Clostridioides difficile-Associated Atypical Hemolytic-Uremic Syndrome Successfully Treated With Eculizumab: A Case Report and Literature Review.
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ABSTRACT: Case summary
We present a case of a previously healthy 21-year-old woman who developed fulminant C. difficile colitis and atypical hemolytic-uremic syndrome requiring abdominal surgery and renal replacement therapy. She was ultimately treated with eculizumab without the use of plasmapheresis and remains in remission with full renal recovery.Conclusions
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. We propose that C. difficile-associated atypical hemolytic-uremic syndrome be defined as primary atypical hemolytic-uremic syndrome and strongly consider eculizumab as first-line therapy.
SUBMITTER: Moulton MN
PROVIDER: S-EPMC8280067 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To describe a case of atypical hemolytic uremic syndrome induced by influenza A infection with the p.Ile1157Thr C3 mutation.Data sourcesClinical observations of a patient.Study selectionCase reports.Data extractionData extracted from medical records, after patient's consent.Data synthesisFour days prior to presentation to our hospital, a 16-year-old adolescent had a fever and arthralgia with hematuria. He was found to be positive for type A influenza and prescribed oseltamivir and acetaminophen by a primary-care physician. A bleeding tendency and purpura in the extremities and on the trunk developed; therefore, he was transferred to Chiba University Hospital. Hematology revealed severe thrombocytopenia, hyperbilirubinemia, and acute kidney injury. Aspartate aminotransferase, lactate dehydrogenase, and potassium could not be determined because of severe hemolysis. Highly elevated blood urea nitrogen and creatinine levels indicated acute kidney injury. A platelet count of 24,000/μL indicated thrombocytopenia, with low hemoglobin level. Peripheral blood profiling identified schistocytes. Continuous hemodiafiltration and plasma infusion were initiated immediately; however, he became oliguric. Plasma exchange was initiated on ICU day 3, but decreased urine output, hemolysis, and thrombocytopenia persisted. IV eculizumab therapy was initiated on day 7 and resulted in recovery of these symptoms and also successful discontinuation of renal support. The patient showed a stable condition without recurrence of hemolytic findings and acute kidney injury and is currently on maintenance therapy of eculizumab (1,200 mg, every other week) without any relapse of atypical hemolytic uremic syndrome symptoms. A plasma sample collected prior to initiation of plasma exchange showed an disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 activity level of 104.9%. The absence of both Shiga toxin-producing Escherichia coli in feces led to suspicion of atypical hemolytic uremic syndrome. Subsequent genetic analysis identified a mutation in C3 (p.Ile1157Thr), confirming the diagnosis of atypical hemolytic uremic syndrome.ConclusionsAlthough managing thrombocytopenia secondary to infection, inclusion of atypical hemolytic uremic syndrome in the differential diagnosis at an early stage is important in clinical practice.
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Project description:The biology of atypical hemolytic uremic syndrome has been shown to involve inability to limit activation of the alternative complement pathway, with subsequent damage to systemic endothelial beds and the vasculature, resulting in the prototypic findings of a thrombotic microangiopathy. Central to this process is the formation of the terminal membrane attack complex C5b-9. Recently, application of a monoclonal antibody that specifically binds to C5, eculizumab, became available to treat patients with atypical hemolytic uremic syndrome, replacing plasma exchange or infusion as primary therapy. This review focuses on the evidence, based on published clinical trials, case series, and case reports, on the efficacy and safety of this approach.
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Project description:Atypical hemolytic uremic syndrome (aHUS) treatment consists of eculizumab. Severe acute respiratory syndrome coronavirus 2 causes severe pneumonia and endothelial injury that leads to a prothrombotic state that may be complicated by macrovascular and microvascular thrombosis. Complement activation is thought to contribute to endothelial injury and there are at least seven ongoing clinical trials testing six different anti-complement strategies for coronavirus disease 2019 (COVID-19), including eculizumab. We herein report on a kidney transplant patient with aHUS on chronic eculizumab therapy that developed severe COVID-19 despite eculizumab administration early in the course of the disease. Although eculizumab was unable to prevent the development of severe endothelial cell injury, as assessed by increasing D-dimer levels from 292 to 10 586 ng/mL, the patient eventually recovered following dexamethasone and convalescent plasma administration.
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Project description:BackgroundSecondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS.MethodsObservational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets.ResultsWe found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort).ConclusionEarly and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.
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Project description:With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.
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Project description:Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disorder for which prompt diagnosis and eculizumab treatment is indicated. The time for relapse and patients at risk for relapse after eculizumab discontinuation are unknown. While some authors believe there is no clinical evidence supporting eculizumab discontinuation, which may be associated with high collateral risks such as loss of renal function, other authors believe that the drug can be safely discontinued with close patient monitoring. In this editorial, we update the pros and cons for eculizumab discontinuation in aHUS.
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Project description:BackgroundThere are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab.MethodsPatients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events.ResultsAmong 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported.ConclusionsThe current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes.Trial registrationClinicalTrials.gov NCT01522170 , January 31, 2012.
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Project description:There is a high incidence of acute kidney injury with COVID-19 infections. The etiologies of acute kidney injury could be ischemic acute tubular necrosis or a complex process of complement activation leading to thrombotic microangiopathy. We present a case of 32-year-old Hispanic male with a history of heart transplant, admitted with COVID-19 and atypical hemolytic uremic syndrome, which was successfully treated with Eculizumab.
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Project description:To describe how maintenance eculizumab sustains improved renal function in severe atypical hemolytic uremic syndrome (aHUS).A previously described 50-year-old woman with aHUS had a remarkable recovery with eculizumab, which safely reversed profound neurologic damage and eliminated the need for dialysis. Her recovery has been sustained on long-term eculizumab treatment. She initially received eculizumab 900 mg weekly for four doses. On week 5 she commenced maintenance therapy starting at 1200 mg every 2 weeks. Due to nausea and vomiting at that dose, the maintenance dosing was reduced to 600 mg weekly, beginning on dose seven. After receiving 600 mg weekly for nine doses, eculizumab was then reduced to 600 mg every 2 weeks, with continued improvement in renal function. This dosing is lower than the usual 1200 mg every 2 weeks described in the adult literature and used in current clinical trials of aHUS.Six months after the initial diagnosis, our patient continues to have improved renal function on maintenance doses of eculizumab as low as 600 mg every 2 weeks.
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Project description:IntroductionThe treatment of choice for Atypical Hemolytic Uremic Syndrome (aHUS) is the monoclonal antibody eculizumab. The objective of this study was to assess the efficacy and safety of eculizumab in a cohort of kidney transplant patients suffering from aHUS.MethodsDescription of the prospective cohort of all the patients primarily treated with eculizumab after transplantation and divided into the therapeutic (onset of aHUS after transplantation) and prophylactic use (patients with previous diagnosis of aHUS undergoing kidney transplantation).ResultsSeven cases were outlined: five of therapeutic use and two, prophylactic. From the five cases of therapeutic use, there was improvement of the thrombotic microangiopathy in the 48 hours following the start of the drug and no patient experienced relapse during an average follow-up of 21 months in the continuous use of eculizumab (minimum of 6 and maximum of 42 months). One patient died at 6 months, due to Aspergillus infection. From the two cases of prophylactic use, one patient experienced relapsed thrombotic microangiopathy after 4 months and another patient remained asymptomatic after 16 months of follow-up, both on chronic treatment.DiscussionThe therapeutic use of eculizumab showed to be effective, with improvement of the microangiopathy parameters and persisting up to the end of the follow-up, without relapses. The additional risk of immunosuppression, leading to opportunistic infections, was well tolerated. The prophylactic use showed to be effective and safe; however, the doses and intervals should be individualized in order to avoid relapsed microangiopathy, especially in patients with factor H mutation.
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