What is the management for a fever that starts a few hours after pembrolizumab (pembrolizumab is an anti-programmed death-1 (PD-1) antibody) infusion?

Management of Fever After Pembrolizumab Infusion

For fever occurring within hours of pembrolizumab infusion, immediately stop or slow the infusion rate, provide symptomatic treatment with antipyretics and antihistamines, and restart at 50% of the previous rate once symptoms resolve if the reaction is Grade 1-2. 1

Immediate Assessment and Grading

When fever develops shortly after pembrolizumab infusion, you must first determine the severity:

• Grade 1-2 reactions present with pyrexia and chills as the primary symptoms, typically without hemodynamic instability 1
• Grade 3-4 reactions involve severe systemic symptoms, hemodynamic compromise, or life-threatening manifestations requiring permanent discontinuation 1

The incidence of infusion reactions with pembrolizumab is approximately 3%, with pyrexia and chills being the most common manifestations 1

Acute Management Protocol

For Grade 1-2 Reactions (Mild to Moderate Fever)

Stop or slow the infusion rate immediately and provide symptomatic treatment 1:

• Administer antipyretics (acetaminophen 650-1000 mg) 1
• Give antihistamines (diphenhydramine 25-50 mg IV or oral equivalent) 1
• Monitor vital signs for 15 minutes until symptoms resolve 2
• Restart the infusion at 50% of the previous rate after complete symptom resolution 1, 2
• If well tolerated for 15 minutes, gradually increase the rate back to the original infusion speed 2

For Grade 3-4 Reactions (Severe)

Permanently discontinue pembrolizumab and provide aggressive symptomatic treatment 1:

• Stop the infusion immediately and do not rechallenge 1
• Administer systemic corticosteroids if severe immune-mediated reaction is suspected 3
• Consider specialty consultation as appropriate 3

Critical Distinction: Infusion Reaction vs. Immune-Mediated Adverse Event

A critical pitfall is failing to distinguish between a simple infusion reaction and an immune-mediated adverse event. Fever occurring hours after pembrolizumab can represent:

1. True infusion reaction: Occurs during or immediately after infusion, typically resolves with symptomatic management 1
2. Immune-mediated adverse event: Can manifest at any time during or after treatment, may require corticosteroids and permanent discontinuation 3

If fever persists beyond the immediate post-infusion period or is accompanied by other symptoms (respiratory, gastrointestinal, neurological), initiate workup to exclude immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, or other organ-specific toxicities 3

Prevention for Subsequent Infusions

Premedication with antipyretic and antihistamine may be considered for patients who have experienced prior infusion reactions 1:

• Administer acetaminophen 1000 mg 30-60 minutes before infusion 2
• Give antihistamine (diphenhydramine 50 mg or equivalent) prior to infusion 2
• Use a slower initial infusion rate 2

Post-Infusion Monitoring

• Observe patients for 1-2 hours after infusion completion, particularly after a reaction has occurred 4, 5, 2
• Educate patients about delayed reactions that can occur up to 24 hours post-infusion, including persistent fever, flu-like symptoms, and other systemic manifestations 4, 2
• Monitor vital signs continuously during any rechallenge after a reaction 2

When to Permanently Discontinue

Do not rechallenge after severe reactions including 2:

• Bronchospasm or severe respiratory compromise
• Severe hypotension requiring vasopressor support
• Angioedema or anaphylaxis
• Any Grade 3-4 infusion reaction 1

Key Clinical Pitfalls to Avoid

• Never restart the infusion at full rate after a reaction—always resume at 50% of the previous rate 1, 2
• Do not dismiss persistent fever as a simple infusion reaction if it continues beyond the immediate post-infusion period; this may represent immune-mediated pneumonitis or other serious adverse events requiring corticosteroids 3, 6
• Do not routinely premedicate all patients—reserve premedication for those with prior reactions, as routine premedication is not recommended for pembrolizumab 1