Hemolytic-uremic syndrome overview

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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] Alberto Castro Molina, M.D.

Overview

In medicine, hemolytic-uremic syndrome (or haemolytic-uraemic syndrome, abbreviated HUS) is a disease characterized by microangiopathic hemolytic anemia, acute renal failure and a low platelet count (thrombocytopenia). 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. 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.

Historical Perspective

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.

Classification

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.

Pathophysiology

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.

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).

Causes

Common causes of HUS may include:

• 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.

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

Differentiating [Disease] from Other Diseases

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).

Epidemiology and Demographics

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.

Risk Factors

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 . 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.

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.

Screening

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

Natural History, Complications, and Prognosis

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.

Diagnosis

History and Symptoms

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.

Physical Examination

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.

Laboratory Findings

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.

Imaging Findings

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 Diagnostic Studies

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.

Treatment

Medical Therapy

• 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

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. 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.

Surgery

• 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

Prevention

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.