Hemolytic Uremic Syndrome Patients Research Articles

Assessment of Pediatric Hemolytic Uremic Syndrome Patients Hospitalized in Pediatric Intensive Care Unit

Aim: It is aimed to describe clinical properties and outcomes of pediatric hemolytic uremic syndrome hospitalized in pediatric intensive care.
 Material and Method: Our study was intended as observatory and retrospective. Symptoms before PICU admission, interventions before PICU admission, time period before PICU admission in days were defined as pre-PICU findings. Glasgow Coma Score (GCS) at admission, Pediatric Risk of Mortality Score (PRİSM-III), laboratory parameters, medical treatments, extracorporeal treatments data was collected as PICU interventions. Outcomes were examined as days in PICU, days in hospital and survival.
 Results: Twenty-three patients were included into study. Before PICU admission more than half of the patients were treated with antibiotics. Twenty-two were suffered from diarrhea. 3 patients had non-bloody diarrhea. 3 patients had central nervous system involvement presented as seizures. Intravenous diuretics (86.9%) and oral antihypertensives (73.9%) were the most common treatments in PICU. Eculizumab treatment was required for 6 patients. All patients got fresh frozen plasma. Nearly all of the patients required erythrocyte transfusions (95.6%). If we evaluated renal replacement therapies, 2 (8.6%) patients needed CRRT and 12 (52.7%) patients needed IHD. Extrarenal involvement was spotted in 5 patients (21.7%). Most of the patients were survived (95.3%).
 Conclusion: Hemolytic uremic syndrome is an important clinic entity. Most patients’ blood pressure could be controlled with oral antihypertensive treatments. Antibiotic prescriptions to diarrhetic patients should be more cautiously. There should be transfusion protocols of clinics about HUS patients to prevent over transfusion.

Review of Escherichia coli O157:H7 Prevalence, Pathogenicity, Heavy Metal and Antimicrobial Resistance, African Perspective.

Escherichia coli O157:H7 is an important food-borne and water-borne pathogen that causes hemorrhagic colitis and the hemolytic-uremic syndrome in humans and may cause serious morbidity and large outbreaks worldwide. People with bloody diarrhea have an increased risk of developing serious complications such as acute renal failure and neurological damage. The hemolytic-uremic syndrome (HUS) is a serious condition, and up to 50% of HUS patients can develop long-term renal dysfunction or blood pressure-related complications. Children aged two to six years have an increased risk of developing HUS. Clinical enteropathogenic Escherichia coli (EPEC) infections show fever, vomiting, and diarrhea. The EPEC reservoir is unknown but is suggested to be an asymptomatic or symptomatic child or an asymptomatic adult carrier. Spreading is often through the fecal-oral route. The prevalence of EPEC in infants is low, and EPEC is highly contagious in children. EPEC disease in children tends to be clinically more severe than other diarrheal infections. Some children experience persistent diarrhea that lasts for more than 14 days. Enterotoxigenic Escherichia coli (ETEC) strains are a compelling cause of the problem of diarrheal disease. ETEC strains are a global concern as the bacteria are the leading cause of acute watery diarrhea in children and the leading cause of traveler’s diarrhea. It is contagious to children and can cause chronic diarrhea that can affect the development and well-being of children. Infections with diarrheagenic E. coli are more common in African countries. Antimicrobial agents should be avoided in the acute phase of the disease since studies showed that antimicrobial agents may increase the risk of HUS in children. The South African National Veterinary Surveillance and Monitoring Programme for Resistance to Antimicrobial Drugs has reported increased antimicrobial resistance in E. coli. Pathogenic bacterial strains have developed resistance to a variety of antimicrobial agents due to antimicrobial misuse. The induced heavy metal tolerance may also enhance antimicrobial resistance. The prevalence of antimicrobial resistance depends on the type of the antimicrobial agent, bacterial strain, dose, time, and mode of administration. Developing countries are severely affected by increased resistance to antimicrobial agents due to poverty, lack of proper hygiene, and clean water, which can lead to bacterial infections with limited treatment options due to resistance.

Etiological diagnosis of post-diarrheal hemolytic uremic syndrome (HUS): humoral response contribution.

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolysis, thrombocytopenia, and thrombus formation leading to tissue injury. HUS is classified according to its etiology as post-diarrheal or atypical HUS. Differential diagnosis of both entities continues to be a challenge for pediatric physicians. The aim was to improve the rapid etiological diagnosis of post-diarrheal HUS cases based on the detection of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection by screening of stx1/stx2 and rfbO157 in cultured stools by multiplex PCR, and the additional detection of anti-lipopolysaccharide (anti-LPS) O157, O145, and O121 antibodies by Glyco-iELISA test. In addition, we studied patients' relatives to detect circulating pathogenic strains that could contribute to HUS diagnosis and/or lead to the implementation of measures to prevent dissemination of familial outbreaks. This study describes the diagnosis of 31 HUS patients admitted to Hospital Municipal de Niños Prof Dr Ramón Exeni during the 2017-2020 period. Stool PCR confirmed the diagnosis of STEC associated with HUS in 38.7% of patients (12/31), while anti-LPS serology did in 88.9% (24/27). In those patients in which both methods were carried out (n = 27), a strong association between the results obtained was found. We found that 30.4% of HUS patients had at least one relative positive for STEC. We could identify 96.3% (26/27) of HUS cases as secondary to STEC infections when both methods (genotyping and serology) were used. The results demonstrated a high circulation of STEC in HUS families and the prevalence of the STEC O157 serotype (83%) in our pediatric cohort. A higher-resolution version of the Graphical abstract is available as Supplementary information.

Comparative Genomics of Shiga Toxin-Producing Escherichia coli Strains Isolated from Pediatric Patients with and without Hemolytic Uremic Syndrome from 2000 to 2016 in Finland.

ABSTRACTShiga toxin-producing Escherichia coli (STEC) infection can cause mild to severe illness, such as nonbloody or bloody diarrhea, and the fatal hemolytic uremic syndrome (HUS). The molecular mechanism underlying the variable pathogenicity of STEC infection is not fully defined so far. Here, we performed a comparative genomics study on a large collection of clinical STEC strains collected from STEC-infected pediatric patients with and without HUS in Finland over a 16-year period, aiming to identify the bacterial genetic factors that can predict the risk to cause HUS and poor renal outcome. Of 240 STEC strains included in this study, 52 (21.7%) were from pediatric patients with HUS. Serotype O157:H7 was the main cause of HUS, and Shiga toxin gene subtype stx2a was significantly associated with HUS. Comparative genomics and pangenome-wide association studies identified a number of virulence and accessory genes overrepresented in HUS-associated STEC compared to non-HUS STEC strains, including genes encoding cytolethal distending toxins, type III secretion system effectors, adherence factors, etc. No virulence or accessory gene was significantly associated with risk factors for poor renal outcome among HUS patients assessed in this study, including need for and duration of dialysis, presence and duration of anuria, and leukocyte counts. Whole-genome phylogeny and multiple-correspondence analysis of pangenomes could not separate HUS STEC from non-HUS STEC strains, suggesting that STEC strains with diverse genetic backgrounds may independently acquire genetic elements that determine their varied pathogenicity. Our findings indicate that nonbacterial factors, i.e., characteristics of the host immunity, might affect STEC virulence and clinical outcomes.IMPORTANCE Shiga toxin-producing Escherichia coli (STEC) is a serious public health burden worldwide which causes outbreaks of gastrointestinal diseases and the fatal hemolytic uremic syndrome (HUS) characterized by the triad of mechanical hemolytic anemia, thrombocytopenia, and acute renal failure. Understanding the mechanism underlying the disease severity and patient outcome is of high importance. Using comparative genomics on a large collection of clinical STEC strains from STEC-infected patients with and without HUS, our study provides a reference of STEC genetic factors/variants that can be used as predictors of the development of HUS, which will aid risk assessment at the early stage of STEC infection. Additionally, our findings suggest that nonbacterial factors may play a primary role in the renal outcome in STEC-infected patients with HUS; further studies are needed to validate this.

POS-044 ECULIZUMAB INTERRUPTION IN KIDNEY TRANSPLANT RECIPIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME: ANALYSIS OF A BRAZILIAN SHORTAGE

IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted.MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy.ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%.ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. After a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. We screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. We analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest This study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.

Ocular involvement in STEC-associated hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a systemic thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, and variable kidney involvement. Extrarenal thrombotic microangiopathy occurs in central nervous system (CNS), colon, and other organ systems, but ocular involvement is rarely recognized. This study aimed to analyze frequency and severity of ocular involvement in STEC-HUS, and the relationship between ocular involvement and disease severity, with emphasis on CNS, kidney, and colonic disease. Prospective, longitudinal, observational study. STEC-HUS patients September 2014-January 2019. Funduscopic examination (FE) was performed within 48h of admission. We evaluated severity of CNS disease, kidney involvement, and presence of hemorrhagic colitis (HC). Ninety-nine patients were included (female 52), mean age 39.4months (DE: 29.8; range 9-132). Thirteen patients (13.1%) had abnormal FE, 10 showing variable degrees of hemorrhagic exudates and 2 with typical Purtscher-like retinopathy. Other findings included tortuous vascularity, cotton wool spots, and transient retinal edema. CNS involvement was present in 16/99 patients, severe in 12 (75%). Abnormal FE occurred in 5/12 (31%) patients with severe CNS involvement vs. 8/87 (9.2%) with mild, moderate, or no CNS disease (p = 0.0191). Abnormal FE was present in 2/33 (6%) patients without dialysis vs. 11/66 (16.6%) requiring dialysis (p = 0.20). Finally, there were FE abnormalities in 6/20 patients with HC vs. 7/79 without HC (p = 0.012). FE abnormalities were present in 13% of HUS patients. Abnormal FE significantly associated with more severe disease, including severe CNS involvement and HC. We suggest FE should be performed in severe HUS, especially in cases with severe CNS disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing

Complement factor H (CFH) and its related proteins have an essential role in regulating the alternative pathway of the complement system. Mutations and structural variants (SVs) of the CFH gene cluster, consisting of CFH and its five related genes (CFHR1-5), have been reported in renal pathologies as well as in complex immune diseases like age-related macular degeneration and systemic lupus erythematosus. SV analysis of this cluster is challenging because of its high degree of sequence homology. Following first-line next-generation sequencing gene panel sequencing, we applied Genomic Vision's Molecular Combing Technology to detect and visualize SVs within the CFH gene cluster and resolve its structural haplotypes completely. This approach was tested in three patients with atypical hemolytic uremic syndrome and known SVs and 18 patients with atypical hemolytic uremic syndrome or complement factor 3 glomerulopathy with unknown CFH gene cluster haplotypes. Three SVs, a CFH/CFHR1 hybrid gene in two patients and a rare heterozygous CFHR4/CFHR1 deletion in trans with the common CFHR3/CFHR1 deletion in a third patient, were newly identified. For the latter, the breakpoints were determined using a targeted enrichment approach for long DNA fragments (Samplix Xdrop) in combination with Oxford Nanopore sequencing. Molecular combing in addition to next-generation sequencing was able to improve the molecular genetic yield in this pilot study. This (cost-)effective approach warrants validation in larger cohorts with CFH/CFHR-associated disease.

Cardiac involvement in pediatric hemolytic uremic syndrome.

Cardiac involvement is a known but rare complication of pediatric hemolytic uremic syndrome (HUS). We conducted a nationwide observational, retrospective case-control study describing factors associated with the occurrence of myocarditis among HUS patients. Cases were defined as hospitalized children affected by any form of HUS with co-existent myocarditis in 8 French Pediatric Intensive Care Units (PICU) between January 2007 and December 2018. Control subjects were children, consecutively admitted with any form of HUS without coexistent myocarditis, at a single PICU in Lyon, France, during the same time period. A total of 20 cases of myocarditis were reported among 8 PICUs, with a mean age of 34.3 ± 31.9months; 66 controls were identified. There were no differences between the two groups concerning the season and the typical, Shiga toxin-producing Escherichia coli (STEC-HUS), or atypical HUS (aHUS). Maximal leukocyte count was higher in the myocarditis group (29.1 ± 16.3G/L versus 21.0 ± 9.9G/L, p = 0.04). The median time between admission and first cardiac symptoms was of 3days (range 0-19days), and 4 patients displayed myocarditis at admission. The fatality rate in the myocarditis group was higher than in the control group (40.0% versus 1.5%, p < 0.001). Thirteen (65%) children from the myocarditis group received platelet transfusion compared to 19 (29%) in the control group (p = 0.03). Our study confirms that myocarditis is potentially lethal and identifies higher leukocyte count and platelet transfusion as possible risk factors of myocarditis. A higher resolution version of the Graphical abstract is available as Supplementary information.

High prevalence and pathogenic potential of Shiga toxin-producing Escherichia coli strains in raw mutton and beef in Shandong, China

Shiga toxin-producing Escherichia coli (STEC) is a foodborne pathogen that can cause severe human diseases such as hemolytic uremic syndrome (HUS). Human STEC infections are frequently caused through consumption of contaminated foods, especially raw meats. This study aimed to investigate the prevalence of STEC in raw meats and to characterize the meat-derived STEC strains using whole genome sequencing. Our study showed that 26.6% of raw mutton, and 7.5% of raw beef samples were culture-positive for STEC. Thirteen serotypes were identified in 22 meat-derived isolates in this study, including the virulent serotypes O157:H7 and O26:H11. Seven Shiga toxin (Stx) subtypes were found in 22 isolates, of these, stx1c and stx1c + stx2b were predominant. The recently-reported stx2k subtype was found in three mutton-sourced isolates. A number of other virulence genes such as genes encoding intimin (eae), enterohemorrhagic E. coli (EHEC) hemolysin (ehxA), EHEC factor for adherence (efa1), heat-stable enterotoxin 1 (astA), type III secretion system effectors, were detected in meat-derived STEC strains. One mutton-sourced isolate was resistant to three antibiotics, i.e., tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. Whole-genome phylogeny indicated the genomic diversity of meat-derived strains in this study. O157:H7 and O26:H11 isolates in this study were phylogenetically grouped together with strains from HUS patients, suggesting their pathogenic potential. To conclude, our study reported high STEC contaminations in retail raw meats, particularly raw mutton, genomic characterization indicated pathogenic potential of meat-derived STEC strains. These findings highlight the critical need for increased monitoring of STEC in retail raw meats in China.

The Deleterious Effects of Shiga Toxin Type 2 Are Neutralized In Vitro by FabF8:Stx2 Recombinant Monoclonal Antibody.

Hemolytic Uremic Syndrome (HUS) associated with Shiga-toxigenic Escherichia coli (STEC) infections is the principal cause of acute renal injury in pediatric age groups. Shiga toxin type 2 (Stx2) has in vitro cytotoxic effects on kidney cells, including human glomerular endothelial (HGEC) and Vero cells. Neither a licensed vaccine nor effective therapy for HUS is available for humans. Recombinant antibodies against Stx2, produced in bacteria, appeared as the utmost tool to prevent HUS. Therefore, in this work, a recombinant FabF8:Stx2 was selected from a human Fab antibody library by phage display, characterized, and analyzed for its ability to neutralize the Stx activity from different STEC-Stx2 and Stx1/Stx2 producing strains in a gold standard Vero cell assay, and the Stx2 cytotoxic effects on primary cultures of HGEC. This recombinant Fab showed a dissociation constant of 13.8 nM and a half maximum effective concentration (EC50) of 160 ng/mL to Stx2. Additionally, FabF8:Stx2 neutralized, in different percentages, the cytotoxic effects of Stx2 and Stx1/2 from different STEC strains on Vero cells. Moreover, it significantly prevented the deleterious effects of Stx2 in a dose-dependent manner (up to 83%) in HGEC and protected this cell up to 90% from apoptosis and necrosis. Therefore, this novel and simple anti-Stx2 biomolecule will allow further investigation as a new therapeutic option that could improve STEC and HUS patient outcomes.

In-Hospital Outcomes of Hemolytic Uremic Syndrome: A Perspective from the Last Decade

Introduction: Hemolytic Uremic Syndrome (HUS) is a condition characterized by progressive renal failure that is associated with microangiopathic hemolytic anemia and thrombocytopenia. It is a clinical syndrome which occurs as an immune reaction, most commonly after a gastrointestinal infection. Several studies have reported the prevalence of HUS among children but it is not well studied among adults. Studies have shown mortality rates ranging up to 20% and may go up to to 50% if HUS is complicated by end stage renal failure. There is limited data regarding HUS, especially among the adult population in regards to hospitalization trends and outcomes. In this study we aimed to describe the hospitalization trend, patient characteristics and in-hospital outcomes of HUS using a nationally representative database.Methods:Study cohort was from the Nationwide Inpatient Sample (NIS) for the years 2008-2017 for hospitalizations due to HUS by using International Classification of Diseases (9th/10th Editions) Clinical Modification diagnosis codes ICD-9-CM/ICD-10-CM). Other diagnosis and comorbidities were also identified by ICD-9/10-CM codes and Elixhauser comorbidity software. Our primary outcome was a discharge disposition following HUS hospitalization. We utilized multivariable survey logistic regression models to analyze and identify predictors of poor outcomes.Results:Between 2007-2018, a total of 8,043 hospitalizations occurred due to HUS. Hospitalization trend due to HUS increased from 528 (6.57%) in 2007 to 800 (9.95%) in 2013 and then reduced to 620 (7.7%) in 2018. Study cohort consisted of children <10 years of age (56.2%) followed by 18-65 years of age (24.7%). Out of total HUS patients, 74.4% were Caucasians and 59.3% were females. Overall in-hospital mortality of hospitalization due to HUS was 3.0%, and discharge to the facility was 15.7%. In trend analysis, the proportion of discharge to facility decreased from 23.1% in 2007 to 14.5% in 2018 but in-house mortality increased from 1% in 2007 to 3.2% in 2018. Median Length of hospital stay was 8-days (interquartile range 3-day to 15-days). Furthermore, in multivariable logistic regression analysis, age above 65 years (OR 2.5; 95%CI 1.4-5.8; p=0.0023), rural hospital (OR 17.9; 95%CI 8.9-36.1; p<0.001) and urban-non teaching hospital (OR 5.2; 95%CI 3.4-8.1; p<0.0001) and small-medium size hospitals were also associated with higher odds of discharge to facility among HUS patients.Conclusion:Our study estimates the epidemiology of hospitalizations due to HUS in the United States from a nationally representative database. In this study we observe that the burden of hospitalizations due to HUS has been increased over the study period. We also identified factors associated with poor discharge outcomes and some of which are modifiable. Further studies are warranted for developing strategies for better risk stratification of HUS patients to improve the overall outcomes. DisclosuresNo relevant conflicts of interest to declare.

Hemolytic Uremic Syndrome in Children.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA), mainly affecting the kidney. The disease is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It is one of the most common causes of acute kidney injury in children. Under this umbrella, there are several different disorders: Shiga toxin-associated HUS, Streptococcus pneumoniae-associated HUS, and HUS associated with complement dysregulation. Several drugs and conditions may also cause HUS. There are many different classification systems, which have been developed during the history of the disease. In recent years, clinical and experimental studies have revealed abnormalities in different pathways beyond complement system. Besides, therapeutic options that are based on the pathophysiology have been available for HUS patients.

Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome.

Haemolytic uraemic syndrome (HUS) is a common cause of acquired kidney failure in children and rarely in adults. The most important risk factor for development of HUS is a gastrointestinal infection by Shiga toxin-producing Escherichia coli (STEC). This review addressed the interventions aimed at secondary prevention of HUS in patients with diarrhoea who were infected with a bacteria that increase the risk of HUS. Our objective was to evaluate evidence regarding secondary preventative strategies for HUS associated with STEC infections. In doing so, we sought to assess the effectiveness and safety of interventions as well as their potential to impact the morbidity and death associated with this condition. We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Studies were considered based on the methods, participants, and research goals. Only randomised controlled trials were considered eligible for inclusion. The participants of the studies were paediatric and adult patients with diarrhoeal illnesses due to STEC. The primary outcome of interest was incidence of HUS. We used standard methodological procedures as recommended by Cochrane. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified four studies (536 participants) for inclusion that investigated four different interventions including antibiotics (trimethoprim-sulfamethoxazole), anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin binding agent (Synsorb Pk: a silicon dioxide-based agent), and a monoclonal antibody against Shiga toxin (urtoxazumab). The overall risk of bias was unclear for selection, performance and detection bias and low for attrition, reporting and other sources of bias. It was uncertain if trimethoprim-sulfamethoxazole reduced the incidence of HUS compared to no treatment (47 participants: RR 0.57, 95% CI 0.11-2.81, very low certainty evidence). Adverse events relative to this review, need for acute dialysis, neurological complication and death were not reported. There were no incidences of HUS in either the bovine colostrum group or the placebo group. It was uncertain if bovine colostrum caused more adverse events (27 participants: RR 0.92, 95% CI 0.42 to 2.03; very low certainty evidence). The need for acute dialysis, neurological complications or death were not reported. It is uncertain whether Synsorb Pk reduces the incidence of HUS compared to placebo (353 participants: RR 0.93, 95% CI 0.39 to 2.22; very low certainty evidence). Adverse events relevant to this review, need for acute dialysis, neurological complications or death were not reported. One study compared two doses of urtoxazumab (3.0 mg/kg and 1.0 mg/kg) to placebo. It is uncertain if either 3.0 mg/kg urtoxazumab (71 participants: RR 0.34, 95% CI 0.01 to 8.14) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) reduced the incidence of HUS compared to placebo (very low certainty evidence). Low certainty evidence showed there may be little or no difference in the number of treatment-emergent adverse events with either 3.0 mg/kg urtoxazumab (71 participants: RR 1.00, 95% CI 0.84 to 1.18) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) compared to placebo. There were 25 serious adverse events reported in 18 patients: 10 in the placebo group, and 9 and 6 serious adverse events in the 1.0 mg/kg and 3.0 mg/kg urtoxazumab groups, respectively. It is unclear how many patients experienced these adverse events in each group, and how many patients experienced more than one event. It is uncertain if either dose of urtoxazumab increased the risk of neurological complications or death (very low certainty evidence). Need for acute dialysis was not reported. The included studies assessed antibiotics, bovine milk, and Shiga toxin inhibitor (Synsorb Pk) and monoclonal antibodies (Urtoxazumab) against Shiga toxin for secondary prevention of HUS in patients with diarrhoea due to STEC. However, no firm conclusions about the efficacy of these interventions can be drawn given the small number of included studies and the small sample sizes of those included studies. Additional studies, including larger multicentre studies, are needed to assess the efficacy of interventions to prevent development of HUS in patients with diarrhoea due to STEC infection.

Volume Resuscitation and Progression to Organ Failure in Shiga Toxin-Producing Escherichia coli Infection in Adults.

OBJECTIVES:Shiga toxin-producing Escherichia coli infection is associated with dysentery and the hemolytic uremic syndrome, marked by the triad of microangiopathic hemolytic anemia, acute kidney failure, and thrombocytopenia. Descriptions of Shiga toxin-producing Escherichia coli outbreaks causing hemolytic uremic syndrome in adults are sparse, and management strategies are largely adapted from pediatric literature where aggressive fluid administration is recommended. However, these may not be ideal for adults.DESIGN:We present a case series of an Shiga toxin-producing Escherichia coli outbreak in U.S. Marine Corps recruits.SETTING:We review the clinical course, laboratory data, and fluid resuscitation used in hospitalized patients during the 2017 Shiga toxin-producing Escherichia coli outbreak at Marine Corps Recruit Depot, San Diego.PATIENTS:Patients admitted to the hospital for complications from Shiga toxin-producing Escherichia coli infection. All were previously healthy men between the ages of 17 and 20 years.INTERVENTIONS:Isotonic crystalloid fluid resuscitation during the first 72 hours.MEASUREMENTS AND MAIN RESULTS:Of 244 identified cases of Shiga toxin-producing Escherichia coli infection, 30 required hospitalization, 15 progressed to hemolytic uremic syndrome, and five required hemodialysis. Patients were admitted and given aggressive IV fluid hydration. Those who progressed to hemolytic uremic syndrome received on average 8.4 L of isotonic crystalloid over the initial 72 hours, with up to 18% of body weight delivered. The six critically ill patients received a mean 12.2 L in the first 72 hours. Those who did not progress to hemolytic uremic syndrome received a mean 3.0 L of crystalloid. If oligoanuria developed, a net-even fluid balance was maintained. The amount of volume infused was not associated with improved outcomes. The patients with the highest fluid balance totals more often required dialysis than those who received less fluid. One hemolytic uremic syndrome patient developed flash pulmonary edema.CONCLUSIONS:The aggressive IV hydration protocols (as a percentage of body weight) in the pediatric literature may not be applicable to adults diagnosed with hemolytic uremic syndrome. A more conservative fluid strategy in adults with hemolytic uremic syndrome merits further investigation.

Whole-genome characterization of hemolytic uremic syndrome-causing Shiga toxin-producing Escherichia coli in Sweden

ABSTRACT Shiga toxin-producing Escherichia coli, a foodborne bacterial pathogen, has been linked to a broad spectrum of clinical outcomes ranging from asymptomatic carriage to fatal hemolytic uremic syndrome (HUS). Here, we collected clinical data and STEC strains from HUS patients from 1994 through 2018, whole-genome sequencing was performed to molecularly characterize HUS-associated STEC strains, statistical analysis was conducted to identify bacterial genetic factors associated with severe outcomes in HUS patients. O157:H7 was the most predominant serotype (57%) among 54 HUS-associated STEC strains, followed by O121:H19 (19%) and O26:H11 (7%). Notably, some non-predominant serotypes such as O59:H17 (2%) and O109:H21 (2%) also caused HUS. All O157:H7 strains with one exception belonged to clade 8. During follow-up at a median of 4 years, 41% of the patients had renal sequelae. Fifty-nine virulence genes were found to be statistically associated with severe renal sequelae, these genes encoded type II and type III secretion system effectors, chaperones, and other factors. Notably, virulence genes associated with severe clinical outcomes were significantly more prevalent in O157:H7 strains. In contrast, genes related to mild symptoms were evenly distributed across all serotypes. The whole-genome phylogeny indicated high genomic diversity among HUS-STEC strains. No distinct cluster was found between HUS and non-HUS STEC strains. The current study showed that O157:H7 remains the main cause of STEC-associated HUS, despite the rising importance of other non-O157 serotypes. Besides, O157:H7 is associated with severe renal sequelae in the follow-up, which could be a risk factor for long-term prognosis in HUS patients.

Neurological manifestations of thrombotic microangiopathy syndromes in adult patients.

The objective of this study was to compare the frequency and severity of neurologic manifestations in adult patients diagnosed with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and atypical HUS (aHUS). This is a retrospective cohort study of adult patients diagnosed with TTP, HUS and atypical HUS hospitalized at a tertiary center between January 2004 and October 2016. A total of 42 TTP, 16 HUS and 20 aHUS episodes were reviewed to collect clinical, laboratory and radiographic data, as well as information regarding long-term functional outcome. Neurologic symptoms are more common in patients with TTP and HUS as compared to aHUS (p < 0.001 and p = 0.002, respectively). Encephalopathy occurred in 29 TTP (69%) and 11 HUS (68%) episodes. Focal deficits were only observed in patients with TTP (n = 8 [19%]). Seizures were most commonly seen in HUS patients (n = 8 [50%]). Posterior reversible encephalopathy syndrome (PRES) was the most common neuroimaging finding in these syndromes; ischemic infarcts and hemorrhages occurred uncommonly. There was no correlation between presence of neurologic symptoms or neuroimaging abnormalities and poor outcome. Patients with TTP and HUS appear to have a similar spectrum of neurologic manifestations, whereas neurologic involvement is less common in aHUS. PRES is the most common imaging abnormality, and may present atypically. Despite presence of neurologic symptoms or neuroimaging abnormalities, patients with thrombotic microangiopathy (TMA) tend to have favorable long-term outcomes.

Hemolytic uremic syndrome caused by sea anemone sting: a case report

BackgroundSome sea anemone toxins cause renal injuries resembling hemolytic uremic syndrome (HUS). To date, only a few cases of HUS caused by sea anemone stings have been reported. In this case report, we have described an HUS case caused by a sea anemone sting.Case presentationIn November 2019, a 37-year-old man with no underlying disease was admitted to our hospital. He presented with intense pain, a rash on, and swelling in his right thigh. Two days prior, he had been stung by a sea anemone while scuba diving in Cebu, Philippines. His blood tests revealed renal dysfunction, and his platelet count was normal. However, on day three, the platelet count decreased rapidly. His blood haptoglobin level decreased, and schistocytes were identified on the peripheral blood smear. We suspected thrombotic microangiopathy and started the conventional treatment, comprising hemodialysis, blood transfusion, and antibiotic administration. ADAMTS-13 and genetic test results associated with atypical HUS were normal. Therefore, the patient was diagnosed with HUS caused by a sea anemone toxin.ConclusionsHUS caused by a sea anemone toxin is rare, but it is a serious medical disease. Clinicians should consider HUS in patients with such clinical presentations, and they should make prompt treatment-related decisions.

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.

Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients. We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. Safe eculizumab interval adjustment is feasible with a PK monitoring.

The Czech Experience with Eculizumab in Severe Paediatric Shiga Toxin-Producing Escherichia coli-Associated Haemolytic Uremic Syndrome Patients.

The Czech Experience with Eculizumab in Severe Paediatric Shiga Toxin-Producing Escherichia coli-Associated Haemolytic Uremic Syndrome Patients.

Early relapse rate determines further relapse risk: results of a 5-year follow-up study on pediatric CFH-Ab HUS

BackgroundThe complement factor H antibody (CFH-Ab)–associated hemolytic uremic syndrome (HUS) forms a distinct subgroup within the complement-mediated HUS disease spectrum. The autoimmune nature of this HUS subgroup implies the potential benefit of a targeted immunosuppressive therapy. Data on long-term outcome are scarce.MethodsThis observational study evaluates the clinical outcome of 19 pediatric CFH-Ab HUS patients from disease onset until their 5-year follow-up.ResultsAll but one relapse occurred during the first 2 years, and patients who had no relapse within the first 6 months were relapse-free until the end of the observation period. Kidney function at disease onset determines long-term kidney function: all individuals with normal kidney function at disease onset had normal kidney function after 5 years, and all patients with reduced kidney function at onset had impaired kidney function at the last follow-up. Level of CFH-Ab titer at disease onset was not correlated with a higher risk of recurrences or worse long-term outcome after 5 years. Resolution of CFH-Ab titers after 5 years was common.ConclusionsCFH-Ab HUS patients have a varied overall long-term course. Early relapses are common, making close surveillance during the first years essential, regardless of the initial CFH-Ab titer.