients treated with eculizumab; in particular, no invasive meningococcal disease or other severe infection. Moderate late-onset alopecia occurred in two children (at 1 and 2 months after the last injection of eculizumab) and resolved without sequelae. DISCUSSION In this single-centre matched cohort study, we found no statistically significant difference at the acute phase of STEC-HUS for the recovery of serum creatinine, platelet count and haemoglobin level within 1 month between 18 patients treated with eculizumab and 36 untreated controls. In addition, intermediate-term renal outcome at 1 year and at 2–5 years of follow-up was comparable between the two groups. The proportion of extrarenal sequelae was higher among patients treated with eculizumab than in controls, likely reflecting the more severe neurological presentation in the eculizumab group at HUS onset. No deaths occurred. Finally, eculizumab was well tolerated, with only two transient moderate adverse drug events. Our findings suggest either a modest effect or a lack of efficacy of eculizumab in STEC-HUS. Reports by Loos et al. [15, 16] about the follow-up of children with STEC-HUS during the German outbreak of 2011 indicated that the 13 cases of HUS with neurological involvement treated with eculizumab (combined with plasmapheresis for 7 of them) have the same outcomes as those treated with supportive treatment only. Conclusions yielded by the study of Kielstein et al. [13] were similar in adult patients from the German STEC-HUS registry following the 2011 O104:H4 outbreak. In the study of Menne et al. [14], 67 adults treated with eculizumab were compared retrospectively with untreated controls with similar disease severity and hospitalized in another centre where eculizumab was unavailable. No significant difference was noted for platelet recovery and levels of lactate dehydrogenase, creatinine or haemoglobin, and the complications rate HUS was also similar between groups. Conversely, in the smaller French O104:H4 outbreak in Bordeaux during the same year, all nine individuals who developed STEC-HUS received eculizumab and recovered with rapid haematological improvement and without severe neurological or renal sequelae [17]. Differences between these studies conclusions may be explained by disparities in sample size and the fact that during the German outbreak, eculizumab was only used to treat the most severely affected patients, contrary to the French outbreak, and was often combined with plasma exchanges, which interferes with eculizumab pharmacokinetics. In a recently published review of the current evidence on eculizumab efficacy in STEC-HUS [18], it is suggested that the delay between HUS diagnosis and eculizumab administration may play a role in patient recovery. During the German HUS outbreak, adult patients received a first dose of eculizumab an average of 10 days after diagnosis [13] and children after a median of 22 days [15], as compared with a median of 1 day in the French outbreak [17]. In the initial case series from Lapeyraque et al. [12], eculizumab was given between 5 and 8 days after STEC-HUS diagnosis. In our study, the interval between STEC-HUS diagnosis and first eculizumab injection was 3 days, with complete complement activity blockade in a majority of cases and a few patients who required an additional injection between Days 3 and 8. All patients from our cohort survived, none showed severe disability, but 13% experienced mild to moderate neurological sequelae during follow-up. In our cohort study, a neurological complication occurred at HUS onset in 25% of patients from the control group, which is in line with the published literature [2], and in 55% of children treated with eculizumab. It has been suggested that eculizumab might improve neurological outcome [22]. In our study, among the 10 patients treated with eculizumab with neurological involvement at onset, 4 had residual neurological changes at the last follow-up. In the acute phase of HUS, two of them needed mechanical ventilation because of repeated seizures and coma. Magnetic resonance imaging (MRI) was abnormal in both cases and an electroencephalogram showed encephalopathy patterns. Improvement of both patients occurred 2–4 days after the first eculizumab injection. The MRI and electroencephalogram normalized during the year after HUS. Our results are somewhat consistent with the single-centre report by Pape et al. [22] where all 11 patients with severe neurological involvement were treated with eculizumab, of whom 1 (9%) died, 2 (18%) had mild or severe neurological sequelae and 8 (72%) had minor or no sequelae. These findings and ours raise the question of the efficacy of eculizumab in patients with neurological involvement. In an uncontrolled cohort of 33 children treated with eculizumab for severe STEC-HUS, including 28 with neurological symptoms, 19 (70%) had a complete neurological recovery, with 17 showing clinical improvement within days following the first eculizumab injection [23]. A review of eculizumab use in STEC-HUS [18] retrieved outcome data from a total of 31 children, including 29 (94%) with neurological involvement [12, 15, 17, 22, 24–26]. Complete recovery or minor sequelae was observed in 24 children (83%), a proportion significantly higher than the recovery rate (58%) reported in a previous French study of 52 children with STEC-HUS and neurological impairment [27]. Contrary to our findings, smaller reports describe dramatic improvement in the outcome of patients with severe neurological involvement treated with eculizumab, including Lapeyraque et al. (three out of three recovered) [12], Ekinci et al. (two out of two recovered) [26] or recently Giordano et al. (four out of five recovered) [28]. We found no statistically significant difference in renal outcome (prevalence of low eGFR, proteinuria or high blood pressure) between the two groups at an intermediate follow-up. When restricting the analysis to patients with a follow-up <6 years, allowing a more comparable follow-up between the two groups, we found similar GFRs and urine protein:creatinine ratios in patients treated with eculizumab and in controls. Our findings are consistent with the 3-year outcomes of 11 out of 13 children treated with eculizumab during the German outbreak [16]. Our study has several limitations, including the retrospective design of the study, missing data and variations over time in eculizumab indications and administration modalities. To limit these weaknesses, we constructed a control group well matched for age, sex and severity of acute kidney injury. However, a selection bias likely persisted with more severe disease among controls, especially regarding neurological complications. Moreover, in order to limit the bias by indication, we selected most patients of the control group [n = 25 (70%)] from the population of paediatric STEC-HUS patients diagnosed before eculizumab use in France (2011). As a consequence, the median follow-up of patients treated with eculizumab is shorter than in the controls (2.5 versus 5 years), inducing another possible bias for the interpretation of long-term outcome data. However, subgroup analysis restricted to patients followed for <6 years led to a comparable follow-up duration between groups and yielded similar results. In conclusion, eculizumab treatment does not seem to improve short- or intermediate-term renal outcome after STEC-HUS in children despite the methodological limitations of this study. However, whether eculizumab has a potential interest for extrarenal outcome remains unknown. Eculizumab appears to be safe in severe forms of STEC-HUS. Investigating eculizumab as a prophylactic therapy before the development of neurological or other severe symptoms associated with STEC-HUS is one of the goals of ongoing randomized placebo-controlled trials [29]. Results of these trials will provide some evidence about eculizumab treatment to improve clinical care of children with STEC-HUS [30]. AUTHORS’ CONTRIBUTIONS C.M.D. and A.C. drafted the manuscript. C.M.D., A.G.D., L.A., C.C.B., Y.D., O.B. and B.L. followed the patients and collected and analysed the data. J.H. designed the study, interpreted data and drafted the manuscript. All authors participated in critically reviewing the article for important intellectual content and approved the final version of the manuscript. CONFLICT OF INTEREST STATEMENT Y.D. has received lecture fees from Alexion Pharmaceuticals. J.H. has received consultancy fees from Alexion Pharmaceuticals. All other authors have no competing interests to declare. REFERENCES 1 Fakhouri F , Zuber J , Frémeaux-Bacchi V et al. . Haemolytic uraemic syndrome . Lancet 2017 ; 390 : 681 – 696 Google Scholar Crossref Search ADS PubMed WorldCat 2 Trachtman H , Austin C , Lewinski M et al. . Renal and neurological involvement in typical Shiga toxin-associated HUS . Nat Rev Nephrol 2012 ; 8 : 658 – 669 Google Scholar Crossref Search ADS PubMed WorldCat 3 Spinale JM , Ruebner RL , Copelovitch L et al. . Long-term outcomes of Shiga toxin hemolytic uremic syndrome . Pediatr Nephrol 2013 ; 28 : 2097 – 2105 Google Scholar Crossref Search ADS PubMed WorldCat 4 Rosales A , Hofer J , Zimmerhackl LB et al. . Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late emerging sequelae . Clin Infect Dis 2012 ; 54 : 1413 – 1421 Google Scholar Crossref Search ADS PubMed WorldCat 5 Monet-Didailler C , Godron-Dubrasquet A , Madden I et al. . Long-term outcome of diarrhea-associated hemolytic uremic syndrome is poorly related to markers of kidney injury at 1-year follow-up in a population-based cohort . Pediatr Nephrol 2019 ; 34 : 657 – 662 Google Scholar Crossref Search ADS PubMed WorldCat 6 Loirat C , Fakhouri F , Ariceta G et al. . An international consensus approach to the management of atypical hemolytic uremic syndrome in children . Pediatr Nephrol 2016 ; 31 : 15 – 39 Google Scholar Crossref Search ADS PubMed WorldCat 7 Legendre CM , Licht C , Muus P et al. . Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome . N Engl J Med 2013 ; 368 : 2169 – 2181 Google Scholar Crossref Search ADS PubMed WorldCat 8 Orth D , Khan AB , Naim A et al. . Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome . J Immunol 2009 ; 182 : 6394 – 6400 Google Scholar Crossref Search ADS PubMed WorldCat 9 Morigi M , Galbusera M , Gastoldi S et al. . Alternative pathway activation of complement by Shigatoxin promotes exuberant C3a formation that triggers microvascular thrombosis . J Immunol 2011 ; 187 : 172 – 180 Google Scholar Crossref Search ADS PubMed WorldCat 10 Noris M , Mescia F , Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation . Nat Rev Nephrol 2012 ; 8 : 622 – 633 Google Scholar Crossref Search ADS PubMed WorldCat 11 Karpman D , Tati R. Complement contributes to the pathogenesis of Shigatoxin-associated hemolytic uremic syndrome . Kidney Int 2016 ; 90 : 726 – 729 Google Scholar Crossref Search ADS PubMed WorldCat 12 Lapeyraque AL , Malina M , Fremeaux-Bacchi V et al. . Eculizumab in severe Shiga-toxin-associated HUS . N Engl J Med 2011 ; 364 : 2561 – 2563 Google Scholar Crossref Search ADS PubMed WorldCat 13 Kielstein JT , Beutel G , Fleig S et al. . Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry . Nephrol Dial Transplant 2012 ; 27 : 3807 – 3815 Google Scholar Crossref Search ADS PubMed WorldCat 14 Menne J , Nitschke M , Stingele R et al. . Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study . BMJ 2012 ; 345 : e4565 Google Scholar Crossref Search ADS PubMed WorldCat 15 Loos S , Ahlenstiel T , Kranz B et al. . An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children . Clin Infect Dis 2012 ; 55 : 753 – 759 Google Scholar Crossref Search ADS PubMed WorldCat 16 Loos S , Aulbert W , Hoppe B et al. . Intermediate follow-up of pediatric patients with hemolytic uremic syndrome during the 2011outbreak caused by E. coli O104:H4 . Clin Infect Dis 2017 ; 64 : 1637 – 1643 Google Scholar Crossref Search ADS PubMed WorldCat 17 Delmas Y , Vendrely B , Clouzeau B et al. . Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab . Nephrol Dial Transplant 2014 ; 29 : 565 – 572 Google Scholar Crossref Search ADS PubMed WorldCat 18 Keenswijk W , Raes A , Johan Vande Walle J. Is eculizumab efficacious in Shigatoxin-associated hemolytic uremic syndrome? A narrative review of current evidence . Eur J Pediatr 2018 ; 177 : 311 – 318 Google Scholar Crossref Search ADS PubMed WorldCat 19 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification . Am J Kidney 2002 ; 39 ( 2 Suppl 1 ): S1 – S266 WorldCat 20 Schwartz GJ , Muñoz A , Schneider MF et al. . New equations to estimate GFR in children with CKD . J Am Soc Nephrol 2009 ; 20 : 629 – 637 Google Scholar Crossref Search ADS PubMed WorldCat 21 Gatault P , Brachet G , Ternant D et al. . Therapeutic drug monitoring of eculizumab: rationale for an individualized dosing schedule . MAbs 2015 ; 7 : 1205 – 1211 Google Scholar Crossref Search ADS PubMed WorldCat 22 Pape L , Hartmann H , Bange FC et al. . Eculizumab in typical hemolytic uremic syndrome (HUS) with neurological involvement . Medicine (Baltimore) 2015 ; 94 : e1000 Google Scholar Crossref Search ADS PubMed WorldCat 23 Percheron L , Gramada R , Tellier S et al. . Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study . Pediatr Nephrol 2018 ; 33 : 1385 – 1394 Google Scholar Crossref Search ADS PubMed WorldCat 24 Saini A , Emke AR , Silva MC et al. . Response to eculizumab in Escherichia coli O157:H7-induced hemolytic uremic syndrome with severe neurological manifestations . Clin Pediatr (Phila) 2015 ; 54 : 387 – 389 Google Scholar Crossref Search ADS PubMed WorldCat 25 Gitiaux C , Krug P , Grevent D et al. . Brain magnetic resonance imaging pattern and outcome in children with haemolytic uraemic syndrome and neurological impairment treated with eculizumab . Dev Med Child Neurol 2013 ; 55 : 758 – 765 Google Scholar PubMed WorldCat 26 Ekinci Z , Candan C , Alpay H et al. . Hemolytic uremic syndrome outbreak in Turkey in 2011 . Turk J Pediatr 2013 ; 55 : 246 – 252 Google Scholar PubMed WorldCat 27 Nathanson S , Kwon T , Elmaleh M et al. . Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome . Clin J Am Soc Nephrol 2010 ; 5 : 1218 – 1228 Google Scholar Crossref Search ADS PubMed WorldCat 28 Giordano P , Netti GS , Santangelo L et al. . A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement . Pediatr Nephrol 2019 ; 34 : 517 – 527 Google Scholar Crossref Search ADS PubMed WorldCat 29 Walsh PR , Johnson S. Eculizumab in the treatment of Shiga toxin haemolytic uraemic syndrome . Pediatr Nephrol 2019 ; 34 : 1485 – 1492 Google Scholar Crossref Search ADS PubMed WorldCat 30 Loos S , Oh J , Kemper MJ. Eculizumab in STEC-HUS: need for a proper randomized controlled trial . Pediatr Nephrol 2018 ; 33 : 1277 – 1281 Google Scholar Crossref Search ADS PubMed WorldCat Author notes Catherine Monet-Didailler and Audrey Chevallier contributed equally to this work. © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Nephrology Dialysis Transplantation – Oxford University Press

Published: Feb 1, 2012

There are no references for this article.