What are the causes and management of fever occurring 24 hours after administration of Keytruda (pembrolizumab) with concurrent blood and iron infusion?

Management of Fever After Keytruda, Blood and Iron Infusion

Fever occurring 24 hours after Keytruda (pembrolizumab) administration with concurrent blood and iron infusion is most likely due to an infusion-related reaction, with cytokine release syndrome being the primary consideration, and requires immediate symptomatic management while ruling out infectious causes.

Potential Causes

1. Infusion-Related Reactions

• Keytruda (Pembrolizumab):

  • Incidence of infusion-related reactions (IRRs) is approximately 5% 1
  • Can cause cytokine release syndrome (CRS) which may present as fever, even days to weeks after administration 2
  • Symptoms include fever, chills, rigors, flushing, and hypotension

• Blood Transfusion:

  • Febrile non-hemolytic transfusion reactions are common within 24 hours 1
  • Symptoms include fever, chills, and mild dyspnea
  • Requires monitoring of vital signs including respiratory rate, pulse, blood pressure, and temperature

• Intravenous Iron:

  • Can cause complement activation-related pseudo-allergy (CARPA) 1
  • Symptoms include fever, flushing, chest tightness, and back pain
  • Different iron formulations have varying reaction profiles

2. Drug-Induced Fever

• Fever may occur days after administration of medications 1
• Mean lag time between drug initiation and fever can be up to 21 days 1

3. Infectious Causes

• Must be ruled out, especially in patients receiving immunotherapy
• Consider opportunistic infections in immunocompromised patients

Assessment and Management Algorithm

Immediate Assessment (First 30 Minutes)

1. Stop any ongoing infusions if fever occurs during administration 1
2. Assess vital signs: Temperature, blood pressure, heart rate, respiratory rate, oxygen saturation
3. Perform focused physical examination:
   • Check for rash, urticaria, angioedema
   • Assess respiratory status (wheezing, stridor)
   • Evaluate for hypotension or signs of shock

Severity Classification

• Mild (Grade 1): Fever only, vital signs stable
• Moderate (Grade 2): Fever with additional symptoms (flushing, mild dyspnea)
• Severe (Grade 3-4): Fever with hypotension, respiratory distress, or altered mental status 1

Management Based on Severity

For Mild-Moderate Reactions (Grade 1-2):

1. Antipyretics:

   • Administer acetaminophen/paracetamol 650-1000mg 1
   • Avoid NSAIDs if patient has thrombocytopenia or renal impairment

2. Supportive care:

   • IV fluids if signs of dehydration
   • Monitor vital signs every 15-30 minutes until resolution

3. For iron infusion reactions specifically:

   • Consider switching to a different iron formulation for future infusions 1, 3
   • Document the reaction for future reference

For Severe Reactions (Grade 3-4):

1. Immediate interventions:

   • Position patient appropriately (Trendelenburg if hypotensive, sitting up if respiratory distress) 1
   • Administer oxygen if needed
   • Call for medical assistance

2. Pharmacologic management:

   • For anaphylaxis: Epinephrine 0.01 mg/kg (1 mg/mL dilution) IM into lateral thigh 1
   • Corticosteroids: Methylprednisolone 1-2 mg/kg IV every 6 hours 1
   • Consider vasopressors for refractory hypotension

3. For suspected cytokine release syndrome:

   • Corticosteroids: Methylprednisolone 1 mg/kg/day 2
   • Monitor for improvement of symptoms

Post-Reaction Monitoring and Follow-up

1. Continue monitoring vital signs for at least 24 hours after severe reactions 1

2. Laboratory evaluation:

   • Complete blood count
   • Basic metabolic panel
   • Blood cultures if infectious cause suspected
   • Consider procalcitonin to differentiate between infection and non-infectious inflammation 1

3. Documentation:

   • Record details of the reaction according to CTCAE criteria 1
   • Document medications used for management
   • Plan for future administrations

Considerations for Future Treatment

For Keytruda (Pembrolizumab):

• If mild-moderate reaction: Consider premedication with antipyretics and antihistamines for future doses 1
• If severe reaction: Permanent discontinuation may be necessary 1

For Blood Transfusions:

• Slow transfusion rate for future administrations
• Consider leukoreduced blood products 1
• Monitor closely for transfusion-associated circulatory overload (TACO) 1

For Iron Infusions:

• Consider switching to a formulation with lower reaction rates 1, 3
• Administer at slower infusion rate (50% of initial rate) 1, 3
• Ensure proper technique and secure IV placement 3

Common Pitfalls and Caveats

1. Delayed reactions: CRS from Keytruda can occur even long after initial administration (documented cases more than 2 years later) 2

2. Misattribution: Don't assume fever is always due to infection; consider drug-related causes, especially with recent multiple infusions 1

3. Overuse of steroids: Avoid indiscriminate use of steroids for mild reactions, as they may further suppress immunity 1

4. Overlooking iron-specific reactions: Different iron formulations have varying side effect profiles; consider this when planning future infusions 1, 3

5. Ignoring fever duration: Fever from induced inflammatory responses can affect serum iron and ferritin concentrations for up to 10 days 4

By following this structured approach, clinicians can effectively manage fever occurring after Keytruda, blood, and iron infusion while ensuring patient safety and optimizing outcomes.