What is the differential diagnosis for a patient presenting with hemolysis and fever?

Differential Diagnosis for Hemolysis Plus Fever

When a patient presents with hemolysis and fever, immediately prioritize life-threatening thrombotic microangiopathies—particularly hemolytic uremic syndrome (HUS)—and severe infections, as these require urgent recognition and treatment to prevent mortality. 1

Immediate Life-Threatening Considerations

Hemolytic Uremic Syndrome (HUS)

• HUS is the leading diagnosis when hemolytic anemia occurs with fever and should be considered first, as it represents a life-threatening thrombotic microangiopathy 1
• Typical HUS follows Shiga toxin-producing E. coli O157:H7 infection, presenting with bloody diarrhea followed by hemolytic anemia, thrombocytopenia, and renal failure approximately 4-5 days after diarrhea onset 1
• Atypical HUS results from complement dysregulation and can occur at any age, though more frequent in childhood 1
• Critical pitfall: Up to 50% of cases may not have all three classic features (hemolytic anemia, thrombocytopenia, renal involvement) at disease onset—do not wait for the complete triad before initiating evaluation 1

Severe Bacterial Infections with Hemolysis

• Clostridium perfringens septicemia causes acute intravascular hemolysis through alpha-toxin production and presents with high fever, chills, and marked hemolysis; this infection progresses rapidly to death within hours 2
• Invasive nontyphoidal Salmonella and noncholera Vibrio infections are associated with hemolytic complications, particularly in patients with underlying hemolytic conditions 1
• Tickborne rickettsial diseases (Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis) present with fever and can cause hemolysis, though rash may be absent in up to 20% of cases 3

Thrombotic Thrombocytopenic Purpura (TTP)

• TTP presents with fever, hemolytic anemia, thrombocytopenia, neurologic symptoms, and renal dysfunction 1
• Urgently measure ADAMTS13 activity when Coombs-negative hemolysis occurs with thrombocytopenia to distinguish TTP from atypical HUS 1

Immune-Mediated Hemolysis with Fever

Autoimmune Hemolytic Anemia (AIHA)

• AIHA can present with fever, weakness, jaundice, dark urine, and inability to perform physical activity 3
• The direct antiglobulin test (Coombs test) is the cornerstone for diagnosing autoimmune forms 4, 5
• Drug-induced hemolytic anemia should be evaluated, particularly with recent exposure to cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, rifampin, or dapsone 3
• Reticulocytopenia occurs in 20-40% of AIHA cases and represents a poor prognostic factor 5

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH presents with acute or fulminant high fever, toxic appearance, lymphoproliferation (diffuse lymphadenopathy, hepatosplenomegaly), and hemolysis 3
• Consider familial HLH or accelerated phase of Chediak-Higashi syndrome, Griscelli syndrome, or Hermansky-Pudlak syndrome 3

Malignancy-Associated Hemolysis

Hematologic Malignancies

• Leukemias (acute and chronic) commonly cause fever through bone marrow infiltration, immune dysfunction, and neutropenia 6
• Non-Hodgkin's lymphoma presents with fever as a paraneoplastic phenomenon, particularly in advanced disease 6
• In patients with hematologic malignancies who develop fever, infections occur in approximately 50-60% of cases—always rule out infection first 6
• Rituximab therapy can cause hemolytic anemia, cytopenias, and increased infection risk 7

Infectious Causes Beyond Bacteria

Viral Infections

• Epstein-Barr virus infection can trigger atypical HUS and presents with fever and hemolysis 8
• Mycoplasma pneumoniae infection causes maculopapular rash and can be associated with hemolysis 3
• Consider human herpesvirus 6, parvovirus B19, and enteroviral infections in the differential 3

Parasitic Infections

• Malaria must be excluded in any patient with fever and hemolysis who has visited a tropical country within 1 year of presentation 3
• Perform three thick films/rapid diagnostic tests over 72 hours to confidently exclude malaria 3
• Leptospirosis presents with fever, proteinuria, and hematuria 3

Diagnostic Algorithm

Initial Laboratory Confirmation

• Confirm hemolysis by obtaining reticulocyte count, LDH, indirect bilirubin, haptoglobin, and peripheral blood smear 1, 4, 5
• Elevated LDH and reduced haptoglobin indicate hemolysis, with marked LDH elevation suggesting intravascular hemolysis 4, 5
• Perform direct antiglobulin test (Coombs test) to distinguish immune from non-immune hemolytic anemia 1, 4

Assessment for Thrombotic Microangiopathy

• Check platelet count, renal function (BUN, creatinine), and examine peripheral smear for schistocytes 1
• Critical pitfall: Absence of schistocytes should not exclude early TMA diagnosis due to low sensitivity 1
• If Coombs-negative with thrombocytopenia, urgently measure ADAMTS13 activity 1

Infection Workup

• Obtain two sets of blood cultures prior to antibiotic therapy 3
• Perform malaria films/rapid diagnostic tests in all patients with tropical travel history 3
• Consider stool cultures for E. coli O157:H7 and Shiga toxin testing if diarrhea present 1
• Evaluate for tickborne diseases based on exposure history and geographic location 3

Additional Studies Based on Clinical Context

• Complete blood count with differential to assess for lymphopenia (viral infections, typhoid), eosinophilia (parasitic infections), or neutropenia (hematologic malignancy) 3
• Comprehensive metabolic panel, liver function tests 3
• Urinalysis for proteinuria, hematuria, or hemoglobinuria 3
• Chest radiograph if respiratory symptoms present 3
• Consider bone marrow analysis if refractory or if myelodysplastic syndrome suspected 3

Critical Pitfalls to Avoid

• Do not delay empiric antibiotics in septic patients—initiate within 1 hour if sepsis suspected, as delay increases mortality 9
• Do not wait for all three features of HUS (hemolysis, thrombocytopenia, renal failure) to be present before evaluation, as up to 50% lack complete triad at onset 1
• Do not overlook non-infectious causes including drug reactions, immune complex-mediated illness, and thrombotic thrombocytopenic purpura 3, 9
• Do not rely solely on schistocytes for TMA diagnosis due to low sensitivity in early disease 1
• Consider atypical presentations in elderly and immunocompromised patients who may have severe infections without fever 9