Misconceptions Regarding Hemolytic Uremic Syndrome

Andrew Shieh, MD
University of Michigan

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy that can be seen after diarrheal illness in young children and consists of the triad of thrombocytopenia, nonimmune hemolytic anemia, and azotemia. The condition traditionally develops about one week after ingestion of food contaminated with Shiga toxin producing Escherichia coli (E. coli) (STEC) in 10% of children. In thrombotic microangiopathy, abnormalities in the wall of arterioles and capillaries lead to microvascular thrombosis, inflammation, and hemolysis of red blood cells. Hematological bloodwork in HUS reveals an elevated total bilirubin, reticulocytes, lactate dehydrogenase, and decreased haptoglobin. Coomb’s test is negative. The following common misconceptions regarding HUS are debunked, and emergency department (ED) physicians should maintain a high index of suspicion for HUS in ill-appearing children with signs of dehydration.

Misconception #1: HUS only occurs during large outbreaks.

Fact: HUS is traditionally caused by exposure to Shiga toxin producing E. coli (STEC-HUS) from pet, farm, or zoo animals. However, 75% of STEC-HUS cases are sporadic and an exposure is unknown 37% of the time. Atypical HUS is triggered by viruses, medications, malignancies, organ transplantation, pregnancy, and autoimmune conditions, such as antiphospholipid syndrome and systemic lupus erythematous. Atypical HUS may also be caused by familial or sporadic complement hyperactivation and is not directly associated with food consumption.

Misconception #2: O157:H7 is responsible for most STEC infections in the world.

Fact: E. coli O157:H7 continues to be responsible for most cases in Latin America. According to the Centers for Disease Control and Prevention (CDC), there has been an increase of reported STEC infections within the past 20 years. A shift in epidemiology occurred in the 2000s, and non-O157 serotypes are now more commonly found in North America and Europe. In North America, STEC infections are most common in the West and Midwest and peak during summer.

Misconception #3: HUS cannot occur with a negative stool culture.

Fact: Specimen collection can be performed by rectal swab or stool culture. Stool culture sensitivity is insufficient to exclude STEC and in patients without diarrhea, a rectal swab should be collected. The diagnosis of STEC must include both culture and nonculture-based assays such as polymerase chain reaction (PCR) to detect STEC toxins or genes. By the time HUS is diagnosed, stool cultures are less likely to be positive for E. coli. Negative immunoassay tests should be confirmed by PCR. PCR can detect the Shiga toxin gene up to 20 days after onset of abdominal symptoms.

Misconception #4: E. Coli is the only bacteria that produces Shiga toxin and causes HUS.

Fact: Both non-O157 and O157 strains of E. Coli produce Shiga toxin. Shiga toxin can also be produced by Shigella, Strep pneumoniae, Salmonella, Campylobacter, and Citrobacter. Patients with pneumococcal-associated HUS typically present with complicated pneumonia or meningitis and are associated with higher mortality and long-term morbidity than STEC disease.

Misconception #5: Nonbloody diarrhea cannot be STEC or cause HUS.

Fact: Although traditionally less common, non STEC-HUS often does not cause diarrhea. Bloody diarrhea is only seen in 65-80% of patients with STEC, and lower in non-O157 infections. Investigation for STEC should be ordered regardless of the presence of blood in stool if HUS is suspected.

Misconception #6: HUS can be managed in the outpatient setting.

Fact: Children diagnosed with HUS should be transferred to a pediatric facility to be evaluated by a pediatric nephrologist and hospitalized. Management is supportive and includes intravenous (IV) fluid hydration, blood pressure management, red blood cell transfusions, and dialysis. Predictors for dialysis in HUS include elevated creatinine, leukocytosis with white blood cell count over 13 K/uL, oliguria in the first 24 hours after admission and hyponatremia. Early volume expansion to maintain intravascular volume is mandatory to reduce need for dialysis and central nervous system complications. Antibiotics should be reserved only for children with sepsis, bacteremia, and another concomitant serious infection (invasive pneumococcal disease, urinary tract infection, etc) because antibiotics can aggravate toxin release.

A good history is key to determine need for bloodwork to evaluate for early HUS in young children with abdominal symptoms, altered mental status, and evidence of dehydration on physical examination. Early diagnosis and initiation of IV fluids decreases dialysis and long-term renal complications. Hospitalization and close monitoring for dialysis needs is mandatory.

Additional Reading

1. Joseph A, Cointe A, Mariani Kurkdjian P, Rafat C, Hertig A. Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review. Toxins (Basel). 2020;12(2):67. doi:10.3390/toxins12020067
2. Michael M, Bagga A, Sartain SE, Smith RJH. Haemolytic uraemic syndrome. Lancet. 2022;400(10364):1722-1740. doi:10.1016/S0140-6736(22)01202-8
3. Ardissino G, Tel F, Possenti I, et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. Pediatrics. 2016;137(1). doi:10.1542/peds.2015-2153
4. Grisaru S. Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovasc Dis. 2014;7:231-239. doi:10.2147/IJNRD.S41837
5. Centers for Disease Control and Prevention (CDC). National Shiga toxin producing Escherichia coli(STEC) Surveillance Annual Report, 2017. Atlanta, Georgia: US Department of Health and Human Services, CDC, 2021.