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Background: Complement activation in atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) may be associated with rare genetic variants. Here we describe gene variants in the Swedish and Norwegian populations. Methods: Patients with these diagnoses (N=141) were referred for genetic screening. Sanger or next-generation sequencing were performed to identify genetic variants in 16 genes associated with these conditions. Nonsynonymous genetic variants are described when they have a minor allele frequency of <1% or were previously reported as being disease-associated. Results: In patients with aHUS (n=94, one also had IC-MPGN) 68 different genetic variants or deletions were identified in 60 patients, of which 18 were novel. Thirty-two patients had more than one genetic variant. In patients with C3G (n=40) 29 genetic variants, deletions or duplications were identified in 15 patients, of which 9 were novel. Eight patients had more than one variant. In patients with IC-MPGN (n=7) five genetic variants were identified in five patients. Factor H variants were the most frequent in aHUS and C3 variants in C3G. Seventeen variants occurred in more than one condition. Conclusion: Genetic screening of patients with aHUS, C3G and IC-MPGN is of paramount importance for diagnostics and treatment. In this study, we describe genetic assessment of Nordic patients in which 26 novel variants were found. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and target organ damage. Pregnancy is associated with several forms of TMA, including preeclampsia (PE), HELLP syndrome, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When HUS is secondary to a deregulation of the alternative complement pathway, it is known as atypical HUS (aHUS). Differential diagnosis is challenging, as these forms share clinical characteristics. However, early diagnosis is crucial for a specific treatment to be established and improve prognosis. We present the case of a 43 year-old primiparous woman admitted to hospital for an urgent C-section at 33 gestational weeks due to a diagnosis of severe preeclampsia and fetal distress. In the immediate postpartum, the patient developed acute liver failure and anuric renal failure in the context of the HELLP syndrome, anemia, thrombocytopenia, arterial hypertension (HTN) and neurological deficit. TMA study and differential diagnosis confirmed pregnancy-associated aHUS. Treatment with eculizumab was initiated, with good response and progressive improvement of clinical and analytical parameters. aHUS is a rare multifactorial disease that used to be associated with high mortality rates before the advent of eculizumab. Due to challenging diagnosis, the clinical laboratory plays a major role in the differential diagnosis and management of the disease. [ABSTRACT FROM AUTHOR]

Objective: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs). Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant, and AMR. Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered. Data Synthesis: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described. Relevance to Patient Care and Clinical Practice: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function. Conclusions: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival. [ABSTRACT FROM AUTHOR]

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes serious gastrointestinal illness, including hemorrhagic colitis and hemolytic uremic syndrome. Two types of Stxs (Stx1 and Stx2) are known and both are encoded by bacteriophages (Stx phages), but the production of Stx2 is known to be a major risk factor for severe STEC infections. The production of Stx2, but not Stx1, is tightly coupled with the induction of Stx phages, and Stx2 production levels vary between STEC strains even within the same serotype. Here, we analyzed the genomic diversity of all Stx phages in 71 strains representing the entire O145:H28 lineage, one of the often highly pathogenic STECs, and the relationship between the variations in Stx phage genomes and the levels of Stx2 production by host strains. Our analysis reveals highly dynamic natures of Stx phages in O145:H28, including the independent acquisition of similar Stx phages by different sublineages, the recent transfer of Stx phage between different sublineages, and the frequent gain and loss of Stx phages in some sublineages. We also show the association of the Stx2 phage types with the Stx2 production levels of host strains: strains carrying short-tailed Stx2 phages exhibited significantly higher Stx2 production levels than those carrying long-tailed Stx2 phages. Detailed analyses of the Stx2 phage genomes revealed that both of short- and long-tailed phages exhibited sequence diversification and they were divided into two groups, respectively, based on the sequence similarity of the phage early region encoding genes responsible for phage induction, short-tailed phages contained early regions clearly different in genetic organization from those in long-tailed phages. Therefore, the variations in the early regions between short-and long-tailed Stx2 phages appeared to be linked to a striking difference in Stx2 production levels in their host strains. These results broaden our understanding of the diversification and dynamism of Stx phages in O145:H28 and the association of Stx2 phage types with the Stx2 production level in this STEC lineage. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes. [ABSTRACT FROM AUTHOR]

Background: The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare. Case Presentation: We describe a 7-month-old male patient presenting with fatigue and edema. His initial laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria. Further examinations reveals hemolysis in peripheral blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported a diagnosis of nephrotic syndrome. The patient's condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement. Discussion/Conclusion: This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again. [ABSTRACT FROM AUTHOR]

Background: Hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury in children. HUS is known as an acute disease followed by complete recovery, but patients may present with kidney abnormalities after long periods of time. This study evaluates the long-term outcome of Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) in pediatric patients, 10 years after the acute phase of disease to identify risk factors for long-term sequelae. Methods: Over a 6-year period, 619 patients under 18 years of age with HUS (490 STEC-positive, 79%) were registered in Austria and Germany. Long-term follow-up data of 138 STEC-HUS-patients were available after 10 years for analysis. Results: A total of 66% (n = 91, 95% CI 0.57–0.73) of patients fully recovered showing no sequelae after 10 years. An additional 34% (n = 47, 95% CI 0.27–0.43) presented either with decreased glomerular filtration rate (24%), proteinuria (23%), hypertension (17%), or neurological symptoms (3%). Thirty had sequelae 1 year after STEC-HUS, and the rest presented abnormalities unprecedented at the 2-year (n = 2), 3-year (n = 3), 5-year (n = 3), or 10-year (n = 9) follow-up. A total of 17 patients (36.2%) without kidney abnormalities at the 1-year follow-up presented with either proteinuria, hypertension, or decreased eGFR in subsequent follow-up visits. Patients needing extracorporeal treatments during the acute phase were at higher risk of presenting symptoms after 10 years (p < 0.05). Conclusions: Patients with STEC-HUS should undergo regular follow-up, for a minimum of 10 years following their index presentation, due to the risk of long-term sequelae of their disease. An initial critical illness, marked by need of kidney replacement therapy or plasma treatment may help predict poor long-term outcome. [ABSTRACT FROM AUTHOR]

Background: Therapeutic apheresis (TA) is already used to treat various diseases in the field of nephrology. The aim of this study was to evaluate the frequency and types of complications that occur during TA in children with kidney disease. Methods: Records of children (≤ 18 years) who underwent TA between 2007 and 2022 were retrospectively reviewed. Children with missing data and those with a diagnosis of nonnephrological disease were excluded. Results: A total of 1214 TA sessions, including 1147 therapeutic plasma exchange (TPE) sessions and 67 immunoadsorption (IA) sessions, were performed on the 108 patients enrolled in the study. Forty-seven percent of the patients were male, and the mean age was 12.22 ± 4.47 years. Posttransplant antibody-mediated rejection (64.8%) and hemolytic uremic syndrome (14.8%) were the most common diagnoses indicating TA. Overall, 17 different complications occurred in 58 sessions (4.8%), and 53 sessions (4.6%) were not completed because of these complications. The distribution of complications among the patients was as follows: 41.4% had technical complications, 25.9% had allergic complications, and 32.7% had others. The most common technical complication was insufficient flow (37.5%). The incidence of complications was greater in patients aged 3–6 years than in patients in the other age groups (p = 0.031). The primary disease, type of vascular access, and rate of fresh frozen plasma/albumin use were similar between patients with and without complications (p values of 0.359 and 0.125 and 0.118, respectively). Conclusions: Our study showed that complications occurred in only 4.8% of TA sessions. The most common complication was technical problems. [ABSTRACT FROM AUTHOR]

Introduction: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real‐world data on patients with aHUS. Methods: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS‐associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti‐complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. Results: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. Conclusion: Our analysis suggests that aHUS‐associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti‐CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment. [ABSTRACT FROM AUTHOR]

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody‐mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model‐informed precision dosing. Biologicals are used for off‐label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof‐of‐concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off‐label in SOT and furthermore to identify the settings where TDM may be beneficial. [ABSTRACT FROM AUTHOR]

Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: No reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies. Case presentation: A 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening. Conclusions: This is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment. [ABSTRACT FROM AUTHOR]

Background: Plasma exchanges (PEX) and immunosuppression are the cornerstone of management of anti-factor H (FH) antibody-associated atypical hemolytic uremic syndrome (aHUS), particularly if access to eculizumab is limited. The duration of therapy with PEX for anti-FH aHUS is empirical. Methods: We compared the efficacy of abbreviated PEX protocol (10–12 sessions) in a prospective cohort of patients diagnosed with anti-FH aHUS (2020–2022), to standard PEX protocol (20–22 sessions) in a historical cohort (2016–2019; n = 65). Efficacy was defined as 70% decline in anti-FH titers or fall to ≤ 1300 AU/ml at 4 weeks. Patients in both cohorts received similar immunosuppression with oral prednisolone, IV cyclophosphamide (5 doses) and mycophenolate mofetil. Outcomes included efficacy, rates of hematological remission and adverse kidney outcomes at 1, 3 and 6 months. Results: Of 23 patients, 8.2 ± 2.1 years old enrolled prospectively, two were excluded for significant protocol deviation. PEX was abbreviated in 18/21 (86%) patients to 11.5 ± 3.3 sessions. Abbreviation failed for lack of hematological remission by day 14 (n = 2) and persistent neurological manifestations (n = 1). All patients in whom PEX was abbreviated achieved > 70% reduction in anti-FH titers at day 28. The percentage fall in anti-FH titers was similar for the abbreviated vs. standard PEX protocols at 1, 3 and 6 months. At last follow-up, at median 50 months and 25 months for standard and abbreviated cohorts, the estimated GFR was similar at 104.8 ± 29.1 vs. 93.7 ± 53.4, respectively (P = 0.42). Conclusion: Abbreviation of the duration of PEX is feasible and efficacious in reducing anti-FH titers. Short-term outcomes were comparable in patients managed by abbreviated and standard PEX protocols. [ABSTRACT FROM AUTHOR]

Shiga toxin-producing Escherichia coli (STEC) causes a wide spectrum of diseases including hemorrhagic colitis and hemolytic uremic syndrome (HUS). Previously, we developed a rapid, sensitive, and potentially portable assay that identified STEC by detecting Shiga toxin (Stx) using a B-cell based biosensor platform. We applied this assay to detect Stx2 present in food samples that have been implicated in previous STEC foodborne outbreaks (milk, lettuce, and beef). The STEC enrichment medium, modified Tryptone Soy Broth (mTSB), inhibited the biosensor assay, but dilution with the assay buffer relieved this effect. Results with Stx2a toxoid-spiked food samples indicated an estimated limit of detection (LOD) of ≈4 ng/mL. When this assay was applied to food samples inoculated with STEC, it was able to detect 0.4 CFU/g or 0.4 CFU/mL of STEC at 16 h post incubation (hpi) in an enrichment medium containing mitomycin C. Importantly, this assay was even able to detect STEC strains that were high expressors of Stx2 at 8 hpi. These results indicate that the STEC CANARY biosensor assay is a rapid and sensitive assay applicable for detection of STEC contamination in food with minimal sample processing that can complement the current Food Safety Inspection Service (US) methodologies for STEC. [ABSTRACT FROM AUTHOR]

Thrombocytopenia, or low platelet count, is a common occurrence in sepsis and can raise concerns for clinicians. This article provides information on measuring platelets, the association between thrombocytopenia and sepsis outcomes, immune mechanisms connecting sepsis to thrombocytopenia, the role of platelets in maintaining vascular integrity, differential diagnoses for sepsis-induced thrombocytopenia, drug-induced thrombocytopenia, the distinction between sepsis-associated coagulation activation and disseminated intravascular coagulation (DIC), the risk of bleeding in thrombocytopenic patients, the association between sepsis and thrombosis, the variable effects of platelet transfusions, and the need for further research in this area. [Extracted from the article]

Shiga toxin-producing Escherichia coli (STEC) poses a significant public health risk due to its zoonotic potential and association with severe human diseases, such as hemorrhagic colitis and hemolytic uremic syndrome. Ruminants are recognized as primary reservoirs for STEC, but swine also contribute to the epidemiology of this pathogen, highlighting the need for effective prevention strategies across species. Notably, a subgroup of STEC that produces Shiga toxin type 2e (Stx2e) causes edema disease (ED) in newborn piglets, economically affecting pig production. This study evaluates the immunogenicity of a chimeric protein-based vaccine candidate against STEC in pregnant sows and the subsequent transfer of immunity to their offspring. This vaccine candidate, which includes chimeric proteins displaying selected epitopes from the proteins Cah, OmpT, and Hes, was previously proven to be immunogenic in pregnant cows. Our analysis revealed a broad diversity of STEC serotypes within swine populations, with the cah and ompT genes being prevalent, validating them as suitable antigens for vaccine development. Although the hes gene was detected less frequently, the presence of at least one of these three genes in a significant proportion of STEC suggests the potential of this vaccine to target a wide range of strains. The vaccination of pregnant sows led to an increase in specific IgG and IgA antibodies against the chimeric proteins, indicating successful immunization. Additionally, our results demonstrated the effective passive transfer of maternal antibodies to piglets, providing them with immediate, albeit temporary, humoral immunity against STEC. These humoral responses demonstrate the immunogenicity of the vaccine candidate and are preliminary indicators of its potential efficacy. However, further research is needed to conclusively evaluate its impact on STEC colonization and shedding. This study highlights the potential of maternal vaccination to protect piglets from ED and contributes to the development of vaccination strategies to reduce the prevalence of STEC in various animal reservoirs. [ABSTRACT FROM AUTHOR]

Background: Mirror syndrome is a rare disease characterized by "triple edema", while Hemolytic Uremic Syndrome (PHUS) is a serious disease that occurs within a short period of time after the end of pregnancy, with a low prevalence and poor prognosis, and it is even rarer for both to occur in the same patient. Methods: We report a case of mirror syndrome combined with PHUS and analyze the clinical data to improve the understanding of the disease. Results: The patient presented clinically with "triple edema" and was diagnosed with mirror image syndrome. After cesarean section, the patient developed cardiac insufficiency, renal insufficiency, hemolysis, and other symptoms and was diagnosed as PHUS. After active treatment, the maternal prognosis was good. Conclusions: Mirror syndrome and PHUS are both clinically rare diseases with poor long-term prognosis if not diagnosed and treated in a timely manner; therefore, awareness of the diseases, early and accurate diagnosis and timely and correct treatment should be improved. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 7-year-old girl who presented with a hypertensive crisis and thrombotic microangiopathy (TMA). The study found that severe hypertension led to TMA in this case, which is rare in children. The patient was treated with intravenous eculizumab and antihypertensive agents, which resulted in improvement in her condition. The article emphasizes the importance of evaluating hypertension-associated TMA for complement defects and initiating aggressive hypertension control and targeted therapies for better outcomes. It also highlights the potential association between severe hypertension and TMA, and the role of complement activation in the pathogenesis. [Extracted from the article]

Introduction: Hemolytic uremic syndrome (HUS) is characterized by progressive kidney injury accompanied by thrombotic microangiopathy, which is clinically defined as microangiopathic hemolytic anemia with thrombocytopenia and organ injury. Shiga toxin-producing Escherichia coli (STEC)-HUS is caused by infection with pathogenic E. coli strains, typically O157, O26, and O111. However, the prevalence of other types of pathogenic E. coli has been increasing, and these pathogens sometimes cause atypical clinical manifestations of STEC-HUS. Case Presentation: We report the case of a 3-year-old girl diagnosed with STEC-HUS associated with a rare O80:H2 stx2 serotype, characterized by an atypical clinical course. She presented with severe hemolytic anemia and mild renal dysfunction but did not have enterohemorrhagic diarrhea. The first culture test of her stool sample collected using a swab upon admission yielded no signs of STEC, leading to an initial diagnosis of atypical HUS; thus, eculizumab was administered adding to red blood cell transfusion and recombinant thrombomodulin alfa and haptoglobin. However, a subsequent culture test of her second stool sample revealed the presence of O80:H2 stx2, confirming the diagnosis of STEC-HUS. Subsequently, the patient’s condition improved, and her serum creatinine level gradually normalized over the course of 3 months. Conclusion: Diligently diagnosis is crucial in cases lacking typical STEC-HUS symptoms. We advocate for repeated stool culture testing to ensure accurate identification and timely management of such cases. [ABSTRACT FROM AUTHOR]

Background: The complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs. Methods: This multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab. Results: Mean age (range) at ravulizumab initiation was 41 years (19–78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3–120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment. Conclusions: This is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function. [ABSTRACT FROM AUTHOR]

Background: Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy resulting from dysregulation of the alternative complement pathway, leading to multi‐organ dysfunction and chronic kidney disease. Eculizumab is an anti‐C5 monoclonal antibody therapy that has significantly improved aHUS disease control and patient outcomes, however it requires fortnightly intravenous dosing. This often necessitates long term central access and a high hospital attendance burden. Ravulizumab is a novel, next‐generation anti‐C5 monoclonal antibody engineered from eculizumab to reduce endosomal degradation of the antibody, increasing the dosing interval up to 8 weeks. Case Series: In this retrospective case series we present the transition of three children with aHUS from eculizumab to ravulizumab from a single tertiary paediatric nephrology service. All patients underwent genomic and immunological work up for aHUS, with no cause found. After stabilisation with eculizumab, two patients developed macrovascular thrombotic complications associated with indwelling central vascular catheters, ultimately leading to central access failure. All patients were transitioned from eculizumab to ravulizumab without relapse of aHUS. One patient successfully underwent deceased donor kidney transplantation with ravulizumab for complement inhibition. All patients have transitioned to peripheral access for infusions given the reduced frequency of dosing, maintaining good control of aHUS for 2–4 years. Conclusion: Ravulizumab permits sufficiently reduced frequency of infusion to allow for administration by peripheral cannulation – removing the risks of long term central vascular access often required to deliver eculizumab to paediatric patients. [ABSTRACT FROM AUTHOR]

Schistocytes are fragmented red blood cells produced as a result of mechanical damage to erythrocytes, usually due to microangiopathic thrombotic diseases or mechanical factors. The early laboratory detection of schistocytes has a critical impact on the timely diagnosis, effective treatment, and positive prognosis of diseases such as thrombocytopenic purpura and hemolytic uremic syndrome. Due to the rapid development of science and technology, laboratory hematology has also advanced. The accuracy and efficiency of tests performed by fully automated hematology analyzers and fully automated morphology analyzers have been considerably improved. In recent years, substantial improvements in computing power and machine learning (ML) algorithm development have dramatically extended the limits of the potential of autonomous machines. The rapid development of machine learning and artificial intelligence (AI) has led to the iteration and upgrade of automated detection of schistocytes. However, along with significantly facilitated operation processes, AI has brought challenges. This review summarizes the progress in laboratory schistocyte detection, the relationship between schistocytes and clinical diseases, and the progress of AI in the detection of schistocytes. In addition, current challenges and possible solutions are discussed, as well as the great potential of AI techniques for schistocyte testing in peripheral blood. [ABSTRACT FROM AUTHOR]

The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases. [ABSTRACT FROM AUTHOR]

Background: The etiology of atypical hemolytic uremic syndrome (aHUS) is unknown in 30–40% of patients. Anti-factor B (FB) antibodies are reported in C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN), though not in aHUS. Methods: We screened patients < 18-year-old from cohorts of aHUS and C3G/idiopathic IC-MPGN. Anti-FB IgG antibodies were measured by ELISA and confirmed by Western blot. Normative levels were based on antibody levels in 103 healthy blood donors. Results: Prevalence of anti-FB antibodies was 9.7% (95% CI 6.1–14.5%; n = 21) in 216 patients with aHUS, including 11.5% (95% CI 6.4–18.5%; n = 14) in anti-FH associated aHUS and 11.8% (95% CI 4.4–23.9%; n = 6) in patients without a definitive genetic or autoimmune etiology. Patients with significant genetic variants did not show anti-FB antibodies. In patients with concomitant anti-FB and anti-FH antibodies, median anti-FH titers were higher (11,312 AU/mL vs. 4920 AU/mL; P = 0.04). Anti-FB antibody titer correlated with disease severity (hemoglobin and platelets; P < 0.05), declined following plasma exchange and increased during relapse. While 4/64 patients with C3G (6.3%) and 1/17 with IC-MPGN showed anti-FB antibodies, titers were higher in aHUS (544.8 AU/mL vs. 1028.8 AU/mL; P = 0.003). Conclusion: Anti-FB antibodies are present in 6–10% of patients with aHUS and C3G/IC-MPGN, with higher titers in the former. The diagnostic and therapeutic implication of anti-FB antibodies in aHUS needs confirmation and further studies. The study shows propensity for autoantibody generation and co-existence of multiple risk factors for aHUS in Indian children. [ABSTRACT FROM AUTHOR]

Background: Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS) is associated with high morbidity and relevant mortality. Previous small studies showed that volume expansion could improve the course and outcome of STEC-HUS. The aim of this single-center study was to evaluate the effect of volume expansion on the clinical course and outcome in STEC-HUS. Methods: Data of pediatric patients with STEC-HUS were analyzed retrospectively. Course and outcome of patients treated with volume expansion (VE) from 2019 to 2022 (n = 38) were compared to historical controls (HC) from 2009 to 2018 (n = 111). Results: Patients in the VE group had a significant relative median weight gain compared to HC (7.8% (3.4–11.3) vs. 1.2% (− 0.7–3.9), p < 0.0001) 48 h after admission. The need for dialysis was not reduced by VE (VE 21/38 (55.3%) vs. HC 64/111 (57.7%), p = 0.8). However, central nervous system involvement (impairment of consciousness, seizures, focal neurological deficits, and/or visual disturbances) was significantly reduced (VE 6/38 (15.8%) vs. HC 38/111 (34.2%), p = 0.039). None of the patients in the VE group died or developed chronic kidney disease (CKD) stage 5, whereas in the HC group, three patients died and three patients had CKD stage 5 at discharge. Conclusions: This study suggests that volume expansion may be associated with the mitigation of the acute course of STEC-HUS, especially severe neurological involvement and the development of CKD. Prospective trials should lead to standardized protocols for volume expansion in children with STEC-HUS. [ABSTRACT FROM AUTHOR]

Background: The gastrointestinal (GI) tract represents one of the main targets of typical hemolytic uremic syndrome (HUS) in children. In this observational study, we tried to establish (1) the main features of GI complications during STEC-HUS and (2) the relationship between Escherichia coli serotypes and Shiga toxin (Stx) variants with hepatopancreatic involvement. Methods: A total of 79 STEC-HUS patients were admitted to our pediatric nephrology department between January 2012 and June 2021. Evidence of intestinal, hepatobiliary, and pancreatic involvements was reported for each patient, alongside demographic, clinical, and laboratory features. Frequency of gastrointestinal complications across groups of patients infected by specific E. coli serotypes and Stx gene variants was evaluated. Results: Six patients developed a bowel complication: two developed rectal prolapse, and four developed bowel perforation which resulted in death for three of them and in bowel stenosis in one patient. Acute pancreatitis was diagnosed in 13 patients. An isolated increase in pancreatic enzymes and/or liver transaminases was observed in 41 and 15 patients, respectively. Biliary sludge was detected in three, cholelithiasis in one. Forty-seven patients developed direct hyperbilirubinemia. Neither E. coli serotypes nor Shiga toxin variants correlated with hepatic or pancreatic involvement. Conclusions: During STEC-HUS, GI complications are common, ranging from self-limited elevation of laboratory markers to bowel perforation, a severe complication with a relevant impact on morbidity and mortality. Hepatopancreatic involvement is frequent, but usually short-lasting and self-limiting. [ABSTRACT FROM AUTHOR]

Crovalimab (派圣凯®; PiaSky) is a humanized, anti-complement component C5 (anti-C5) recycling monoclonal antibody developed by Chugai Pharmaceutical, in collaboration with Roche, which is being investigated for the treatment of complement-mediated diseases, including paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uremic syndrome, lupus nephritis and sickle cell disease. Crovalimab targets C5, inhibiting its cleavage to C5a and C5b, thus blocking the terminal complement pathway and preventing intravascular haemolysis in PNH. Crovalimab is designed to bind to the antigen repeatedly, resulting in sustained complement inhibition at a lower dosage, and allowing for once-monthly subcutaneous administration. In February 2024, subcutaneous crovalimab received its first approval in China for the treatment of adolescents and adults (aged ≥ 12 years) with PNH who have not been previously treated with complement inhibitors. Crovalimab has since been approved in Japan in March for use in the treatment of PNH, including in treatment-naïve and previously treated patients. Crovalimab is also under regulatory review for the treatment of naïve and previously treated patients with PNH in multiple countries, including the USA and the European Union. This article summarizes the milestones in the development of crovalimab leading to this first approval in China for the treatment of PNH. [ABSTRACT FROM AUTHOR]

Background and Objectives: Escherichia coli O157: H7 is one of the most important causes of hemorrhagic colitis, and hemolytic uremic syndrome. The present study aimed to isolate E. coli O157: H7 from foods and patients with hemorrhagic colitis, and identify Shiga toxin genes, phylogenetic comparison, and antibiotic resistance of the isolates. Materials and Methods: In total 400 samples, including patients stool and food were taken in Isfahan-Iran province. Phenotypic tests and PCR were performed to identify Shiga toxin-producing E. coli. The isolated strains were compared phylogenetically by PFGE. Agar disk diffusion was performed to identify the antibiotic resistance of the isolates. Results: Totally, 5 isolates of fecal samples were E. coli O157, but only 2 isolates carried H7 gene. Also, 9 isolates of E. coli O157 were isolated from food samples that 3 isolates were E. coli O157: H7. The isolates carried stx1, stx2, hlyA and eaeA genes. Also, E. coli non-O157: H7 identified from samples that contained stx1, stx2, hlyA genes. The highest susceptibility to imipenem and the highest resistance to ampicillin and ciprofloxacin were observed. There was a similarity of 100% between the E. coli O157: H7 strains isolated from patients and raw milk and minced beef samples. Conclusion: Serotypes other than the O157 of E. coli are more prevalent in patients and food. The E. coli O157: H7 isolates from patients had 100% genetic similarity with minced meat and cow milk isolates, which indicates cattle are the most important reservoir of this bacterium in Iran. [ABSTRACT FROM AUTHOR]

Shiga toxin-producing Escherichia coli (STEC) are zoonotic pathogens causing hemorrhagic colitis and hemolytic uremic syndrome (HUS) in children and the elderly. Stool samples were collected from 180 children hospitalized in five pediatric centers in Poland in 2018–2022. Direct stx1/stx2 gene detection by PCR in feces and E. coli isolates was performed. Antibiotic susceptibility was tested according to EUCAST v.12. Randomly selected isolates were serotyped with O157 antiserum and genotyped by pulsed-field gel electrophoresis (PFGE). A total of 44 E. coli isolates were confirmed as STEC by PCR. Among them, 84.4% were positive for stx2, and equally 6,8% for only stx1 and both stx1 and stx2 genes. The stx1 gene was also found in one Citrobacter freundii isolate. E. coli serotype O157 was present in 97.6% of the isolates. STEC infections most often occurred between June-October with a peak in July and August (51%). The highest, 77.8% of STEC isolates were found in the 1–5 years old group. No extended-spectrum β-lactamases (ESBL) were found. Resistance only to amoxicillin/clavulanic acid (24.4%), piperacillin/tazobactam (3%), cefotaxime (6%), gentamicin (6%), ciprofloxacin (3%), azithromycin (3%), trimethoprim/sulfamethoxazole (24,2%) was detected. PFGE analysis showed 18 PFGE types with no clonal distribution. Eight isolates with A, B, and C PFGE types showed genetic relatedness in the type with no detection of transmission way of distribution. STEC strains pose a serious threat to human health, therefore demographic and epidemiological characteristics are crucial for their surveillance. [ABSTRACT FROM AUTHOR]

Infections with Shiga toxin-producing Escherichia coli (STEC) are increasing in Denmark and elsewhere. STEC is also the most frequent cause of haemolytic uraemic syndrome (HUS) in Danish children. Most cases are considered sporadic, while approximately one-third can be attributed to a known source of infection. Hence, we examined sources of sporadic STEC infection in Denmark. From January 2018 to December 2020, we conducted a prospective nationwide case–control study among Danish adults and children. Cases with confirmed positive STEC infection were notified infections within the national laboratory surveillance system. Control persons were randomly selected from the Danish Civil Registration System, individually matched in age in 5-year bands and sex. Participants were invited by an electronic letter to complete either an adult or child questionnaire online. Univariate and adjusted matched odds ratios were computed for adults and children using conditional logistic regression. The study recruited 1583 STEC cases and 6228 controls. A total of 658 cases (42%) and 2155 controls (35%) were included in the analysis. Depending on age, univariate analysis adjusted for socio-demographic determinants showed that the consumption of boiled beef (mOR = 2.2, 95% confidence interval (CI): 1.6–3.1) and fried minced beef (mOR = 1.6, CI: 1.2–2.1), drinking raw (unpasteurized) milk (mOR = 11, CI 1.1–110), eating grilled food (mOR = 9.8, CI: 5.6–17) and having a household member using diapers (mOR = 2.1, CI: 1.4–3.2) were determinants of sporadic STEC infection. Further multivariate adjusted analysis resulted in the same determinants. This study confirms that beef is an overall important risk factor for STEC infection in Denmark. We also present evidence that a proportion of sporadic STEC infections in Denmark are determined by age-specific eating habits, environmental exposures and household structure, rather than being exclusively food-related. These findings are relevant for targeted public health actions and guidelines. [ABSTRACT FROM AUTHOR]

Introduction: The predominant hybrid pathogenic E. coli, enterohemorrhagic E. coli (EHEC), combines characteristics of Shiga toxin-producing E. coli (STEC) and enteropathogenic E. coli (EPEC), contributing to global outbreaks with severe symptoms including fatal consequences. Since EHEC infection was designated as a notifiable disease in 2000 in South Korea, around 2000 cases have been reported, averaging approximately 90 cases annually. Aim: In this work, genome-based characteristic analysis and cell-based assay of hybrid STEC/aEPEC strains isolated from livestock feces, animal source foods, and water in South Korea was performed. Methods: To identify the virulence and antimicrobial resistance genes, determining the phylogenetic position of hybrid STEC/aEPEC strains isolated in South Korea, a combination of real-time PCR and whole-genome sequencing (WGS) was used. Additionally, to assess the virulence of the hybrid strains and compare them with genomic characterization, we performed a cell cytotoxicity and invasion assays. Results: The hybrid STEC/aEPEC strains harbored stx and eae genes, encoding Shiga toxins and E. coli attachment/effacement related protein of STEC and EPEC, respectively. Furthermore, all hybrid strains harbored plasmid-carried enterohemolysin(ehxCABD), a key virulence factor in prevalent pathogenic E. coli infections, such as diarrheal disease and hemolytic-uremic syndrome (HUS). Genome-wide phylogenetic analysis revealed a close association between all hybrid strains and specific EPEC strains, suggesting the potential acquisition of Stx phages during STEC/aEPEC hybrid formation. Some hybrid strains showed cytotoxic activity against HeLa cells and invasive properties against epithelial cells. Notably, all STEC/aEPEC hybrids with sequence type (ST) 1,034 (n = 11) exhibited higher invasiveness than those with E2348/69. This highlights the importance of investigating potential correlations between STs and virulence characteristics of E. coli hybrid strains. Conclusion: Through genome-based characterization, we confirmed that the hybrid STEC/aEPEC strains are likely EPEC strains that have acquired STEC virulence genes via phage. Furthermore, our results emphasize the potential increased danger to humans posed by hybrid STEC/aEPEC strains isolated in South Korea, containing both stx and eaeA, compared to STEC or EPEC alone. [ABSTRACT FROM AUTHOR]

Enterohemorrhagic E. coli (EHEC) is considered to be the most dangerous pathotype of E. coli, as it causes severe conditions such as hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). Antibiotic treatment of EHEC infections is generally not recommended since it may promote the production of the Shiga toxin (Stx) and lead to worsened symptoms. This study explores how exposure to the fluoroquinolone ciprofloxacin reorganizes the transcriptome and proteome of EHEC O157:H7 strain EDL933, with special emphasis on virulence-associated factors. As expected, exposure to ciprofloxacin caused an extensive upregulation of SOS-response- and Stx-phage proteins, including Stx. A range of other virulence-associated factors were also upregulated, including many genes encoded by the LEE-pathogenicity island, the enterohemolysin gene (ehxA), as well as several genes and proteins involved in LPS production. However, a large proportion of the genes and proteins (17 and 8%, respectively) whose expression was upregulated upon ciprofloxacin exposure (17 and 8%, respectively) are not functionally assigned. This indicates a knowledge gap in our understanding of mechanisms involved in EHECs response to antibiotic-induced stress. Altogether, the results contribute to better understanding of how exposure to ciprofloxacin influences the virulome of EHEC and generates a knowledge base for further studies on how EHEC responds to antibiotic-induced stress. A deeper understanding on how EHEC responds to antibiotics will facilitate development of novel and safer treatments for EHEC infections. [ABSTRACT FROM AUTHOR]