In a 43‑year‑old woman who received a red blood cell transfusion 14 days ago and now presents with fever, anemia (hemoglobin 7 g/dL), leukopenia (total leukocyte count 2,300/µL) with neutropenia (30% neutrophils), and mild hyperbilirubinemia (bilirubin 1.4 mg/dL), what are the differential diagnoses and appropriate management?

Differential Diagnosis and Management

Most Likely Diagnosis

This patient most likely has post-transfusion cytomegalovirus (CMV) infection presenting as a mononucleosis-like syndrome with pancytopenia, which should be confirmed with CMV quantitative PCR and managed supportively while ruling out other serious causes including acute leukemia, hemolytic anemia, and sepsis. 1

Key Differential Diagnoses

1. Post-Transfusion CMV Infection (Most Likely)

• Symptoms typically begin approximately 1 month after transfusion (this patient is at 19 days post-transfusion, within the expected window) 1
• Classic mononucleosis features are usually absent; instead patients develop high fever leading to empirical antimicrobial therapy 1
• Pancytopenia with atypical lymphocytosis (60% lymphocytes suggests this) and mild elevations of liver function tests are diagnostic clues 1
• Immunocompetent patients lack clinical toxicity despite daily fever as high as 40°C 1
• Diagnosis is made using quantitative molecular nucleic acid amplification tests to measure serum viral load 1

2. Acute Leukemia (Must Rule Out Urgently)

• Can present insidiously with fever, mild cytopenias, and constitutional symptoms before progressing to life-threatening pancytopenia 2
• The combination of anemia (Hb 7), leukopenia (TLC 2,300), and relative lymphocytosis warrants immediate evaluation
• Peripheral blood smear examination by hematopathologist is mandatory to assess for abnormal or immature cells 2

3. Hemolytic Anemia

• Mild hyperbilirubinemia (1.4 mg/dL) suggests ongoing hemolysis 3
• Drop in hemoglobin from 10.5 to 7 g/dL over 5 days is concerning for hemolysis
• Laboratory confirmation requires reticulocyte count, lactate dehydrogenase (LDH), haptoglobin, and indirect bilirubin 4, 3
• A reticulocyte count >10 × 10⁹/L indicates regenerative anemia (hemolysis or bleeding); low/normal count suggests production defect 4

4. Sepsis with Bone Marrow Suppression

• Neutropenia (30% of 2,300 = 690 cells/µL) with fever constitutes febrile neutropenia 2
• Absolute neutrophil count <1,000 cells/µL with fever requires immediate empirical broad-spectrum antibiotics 4, 2

Immediate Management Algorithm

Step 1: Stabilization and Urgent Diagnostics (Within 1 Hour)

Transfusion:

• Transfuse 2-3 units packed red blood cells immediately to achieve hemoglobin 7-8 g/dL 4
• Hemoglobin of 7 g/dL meets the restrictive transfusion threshold for stable patients 1, 4
• Use irradiated blood products to prevent transfusion-associated graft-versus-host disease given prior transfusion and potential immunosuppression 1

Antibiotics:

• Start empirical broad-spectrum antibiotics immediately (cefepime, ceftazidime, or meropenem as monotherapy) 2
• Add vancomycin if signs of severe sepsis, hemodynamic instability, or suspected catheter-related infection 2
• Obtain at least two sets of blood cultures before antibiotics 2

Laboratory Tests:

• Complete blood count with differential and reticulocyte count 4, 2
• Peripheral blood smear reviewed by hematopathologist to rule out acute leukemia and assess for schistocytes, abnormal cells 4, 2
• LDH, haptoglobin, indirect bilirubin (to assess hemolysis) 4, 3
• Comprehensive metabolic panel, coagulation studies (PT, aPTT, fibrinogen, D-dimer) 2
• CMV quantitative PCR (most important given timing and presentation) 1
• Direct antiglobulin test (Coombs test) to differentiate immune from non-immune hemolysis 3

Step 2: Risk Stratification

Neutropenia Assessment:

• Absolute neutrophil count = 2,300 × 0.30 = 690 cells/µL
• This is moderate neutropenia (500-1,000 cells/µL) with fever, requiring hospitalization 2, 5

Infection Evaluation:

• Chest radiograph if respiratory symptoms present 4
• Urinalysis and urine culture 4
• Cultures from any skin lesions or suspected infection sites 4

Step 3: Specific Diagnostic Considerations

If Reticulocyte Count is Elevated (>10 × 10⁹/L):

• Suggests hemolysis or bleeding 4
• Check LDH (elevated), haptoglobin (decreased), indirect bilirubin (elevated) to confirm hemolysis 3, 6
• Peripheral smear for schistocytes (microangiopathic hemolysis), spherocytes (hereditary spherocytosis), or parasites 4, 3

If Reticulocyte Count is Low/Normal:

• Suggests bone marrow production defect 4
• Consider bone marrow aspiration and biopsy if peripheral smear shows abnormal cells or if pancytopenia persists 2

If CMV PCR is Positive:

• Supportive care is primary treatment for immunocompetent patients 1
• Monitor for resolution of fever and improvement in blood counts
• Patients typically lack clinical toxicity despite high fevers 1

Step 4: Monitoring

• Complete blood counts every 12-24 hours to assess trajectory of cytopenias 2
• Daily comprehensive metabolic panel, LDH, coagulation studies 2
• Reassess at 3-5 days if fever persists despite appropriate antibiotics, considering fungal infection, resistant bacteria, drug fever, or non-infectious etiology 2

Critical Pitfalls to Avoid

1. Do not delay antibiotics in neutropenic fever—this is a medical emergency 2
2. Do not miss acute leukemia—peripheral smear review by hematopathologist is non-negotiable 2
3. Do not overlook CMV in post-transfusion patients with unexplained fever and pancytopenia 1
4. Do not transfuse non-irradiated blood products in previously transfused patients with potential immunosuppression 1
5. Do not use liberal transfusion targets (>10 g/dL)—restrictive strategy (7-8 g/dL) is evidence-based 1, 4

Additional Considerations

If patient had received azathioprine or 6-mercaptopurine:

• These drugs cause bone marrow toxicity including pancytopenia and leukopenia in 3.2% of patients 1
• Consider drug-induced marrow suppression in the differential

Growth factor support:

• Consider G-CSF on case-by-case basis only if active infection with prolonged neutropenia expected 1
• Avoid in moderate-to-severe COVID-19 if applicable 4