What are the differential diagnoses and initial management strategies for a patient presenting with symptoms similar to Hemolytic Uremic Syndrome (HUS)?

HUS Mimics: Differential Diagnosis and Management

Primary Differential Diagnoses

When a patient presents with the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal involvement, you must urgently distinguish between atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP), STEC-HUS, and secondary causes of thrombotic microangiopathy (TMA). 1

Key Conditions That Mimic HUS

Thrombotic Thrombocytopenic Purpura (TTP)

• Distinguished by severely deficient ADAMTS13 activity (<10 IU/dL) 1
• More prominent neurological involvement compared to HUS 2
• Requires urgent ADAMTS13 testing before initiating plasma therapy 1, 3
• Platelet count and serum creatinine can predict ADAMTS13 deficiency with good accuracy 2

STEC-HUS (Shiga Toxin-Producing E. coli)

• Typically follows bloody diarrhea by 4-5 days 1
• Requires stool culture and PCR for Shiga toxins, plus serology for anti-lipopolysaccharide antibodies 4
• Critical distinction: If diarrhea and HUS appear simultaneously or diarrhea is brief, suspect aHUS rather than STEC-HUS 1
• Eculizumab is NOT indicated for STEC-HUS 5

Secondary TMA Causes

• Systemic Lupus Erythematosus/Lupus Nephritis: Monoclonal immunoglobulins acting as autoantibodies against complement regulatory proteins 6
• Antiphospholipid Syndrome: Inhibits prostacyclin formation and protein C activation 6
• Disseminated Intravascular Coagulation (DIC): Must be recognized and treated before discriminating among other TMAs 3
• Chronic Hemolytic Anemias: Sickle cell disease, thalassemia, hereditary spherocytosis causing TMA through high nitric oxide consumption 6
• Drug-Induced TMA: Various medications can trigger TMA 7
• Malignancy-Associated TMA 7
• Pregnancy-Associated TMA 1

Metabolic Causes in Infants

• When aHUS presents in the first year of life, consider mutations in complement-unrelated genes (DGKE, WT1) 1
• Methylmalonic acidemia with homocystinuria cblC type (MMACHC) causing cobalamin deficiency 1

Initial Diagnostic Workup

Immediate First-Level Tests (Order Simultaneously)

For any patient presenting with anemia plus thrombocytopenia in the emergency setting, immediately obtain: 1

• Complete blood count with platelet count (thrombocytopenia defined as <150,000/mm³ or 25% reduction) 1
• Peripheral blood smear for schistocytes (>1% supports TMA, but absence does not exclude early diagnosis due to low sensitivity) 1
• LDH (elevated in hemolysis) 1
• Haptoglobin (reduced in hemolysis) 1
• Indirect bilirubin (elevated in hemolysis) 1
• Direct Coombs test (must be negative to confirm non-immune hemolysis) 1
• Renal function: Creatinine, BUN, urinalysis for hematuria/proteinuria 1
• ADAMTS13 activity assay (urgent, before plasma therapy initiation) 1, 3
• Stool culture and Shiga toxin testing (PCR for VTEC) 1, 4

Second-Level Tests

• Complement studies: C3, C4, CH50 (classical pathway), AP50 (alternative pathway), factor H, factor I levels 1, 8
• Anti-factor H antibodies (present in 6-10% of aHUS patients) 4
• Genetic screening for complement pathway mutations (CFH, CFI, CD46/MCP, C3, CFB, THBD, CFHR1-5) 1, 8, 4
• Anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA) for lupus-associated TMA 1
• Antiphospholipid antibodies: Lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I 1
• ANCA testing (c-ANCA, p-ANCA) for vasculitis-associated TMA 1
• Coagulation studies: PT, PTT, INR, fibrinogen to exclude DIC 1

Neurological Assessment (If Indicated)

Neurological involvement occurs in 10-20% of aHUS patients and is the first cause of death 1, 6

• Obtain neurological consultation if patient exhibits: neurological symptoms, motor deficits, generalized weakness, vision changes, seizures, or encephalopathy 1
• EEG and brain MRI with FLAIR and T2-weighted sequences 1
• Look for bilateral symmetrical hyperintensities in basal ganglia, cerebral peduncles, caudate nuclei, putamen, thalami, hippocampi, insulae, or brainstem 1

Diagnostic Algorithm

Step 1: Confirm TMA

• Microangiopathic hemolytic anemia (negative Coombs, elevated LDH, reduced haptoglobin, schistocytes) 1
• Thrombocytopenia (<150,000/mm³ or 25% reduction) 1
• Organ involvement (typically renal: hematuria, proteinuria, elevated creatinine) 1

Step 2: Exclude DIC

• Check PT, PTT, fibrinogen, D-dimer 3
• If DIC present, treat before proceeding with TMA differential 3

Step 3: Distinguish Among TMAs

ADAMTS13 <10 IU/dL → TTP 1, 2

• Initiate plasma exchange immediately
• Do not use eculizumab

Positive Shiga toxin/STEC in stool → STEC-HUS 1, 4

• Supportive care only
• Do not use eculizumab 5
• Do not use antibiotics (may worsen outcomes) 6

ADAMTS13 >10 IU/dL + Negative STEC + Evidence of complement activation → aHUS 1

• Proceed to complement testing
• Consider immediate eculizumab therapy

Identify secondary causes:

• Positive ANA/anti-dsDNA → Lupus-associated TMA 1
• Positive antiphospholipid antibodies → Antiphospholipid syndrome 1
• Recent pregnancy → Pregnancy-associated aHUS 1
• Drug exposure → Drug-induced TMA 7

Initial Management Strategies

For Suspected aHUS (Before Definitive Diagnosis)

Initiate eculizumab within 4-8 hours of diagnosis, as delays are associated with worse outcomes 1

Pre-Treatment Requirements:

• Meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before first dose 5
• If urgent therapy needed before vaccination: provide antibacterial prophylaxis (penicillin or macrolides for penicillin-allergic patients) and vaccinate as soon as possible 1, 5
• Enroll in ULTOMIRIS and SOLIRIS REMS program 5

Eculizumab Dosing for aHUS (Adults ≥18 years):

• 900 mg IV weekly × 4 weeks 5
• Then 1200 mg at week 5 5
• Then 1200 mg every 2 weeks thereafter 5

Supportive Care for All HUS Presentations

• IV fluid resuscitation (reduces risk of oligoanuric renal failure in children, decreases dialysis need) 6
• Monitor daily: Hemoglobin, platelets, LDH, creatinine, electrolytes, BUN 8, 6
• Blood pressure control and volume management 6
• Renal replacement therapy if indicated (severe uremia, hyperkalemia, volume overload, acidosis) 6
• Red blood cell transfusions for symptomatic anemia 6
• Platelet transfusions only if life-threatening bleeding (may worsen TMA) 7

Plasma Exchange Considerations

• First-line for TTP (continue until ADAMTS13 >50%) 2
• May be initiated empirically while awaiting ADAMTS13 results if TTP cannot be excluded 7, 3
• Much less effective in aHUS compared to eculizumab 2, 4
• If plasma exchange initiated for presumed TTP but ADAMTS13 returns normal, transition to eculizumab for aHUS 7

Critical Pitfalls to Avoid

• Do not wait for genetic testing results to initiate eculizumab in suspected aHUS - genetic results take weeks to months, but treatment must begin within hours 1, 8
• Do not exclude TMA based on absence of schistocytes - sensitivity is low, especially early in disease 1
• Do not assume all three criteria (anemia, thrombocytopenia, renal involvement) must be present - up to 50% of aHUS cases lack one parameter at onset 1
• Do not use antibiotics in suspected STEC-HUS - may increase HUS risk and worsen outcomes 6
• Do not delay eculizumab for meningococcal vaccination if patient is critically ill - provide antibiotic prophylaxis and vaccinate concurrently 1, 5
• Following renal transplant, absence of marked thrombocytopenia or anemia should not exclude TMA diagnosis 1
• Monitor for meningococcal infection throughout eculizumab therapy - patients remain at increased risk even after vaccination 5