What are the causes, clinical presentation, and management of hemolytic‑uremic syndrome (HUS) in children versus adults?

Hemolytic Uremic Syndrome (HUS)

Definition and Core Diagnostic Triad

HUS is diagnosed when three elements occur simultaneously: microangiopathic hemolytic anemia (elevated LDH, low/absent haptoglobin, schistocytes on smear), thrombocytopenia (platelets <150,000/mm³), and acute renal injury (hematuria, proteinuria, or elevated creatinine). 1, 2

• Up to 50% of cases may present without the full triad initially, but at least one laboratory abnormality is always detectable at disease onset 2
• The direct Coombs test must be negative, confirming non-immune hemolysis 2, 3

Causes: Typical vs. Atypical HUS

Typical (Diarrhea-Associated) HUS

Shiga toxin-producing E. coli (STEC), particularly O157:H7, causes approximately 90-95% of HUS cases, predominantly affecting children under 5 years. 1

• Diarrhea precedes HUS by 4-5 days in typical cases; bloody diarrhea occurs in 60% 1
• Non-O157 STEC strains (O26, O45, O103, O111, O121, O145) also cause HUS but less frequently 1
• Transmission occurs through undercooked ground beef, unpasteurized juice/milk, contaminated water, and person-to-person contact in childcare settings 1
• The infectious dose is remarkably low: <100 organisms for O157 and O111 strains 1
• Shigella dysenteriae type 1 can also produce Shiga toxin and cause HUS, especially in travelers to endemic areas 1

Atypical HUS (aHUS)

Atypical HUS represents 5-10% of cases and results from genetic mutations in complement regulatory proteins (60% of cases) or autoantibodies against these proteins. 1, 4

• Genetic mutations occur in CFH, CFI, CD46, C3, CFB, THBD, and CFHR1-5 genes 1, 2
• 40-50% of aHUS patients have no identifiable mutation but can still be diagnosed based on clinical criteria 2
• Simultaneous onset of diarrhea and HUS suggests aHUS rather than STEC-HUS 1, 2
• aHUS has a relapsing course with >50% progressing to chronic renal dysfunction and 10% mortality 1

Special Populations and Secondary Causes

• In infants <1 year old with aHUS, test for complement-unrelated genes (DGKE, WT1) and cobalamin metabolism defects (MMACHC) 1, 2
• Secondary causes include systemic lupus erythematosus, antiphospholipid syndrome, chronic hemolytic anemias (sickle cell, thalassemia), and certain medications 1

Clinical Presentation

Children (Typical HUS)

Children under 5 years have the highest incidence of STEC infection and greatest risk for HUS progression; typical HUS is the most common cause of acute renal failure requiring dialysis in this age group. 1

• Prodrome of diarrhea (bloody in 60%) for 4-5 days before HUS onset 1
• Neurological involvement occurs in 10-20% and is the first cause of death 1
• Dehydration at admission is associated with increased need for dialysis 1

Adults

Diarrhea-associated HUS in adults is relatively rare but follows the same clinical pattern as in children, with supportive management remaining the cornerstone of therapy. 5

• Adults may present with more severe disease and higher mortality 5
• The same diagnostic triad applies: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury 5
• ADAMTS13 activity must be checked urgently to exclude thrombotic thrombocytopenic purpura (TTP), which requires immediate plasma exchange 5

Diagnostic Workup

Immediate Laboratory Panel (Within 1-2 Hours)

When anemia plus thrombocytopenia presents in the emergency setting, immediately obtain LDH, haptoglobin, indirect bilirubin, Direct Coombs test, and peripheral blood smear for schistocytes. 1, 2, 3

• Complete blood count with platelet count to confirm thrombocytopenia (<150,000/mm³ or ≥25% drop from baseline) 2, 3
• Hemolysis markers: elevated LDH, reduced/absent haptoglobin, elevated indirect bilirubin, reticulocytosis 2, 3
• Peripheral smear for schistocytes, burr cells, or helmet cells (though absence does not exclude early disease due to low sensitivity) 1, 2
• Renal function: serum creatinine, BUN, electrolytes, urinalysis for hematuria and proteinuria 2, 3
• ADAMTS13 activity must be tested urgently; activity <10% indicates TTP and mandates immediate plasma exchange rather than HUS management 2, 3

Etiologic Testing

When clinical history suggests Shiga toxin-producing organism, test stool for both STEC O157 culture AND Shiga toxin/genes; distinguish between Shiga toxin 1 and 2 (stx2 is more potent and associated with higher HUS risk). 1, 3

• If stool testing is negative but HUS is present, serologic testing for STEC (O157 and O111 serogroups) may aid diagnosis 2
• Complement studies: C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) when aHUS is suspected 2, 3
• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) to exclude disseminated intravascular coagulation 3

Genetic Testing for Atypical HUS

Genetic testing should be performed in all suspected aHUS cases through next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB), but treatment should not be delayed for results. 2

• Multiplex ligation-dependent probe amplification of CFHR genes is also recommended 2
• Results ideally available within a few months for prognostic and family-planning purposes 2
• Remember that 40-50% of aHUS cases have no detectable mutation 2

Monitoring Protocol for STEC Infection

For diagnosed or suspected STEC infection, perform daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period (days 1-14). 1, 2

• Monitoring can stop when platelet count begins to increase or stabilize with resolved symptoms 2
• If platelet count obtained within 7 days after gastrointestinal illness onset is not below 150,000/mm³, consider alternative diagnoses 1, 2

Management

Typical (STEC-Associated) HUS

Administering IV fluids during the diarrhea phase reduces the risk of oligoanuric renal failure in children who subsequently develop HUS; management is entirely supportive. 1

• Do not use antibiotics during the acute diarrheal phase or established STEC-HUS, as they may increase Shiga toxin release and worsen outcomes 1, 3, 6
• Do not use plasma exchange for typical STEC-HUS; evidence shows no benefit and adds procedural risk 3, 6
• Avoid antimotility agents, narcotics, and NSAIDs during the acute phase 6
• Early hydration assessment and aggressive fluid management are critical 1

Atypical HUS

Initiate complement inhibition (eculizumab or ravulizumab) within 4-8 hours of confirming the full TMA triad (hemolysis + thrombocytopenia + renal injury); delays increase morbidity and mortality. 2

• Treatment should not be delayed for genetic results; 40-50% of patients have no identifiable complement-gene mutation 2
• Do not start eculizumab without laboratory-confirmed active TMA, as unnecessary complement inhibition carries high risk of meningococcal infection 2
• Carrying a complement-gene mutation alone does not justify complement blockade; treatment requires active disease evidence 2

Vaccination and Infection Prophylaxis

Prior to starting eculizumab or ravulizumab, administer both the quadrivalent meningococcal conjugate vaccine (serogroups A, C, W, Y) and the serogroup B vaccine. 2

• Provide lifelong antibiotic prophylaxis (penicillin or a macrolide for penicillin-allergic patients) during complement-inhibitor therapy 2

Intensive Care Criteria

Admit to an intensive-care unit when any of the following are present: platelet count <20 × 10³/mm³, altered mental status, seizures, severe hypertension, or oliguria/anuria. 3

• Prompt organ-support measures—including respiratory support, hemodynamic stabilization, and aggressive control of severe hypertension—are essential 3
• Neurological involvement occurs in 10-20% and is the first cause of death; obtain neurological consultation, EEG, and brain MRI if symptoms arise 1, 2, 3

Monitoring During Acute Phase

Daily laboratory monitoring of hemoglobin, platelet count, LDH, creatinine, and electrolytes is required during the acute phase. 2

• Regular follow-up is recommended until laboratory and clinical parameters normalize 1
• Patients with increasing creatinine, elevated blood pressure, and volume overload require close monitoring in centers capable of managing acute renal failure 2

Critical Pitfalls to Avoid

• Do not delay ADAMTS13 testing; each hour of delay in initiating plasma exchange for TTP increases mortality 3
• Do not administer plasma exchange for typical STEC-HUS, as it provides no therapeutic advantage and increases complication risk 3
• Do not use antibiotics in STEC infections, as they may worsen outcomes and potentially increase HUS risk 1, 6
• Do not start complement inhibition without laboratory-confirmed active TMA; unnecessary eculizumab exposes patients to serious infection risk without proven benefit 2
• Do not rely on normal complement levels to exclude aHUS; baseline C3/C4/CH50/AP50 are often normal and are useful mainly for monitoring 2
• Recognize that aHUS is a diagnosis of active thrombotic microangiopathy, not a chronic intermittent hemolytic disorder; episodic hemoglobinuria with full laboratory normalization between events is inconsistent with complement-mediated TMA 2

Prognosis

Typical HUS

• Immediate outcome is most often favorable in children with supportive care 7
• Long-term renal sequelae are frequent due to nephron loss 7
• Early recognition, appropriate treatment, and multidisciplinary approach are critical to reduce risk of irreversible organ damage or death 1

Atypical HUS

• More than 50% of patients progress to chronic renal dysfunction and 10% mortality 1
• Recurrence after renal transplantation is frequent 7, 4
• The underlying genetic defect predicts prognosis both in native kidneys and after renal transplantation 4