Eculizumab Use in a Temporarily Dialysis-Dependent Patient With Shiga Toxin–Producing Escherichia Coli Hemolytic Uremic Syndrome With Neurological Complications

Abstract

Shiga toxin–producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the most common cause of acute renal failure in children, and it is associated with thrombocytopenia and hemolytic anemia. Although this disease primarily affects the kidney, it can also contribute to cellular damage in other organ systems, such as the CNS. Eculizumab is a monoclonal antibody that binds to complement proteins to prevent complement-mediated intravascular hemolysis in atypical HUS. In STEC-HUS, complement activation also occurs by Shiga toxin, and previous cases of eculizumab use in the setting of neurological involvement have been shown to be successful. We report the successful use of eculizumab in the setting of typical STEC-HUS–induced neurological symptoms including seizure, altered mental status, and left arm weakness. The patient also experienced concomitant renal failure requiring dose adjustment for hemodialysis. Following 2 doses of eculizumab, our patient was discharged to an inpatient rehabilitation facility with resolution of her renal injury, seizures, and altered mentation without adverse effects from eculizumab throughout the admission. Based on our case study, it appears that eculizumab may be given during or between hemodialysis without dose adjustment.

Introduction

Hemolytic uremic syndrome (HUS) is usually categorized as typical when caused by a Shiga toxin–producing Escherichia coli infection, as atypical when caused by uncontrolled complement activation, or as secondary when with a coexisting disease. Shiga toxin producing E coli hemolytic uremic syndrome (STEC-HUS) is the most common cause of acute renal failure in children, and it is accompanied by thrombocytopenia and hemolytic anemia.^1–6 STEC-HUS has been attributed to endothelial damage and activation of the complement cascade, thereby inducing thrombotic microangiopathy secondary to release of Shiga toxin.² This damage primarily affects the kidneys, although it can also lead to cellular damage of other organ systems, such as the CNS.³ Twenty to fifty percent of STEC-HUS patients will exhibit neurological symptoms characterized by seizure, paresis, coma, confusion, and visual disturbance.^1,3,4 Eculizumab has been shown to be an effective therapy for the treatment of atypical HUS.^6–8 Eculizumab is a monoclonal antibody that binds to complement protein C5, thereby preventing downstream activation of the complement complex C5b-9, which in turn inhibits complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and atypical HUS.^7–9

In STEC-HUS, complement activation occurs by Shiga toxin, and previous case reports as well as 1 meta-analysis have described neurological recovery with eculizumab in STEC-HUS.^1,10 We report a case of intradialytic eculizumab dosing in the setting of STEC-HUS with neurological symptoms to add to the growing body of literature. As this is a rare condition, and given the sensitive timing of eculizumab administration, randomized controlled trials have not yet been completed. There are currently 2 clinical trials for pediatric patients in progress. Informed consent for publication of this patient case was not obtained because it was not required by the institutional review board with appropriate protection of patient-specific information.

Case Report

A 13-year-old Caucasian female, weighing 53 kg on admission, was admitted for uremia and oliguria in the setting of STEC-HUS. Seven days prior to presentation, she experienced nausea, vomiting, and diarrhea that progressed to bloody stools. Stool cultures sent from an outside hospital emergency department were positive for Shiga toxin–producing E coli. She was discharged from the outside hospital emergency department. On admission to our hospital, the patient reported low-grade fevers, non-significant urinary changes, and refractory epistaxis. Laboratory values were notable for leukocytosis, thrombocytopenia, azotemia, elevated serum creatinine (SCr), and elevated lactate dehydrogenase (Table). She was oliguric on admission with 60 mL urine output during the first 12 hours of admission. Complement factors were drawn for detection of atypical HUS. These factors were not resulted in the electronic medical record during her hospital stay; however, all eventually returned to within normal limits. She had no known drug allergies and no medications prior to admission. Past medical history was significant for a single seizure in January 2017 with an electroencephalogram suggestive of benign rolandic epilepsy. She was not on antiepileptic medications for this condition prior to admission, and other than this 1 episode of seizure that had not recurred, she was in her usual good state of health. The patient was initially managed with 2 intravenous doses of furosemide, 40 mg initially with an additional 80 mg administered 4 hours later for a total dose of 2 mg/kg and intravenous fluids in the setting of oliguria and elevated blood urea nitrogen and SCr. Due to ongoing oliguria despite furosemide, and increasing laboratory values for renal function (Figure 1), intermittent hemodialysis was initiated on the evening of hospital day 1. The patient continued to require hemodialysis on hospital day 2, and no other interventions were required.

Table.

Laboratory Values Upon Admission

Laboratory Test	Patient Value	Reference Ranges
White blood cell count, × 109/L	15.8	3.8–10.4
Platelet count, × 103/L	40	177–381
Blood urea nitrogen, mg/dL	62	7–20
Serum creatinine, mg/dL	2.5	0.35–0.86
Lactate dehydrogenase, U/L	1797	110–283
Sodium, mEq/L	130	135–145
Chloride, mEq/L	92	102–112
Bicarbonate, mEq/L	26	22–29
Factor I, mg/dL	4.1	2.4–4.9
Factor B, mg/dL	17.8	15.2–42.3

Figure 1.

Renal laboratory values and urine output throughout the patient's hospital stay.

On hospital day 3 she developed altered mental status, which included somnolence and an inability to follow commands. On physical examination, she demonstrated persistent upper extremity hypotonia. Neurological involvement progressed to a tonic-clonic seizure, which resolved after administration of single doses of lorazepam 0.04 mg/kg and intravenous levetiracetam 35 mg/kg. The patient was in a post-ictal state after seizure resolution and maintenance doses of levetiracetam 10 mg/kg twice daily were initiated. In the setting of acute change in neurological status, time sensitivity related to the efficacy of eculizumab,² and growing body of literature for eculizumab for this indication, the decision was made to administer eculizumab 900 mg (15.5 mg/kg) over 4 hours after hemodialysis. MRI of the brain with and without contrast was performed upon seizure resolution and was normal. Based on a previous case report regarding eculizumab and hemodialysis and the monoclonal antibody's large molecular weight and pharmacokinetic properties, there were no dose adjustments made for hemodialysis.^{10, 11,12} The patient received prophylaxis with penicillin and immunization against encapsulated organisms following eculizumab administration. All other treatments were supportive. Following this initial dose of eculizumab, the patient had no further seizure activity; however, no improvement in her neurological examination was observed. She remained unable to answer questions, follow commands, or move her limbs spontaneously. The following day (hospital day 4), the patient was febrile (40.5°C). Blood cultures were negative, and a respiratory culture from her endotracheal tube along with a chest x-ray was not suggestive of pneumonia. The patient remained anuric and continuous renal replacement therapy (CRRT) was initiated on hospital day 5 as she demonstrated disequilibrium during hemodialysis. The patient's SCr peaked at 6.31 mg/dL on this day. Figures 1 and 2 depict the patient's laboratory values throughout her hospital stay until her date of discharge. A seizure recurred on hospital day 6, which was unresponsive to a single dose of intravenous lorazepam 0.1 mg/kg and intravenous levetiracetam 30 mg/kg and required 2 subsequent doses of fosphenytoin totaling 30 mg/kg. A repeat MRI of the brain with and without contrast was again normal on hospital day 8.

Figure 2.

Platelet laboratory values throughout the patient's hospital stay.

On hospital day 10, a second 900-mg dose of eculizumab was given due to a lack of neurological improvement. Based on limited data to regarding the duration of eculizumab therapy, as well as ongoing renal and platelet recovery, decreasing lactate dehydrogenase, and lack of recurrent seizures, additional doses of eculizumab were deferred. SCr continued to trend down over the course of her hospitalization, ultimately normalizing 30 days following admission; CRRT ended on hospital day 10 and the patient remained hemodynamically stable, making her own urine adequately. By hospital day 14, she was becoming more interactive; able to mouth “yes” and “no” when asked questions. She began to move her arm on hospital day 15. No further seizures presented over the remainder of this admission. On hospital day 22, she was discharged to an inpatient rehabilitation facility in the setting of ongoing left arm weakness. No adverse drug events were identified that could be attributed to eculizumab during her hospital course.

Discussion

Eculizumab is indicated for treatment of paroxysmal nocturnal hemoglobinuria and atypical HUS. Atypical HUS is a rare disorder caused by overactivation of the alternative pathway of complement and is primarily characterized by thrombotic microangiopathy, which is understood to be the underlying pathophysiology of CNS complications in STEC-HUS.^4,11 Eculizumab was shown to be effective in patients with atypical HUS in 5 clinical studies, resulting in resolution and prevention of complement-mediated thrombotic microangiopathy, improved renal function, and hematologic outcomes.⁷ In STEC-HUS, complement activation also occurs by Shiga toxin, and previous cases of eculizumab use in the setting of neurological involvement have been shown to be successful.^1,3 Although limited data exist for the use of eculizumab in patients with typical HUS and the use of this medication with hemodialysis is not well described, eculizumab was selected because the patient quickly developed severe neurological complications from the disease. To our knowledge, only 1 other report describes the timing of eculizumab administration in relation to hemodialysis sessions while treating atypical HUS.¹¹ The authors reported that based on the large molecular weight of the antibody, a minimal amount was expected to be removed by dialysis. This patient received eculizumab during the last 60 minutes of the dialysis sessions because the hemodialysis catheter was used as the route of administration. After monitoring eculizumab levels throughout dialysis, the authors concluded that intradialytic administration of the therapy might not affect eculizumab pharmacokinetics. This was because the minimum serum concentration prior to dose administration was 138.7 mg/L and the maximum serum concentration obtained 1 hour after the end of infusion and dialysis was 523.4 mg/L. The minimum threshold required in vitro for complete blockage of complement activity was 99 mg/L, and the upper limit of safety reported in literature was 700 mg/L. Our patient received both eculizumab doses in the setting of intermittent hemodialysis without dose adjustments. For the first dose, eculizumab was administered in the evening, 9 hours after the end of her dialysis session. The second dose was administered in the afternoon, 2 hours after the completion of dialysis. Serum for eculizumab concentration was drawn 4 hours after the completion of drug administration from the second dose and was reported as 190 mg/L. The resultant drug concentration drawn suggested that the patient had a therapeutic concentration based on atypical HUS pharmacokinetic studies.¹³ The weekly dosing interval was selected based on the manufacturer's recommendations. Subsequent concentrations were not measured as there are limited data to describe clinical efficacy with measured eculizumab serum concentrations in this setting.

We have summarized the relevant literature supporting the use of eculizumab in STEC-HUS with neurological involvement. The first report of eculizumab use for STEC-HUS was published in 2011.¹³ Lapeyraque et al¹³ described three 3-year-old patients requiring intermittent and continuous hemodialysis with severe CNS involvement, not further described in the case series. Two patients received 2 doses of eculizumab in weekly intervals, while 1 patient received 4 doses. Two of 3 patients also received 5 days of plasma exchange prior to initiation with eculizumab, yet they demonstrated progressive involvement of the CNS. In all 3 patients, neurological status improved 24 hours after the first eculizumab infusion. Gitiaux et al⁴ reported a single-center, prospective cohort study describing the MRI findings of 7 patients with STEC-HUS and acute neurological impairment, which included disturbances of consciousness, seizures, and focal neurological signs (paresthesias), treated with eculizumab. Three of 7 patients underwent plasma exchange in addition to eculizumab. The 6-month follow-up MRI and neurological examination were normal in the 5 surviving patients. Ekinci et al¹⁴ described another case series of 2 females, a 9.5-year-old and a 20-month-old, to whom eculizumab was administered in the setting of STEC-HUS complicated by altered consciousness, somnolence, and visual hallucinations; these complications progressed to tonic-clonic seizure in the 9.5-year-old and dystonic movements in the toddler.¹⁴ One of the 2 patients underwent plasmapheresis. For both patients, all neurological symptoms improved within 48 hours of the first infusion. Pape et al¹ reported a retrospective analysis with a prospective enrollment that evaluated 11 patients receiving eculizumab.¹ Patients were started on eculizumab therapy within 4 hours of seizure onset and continued eculizumab therapy weekly as long as they were having symptomatic HUS with neurological involvement. None of these patients underwent plasmapheresis. The authors found that the early use of eculizumab was beneficial for typical HUS and neurological involvement; however, late treatment in patients with severe HUS with rapid progression of multiple organ involvement was less beneficial. Interestingly, a recent case report of a 10-year-old male described neurological recovery with late eculizumab treatment in the setting of severe neurological involvement.³ This 10-year-old male presented with numbness and tingling of left arm and cheek and dysarthric speech that progressed to left facial droop, left-sided weakness, and 2 episodes of brief tonic-clonic seizures. Eculizumab was started 4 days after onset of neurological symptoms, and the patient was placed on CRRT; he required non-invasive respiratory support throughout this admission. He was given 3 total doses of eculizumab without plasma exchange. The authors reported some improvement on neurological symptoms, not otherwise described, 4 days after the initial dose of eculizumab. At follow-ups at 2, 8, and 14 months from the onset of his illness, he demonstrated full recovery from neurological symptoms. Loos et al¹⁵ described the intermediate follow-up of 13 pediatric patients who were treated with eculizumab for a variety of indications, including neurological involvement, following the 2011 E coli O104:H4 outbreak in Germany. One of the patients who received eculizumab still demonstrated neurological symptoms at the latest follow-up, and the median duration of follow-up was 3 years. However, other neurological outcomes were not described in this follow-up.

In summary, most current case reports and series describe the immediate improvement in neurological complications of typical HUS following the first dose of eculizumab.^1,3,13,14 One prospective cohort study provided a 6-month follow-up with normal MRI findings.⁴ One retrospective cohort study was neutral to eculizumab use in this population because 1 of 72 (1.4%) of individuals displayed ongoing dystonia, dysphagia, and dysarthria.¹⁶

Recently, a systematic review evaluated current evidence describing the use of eculizumab in the setting of STEC-HUS with neurological involvement.¹⁰ The authors concluded that while the quality of the evidence was low, some of the studies reviewed indicated a positive clinical improvement with eculizumab treatment.

In the case presented, the timing of eculizumab administration in the setting of hemodialysis was important to the patient's family and members participating in the patient's care. This was because both groups hoped to optimize the drug's possible benefits for controlling the patient's neurological symptoms. In the setting of the drug's high cost and lack of approval by the US Food and Drug Administration for this indication, which create barriers for insurance approval, our team looked to available information from the manufacturer and literature to address this concern. With the limited information available, we administered 2 total doses of eculizumab around hemodialysis and the patient displayed improvements in hematologic values, notably platelet recovery by hospital day 15, renal function return to baseline by hospital day 15, and neurological symptoms alleviated with cessation of seizures after the second dose of eculizumab.

Conclusion

Due to the lack of controlled data available, case reports and series coupled with direct application of pharmacologic properties have been the sole guidance for the use of eculizumab for STEC-HUS with neurological involvement.^1–16 No literature exists to direct decision-making with regard to the timing of eculizumab and hemodialysis. In this patient with severe neurological involvement, eculizumab was well tolerated and its use corresponded with initial symptom improvement. We are unable to comment on eculizumab's efficacy; however, we do suggest eculizumab is a reasonable option based on this course. Our report adds to present literature describing the successful recovery from neurological symptoms following early eculizumab administration in the setting of intermittent hemodialysis. It seems eculizumab may be given during or between hemodialysis without dose adjustment based on our case study. More controlled studies will be useful to aid in decision-making with regard to initiating eculizumab in STEC-HUS with neurological involvement, as well as drug dosing in hemodialysis. A randomized controlled trial in pediatric patients is currently underway to examine the use of eculizumab in STEC-HUS with secondary outcomes including neurological involvement¹⁷.

ABBREVIATIONS

CNS

central nervous system

CRRT

continuous renal replacement therapy

HUS

hemolytic uremic syndrome

MRI

magnetic resonance imaging

SCr

serum creatinine

STEC-HUS

Shiga toxin producing Escherichia coli hemolytic uremic syndrome