Hemolytic-uremic syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anila Hussain, MD [3] Alberto Castro Molina, M.D. Parth Vikram Singh, MBBS

In medicine, hemolytic-uremic syndrome (or haemolytic-uraemic syndrome, abbreviated HUS) is a disease characterized by microangiopathic hemolytic anemia (hematocrit below 30%), acute renal failure and a low platelet count i.e thrombocytopenia (platelet count below 150,000/mm3). It is due to the abnormal blood clotting within the capillaries leading to RBC shearing and destruction while passing through clogged capillaries and obstruction of kidney filtration system by damaged RBC’s lead to acute kidney injury and is one of the leading causes of acute renal failure in children. The two main types are typical and atypical Hemolytic uremic syndrome(HUS). Typical HUS is caused following a diarrheal infection by E.coli OH157: H7 and is responsible for 90 percent of HUS cases in Children. Atypical HUS is not associated with gastrointestinal symptoms and also has a less favorable outcome.

Shiga toxin-producing E. coli (STEC) is the leading infectious trigger of diarrhea-associated HUS in children, and optimized early diagnostics and supportive management can reduce morbidity.^[1] In contrast, complement-mediated HUS (often referred to clinically as atypical HUS) is driven by dysregulation of the alternative complement pathway and may require complement inhibition (for example with eculizumab) as disease-modifying therapy.^[2] Although several microbial pathogens can precipitate HUS, STEC are responsible for most cases in children worldwide. Contemporary reviews classify HUS within the broader thrombotic microangiopathy spectrum.^[3] In this framework, atypical HUS denotes a primary complement regulatory disorder, whereas STEC-HUS is a secondary thrombotic microangiopathy triggered by microbial injury. STEC that produce Shiga toxin 2 are high-risk pathogens and account for almost all cases of diarrhea-associated HUS. STEC that produce Shiga toxin 1 without Shiga toxin 2 are low-risk pathogens and rarely lead to HUS.

In 1955, Gasser et al first described hemolytic-uremic syndrome (HUS). There have been several outbreaks of HUS all over the world over past years.

Forty years ago, E. coli O157:H7 was identified as a cause of bloody diarrhea. Soon thereafter, stools from children with HUS were shown to contain E. coli of varying serotypes that produced toxins lethal to cultured Vero cells. These toxins came to be known as Shiga toxins, and the responsible organisms are now referred to as STEC.^[4]

The importance of toxin genotype rather than serogroup alone was highlighted by the 2011 Shiga toxin 2-producing E. coli O104:H4 outbreak, which caused more than 4000 infections in 16 countries, 908 cases of HUS, and 50 deaths.

HUS may be classified as typical (Caused by Shiga-toxin producing E.coli/ Shigella Infection) or atypical (caused by complement factor abnormalities, other viral or bacterial infections, HIV, malignancy, organ transplantation, and rarely SLE and pregnancy related).

Contemporary reviews often categorize HUS within the broader spectrum of thrombotic microangiopathy (TMA), distinguishing STEC-HUS from complement-mediated HUS and secondary TMAs triggered by drugs, pregnancy, transplantation, malignancy, or severe infection, because evaluation and treatment differ by mechanism.^[1]

HUS is commonly discussed within the broader category of thrombotic microangiopathy. In this framework, atypical HUS denotes a primary thrombotic microangiopathy caused by dysregulation of the complement system, whereas STEC-associated HUS is a secondary thrombotic microangiopathy triggered by microbial factors that activate endothelial cells and initiate the microangiopathic cascade.^[5]

It is understood that hemolytic uremic syndrome is the result of microvascular endothelial cell damage characterized by thrombotic microangiopathy (TMA) in renal glomeruli, gastrointestinal tract, brain and pancreas in all of which the main lesion is the thickening of vessel wall (mainly in capillaries and arterioles), microthrombi in platelets and obstruction of vessel lumen( partial or complete). Loss of physiological resistance to thrombus formation, complement consumption, leukocyte adhesion to damaged endothelium, the abnormal release of Von Willibrand Factor (vWF) and fragmentation, and increased vascular shear stress lead to further amplification of microangiopathy. Typical/ Shiga-toxin-associated hemolytic uremic syndrome (HUS) is usually caused by E.Coli and serotype O157: H7 is most common while congenital predisposing conditions like complement factor abnormalities may play a role in recurrent and familial forms^[6].

In STEC-HUS, Shiga toxin is the key virulence factor and risk is higher with strains producing Shiga toxin 2. In complement-mediated HUS, complement dysregulation is central and informs treatment (complement inhibition).^[1][2] Shiga toxin 1 and Shiga toxin 2 each consist of a single A subunit and a pentameric B subunit. Disease begins when the B subunit binds globotriaosylceramide (Gb3) on eukaryotic cells. The holotoxin is internalized, traffics retrogradely through the Golgi apparatus to the endoplasmic reticulum, and releases an enzymatically active A1 fragment that cleaves 28S ribosomal RNA and inhibits protein synthesis. The pathogenicity of STEC is determined mainly by whether the organism expresses Shiga toxin 1, Shiga toxin 2, or both. STEC that produce Shiga toxin 2 usually cause bloody diarrhea and account for almost all cases of diarrhea-associated HUS. Because E. coli O157 almost universally produces Shiga toxin 2, it is generally considered a high-risk STEC. Circulating Shiga toxin is thought to underlie the vascular injury leading to HUS, with the most pronounced end-organ damage occurring in the kidneys. Organ-specific microvascular injury initiates thrombotic responses, including intraglomerular microthrombi and platelet adhesion, leading to thrombocytopenia, hemolysis, and end-organ damage.

Activation of the microvascular endothelium is believed to contribute to the gastrointestinal manifestations of STEC infection. Early colonic histology shows superficial inflammation and focal necrosis with preserved deep crypts, findings that suggest ischemia. During the diarrheal phase, reported hematologic abnormalities include increased plasminogen activator inhibitor type 1 activity, elevated D-dimer and prothrombin activation fragments 1 and 2, increased platelet-activating factor, sheared von Willebrand factor, and dysregulated angiopoietin 1 and 2 activity.

Common causes of HUS may include:^{[7][8][9][10]}

• E. coli (70%)- Shiga-Toxin producing E.Coli (STEC)
  • primary source of infection is usually undercooked or raw ground meat products, raw milk, or fecal contamination of vegetables
  • other sources include swimming pools or lakes contaminated with feces
  • usually cause self-limiting infection but can lead to HUS in some, particularly in young children and elderly
  • STEC is heat sensitive and destroyed by thorough cooking and WHO recommended guidelines for safer food should be used to prevent infections with foodborne organisms like STEC.
• Other Shiga-Toxin bacteria like Shigella Dysenteriae type-1.
• Among other infectious causes, Streptococcus pneumoniae and influenza virus are notable non-STEC triggers of HUS.

Less common causes include:

• Genetic mutations of complement genes/ Complement Factor abnormalities
• Infection with Campylobacter Jejuni or Salmonella Typhi
• Pneumococcal infection (commonly pneumonia, empyema, meningitis, and less commonly pericarditis, peritonitis, otitis media and bacteremia
• Pregnancy
• Autoimmune disease for example SLE, antiphospholipid syndrome
• Drug associated
  • Antineoplastic, immunosuppressive and anti platelet
• Organ Transplantation
• Human immunodeficiency viral infection such as HIV/AIDS

For STEC-HUS, important alternatives include thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies. When available, ADAMTS13 testing supports evaluation for TTP, and complement evaluation may be considered when complement-mediated HUS is suspected (recurrent disease, family history, absence of diarrheal prodrome, or persistent hypocomplementemia).^[1]

Rapid identification of the cause of thrombotic microangiopathy is important because therapy differs. Prompt anticomplement therapy improves kidney-related outcomes in atypical HUS, whereas unwarranted use of such therapy in STEC-HUS may be detrimental.^[11]

The highest proportion of HUS cases (15.3%) occurred among children aged <5 years. HUS affects female more than male and white race more than other races. Mortality is more commonly seen in elderly patients in which disease is less common but more dangerous

Large outbreaks have occurred internationally, including the 2011 E. coli O104:H4 outbreak, which highlighted the role of prompt supportive care and the risks of unproven therapies in outbreak settings.^[12]

The incidence of STEC infection peaks during summer and fall and is greatest among children younger than 5 years of age, the group at highest risk for HUS. Predominant STEC serogroups vary by region. E. coli O157 is the most commonly identified serogroup in symptomatic persons worldwide, whereas O26 is the serogroup most often associated with HUS in the European Union.

Among children infected with high-risk STEC, HUS develops in approximately 15 to 20% of cases. In a multinational emergency-department cohort of 927 STEC-infected children, 4% presented with HUS and an additional 14% subsequently developed HUS.

The case-fatality rate for STEC-associated HUS remains approximately 3% among children and may be as high as 20% among middle-aged and older adults.

Children younger than 5 years of age are the group at highest risk for the development of HUS after STEC infection.

In the United States, E. coli O157 is identified in most HUS cases, whereas in the European Union O26 is more often associated with HUS.

The most potent risk factor in the development of Hemolytic Uremic Syndrome in childhood is infection with Verocytotoxin (Shiga-like toxin)-producing bacteria, usually Enterohemorrhagic Escherichia coli (VTEC/STEC),and in some tropical regions Shigella dysenteriae type I^[13] . Other risk factors include genetic mutations in Complement factors, Pneumococcal infections, autoimmune diseases like SLE and antiphospholipid Syndrome, pregnancy, antineoplastic and immunosuppressive drugs, HIV infection and organ transplantation.

In suspected STEC infection, exposures that may increase HUS risk include antibiotic therapy (especially certain classes) and antimotility agents. A meta-analysis found an association between antibiotic exposure and subsequent HUS among patients with STEC infection, supporting guideline recommendations to avoid empiric antibiotics when STEC is suspected in immunocompetent patients with bloody diarrhea.^[14][15]

Dehydration and hemoconcentration during the diarrheal phase are associated with worse kidney outcomes, and early isotonic intravenous fluid administration during high-risk STEC diarrhea has been associated with lower rates of oligoanuric kidney failure in observational studies.^[16][17][18]

Risk factors for progression from high-risk STEC infection to HUS include the following unmodifiable factors:^[19]

–       younger age below 5 years, older age above 75 years,

–       female sex,

–       bloody diarrhea,

–       vomiting,

–       absence of Shiga toxin 1 when Shiga toxin 2 is present,

–       white-cell count of at least 13,000/mm3,

–       and an initial platelet count below 250,000/mm3.

Potentially modifiable or possibly modifiable risk factors include:^[20]

–       antibiotic exposure,

–       narcotic or antidiarrheal medication use,

–       dehydration,

–       relative hemoconcentration, and

–       hyponatremia.

Risk factors for progression to severe HUS include:^[21]

–       shorter diarrheal prodrome,

–       hyponatremia,

–       lack of parenteral volume expansion,

–       delayed pathogen identification,

–       antibiotic administration, and,

–       at the time of HUS diagnosis, hypocalcemia, central nervous system involvement, increased neutrophil count, relative hemoconcentration, hyponatremia, hypoalbuminemia, and antecedent respiratory infection.

There is insufficient evidence to recommend screening for Hemolytic-Uremic Syndrome

5 percent of patients with EHEC or Shiga toxin-producing E.coli infection will develop HUS presenting with bloody diarrhea, nausea, vomiting, and decreased urination. Common complications of HUS include renal failure which can be acute (AKI) or develop over time(chronic renal failure), hypertension, neurological problems like stroke, seizure, coma and eventually death. Prognosis depends on the associated complications and about 12% of patients with diarrhea-associated HUS progress to end-stage renal failure within 4 years and about 25% have long-term renal impairment leading to 9% renal transplants in children and adolescents.

In hospitalized U.S. children with postdiarrheal HUS, predictors of severe outcomes and in-hospital death have been described, supporting careful monitoring for neurologic involvement and multisystem complications in high-risk patients.^[22]

The first day of diarrhea is generally considered day 1 of illness. A median 3-day interval from exposure to the first loose stool has been reported. Visible blood appears in the stool 1 to 3 days after diarrhea begins in nearly two thirds of reported E. coli O157 infections, and the diarrhea usually abates by day 7 of illness. HUS most often develops between days 5 and 14 of illness. Microangiopathic changes are usually apparent by day 8 or 9, and if anuria occurs it rarely begins after day 10. Rapidly progressive thrombocytopenia is the hallmark hematologic abnormality in patients in whom HUS develops.^[23]

Oligoanuria has been reported in 50 to 60% of children with STEC-associated HUS. Most children with oligoanuria require kidney-replacement therapy until urine flow resumes, usually within 2 weeks after dialysis is started. Neurologic complications such as seizures, coma, and stroke are particularly threatening. Cardiac involvement, like ischemia, arrhythmias, cardiomyopathy, and pericardial effusion, has been reported in less than 10% of children. Rare, but dangerous, intestinal complications include bowel necrosis and perforation. Other acute complications include hypertension, pancreatitis or elevated lipase, elevated aminotransferases, cholestasis, respiratory distress syndrome, pulmonary hemorrhage, volume overload, pleural effusion, insulin-dependent hyperglycemia, and disseminated intravascular coagulation.

Chronic kidney disease may become apparent at variable intervals after acute STEC-HUS and is associated with the duration of anuria, receipt of kidney-replacement therapy, or both during the acute illness. Chronic kidney injury may be detected in up to one third of children who had HUS but did not receive kidney-replacement therapy. Although end-stage kidney disease is uncommon, hypertension, proteinuria, and reduced glomerular filtration rate may appear years later, so follow-up throughout childhood is prudent.

It usually starts with gastrointestinal prodrome including bloody diarrhea and fever that may occur 2-7 days before the onset of renal failure. Other symptoms include nausea, vomiting, abdominal pain and swelling, decreased urination, fatigue, irritability, and swelling of the body.

High-risk STEC infection often begins with abdominal pain, vomiting, and fever, followed by diarrhea that may become bloody 1 to 3 days after onset. Early diagnosis is important. Stool testing should be obtained from all patients with hematochezia and from children with nonbloody diarrhea accompanied by tenesmus or severe abdominal pain. The absence of fever does not exclude STEC infection.

Common physical examination findings of Hemolytic Uremic Syndrome include edema and fluid overload, high blood pressure and often severe pallor. Gastrointestinal findings may include abdominal tenderness, distension and guarding. Bruising, purpura, petechiae or oozing from the site of venipuncture may b seen sometimes.

The classic laboratory findings in HUS include anemia, thrombocytopenia, and acute renal damage. Anemia is microangiopathic hemolytic anemia which low hemoglobin often < 8g/dl, high reticulocyte count and LDH, low Haptoglobin level as well as fragmented RBC’s and Schistiocytes on the peripheral blood smear. Platelets are frequently less than 60,000 without active bleeding usually and renal damage is seen in form of high creatinine, BUN, and electrolyte abnormalities.

If STEC infection is strongly suspected, the hemoglobin level, hematocrit, platelet count, and urea, creatinine, and electrolyte levels, along with a blood smear, should be assessed on initial evaluation and monitored during the illness. Baseline values are useful because they aid interpretation of repeat tests obtained 1 or 2 days later. Early progression toward HUS may be reflected by decreasing platelet count, decreasing hemoglobin level, or increasing creatinine level. Elevated lactate dehydrogenase may also be an early marker. Hemoglobinuria reflects intravascular hemolysis, depletion of circulating haptoglobin, and plasma hemoglobin levels that exceed renal reabsorptive capacity.

X-ray: The classic laboratory findings in HUS include anemia, thrombocytopenia, and acute renal damage. Anemia is microangiopathic hemolytic anemia which low hemoglobin often < 8g/dl, high reticulocyte count and LDH, low Haptoglobin level as well as fragmented RBC’s and Schistiocytes on the peripheral blood smear. Platelets are frequently less than 60,000 without active bleeding usually and renal damage is seen in form of high creatinine, BUN, and electrolyte abnormalities.

USG abdomen: Abdominal ultrasound findings seen in HUS may include Increased parenchymal density/echogenicity in kidneys, hepatomegaly, splenomegaly, ascites, and pleural effusions.

MRI Brain: BrainMRI may be helpful in the diagnosis of pathological changes in patients with CNS manifestations/ complications like seizures, AMS, visual changes or others in patients of HUS. Findings on MRI may include basal ganglia, brainstem, cerebellar or thalamic lesions.

Other important diagnostic tests include

• Stool culture on Sorbitol MacConkey’s agar or detection of Shiga toxin with serological testing
• Genetic testing if suspicion of genetic or complement-mediated HUS/ recurrent HUS
• Blood, spinal, organ/tissue cultures may be needed in case of suspicion of other sources of HUS, for example, Pneumococcal infection

For suspected infectious diarrhea with hematochezia, guidelines recommend early stool testing for bacterial pathogens including STEC, using culture and or Shiga toxin testing (antigen or molecular), because detection becomes less sensitive as time from diarrhea onset increases.^[15]

Laboratory approaches for stool detection of STEC include agar-based isolation, Shiga toxin antigen detection, and nucleic acid amplification of Shiga toxin genes. The ideal diagnostic approach combines methods that rapidly identify whether a high-risk pathogen is present. Because the ability to identify STEC in stool diminishes daily after the onset of diarrhea, specimens should be obtained promptly. If bulk stool is not immediately available, a rectal swab specimen should be obtained and processed; stool should also be tested when it becomes available if clinical suspicion remains high. Shiga toxin antigen detection should not be used as the sole screening method. Detection of E. coli O157 generally implies high risk because O157 almost always produces Shiga toxin 2; however, in non-O157 STEC infection, toxin genotype is more clinically useful than serogrouping for estimating HUS risk. In most cases of STEC-associated HUS, routine screening for complement regulatory gene mutations is not warranted on the basis of current data.

• The main stray of therapy for HUS is supportive.
• RBC transfusion indicated for low hemoglobin ( Hb < 6-7 g/dl)
• Platelet infusion indicated only if massive hemorrhage or surgical procedure is needed, generally platelet infusion can worsen thrombotic microangiopathy
• Fluid and electrolyte replacement
• Dialysis may be recommended for patients with azotemia and fluid electrolyte imbalance not responding to general medical therapy
• Plasma exchange is used for the treatment of atypical HUS and for TTP. Not a first-line therapy in patients with typical/ Diarrheal HUS
• Eculizumab can also be used in the treatment of atypical HUS
• Potentially harmful interventions should be avoided. Multiple studies have shown an association between antibiotic administration and increased risk of HUS among patients infected with high-risk STEC; therefore, empiric antibiotics should be avoided in immunocompetent patients with bloody diarrhea when STEC is suspected. Narcotics and antimotility drugs may prolong bloody diarrhea and have been associated with increased risk of HUS and neurologic complications. Nonsteroidal antiinflammatory drugs may precipitate acute kidney injury and should be avoided. A single oral dose of ondansetron may facilitate oral rehydration, but multiple-dose or intravenous ondansetron should not be routinely used.^[24]

In suspected STEC diarrhea, empiric antibiotics are generally avoided in immunocompetent patients because antibiotic exposure has been associated with increased risk of HUS in meta-analysis and is discouraged by infectious diarrhea guidelines when STEC is suspected.^[14][15] Early isotonic intravenous fluid administration during the diarrheal phase and early HUS has been associated with improved kidney outcomes and reduced oligoanuria in observational pediatric studies.^[16][17][18]

• Surgical intervention may be required in some patients who have gastrointestinal complications with severe colitis that progress to necrosis and in some cases lead to intestinal perforation
• Renal transplantation is recommended for children with end stage renal disease (ESRD) following typical HUS or HUS with diarrhea and recurrence rate is extremely low. However transplantation is not recomended in atypical HUS induced renal disease as approximately 50 percent of patients can relapse^[25]

Food and water safety measures reduce STEC transmission, including thorough cooking of ground beef, avoidance of unpasteurized dairy, and hand hygiene to prevent person-to-person spread. Public health notification is important for outbreak investigation and prevention of secondary transmission.^[1]

Expeditious reporting is encouraged because any STEC infection may signify a previously unrecognized outbreak. Daycare and household contacts should be monitored closely, since case clusters are common.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]Parth Vikram Singh, MBBS

In 1955, Gasser et al first described hemolytic-uremic syndrome (HUS). There have been several outbreaks of HUS all over the world over past years.

• In 1955, Gasser et al first described hemolytic-uremic syndrome (HUS).^[1]
• In 1983, Karmali et al discovered the association between Escherichia coli, Shiga-toxin-producing bacteria, and the development of HUS.^[2]
• Forty years ago, E. coli O157:H7 was identified as a cause of bloody diarrhea. Soon thereafter, stools from children with HUS were shown to contain E. coli of varying serotypes that produced toxins lethal to cultured Vero cells. These toxins came to be known as Shiga toxins, and the responsible organisms are now referred to as STEC.^[3]

There have been several outbreaks of HUS, which are summarized below:

• In Febryary 2006, HUS outbreak in Norway.^[4]
• 2011 EHEC/HUS outbreak in Germany.^[5]
• 2011 HUS outbreak nationwide in Norway.^[6]
• In June 2011, HUS outbreak from Shiga toxin-secreting Escherichia coli (STEC) O104:H4 from contaminated fenugreek sprouts occurred near Bordeaux, France.^[7] The importance of toxin genotype rather than serogroup alone was highlighted by the 2011 Shiga toxin 2-producing E. coli O104:H4 outbreak, which caused more than 4000 infections in 16 countries, 908 cases of HUS, and 50 deaths.^[8]
• In December 2016, HUS outbreak in Germany.^[9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3]Parth Vikram Singh, MBBS[4]

HUS may be classified as typical (caused by Shiga-toxin producing E. coli/ Shigella infection) or atypical (caused by complement factor abnormalities, other viral or bacterial infections, HIV, malignancy, organ transplantation, and rarely SLE and pregnancy related).

HUS is commonly discussed within the broader category of thrombotic microangiopathy. In this framework,^[1] atypical HUS denotes a primary thrombotic microangiopathy caused by dysregulation of the complement system, whereas STEC-associated HUS is a secondary thrombotic microangiopathy triggered by microbial factors that activate endothelial cells and initiate the microangiopathic cascade.

Hemolytic-uremic syndrome (HUS) may be classified as follows:

• Shiga toxin producing E. Coli/ Shigella infection

• Complement factor abnormalities
  • Complement factor H (CFH) mutation/ factor H deficiency (autosomal dominant)^[2]
  • Complement factor I (CFI) deficiency (acquired antibody mediated)^[3][4]
  • Membrane co-factor protein deficiency (MCP, CD46)^[5][6]
  • Factor B overactivity (complement factor B mutation)^[7]
  • Diacylglycerol kinase epsilon gene mutations^[8]

• Infection
  • Pneumococcal infection (commonly pneumonia, empyema, meningitis, and less commonly pericarditis, peritonitis, otitis media, and bacteremia)^[9]
  • HIV
  • Other viral or bacterial infections
• Drug associated
  • Antineoplastic
  • Immunosuppressive
  • Anti-platelet
• Malignancy
• Pregnancy^[10]
• Organ transplantation
• Other medical conditions( antiphospholipid syndrome, scleroderma, lupus)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3]Parth Vikram Singh, MBBS[4]

It is understood that hemolytic-uremic syndrome (HUS) is the result of microvascular endothelial cell damage characterized by thrombotic microangiopathy (TMA) in renal glomeruli, gastrointestinal tract, brain and pancreas in all of which the main lesion is the thickening of vessel wall (mainly in capillaries and arterioles), microthrombi in platelets and obstruction of vessel lumen ( partial or complete). Loss of physiological resistance to thrombus formation, complement consumption, leukocyte adhesion to damaged endothelium, the abnormal release of von Willibrand Factor (vWF) and fragmentation, and increased vascular shear stress lead to further amplification of microangiopathy. Typical/ Shiga-toxin-associated hemolytic uremic syndrome (HUS) is usually caused by E.Coli and serotype O157: H7 is most common while congenital predisposing conditions like complement factor abnormalities may play a role in recurrent and familial forms.

Shiga toxin production is the cardinal virulence trait of STEC. Shiga toxin 1 and Shiga toxin 2 each consist of a single A subunit and a pentameric B subunit. Disease begins when the B subunit binds globotriaosylceramide (Gb3) on eukaryotic cells. The holotoxin is internalized, traffics retrogradely through the Golgi apparatus to the endoplasmic reticulum, and releases an enzymatically active A1 fragment that cleaves 28S ribosomal RNA and inhibits protein synthesis. The pathogenicity of STEC is determined mainly by whether the organism expresses Shiga toxin 1, Shiga toxin 2, or both. STEC that produce Shiga toxin 2 usually cause bloody diarrhea and account for almost all cases of diarrhea-associated HUS. Because E. coli O157 almost universally produces Shiga toxin 2, it is generally considered a high-risk STEC.

• Circulating Shiga toxin is thought to underlie the vascular injury leading to HUS, with the most pronounced end-organ damage occurring in the kidneys. Organ-specific microvascular injury initiates thrombotic responses, including intraglomerular microthrombi and platelet adhesion, leading to thrombocytopenia, hemolysis, and end-organ damage. Activation of the microvascular endothelium is believed to contribute to the gastrointestinal manifestations of STEC infection. Early colonic histology shows superficial inflammation and focal necrosis with preserved deep crypts, findings that suggest ischemia. During the diarrheal phase, reported hematologic abnormalities include increased plasminogen activator inhibitor type 1 activity, elevated D-dimer and prothrombin activation fragments 1 and 2, increased platelet-activating factor, sheared von Willebrand factor, and dysregulated angiopoietin 1 and 2 activity.^[1]
• It is understood that hemolytic-uremic syndrome (HUS) is the result of microvascular endothelial cell damage characterized by thrombotic microangiopathy (TMA) in renal glomeruli, gastrointestinal tract, brain and pancreas in all of which the main lesion is the thickening of vessel wall (mainly in capillaries and arterioles), microthrombi in platelets and obstruction of vessel lumen( partial or complete).
• Loss of physiological resistance to thrombus formation, complement consumption, leukocyte adhesion to damaged endothelium, the abnormal release of von Willibrand Factor (vWF) and fragmentation, and increased vascular shear stress lead to further amplification of microangiopathy.
• Congenital predisposing conditions like complement factor abnormalities may play a role in recurrent and familial forms.^[2]
• Typical/ Shiga-toxin-associated hemolytic uremic syndrome (HUS) is usually caused by E.Coli.
• Serotype O157: H7 is most commonly seen in the USA and Europe, although other serotypes less commonly associated include O26:H11, O103:H2, O121:H19, O145:NM and O111:NM. Other strains, especially O111:H-serotype is frequently found in other countries as well.
• EHEC produce several virulence factors including Shiga-Toxin and that gain access to the blood circulation after damaging the intestinal endothelium and later affect the target organs
• Pathogen is usually transmitted via the ingestion of undercooked ground meat to the human host.
• Following transmission/ingestion, the EHEC is assumed to bind to the small intestine followed by colonization of colon.^[3]
• EHEC interacts with intestinal microflora as well as host hormonal response thus leading to the activation of several virulence factors including Shiga-Toxin (Stx) and others that enable attachment of pathogen to the instestinal epithelial cell and enhancing the mobility of flagella thus leading to induction of Stx which adheres to the endothelium of the intestine and lead to ulceration and hemorrhaging^[4][5][6]
• Intestinal epithelial damage allows bacterial virulence factors to enter the circulation after which Stx in circulation binds to the platelets, neutrophils, and monocytes as well as to platelet–monocyte and platelet–neutrophils in complexes leading to tissue-factor (TF) expressing microparticle release.^[7]
• Aggregates are formed between monocyte and platelets and also between neutrophils and platelets. Stx can also bind to the blood cells via G3b receptors in addition to other glycolipid receptors where as lipopolysaccharide or LPS binds via TLR-4 or Toll like receptor, which is in complex with CD62 on platelets.^[8]
• Platelet activation lead to prothrombotic state and microthrombi lead to thrombocytopenia. In presence of a circulation with high resistance like renal microcirculations, these effects are enhanced. Other G3b expressing organs like including brain can also be affected.
• Stx induces cell death by inhibiting the protein synthesis or by apoptosis.^[9]
• Neutrophils, monocytes and IgM-producing B lymphocytes show resistance to cytotoxic effects of shiga toxin. In macrophage-like THP-1 cells, both apoptotic and cell survival signaling pathways were activated after they were exposed to Shiga toxin-1, hence, most leukocytes being exposed to Shiga toxin will not undergo cell death, allowing the toxin to circulate bound to their cell membrane.^[10]
• Endothelial cell damage of glomerular capillaries is the main feature in the pathogenesis of HUS.
• Stx exerts cytotoxic and apoptotic effects on glomerular endothelial and epithelial cells^[11][12].
• The pathogenesis in complement mediated or atypical HUS may include complement mediated platelet activation and endothelial damage and usually have low complement levels.

Mutations in the genes associated with atypical HUS can cause uncontrolled complement system activation which attacks endothelial cells leading to inflammation and thrombi formation and may lead to kidney injury and renal failure. Examples include:^[13][14][15]

• Complement factor H (CFH) mutation/ factor H deficiency (autosomal dominant)
• Membrane co-factor protein deficiency (MCP; CD46)
• Factor B overactivity (Complement Factor B mutation)
• Diacylglycerol kinase epsilon gene mutations
• Factor I (IF) mutation

Other genetic conditions predisposing to atypical HUS include:

• Mutations in the MMACHC (methyl malonic aciduria and homocystinuria type C) gene^[16]
• Genetic disorders of ADAMTS13^[17]

Conditions associated with HUS include:

• Malignancy, cancer chemotherapy and ionizing radiation
• Calcineurin inhibitors and transplantation
• Pregnancy, HELLP syndrome, and oral contraceptive pill
• Systemic lupus erythematosus and antiphospholipid antibody syndrome
• Glomerulopathy

On gross pathology, [feature2], and [feature3] are characteristic findings of HUS.

On microscopic histopathological analysis finding of HUS.

• Granular (muddy brown) casts

• Characteristic fibrin thrombi in glomerular and interstitial capillaries
• Slough into tubular lumen

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]Parth Vikram Singh, MBBS

The major cause of HUS in childhood is gastrointestinal infection with verocytotoxin (Shiga-like toxin)-producing bacteria, usually enterohemorrhagic Escherichia coli (VTEC/STEC), and in some tropical regions Shigella dysenteriae type I.Verocytotoxin-producing citrobacter freundii has also been reported. Within STEC infections, risk is determined more precisely by Shiga toxin genotype than by serogroup alone; STEC that produce Shiga toxin 2 are high-risk pathogens. E. coli O157 remains the best-characterized high-risk STEC, but clinically important non-O157 STEC also occur. In America and the UK, most cases are associated with E. coli serotype O157:H7, while other serotypes such as O26, O111, O103, and O145 are increasingly reported in Europe and elsewhere.

VTEC strains produce various toxins, the major ones being verocytotoxin-1 (Stx1) and verocytotoxin-2 (Stx2). Verocytotoxin-1 differs by one amino acid from Shiga toxin produced by Shigella dysenteriae type 1. Verocytotoxin-2 has multiple variants that are closely related to each other but have 55–60% homology to verocytotoxin1. HUS is mostly caused by verocytotoxin-2-producing strains.HUS can occur in the course of systemic diseases or physiopathological conditions such as pregnancy, after transplantation or after drug assumption.

Among other infectious causes, Streptococcus pneumoniae and influenza virus are notable non-STEC triggers of HUS.

Common causes of HUS may include:^[1][2][3][4]

• E. coli (70%)- Shiga-Toxin producing E.Coli (STEC)
  • Primary source of infection is usually undercooked or raw ground meat products, raw milk, or fecal contamination of vegetables
  • Other sources include swimming pools or lakes contaminated with feces
  • Usually cause self-limiting infection but can lead to HUS in some, particularly in young children and elderly
  • STEC is heat sensitive and destroyed by thorough cooking and WHO recommended guidelines for safer food should be used to prevent infections with foodborne organisms like STEC^[5].
• Other Shiga-Toxin bacteria like Shigella dysenteriae type-1. Among other infectious causes, Streptococcus pneumoniae and influenza virus are notable non-STEC triggers of HUS.^[6]

Less common causes of HUS include ^{[7][8][9][10]}

• Genetic mutations of complement genes/ complement factor abnormalities
• Infection with Campylobacter Jejuni or Salmonella Typhi
• Pneumococcal infection (commonly pneumonia, empyema, meningitis, and less commonly pericarditis, peritonitis, otitis media and bacteremia
• Pregnancy
• Autoimmune disease such as SLE, Antiphospholipid Syndrome
• Drug associated
  • Antineoplastic, immunosuppressive and anti platelet
• Organ Transplantation
• Human immunodeficiency viral infection such as HIV/AIDS

List the causes of the disease in alphabetical order:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS

Rapid identification of the cause of thrombotic microangiopathy is important because therapy differs. Prompt anticomplement therapy improves kidney-related outcomes in atypical HUS, whereas unwarranted use of such therapy in STEC-HUS may be detrimental.^[1]

[HUS] must be differentiated from other diseases that cause Clinical signs and symptoms may overlap among the different forms of HUS. OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [differential dx1], [differential dx2], and [differential dx3].

OR

As [disease name] manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. [Subtype name 1] must be differentiated from other diseases that cause [clinical feature 1], such as [differential dx1] and [differential dx2]. In contrast, [subtype name 2] must be differentiated from other diseases that cause [clinical feature 2], such as [differential dx3] and [differential dx4].

On the basis [symptom 1], [symptom 2], and [symptom 3], [disease name] must be differentiated from [disease 1], [disease 2], [disease 3], [disease 4], [disease 5], and [disease 6].

Diseases	Clinical manifestations						Para-clinical findings							Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings			Imaging			Histopathology
	Symptom 1	Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3
Differential Diagnosis 1
Differential Diagnosis 2
Differential Diagnosis 3
Diseases	Symptom 1	Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3	Histopathology	Gold standard	Additional findings
Differential Diagnosis 4
Differential Diagnosis 5
Differential Diagnosis 6

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3] Parth Vikram Singh, MBBS[4]

The highest proportion of hemolytic uremic syndrome (HUS) cases (15.3%) occurred among children aged <5 years. The incidence of STEC infection peaks during summer and fall. HUS affects female more than male and white race more than other races. Mortality is more commonly seen in elderly patients in which disease is less common but more dangerous.The incidence of atypical HUS in The United States of America is approximately two per million. Predominant STEC serogroups vary by region. E. coli O157 is the most commonly identified serogroup in symptomatic persons worldwide, whereas O26 is the serogroup most often associated with HUS in the European Union.^[1]

• In children less than 5 years of age, the incidence of hemolytic uremic syndrome (HUS) is approximately 8.5 per 100,000.^[2]
• The incidence of atypical HUS in the United States of America is approximately 0.2 per 100,00 individuals.^[3]
• Among children infected with high-risk STEC, HUS develops in approximately 15 to 20% of cases. In a multinational emergency-department cohort of 927 STEC-infected children, 4% presented with HUS and an additional 14% subsequently developed HUS.^[4]

• Mortality is more commonly seen in elderly patients in which disease is less common but more dangerous.^[5]

• In 2017, the mortality of hemolytic uremic syndrome (HUS) is estimated to approximately 10%.^[6]
• The case-fatality rate for STEC-associated HUS remains approximately 3% among children and may be as high as 20% among middle-aged and older adults.^[7]

• Patients of all age groups may develop hemolytic uremic syndrome (HUS).
• The incidence of HUS increases with age; the median age at diagnosis is younger than 5 years.^[8]

• HUS commonly affects individuals younger than 5 years of age.^[8]

• HUS usually affects individuals of the White race (82%).^[9]

• HUS affects female more than male. Approximately 59% of affected individuals are female.^[9]

• In the United States and Western Europe, the reported annual incidence of STEC (Shiga Toxin-Producing E.coli) HUS is approximately two to three per 100,000 children less than five years of age.^[10]
• Data on paediatric HUS established for some European countries (France, Germany, Austria and Italy) show an estimated prevalence of atypical HUS of 7 per million children in the whole of the European Community.^[11]
• In the United States, E. coli O157 is identified in most HUS cases, whereas in the European Union O26 is more often associated with HUS.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3] Parth Vikram Singh, MBBS[4]

The most potent risk factor in the development of hemolytic uremic syndrome (HUS) in childhood is infection with verocytotoxin (shiga-like toxin)-producing bacteria, usually enterohemorrhagic Escherichia coli (VTEC/STEC),and in some tropical regions Shigella dysenteriae type I . Other risk factors include genetic mutations in complement factors, pnemumococcal infections, autoimmune diseases like SLE and antiphospholipid syndrome, pregnancy, antineoplastic and immunosupressive drugs, HIV infection and organ transplantation.

The most potent risk factor in the development of HUS is etiology advanced and clinical associations.

etiology advance

• Infection induced^[1][2]

1. Shiga and verocytotoxin (shiga-like toxin)-producing bacteria; enterohemorrhagic Escherichia coli, Shigella dysenteriaen type 1, Citrobacter
2. Streptococcus pneumoniae, neuraminidase, and T-antigen exposure

• Disorders of complement regulation^[3][4]
  • Complement factor H (CFH) mutation/ factor H defeciency (autosomal dominant)
  • Complement factor I(CFI) defeciency (acquired antibody mediated)
  • Membrane co-factor protein defeciency (MCP; CD46)
  • Factor B overactivity (Complement factor B mutation)
  • Diacylglycerol kinase epsilon gene mutations

• von Willebrand proteinase, ADAMTS13 deficiency

1. Genetic disorders of ADAMTS13^[5]
2. Acquired von Willebrand proteinase deficiency; autoimmune, drug induced

• Defective cobalamine metabolism^[6].

Clinical associations with following diseases:

1. Malignancy, cancer chemotherapy and ionizing radiation
2. Calcineurin inhibitors and transplantation
3. Pregnancy, HELLP syndrome and oral contraceptive pill
4. Systemic lupus erythematosis and antiphospholipid antibody syndrome
5. Glomerulopathy
6. Familial, not included in part 1
7. Unclassified

Risk factors for progression from high-risk STEC infection to HUS include the following unmodifiable factors:^[7]

1. younger age below 5 years, older age above 75 years,
2. female sex,
3. bloody diarrhea,
4. vomiting,
5. absence of Shiga toxin 1 when Shiga toxin 2 is present,
6. white-cell count of at least 13,000/mm3,
7. and an initial platelet count below 250,000/mm3.

Potentially modifiable or possibly modifiable risk factors include:

1. antibiotic exposure,
2. narcotic or antidiarrheal medication use,
3. dehydration,
4. elative hemoconcentration, and
5. hyponatremia.

Risk factors for progression to severe HUS include:

1. shorter diarrheal prodrome,
2. hyponatremia,
3. lack of parenteral volume expansion,
4. delayed pathogen identification,
5. antibiotic administration, and,
6. at the time of HUS diagnosis, hypocalcemia, central nervous system involvement, increased neutrophil count, relative hemoconcentration, hyponatremia, hypoalbuminemia, and antecedent respiratory infection.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3]

There is insufficient evidence to recommend screening for hemolytic uremic syndrome (HUS).

There is insufficient evidence to recommend routine screening for HUS.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2], Anila Hussain, MD [3] Parth Vikram Singh, MBBS[4]

Approximately 15 percent of patients with EHEC or Shiga toxin producing E.coli infection will develop HUS presenting with blood diarrhea, nausea, vomiting, and decreased urination. Common complications of HUS include renal failure which can be acute (AKI) or develop over time (chronic renal failure), hypertension, neurological problems such as stroke, seizure, coma and eventually death. Prognosis depend on the associated complications and about 12% of patients with diarrhea-associated HUS progress to end stage renal failure within 4 years and about 25% have long term renal impairment leading to 9% renal transplants in children and adolescents.

• The first day of diarrhea is generally considered day 1 of illness. A median 3-day interval from exposure to the first loose stool has been reported. Visible blood appears in the stool 1 to 3 days after diarrhea begins in nearly two thirds of reported E. coli O157 infections, and the diarrhea usually abates by day 7 of illness. HUS most often develops between days 5 and 14 of illness. Microangiopathic changes are usually apparent by day 8 or 9, and if anuria occurs it rarely begins after day 10. Rapidly progressive thrombocytopenia is the hallmark hematologic abnormality in patients in whom HUS develops.^[1]
• The symptoms of HUS usually develop after eating of contaminated food in the first diarrhea is watery and become to bloody later and start with symptoms such as abdominal pain, nausea and vomiting accompany diarrhea, fever is observed less commonly.^[2]
• The symptoms of HUS typically develop 5–15% of the cases.^[3]
• If left untreated 15% of patients with HUS may progress to develop rectal prolapse, acute renal failure, colonic gangrene, and mortality.^[4]

Oligoanuria has been reported in 50 to 60% of children with STEC-associated HUS. Most children with oligoanuria require kidney-replacement therapy until urine flow resumes, usually within 2 weeks after dialysis is started. Neurologic complications such as seizures, coma, and stroke are particularly threatening.^[5]

Cardiac involvement, like ischemia, arrhythmias, cardiomyopathy, and pericardial effusion, has been reported in less than 10% of children. Rare, but dangerous, intestinal complications include bowel necrosis and perforation. Other acute complications include hypertension, pancreatitis or elevated lipase, elevated aminotransferases, cholestasis, respiratory distress syndrome, pulmonary hemorrhage, volume overload, pleural effusion, insulin-dependent hyperglycemia, and disseminated intravascular coagulation.^[6]

Some common complications of HUS include:^[4][7][8][9]

• Acute kidney injury (AKI) in childern (Most common)
• Hypertension (HTN)
• End-stage renal disease
• Renal transplants in children and adolescents (Approximately 9%)
• Neurological complications (10-50%)
  • hemiparesis
  • seizure
  • coma
  • stroke
• Death

Chronic kidney disease may become apparent at variable intervals after acute STEC-HUS and is associated with the duration of anuria, receipt of kidney-replacement therapy, or both during the acute illness. Chronic kidney injury may be detected in up to one third of children who had HUS but did not receive kidney-replacement therapy. Although end-stage kidney disease is uncommon, hypertension, proteinuria, and reduced glomerular filtration rate may appear years later, so follow-up throughout childhood is prudent.^[10]

Common complications of HUS include:^{[4][7][8][9][11]}

• Approximately 15% of patients of EHEC‐associated gastroenteritis will develop HUS although it is dependent on bacterial strain and geographic location.
• About 12% of patients with diarrhea-associated HUS progress to end stage renal failure within 4 years and about 25% have long term renal impairment.
• 9% renal transplants in children and adolescents.
• Encephalopathy occurs in patients infected with enterohemorrhagic Escherichia coli (E. coli) has a high mortality rate and patients sometimes present sequelae.

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