What are the next steps for a patient experiencing fever and chills after receiving Keytruda (pembrolizumab), iron, and blood transfusions?

Management of Fever and Chills Following Keytruda, Iron, and Blood Transfusion

Immediate evaluation and management of fever and chills after Keytruda (pembrolizumab), iron, and blood transfusions should focus on identifying the most likely cause and initiating appropriate treatment, as these symptoms could indicate potentially life-threatening reactions requiring prompt intervention.

Initial Assessment and Differential Diagnosis

When a patient presents with fever and chills following administration of Keytruda, iron, and blood transfusions, several potential causes must be considered:

1. Pembrolizumab (Keytruda) infusion reaction

   • Incidence: 3% of patients 1
   • Symptoms: Fever, chills, rigors, facial flushing 1
   • Timing: Usually occurs during or shortly after infusion

2. Blood transfusion reaction

   • Types:
     • Acute hemolytic reaction
     • Febrile non-hemolytic reaction
     • Transfusion-related acute lung injury (TRALI)
     • Transfusion-associated circulatory overload (TACO)
     • Post-transfusion CMV mononucleosis syndrome 1

3. IV iron infusion reaction

   • Symptoms: Fever, chills, flushing, urticaria, myalgias, arthralgias 1
   • Timing: Can occur during infusion or as delayed reactions hours to days after infusion 1

4. Immune-related adverse events (irAEs) from Keytruda

   • Hematologic complications: Autoimmune hemolytic anemia 2, 3, thrombotic thrombocytopenic purpura 4
   • Timing: Can occur after first dose or multiple cycles 2, 3

5. Infection

   • Particularly concerning in immunocompromised patients receiving immunotherapy

Immediate Management Steps

1. Assess Vital Signs and Severity

• Monitor temperature, blood pressure, heart rate, respiratory rate, and oxygen saturation
• Assess for signs of anaphylaxis, hemodynamic instability, or respiratory distress

2. Laboratory Evaluation

• Complete blood count with differential
• Complete metabolic panel
• Blood cultures (if fever ≥38.3°C or ≥38.0°C for >1 hour) 1
• Lactate dehydrogenase (LDH), haptoglobin, and direct/indirect Coombs test (to assess for hemolysis) 2, 3
• Procalcitonin (to help distinguish bacterial infection from other inflammatory processes) 1

3. Management Based on Timing and Suspected Cause

If symptoms occur during or immediately after infusion:

For Keytruda infusion reaction:

• Stop or slow the infusion rate
• Provide symptomatic treatment with antipyretics
• For Grade 1/2 reactions: Consider restarting at slower rate after symptoms resolve
• For Grade 3/4 reactions: Permanently discontinue Keytruda 1

For IV iron infusion reaction:

• Stop the infusion
• Monitor vital signs
• For mild-moderate reactions: Consider rechallenge at 50% of initial infusion rate after symptoms resolve
• Avoid first-generation antihistamines (diphenhydramine) as they may worsen hypotension 1
• Consider second-generation antihistamines for urticaria and 5-HT3 antagonists for nausea 1

For acute blood transfusion reaction:

• Stop the transfusion immediately
• Maintain IV access
• Send blood product and patient blood sample to blood bank for investigation
• Provide supportive care based on symptoms

If symptoms occur hours to days after infusions:

For delayed reactions to IV iron:

• NSAIDs for flu-like symptoms, arthralgias, myalgias, and fever 1
• Monitor for hypophosphatemia, especially if ferric carboxymaltose was used 1

For post-transfusion CMV mononucleosis syndrome:

• Consider in patients with persistent fever despite antibiotics
• Look for pancytopenia with atypical lymphocytosis and mild liver function test elevations
• Diagnosis can be confirmed with quantitative molecular nucleic acid amplification tests for CMV viral load 1
• Usually self-limited in immunocompetent patients but can cause serious disease in immunocompromised patients 1

For immune-related adverse events from Keytruda:

• If autoimmune hemolytic anemia is suspected (jaundice, severe anemia, elevated LDH):
  • Administer high-dose corticosteroids (methylprednisolone 1-2 mg/kg IV every 6 hours) 5, 2
  • Consider intravenous immunoglobulins for severe cases 2, 6
  • Discontinue Keytruda 2

4. Monitoring and Follow-up

• Continue monitoring vital signs until stable
• For patients with suspected infection, empiric antibiotics should be initiated promptly 1
• For patients with suspected immune-related adverse events, close monitoring of organ function and response to corticosteroids is essential

Special Considerations

1. Immunocompromised patients:

   • Higher risk for serious infections and more severe immune-related adverse events
   • Lower threshold for initiating empiric antibiotics
   • May develop more severe manifestations of post-transfusion CMV syndrome 1

2. Patients with history of autoimmune disorders:

   • Higher risk for immune-related adverse events from Keytruda
   • May require more aggressive immunosuppressive therapy

3. Patients with cardiac or pulmonary comorbidities:

   • Higher risk for complications from volume overload
   • Careful monitoring for respiratory symptoms

Common Pitfalls to Avoid

1. Attributing fever solely to Keytruda without considering other causes

   • Always consider infection in immunocompromised patients
   • Blood transfusion reactions can occur simultaneously

2. Delaying corticosteroids when immune-related adverse events are suspected

   • Early initiation of corticosteroids is crucial for managing severe immune-related adverse events

3. Overlooking delayed reactions

   • Some reactions may occur days after administration
   • Educate patients about potential delayed symptoms

4. Restarting Keytruda after severe immune-related adverse events

   • Permanently discontinue after Grade 3-4 reactions 1