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Case Report

Clostridioides difficile-Associated Atypical Hemolytic-Uremic Syndrome Successfully Treated With Eculizumab: A Case Report and Literature Review

Moulton, Michael N. DO1; Kay, Carl L. MD1; Romain, Joshua T. MD2; Morrow, Benjamin D. MD3; Bobele, Gilda M. MD4

Author Information
Critical Care Explorations: July 2021 - Volume 3 - Issue 7 - p e0475
doi: 10.1097/CCE.0000000000000475


Thrombotic microangiopathies (TMAs) comprise a group of diseases characterized by diffuse microthrombi with associated hemolytic anemia and thrombocytopenia. The microthrombi can occur anywhere in the vascular system and lead to multiple organ failure, but have a predilection to affect the kidneys. Hemolytic-uremic syndrome (HUS) is a form of TMA with two types: typical and atypical. Typical HUS is precipitated by Shiga-toxin, usually from Escherichia coli 0157:H7 or Shigella (1). Atypical HUS (aHUS) is a rare subtype (approximately 10%) of HUS, which can be subclassified into primary and secondary aHUS (1) based on their relationship to the complement pathway. Primary aHUS results from dysregulation of the alternative complement pathway, whereas secondary aHUS is due to known precipitants (cancer, chemotherapy, solid organ transplant, pregnancy, or autoimmune diseases) not directly related to complement dysregulation (1). Primary aHUS has been attributed to infections such as Streptococcus pneumoniae, but a possible relationship with Clostridioides difficile infections has also been described. Our literature review demonstrates nine adult patients diagnosed with C. difficile-associated aHUS (CD-aHUS) (2–7), although the exact mechanism is poorly understood (8). Of these cases, only two have been treated effectively with plasmapheresis and eculizumab. We present the 10th known case in adults and the only patient with severe CD-aHUS effectively treated with eculizumab without plasmapheresis. Our patient provided consent for publication.


A 21-year-old previously healthy woman presented to the hospital with 4 days of diffuse abdominal pain, dysuria, multiple episodes of bloody diarrhea associated with nausea, and nonbloody, nonbilious emesis. She had no recent antibiotic use, took no medications, and denied supplement use. She had no family history of inflammatory bowel disease or other autoimmune diseases. Her vital signs on presentation were normal and her physical examination was only notable for diffuse abdominal tenderness without rigidity or distention.

Laboratory evaluation revealed leukocytosis of 21,000 cells/mm3, hemoglobin 15.8 g/dL, platelet count (PLT) 247,000 cells/mm3, and normal kidney function (creatinine 0.65 mg/dL) with a bland urinalysis. Stool studies were positive for C. difficile toxin B (tcdB) gene DNA. Additional stool studies were negative, including Shigella, Campylobacter, Salmonella, and E. coli 0157:H7 with enteric parasite polymerase chain reaction negative. CT abdomen/pelvis was notable for severe colitis extending from cecum to the proximal descending colon. The patient was diagnosed with severe C. difficile colitis and was started on oral vancomycin and IV metronidazole.

Despite 2 days of appropriate antimicrobials, she had increasing abdominal pain and developed oliguria by hospital day (HD) 3. Abdominal radiography was negative for pneumoperitoneum and toxic megacolon, but laboratory parameters mirrored her clinical worsening: creatinine 1.8 mg/dL, WBC 23,900 cells/mm3, PLT 65,000 cells/mm3, hemoglobin 11.7 g/dL, fibrin d-dimer greater than 20 µg/mL, slight schistocytes present, fibrinogen 486, prothrombin time 17.2 seconds, and direct antiglobulin test negative. In the setting of multiple organ system failure attributed to fulminant C. difficile colitis, she underwent total abdominal colectomy with end ileostomy. Her intraoperative course was uneventful with minimal blood loss and no vasopressor requirement. She received approximately 2 L of crystalloid and 1 unit of FFP. Postoperative labs were pertinent for serum creatinine 3.9 mg/dL, hemoglobin 6.5 g/dL, and PLT 76,000 cells/mm3. She was started on continuous renal replacement therapy for anuric acute kidney injury (AKI) with clinically significant acidosis.

On HD 6, she acutely developed severe agitation and visual hallucinations, fever of 104 °F, and generalized tonic-clonic movements concerning for seizure, requiring intubation for airway protection. A lumbar puncture found normal opening pressure and unremarkable cerebral spinal fluid with exception of protein elevation at 114 mg/dL. Electroencephalography (EEG) was abnormal with noted asymmetry between the left and right hemispheres. MRI demonstrated new bilateral thalamic T2 and diffusion-weighted imaging abnormalities, multifoci of susceptibility with the corpus callosum, and right cortical Fluid Attenuated Inversion Recovery signal all concerning for encephalitis.

Extensive infectious, hematologic, hereditary, metabolic, and autoimmune evaluations were performed, as demonstrated in Supplemental Table 1 ( Hematologic workup was notable for haptoglobin level (less than 15 mg/dL), marked schistocytes, and elevated lactate dehydrogenase (peak value 1,984 U/L) with hemoglobin and platelet nadir of 5.2 g/dL and 42 cells/mm3, respectively. Peripheral flow cytometry was negative for clonal process. ADAM Metallopeptidase With Thrombospondin Type 1 Motif 13 activity resulted at 61%, C3 57 mg/dL, C4 less than 12 mg/dL, factor H antibody 2.5% (reference 0–7.3%), and total complement activity 40 U/mL (reference greater than 41 U/mL). Renal biopsy was considered but ultimately not pursued given her critically ill state and overall lack of change in management. After a multidisciplinary discussion with hematology, nephrology, neurology, and the intensive care team, the patient was started on eculizumab on HD 12 for presumptive diagnosis of aHUS triggered by fulminant C. difficile colitis. With autoimmune encephalitis workup pending, she was also started on high-dose steroids (1,000-mg methylprednisolone daily) for possible autoimmune and inflammatory processes contributing to her encephalopathy. She was empirically covered for serotonin syndrome and neuroleptic malignant syndrome even without an obvious trigger, as she had received low doses of fentanyl and haloperidol in the preceding 24 hours.

She had rapid improvement in renal function and neurologic status over the next 72 hours. Interval MRI brain demonstrated resolution of aforementioned thalamic abnormalities. She continued on weekly eculizumab 900 mg for 4 weeks followed by biweekly 1,200 mg dosing. Her last intermittent hemodialysis session was on HD 16, and she was discharged with full renal recovery. Her hospital course is summarized in Figure 1. Renal, neurologic, and hematologic parameters returned to normal within 2 months of discharge.

Figure 1.
Figure 1.:
Overview of hospital course. CRRT = continuous renal replacement therapy, IHD = intermittent hemodialysis, LDH = lactate dehydrogenase.

Pathology results from her colectomy were not consistent with inflammatory bowel disease but did demonstrate superficial mucosal evidence of TMA with other features consistent with pseudomembranous colitis. Full exome sequencing along with targeted aHUS related genes was unremarkable. She completed 2 months of therapy of eculizumab, and after risk benefit discussion with her hematologist, the patient opted to trial active surveillance with biweekly laboratory observation. She remains in remission 4 months after discharge with successful ileostomy takedown and ileorectal anastomosis.


aHUS can be fatal with mortality of approximately 25% and significant morbidity, with 50% of patients developing end-stage renal disease (1). This is likely due to the difficulty in diagnosis; there is no definitive testing modality, and the disease is rare in the adult population (9). Prompt diagnosis requires maintaining a broad differential diagnosis on patient presentation and throughout the clinical course, and recognizing the therapeutic benefit of eculizumab in promoting renal recovery in complement-mediated aHUS (10).

This patient presented with signs and symptoms consistent with fulminant C. difficile with severe AKI, anemia, and thrombocytopenia—all of which were thought to have secondary etiologies (i.e., sepsis, prerenal AKI, and disseminated intravascular coagulation). Her significant neurologic manifestations, with objectifiable abnormal findings on MRI and EEG, further confounded her clinical picture. We considered performing plasma exchange, but the coronavirus disease 2019 pandemic created significant system limitations that rendered this infeasible. Thus, the patient was initiated on eculizumab for suspected complement-mediated aHUS in the setting of low C3 and C4 levels, as typical HUS had been ruled out with stool studies, and there will always be some components of diagnostic uncertainty given the difficulty in diagnosis of aHUS (9).

Our patient’s clinical improvement and laboratory markers all support eculizumab as the treatment modality that reversed her disease course and led to her remission. As demonstrated in Figure 1, there is clear improvement in her renal function associated with the initation of eculizumab in the timeframe expected based on the drug’s 11-hour half-life (1). Furthermore, her hemolysis laboratory trend (Fig. 1) and resolution of thalamic abnormalities are also temporally correlated with its initiation. With 2 months of continued therapy, our patient’s anemia (nadir Hg 5.2 g/dL, HD) and thrombocytopenia (nadir PLT 43 cells/mm3) resolved, her renal function recovered, and her neurologic deficits improved.

The hypothesized pathopysiology of CD-aHUS is that cytotoxins A and B bind to colonic cell membranes and activate proinflammatory cytokines leading to microvascular damage (8). The robust response to a terminal complement inhibitor without the use of plasmaphoresis in our patient suggests that there is a distinct role of the alternative complement cascade in addition to an inflammatory cytokine storm. With this, we suggest that CD-aHUS be classified as a primary aHUS or secondary aHUS with the addition of C. difficile as a known trigger in the medical literature (9). However, we favor primary aHUS as there seems to be a clear connection to complement dysregulation in CD-aHUS, as evidence by our patient’s rapid improvement with eculizumab therapy only, without the use of plasmaphoresis. As previous reports of known complement-mediated aHUS have shown more renal recovery with anticomplement therapy, eculizumab may be considered as the first-line therapy over plasmaphoresis (1,10). Careful consideration should be given in septic patients as eculizumab could worsen clinical picture if there is no dysregulation of the complement pathway, as there will always be a level of ambiguity with our current diagnostic tests for aHUS, which is demonstrated in our case.

There are several other features of our case that are distinct from previous nine cases of CD-aHUS in adults (Table 1). First, our patient was the only case who required surgical intervention as part of management for fulminant C. difficile infection. Second, our patient had no classic risk factor for C. difficile infection, suggesting this is the only case of community-acquired C. difficile infection. Finally, our patient had significant neurologic symptoms to include seizures, EEG, and MRI findings as discussed above, leading to mechanical intubation for several days. In previously reported cases, only four other patients had neurologic symptoms, however none as profound as our patients (2–7). This case highlights that the high morbidity and mortality associated with aHUS likely also present with CD-aHUS and that timely recognition and initiation of appropriate therapy are integral to improving outcomes.

TABLE 1. - Summary of Cases of Clostridioides difficile-Associated Atypical Hemolytic-Uremic Syndrome in Adults
Age/Sex Clinical Features Risk Factors for Clostridioides difficile Surgery Required Treatment Renal Replacement Therapy Outcome References
51/woman Watery diarrhea and confusion Recent antibiotics No Oral and rectal vancomycin, FFP transfusions (BT) No Recovery Mogyorosi et al (2)
46/woman Bloody diarrhea and vomiting Recent antibiotics No Oral metronidazole and PLEX Yes Recovery Mbonu et al (8)
62/woman Watery diarrhea Age No IV metronidazole, PLEX, steroids, and transfusions (BT) Yes Recovery Keshtkar-Jahromi et al (3)
73/woman Watery diarrhea, respiratory distress, chills, anuria, and membrane cofactor protein deficiency Age No Metronidazole and steroids Yes Recovery Kalmanovich et al (4)
29/woman Diarrhea, anuria, and renal transplant patient Immunosuppression No Vancomycin Yes Recovery Alvarado et al (5)
52/woman Fever, diarrhea, nausea, vomiting, encephalopathy, and renal transplant patient Immunosuppression No Oral metronidazole and PLEX Yes Allograph failure, transplant nephrectomy Alvarado et al (5)
63/woman Bloody diarrhea, fever, and confusion Age No IV metronidazole, vancomycin, and PLEX Yes Partial renal recovery Alvarado et al (5)
46/man Watery diarrhea, oliguria, and encephalopathy Recent antibiotics, hospitalization, and bowel surgery No Metronidazole, vancomycin, PLEX, eculizumab, transfusions (PRBC), and intubation and mechanical ventilation Yes Recovery Inglis et al (6)
60/woman Watery diarrhea, vomiting, and oliguria Recent antibiotics No IV metronidazole, vancomycin, PLEX, and eculizumab Yes Recovery Khurshid et al (7)
21/woman Bloody diarrhea, dysuria, fever, profound encephalopathy, thalamic lesions, and seizures None Yes IV metronidazole, vancomycin, steroids, transfusions (PRBC, FFP), eculizumab, and intubation and mechanical ventilation Yes Recovery Moulton et al
BT = blood transfusion not otherwise specified, FFP = fresh frozen plasma, PLEX = plasma exchange, PRBC = packed RBC, RRT = renal replacement therapy.


Our patient’s significant response to terminal complement inhibitor, without the use of plasmapheresis, suggests that the underlying pathology is significantly driven by the alternative complement pathway. Therefore, we propose that CD-aHUS be defined as primary atypical hemolytic-uremic syndrome. We also propose clinicians to strongly consider eculizumab as first-line therapy for CD-aHUS.


1. Afshar-Kharghan V. Atypical hemolytic uremic syndrome. Hematology 2016; 12:217–225
2. Mogyorosi A, Carley MD. Hemolytic-uremic syndrome associated with pseudomembranous colitis caused by Clostridium difficile. Nephron 1997; 76:491
3. Keshtkar-Jahromi M, Mohebtash M. Hemolytic uremic syndrome and Clostridium difficile colitis. J Community Hosp Intern Med Perspect 2012; 2:19064
4. Kalmanovich E, Kriger-Sharabi O, Shiloah E, et al. Atypical hemolytic uremic syndrome associated with Clostridium difficile infection and partial membrane cofactor protein (CD46) deficiency. Isr Med Assoc J 2012; 14:586–587
5. Alvarado AS, Brodsky SV, Nadasdy T, et al. Hemolytic uremic syndrome associated with Clostridium difficile infection. Clin Nephrol 2014; 81:302–306
6. Inglis JM, Barbara JA, Juneja R, et al. Atypical haemoltyic uraemic syndrome associated with Clostridium difficile infection successfully treated with eculizimab. Case Rep Nephrol 2018; 5:1–4
7. Khurshid Q, Mahmoud A, Shahid M, et al. Atypical hemolytic uremic syndrome associated with clostridium difficile infection. Cureus 2020; 12:e9005
8. Mbonu CC, Davison DL, El-Jazzar KM, et al. Clostridium difficile colitis associated with hemolytic-uremic syndrome. Am J Kidney Dis 2003; 41:E14
9. 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
10. Berabeu A, Escribano T, Vilarino M. Atypical hemolytic uremic syndrome: New challenges in the complement blockage era. Nephron 2020; 144:537–549

case report; Clostridioides difficile; eculizumab; hemolytic-uremic syndrome; renal replacement therapy; thrombotic microangiopathies

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