Development Of Hemolytic Uremic Syndrome Research Articles

Hypogammaglobulinemia in a child with atypical hemolytic-uremic syndrome

We present a unique clinical case of an atypical hemolytic-uremic syndrome in a child. The mutation in exon 6 of the CD46 gene (chr1:207940532G>C) leads to a homozygous or hemizygous missense substitution. An 8-year-old girl was urgently hospitalized with symptoms of hemorrhagic syndrome and acute kidney injury. The child from the second pregnancy with an aggravated obstetric anamnesis, the first operative labor at the 38th week, who has an aggravated genealogical anamnesis. Initially, the disease developed in the guise of gastroenterological pathology: the girl had dyspeptic disorders, most likely associated with pathology of carbohydrate metabolism, also frequent infectious diseases and a lag in physical development. From the age of 4 years, the girl suffered from persistent hypoalbuminemia, hypoproteinemia and hypogammaglobulinemia, requiring replacement therapy with intravenous immunoglobulins. She was repeatedly examined in gastroenterological departments in Yekaterinburg and Moscow in 2021-2023, but no data concerning protein-losing enteropathies or primary immunodeficiency was obtained. Also, the whole-exome sequencing with result validation hasn’t confirmed an inherited etiology of the presumed congenital immune error. However, a CD46 gene mutation, associated with the development of hemolytic-uremic syndrome in some publications, was identified in the study. The signs of thrombotic microangiopathy were preceded by fever of unspecified etiology: microangiopathic hemolysis, thrombocytopenia, hyperazotemia, C3 consumption, proteinuria, and macrohematuria; hypercholesterolemia, protein metabolism disorder, increased transaminases, ferritin were also noted. According to the ultrasound of the kidneys there were diffuse changes in the parenchyma, decreased velocity indices of blood flow in both renal arteries at all levels. Differential diagnosis was carried out with thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, antinuclear form of atypical hemolytic-uremic syndrome, viral and bacterial infections, systemic pathology, antiphospholipid syndrome, and hemoblastosis. The girl didn’t need a renal replacement therapy. When complement-blocking therapy with eculizumab was initiated on vital indications, the signs of the disease were gradually eliminated. The prolonged absence of nephropathy in the child may indicate the diversity of the CD46 gene’s functions and different phenotypic manifestation of its mutations. Analysis of literature sources and detection of CD46 “environment” genes (CYBA, LYST, ARPCIB) by full-exome sequencing suggest ambiguity and polymorphism of phenotypic manifestations of complement-mediated mutation.

Humoral immune response to shiga toxin 2 (Stx2) in children with escherichiosis with hemolytic-uremic syndrome

Shiga toxin-producing Escherichia coli (STEC) causes acute intestinal infections and also causes acute renal failure, especially in children. Shiga toxins (Stx) occupy a central place in the pathogenesis of hemolytic uremic syndrome (HUS) in Escherichiosis. The presented work analyzes the effectiveness of laboratory diagnostics of enterohemorrhagic escherichiosis in patients at the stage of manifestation of HUS and/or acute renal failure using microbiological, immunological research methods and PCR analysis. The study used clinical material from 30 patients in the pediatric intensive care unit of the St. Vladimir Children’s City Clinical Hospital in Moscow with symptoms of HUS aged from 8 months to 5 years. Blood sera from 20 healthy donors were used as control. As a result of PCR analysis, stx2 DNA was detected in 23.3% of cases. Bacteriological research made it possible to sow a pure culture of Escherichia coli O157:H7 in only 3.3% of cases. Since the development of HUS begins in patients with acute intestinal infection caused by Shiga toxin-producing microorganisms starting from the 5th day of the disease, when antibiotic therapy is already carried out, the bacteria can be completely destroyed, which makes it difficult to identify them by bacteriological methods, as well as to detect genes encoding Shiga toxin in PCR analysis. Typically, patients with HUS are admitted to the intensive care unit 5–7 days after the onset of the disease, when class G immunoglobulins specific to the pathogen are already beginning to circulate in the blood. In this regard, the use of immunological tests can be effective to confirm the diagnosis of STEC infection. In our studies, enzyme immunoassay allowed us to detect antibodies to Stx2A in 63.3% and to Stx2B in 43.3% of patients. Using immunoblotting, antibodies to Stx2A were detected in all sera obtained from patients and in 66.7% of cases to Stx2B. Immunoblot analysis was characterized by higher sensitivity for detecting antibodies to Stx2, however, due to the presence of an immunological layer among healthy people, it is preferable to use ELISA analysis. In healthy donors with antibodies to Stx2, the antibody titer was significantly lower than in patients. Laboratory confirmation of the diagnosis of STEC infection is difficult when conducting microbiological and molecular genetic studies, which is confirmed in this work. The effectiveness of laboratory diagnostics can be expanded by performing an ELISA aimed at detecting antibodies to Stx2A.

Deletion of Sphingosine Kinase 2 Attenuates Acute Kidney Injury in Mice with Hemolytic-Uremic Syndrome.

Typical hemolytic uremic syndrome (HUS) can occur as a severe systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli. Its pathology can be induced by Stx types, resulting in toxin-mediated damage to renal barriers, inflammation, and the development of acute kidney injury (AKI). Two sphingosine kinase (SphK) isozymes, SphK1 and SphK2, have been shown to be involved in barrier maintenance and renal inflammatory diseases. Therefore, we sought to determine their role in the pathogenesis of HUS. Experimental HUS was induced by the repeated administration of Stx2 in wild-type (WT) and SphK1 (SphK1-/-) or SphK2 (SphK2-/-) null mutant mice. Disease severity was evaluated by assessing clinical symptoms, renal injury and dysfunction, inflammatory status and sphingolipid levels on day 5 of HUS development. Renal inflammation and injury were found to be attenuated in the SphK2-/- mice, but exacerbated in the SphK1-/- mice compared to the WT mice. The divergent outcome appeared to be associated with oppositely altered sphingolipid levels. This study represents the first description of the distinct roles of SphK1-/- and SphK2-/- in the pathogenesis of HUS. The identification of sphingolipid metabolism as a potential target for HUS therapy represents a significant advance in the field of HUS research.

Farm animal exposure setting impacts hemolytic uremic syndrome risk among Shiga toxin-producing Escherichia coli cases: Minnesota, 2010-2019.

Shiga toxin-producing Escherichia coli (STEC) transmission occurs in ruminant contact settings and can lead to post-diarrheal hemolytic uremic syndrome (HUS). We investigated whether exposure setting (ruminant exposure from living or working on a farm, visiting a farm or animal contact venue, or both) influenced HUS development among individuals with laboratory-confirmed STEC infections using Minnesota surveillance data from 2010 to 2019. Logistic regression was performed to determine whether exposure setting was associated with HUS independent of age, gender, stx2 gene detection, and county ruminants per capita. Among confirmed STEC cases, ruminant exposure only from living or working on a farm was not significantly associated with HUS compared to cases without any ruminant exposure (OR: 1.25; 95% CI: 0.51, 3.04). However, ruminant exposure only from visiting a farm or public animal contact venue was associated with HUS (OR: 2.53; 95% CI: 1.50, 4.24). Exposure from both settings was also associated with HUS (OR: 3.71; 95% CI: 1.39, 9.90). Exposure to ruminants when visiting farms or animal contact venues is an important predictor of HUS, even among people who live or work on farms with ruminants. All people, regardless of routine ruminant exposure, should take care in settings with ruminants to avoid infection with STEC.

Further Evaluation of Enterohemorrhagic Escherichia coli Gold Nanoparticle Vaccines Utilizing Citrobacter rodentium as the Model Organism.

Enterohemorrhagic E. coli (EHEC) is a group of pathogenic bacteria that is associated with worldwide human foodborne diarrheal illnesses and the development of hemolytic uremic syndrome, a potentially deadly condition associated with Shiga toxins (Stxs). Currently, approved vaccines for human prophylaxis against infection do not exist, and one barrier preventing the successful creation of EHEC vaccines is the absence of dependable animal models, including mice, which are naturally resistant to EHEC infection and do not manifest the characteristic signs of the illness. Our lab previously developed gold nanoparticle (AuNP)-based EHEC vaccines, and assessed their efficacy using Citrobacter rodentium, which is the mouse pathogen counterpart of EHEC, along with an Stx2d-producing strain that leads to more consistent disease kinetics in mice, including lethality. The purpose of this study was to continue evaluating these vaccines to increase protection. Here, we demonstrated that subcutaneous immunization of mice with AuNPs linked to the EHEC antigens EscC and intimin (Eae), either alone or simultaneously, elicits functional robust systemic humoral responses. Additionally, vaccination with both antigens together showed some efficacy against Stx2d-producing C. rodentium while AuNP-EscC successfully limited infection with non-Stx2d-producing C. rodentium. Overall, the collected results indicate that our AuNP vaccines have promising potential for preventing disease with EHEC, and that evaluation of novel vaccines using an appropriate animal model, like C. rodentium described here, could be the key to finally developing an effective EHEC vaccine that can progress into human clinical trials.

A 6-year retrospective study of clinical features, microbiology, and genomics of Shiga toxin-producing Escherichia coli in children who presented to a tertiary referral hospital in Costa Rica.

Shiga-toxin-producing Escherichia coli (STEC) is associated with diarrhea and hemolytic uremic syndrome (HUS). STEC infections in Costa Rica are rarely reported in children. We gathered all the records of STEC infections in children documented at the National Children's Hospital, a tertiary referral hospital, from 2015 to 2020. Clinical, microbiological, and genomic information were analyzed and summarized. A total of 3,768 diarrheal episodes were reviewed. Among them, 31 STEC were characterized (29 fecal, 1 urine, and 1 bloodstream infection). The prevalence of diarrheal disease due to STEC was estimated at 0.8% (n = 29/3,768), and HUS development was 6.4% (n = 2/31). The stx1 gene was found in 77% (n = 24/31) of STEC strains. In silico genomic predictions revealed a predominant prevalence of serotype O118/O152:H2, accompanied by a cluster exhibiting allele differences ranging from 33 to 8, using a core-genome multilocus sequence typing (cgMLST) approach. This is the first study using a genomic approach for STEC infections in Costa Rica.IMPORTANCEThis study provides a comprehensive description of clinical, microbiological, genomic, and demographic data from patients who attended the only pediatric hospital in Costa Rica with Shiga-toxin-producing Escherichia coli (STEC) infections. Despite the low prevalence of STEC infections, we found a predominant serotype O118/O152:H2, highlighting the pivotal role of genomics in understanding the epidemiology of public health threats such as STEC. Employing a genomic approach for this pathogen for the first time in Costa Rica, we identified a higher prevalence of STEC in children under 2 years old, especially those with gastrointestinal comorbidities, residing in densely populated regions. Limitations such as potential geographic bias and lack of strains due to direct molecular diagnostics are acknowledged, emphasizing the need for continued surveillance to uncover the true extent of circulating serotypes and potential outbreaks in Costa Rica.

The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome.

Hemolytic uremic syndrome (HUS) is an acute disease and the most common cause of childhood acute renal failure. HUS is characterized by a triad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In most of the cases, HUS occurs as a result of infection caused by Shiga toxin-producing microbes: hemorrhagic Escherichia coli and Shigella dysenteriae type 1. They account for up to 90% of all cases of HUS. The remaining 10% of cases grouped under the general term atypical HUS represent a heterogeneous group of diseases with similar clinical signs. Emerging evidence suggests that in addition to E. coli and S. dysenteriae type 1, a variety of bacterial and viral infections can cause the development of HUS. In particular, infectious diseases act as the main cause of aHUS recurrence. The pathogenesis of most cases of atypical HUS is based on congenital or acquired defects of complement system. This review presents summarized data from recent studies, suggesting that complement dysregulation is a key pathogenetic factor in various types of infection-induced HUS. Separate links in the complement system are considered, the damage of which during bacterial and viral infections can lead to complement hyperactivation following by microvascular endothelial injury and development of acute renal failure.

Detection of Cleaved Stx2a in the Blood of STEC-Infected Patients.

Typical hemolytic uremic syndrome (HUS) is mainly caused by Shiga toxin-producing Escherichia coli (STEC) releasing Shiga toxin 2 (Stx2). Two different structures of this AB5 toxin have been described: uncleaved, with intact B and A chains, and cleaved, with intact B and a nicked A chain consisting of two fragments, A1 and A2, connected by a disulfide bond. Despite having the same toxic effect on sensitive cells, the two forms differ in their binding properties for circulating cells, serum components and complement factors, thus contributing to the pathogenesis of HUS differently. The outcome of STEC infections and the development of HUS could be influenced by the relative amounts of uncleaved or cleaved Stx2 circulating in patients' blood. Cleaved Stx2 was identified and quantified for the first time in four out of eight STEC-infected patients' sera by a method based on the inhibition of cell-free translation. Cleaved Stx2 was present in the sera of patients with toxins bound to neutrophils and in two out of three patients developing HUS, suggesting its involvement in HUS pathogenesis, although in association with other bacterial or host factors.

A novel Shiga toxin 2a neutralizing antibody therapeutic with low immunogenicity and high efficacy.

Shiga toxin-producing Escherichia coli infections are difficult to treat due to the risk of antibiotic-induced stress upregulating the production of toxins, medical treatment is consequently limited to supportive care to prevent the development of hemolytic uremic syndrome (HUS). Here, we introduce a potentially therapeutic humanized mouse monoclonal antibody (Hu-mAb 2-5) targeting Stx2a, the most common Shiga toxin subtype identified from outbreaks. We demonstrate that Hu-mAb 2-5 has low immunogenicity in healthy adults ex vivo and high neutralizing efficacy in vivo, protecting mice from mortality and HUS-related tissue damage.

Detection and characterization of circulating microvesicles containing Shiga toxin type 2 in a rat model of Hemolytic Uremic Syndrome

Shiga toxin producing Escherichia coli (STEC) are foodborne pathogens that release Shiga toxin (Stx), virulence factor responsible for the development of Hemolytic Uremic Syndrome (HUS). Stx causes endothelial cell damage, which leads to platelets deposition and thrombi formation within the microvasculature. It has been described that Stx activates blood cells and induces the shedding of proinflammatory and prothrombotic microvesicles (MVs) containing the toxin. In this sense, it has been postulated that MVs containing Stx2 (MVs-Stx2+) can contribute to the physiopathology of HUS, allowing Stx2 to reach the target organs while evading the immune system. In this work, we propose that circulating MVs-Stx2+ can be a potential biomarker for the diagnosis and prognosis of STEC infections and HUS progression. We developed a rat HUS model by the intraperitoneal injection of a sublethal dose of Stx2 and observed: decrease in body weight, increase of creatinine and urea levels, decrease of creatinine clearance and histological renal damages. After characterization of renal damages, we investigated circulating total MVs and MVs-Stx2+ by flow cytometry at different times after Stx2 injection. Additionally, we evaluated the correlation of biochemical parameters such as creatinine and urea in plasma with MVs-Stx2+. As a result, we found a significant circulation of MVs-Stx2+ at 72 and 96 h after Stx2 injection, nevertheless no correlation with creatinine and urea plasma levels were detected. Our results suggest that MVs-Stx2+ may be an additional biomarker for the characterization and diagnosis of HUS progression. A further analysis is required in order to validate MVs-Stx2+ as biomarker of the disease.

Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: a multinational embedded cluster crossover randomized trial (the HIKO STEC trial)

BackgroundShiga toxin-producing E. coli (STEC) infections affect children and adults worldwide, and treatment remain solely supportive. Up to 15–20% of children infected by high-risk STEC (i.e., E. coli that produce Shiga toxin 2) develop hemolytic anemia, thrombocytopenia, and kidney failure (i.e., hemolytic uremic syndrome (HUS)), over half of whom require acute dialysis and 3% die. Although no therapy is widely accepted as being able to prevent the development of HUS and its complications, several observational studies suggest that intravascular volume expansion (hyperhydration) may prevent end organ damage. A randomized trial is needed to confirm or refute this hypothesis.MethodsWe will conduct a pragmatic, embedded, cluster-randomized, crossover trial in 26 pediatric institutions to determine if hyperhydration, compared to conservative fluid management, improves outcomes in 1040 children with high-risk STEC infections. The primary outcome is major adverse kidney events within 30 days (MAKE30), a composite measure that includes death, initiation of new renal replacement therapy, or persistent kidney dysfunction. Secondary outcomes include life-threatening, extrarenal complications, and development of HUS. Pathway eligible children will be treated per institutional allocation to each pathway. In the hyperhydration pathway, all eligible children are hospitalized and administered 200% maintenance balanced crystalloid fluids up to targets of 10% weight gain and 20% reduction in hematocrit. Sites in the conservative fluid management pathway manage children as in- or outpatients, based on clinician preference, with the pathway focused on close laboratory monitoring, and maintenance of euvolemia. Based on historical data, we estimate that 10% of children in our conservative fluid management pathway will experience the primary outcome. With 26 clusters enrolling a mean of 40 patients each with an intraclass correlation coefficient of 0.11, we will have 90% power to detect a 5% absolute risk reduction.DiscussionHUS is a devastating illness with no treatment options. This pragmatic study will determine if hyperhydration can reduce morbidity associated with HUS in children with high-risk STEC infection.Trial registrationClinicalTrials.gov NCT05219110. Registered on February 1, 2022.

Genome-wide association study of hemolytic uremic syndrome causing Shiga toxin-producing Escherichia coli from Sweden, 1994–2018

Shiga toxin-producing Escherichia coli (STEC) infection can cause clinical manifestations ranging from diarrhea to potentially fatal hemolytic uremic syndrome (HUS). This study is aimed at identifying STEC genetic factors associated with the development of HUS in Sweden. A total of 238 STEC genomes from STEC-infected patients with and without HUS between 1994 and 2018 in Sweden were included in this study. Serotypes, Shiga toxin gene (stx) subtypes, and virulence genes were characterized in correlation to clinical symptoms (HUS and non-HUS), and pan-genome wide association study was performed. Sixty-five strains belonged to O157:H7, and 173 belonged to non-O157 serotypes. Our study revealed that strains of O157:H7 serotype especially clade 8 were most commonly found in patients with HUS in Sweden. stx2a and stx2a + stx2c subtypes were significantly associated with HUS. Other virulence factors associated with HUS mainly included intimin (eae) and its receptor (tir), adhesion factors, toxins, and secretion system proteins. Pangenome wide-association study identified numbers of accessory genes significantly overrepresented in HUS-STEC strains, including genes encoding outer membrane proteins, transcriptional regulators, phage-related proteins, and numerous genes related to hypothetical proteins. Whole-genome phylogeny and multiple correspondence analysis of pangenomes could not differentiate HUS-STEC from non-HUS-STEC strains. In O157:H7 cluster, strains from HUS patients clustered closely; however, no significant difference in virulence genes was found in O157 strains from patients with and without HUS. These results suggest that STEC strains from different phylogenetic backgrounds may independently acquire genes determining their pathogenicity and confirm that other non-bacterial factors and/or bacteria-host interaction may affect STEC pathogenesis.

Нарушение функции почек у детей с острыми кишечными инфекциями без развития гемолитико-уремического синдрома

Issues of nephrological complications of the acute period of acute intestinal infections (AII) are currently concentrated mainly on the problem of critical conditions associated with the development of hemolytic-uremic syndrome (HUS). Taking into account the introduction into clinical practice of new highly specific biological markers of acute kidney injury (AKI), which make it possible to diagnose this condition before the development of uremia, new prospects for the early diagnosis of AKI are opening up, which will allow timely modification of treatment tactics that prevent its progression to chronic kidney disease and reduce disability in patients, which is important at the present stage of development of pediatrics and infectious diseases. Objective. To assess the prevalence of AKI in children with moderate AII without the formation of HUS, as well as to asses the diagnostic significance of modern biological markers of kidney damage. Patients and methods. 270 patients aged 1 to 7 years with moderate AII without the development of HUS (study group), as well as 55 somatic healthy children (comparison group) were examined. Over time, standard laboratory and instrumental studies were carried out, assessment of the levels of biomarkers of structural kidney damage (lipocalin-2, cystatin C, acute kidney injury molecules-1 (KIM-1)), as well as calculation of glomerular filtration rate using various formulas. Results. It was found that upon admission, 38% of children in the main group had reduced diuresis, 13% had an increase in serum creatinine levels, while the urea level was increased in only 3% of children. When assessing the level of AKI markers in patients with AII upon admission, an increase in the level of KIM-1 in the urine was detected in 90% of patients, cystatin C and lipocalin-2 in the blood serum in 18.9% of patients. A comprehensive assessment of identified renal dysfunction (based on decreased diuresis, increased serum creatinine, decreased glomerular filtration rate) in AEI without the development of HUS made it possible to diagnose the development of AKI in 13.7%, predominantly (in 97.3% of cases) – 1th stage according to KDIGO. Among the factors of unfavorable premorbid background in children of the main group who developed AKI, anemia (in 62.2% of patients) suffered during the last 6 months was significantly more common. AII (51.4%) and SARS (51.4%) (p < 0.001). Conclusion. With moderate AII in children, the development of AKI is registered in 13.7% of cases. Clinical factors associated with the development of AKI are: febrile fever lasting 4–6 days, degree II exacerbation, repeated vomiting lasting more than 3 days, diarrhea lasting 5–8 days, and the predominance of viral etiology of the disease. In order to optimize the diagnosis of AKI in children with AII, it is advisable to include in the examination plan the determination of the level of cystatin C and lipocalin-2 in the blood serum, which have a significantly higher sensitivity (94.6 and 97.3%) and specificity (84.5 and 85.8% respectively) compared to creatinine levels. Key words: children, acute intestinal infection, acute kidney injury, cystatin C, lipocalin-2, NGAL, KIM-1

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.

Beneficial effect of fresh frozen plasma in reducing renal complications in Hemiscorpius lepturus scorpion envenomated children with severe hemoglobinuria: an open label randomized clinical trial

Acute kidney injury is a common complication of Hemiscorpius lepturus (HL) scorpion envenomation, via several mechanisms including pigment nephropathy, direct nephrotoxic effects of scorpion venom, hemolytic uremic syndrome (HUS), and acute interstitial nephritis. ADAMTS13 deficiency is highly prevalent in patients with severe HL scorpion envenomation and is effective in the development of HUS. Fresh frozen plasma (FFP), by replacing ADAMTS13, has proven effects on HL scorpion envenomated patients with HUS. This study evaluated the role of FFP in reducing of kidney injuries in complicated cases. In this open label randomized clinical trial, a total of 98 patients with massive hemoglobinuria following HL scorpion envenomation were included in the intervention and control groups (49 patients per group). The intervention group received FFP (10 cc/kg every 12 hours for three days) in addition to the anti-venom and other current therapies. Laboratory findings of renal activity, hemolysis, and urinalysis were evaluated in both groups, and maximum changes were compared. Comparison of maximum changes in laboratory findings between the two groups showed that administration of FFP can significantly reduce the deterioration of Blood Urea Nitrogen (BUN) and Creatinine (Cr) levels in the intervention group (p < 0.001 and p = 0.003, respectively). In comparison with the control group, the incidence of proteinuria was significantly lower (p = 0.012), reduction of platelet count was significantly less (p = 0.044), and increase of lactate dehydrogenase (LDH) and leukocytosis was lower in the intervention group (p = 0.037 and p = 0.007, respectively). The mean length of hospital stay was 5.44 days in the intervention group and 5.933 days in the control group (p = 0.149). According to the present findings, FFP can significantly reduce the development of kidney damage after HL scorpion envenomation and can be safely used against the fatal progression of venom complications in severe cases, along with other common treatments.

Gene expression profile and injury sites in mice treated with Shiga toxin 2 and lipopolysaccharide as a Shiga toxin-associated hemolytic uremic syndrome model.

Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS) contribute to the development of hemolytic uremic syndrome (HUS). Mouse models of HUS induced by LPS/Stx2 have been used for elucidating HUS pathophysiology and for therapeutic development. However, the underlying molecular mechanisms and detailed injury sites in this model remain unknown. We analyzed mouse kidneys after LPS/Stx2 administration using microarrays. Decreased urinary osmolality and urinary potassium were observed after LPS/Stx2 administration, suggestive of distal nephron disorders. A total of 1,212 and 1,016 differentially expressed genes were identified in microarrays at 6 h and 72 h after LPS/Stx2 administration, respectively, compared with those in controls. Ingenuity pathway analysis revealed activation of TNFR1/2, iNOS, and IL-6 signaling at both time points, and inhibition of pathways associated with lipid metabolism at 72 h only. The strongly downregulated genes in the 72-h group were expressed in the distal nephrons. In particular, genes associated with distal convoluted tubule (DCT) 2/connecting tubule (CNT) and principal cells of the cortical collecting duct (CCD) were downregulated to a greater extent than those associated with DCT1 and intercalated cells. Stx receptor globotriaosylceramide 3 (Gb3) revealed no colocalization with DCT1-specific PVALB and intercalated cell-specific SLC26A4 but did present colocalization with SLC12A3 (present in both DCT1 and DCT2), and AQP2 in principal cells. Gb3 localization tended to coincide with the segment in which the downregulated genes were present. Thus, the LPS/Stx2-induced kidney injury model represents damage to DCT2/CNT and principal cells in the CCD, based on molecular, biological, and physiological findings.

Interventions for Shiga toxin-producing Escherichia coli gastroenteritis and risk of hemolytic uremic syndrome: A population-based matched case control study.

The role of antibiotics in the treatment of Shiga toxin-producing Escherichia coli (STEC) infection is controversial. To evaluate the association between treatment (antibiotics, antidiarrheal agents, and probiotics) for STEC infection and hemolytic uremic syndrome (HUS) development. We performed a population-based matched case-control study using the data from the National Epidemiological Surveillance of Infectious Diseases (NESID) between January 1, 2017 and December 31, 2018. We identified all patients with STEC infection and HUS as cases and matched patients with STEC infection without HUS as controls, with a case-control a ratio of 1:5. Further medical information was obtained by a standardized questionnaire. Multivariable conditional logistic regression model was used. 7760 patients with STEC infection were registered in the NESID. 182 patients with HUS and 910 matched controls without HUS were selected. 90 patients with HUS (68 children and 22 adults) and 371 patients without HUS (266 children and 105 adults) were included in the main analysis. The matched ORs of any antibiotics and fosfomycin for HUS in children were 0.56 (95% CI 0.32-0.98), 0.58 (0.34-1.01). The matched ORs for HUS were 2.07 (1.07-4.03), 0.86 (0.46-1.61) in all ages treated with antidiarrheal agent and probiotics. Antibiotics, especially fosfomycin, may prevent the development of HUS in children, while use of antidiarrheal agents should be avoided.

AB5 Enterotoxin-Mediated Pathogenesis: Perspectives Gleaned from Shiga Toxins.

Foodborne diseases affect an estimated 600 million people worldwide annually, with the majority of these illnesses caused by Norovirus, Vibrio, Listeria, Campylobacter, Salmonella, and Escherichia coli. To elicit infections in humans, bacterial pathogens express a combination of virulence factors and toxins. AB5 toxins are an example of such toxins that can cause various clinical manifestations, including dehydration, diarrhea, kidney damage, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Treatment of most bacterial foodborne illnesses consists of fluid replacement and antibiotics. However, antibiotics are not recommended for infections caused by Shiga toxin-producing E. coli (STEC) because of the increased risk of HUS development, although there are conflicting views and results in this regard. Lack of effective treatment strategies for STEC infections pose a public health threat during outbreaks; therefore, the debate on antibiotic use for STEC infections could be further explored, along with investigations into antibiotic alternatives. The overall goal of this review is to provide a succinct summary on the mechanisms of action and the pathogenesis of AB5 and related toxins, as expressed by bacterial foodborne pathogens, with a primary focus on Shiga toxins (Stx). The role of Stx in human STEC disease, detection methodologies, and available treatment options are also briefly discussed.

Why antibiotics should not be used to treat Shiga toxin-producing Escherichia coli infections.

There has been much debate about treating Shiga toxin-producing Escherichia coli (STEC) infections with antibiotics. No data convincingly demonstrate that antibiotics are better than no antibiotic treatment at all, and many studies suggest antibiotics increase the risk of developing the hemolytic uremic syndrome (HUS). This topic is timely, because emerging technology enables rapid identification of STEC-infected patients, and we anticipate questions about management will increase. This review is designed to familiarize readers with the series of observations that underlie our recommendations. The long debate over antibiotics in STEC infections appears resolved by gradually accruing information that show that antibiotics do not benefit infected patients. In fact, they are associated with an increased likelihood of developing HUS. A meta-analysis published in 2016 demonstrated that low risk of bias studies find a clear association between antibiotic use and development of HUS. Subsequent publications do not refute these findings. In high-income countries, antibiotics should not routinely be given to patients with acute diarrhea unless testing demonstrates a pathogen for which antibiotics are indicated, and STEC infection has been excluded. Future work to prevent HUS should focus on preventing primary infections, and mitigating extraintestinal consequences of STEC gut infections.

Risk of Hemolytic Uremic Syndrome Related to Treatment of Escherichia coli O157 Infection with Different Antimicrobial Classes.

Treatment of Shiga toxin-producing Escherichia coli O157 (O157) diarrhea with antimicrobials might alter the risk of hemolytic uremic syndrome (HUS). However, full characterization of which antimicrobials might affect risk is lacking, particularly among adults. To inform clinical management, we conducted a case-control study of residents of the FoodNet surveillance areas with O157 diarrhea during a 4-year period to assess antimicrobial class-specific associations with HUS among persons with O157 diarrhea. We collected data from medical records and patient interviews. We measured associations between treatment with agents in specific antimicrobial classes during the first week of diarrhea and development of HUS, adjusting for age and illness severity. We enrolled 1308 patients; 102 (7.8%) developed confirmed HUS. Antimicrobial treatment varied by age: <5 years (12.6%), 5–14 (11.5%), 15–39 (45.4%), ≥40 (53.4%). Persons treated with a β-lactam had higher odds of developing HUS (OR 2.80, CI 1.14–6.89). None of the few persons treated with a macrolide developed HUS, but the protective association was not statistically significant. Exposure to “any antimicrobial” was not associated with increased odds of HUS. Our findings confirm the risk of β-lactams among children with O157 diarrhea and extends it to adults. We observed a high frequency of inappropriate antimicrobial treatment among adults. Our data suggest that antimicrobial classes differ in the magnitude of risk for persons with O157 diarrhea.