What is the appropriate management of fever that develops during intravenous immunoglobulin (IVIG) infusion?

Management of Fever During IVIG Infusion

For mild to moderate fever developing during IVIG infusion, slow or temporarily stop the infusion, provide symptomatic treatment with antipyretics, and restart at a reduced rate once symptoms resolve; for severe reactions with hypotension or respiratory compromise, immediately discontinue the infusion and provide aggressive supportive care including epinephrine, oxygen, IV steroids, and cardiorespiratory support. 1

Grading the Severity of Fever During Infusion

Grade 1-2 (Mild to Moderate) Reactions

• Fever with or without chills, headache, myalgia, and fatigue that begins at the end of infusion or within hours afterward represents the most common adverse reaction pattern 1
• These symptoms can persist for hours but are generally self-limited 1
• Fever occurring within 1-6 hours from onset of IVIG infusion is the typical timeframe for infusion-related reactions 2

Grade 3-4 (Severe) Reactions

• Fever accompanied by hypotension, anaphylaxis, bronchospasm, cyanosis, or loss of consciousness indicates a severe systemic reaction requiring immediate intervention 1, 3
• Serious adverse events include hypotension, anaphylaxis and anaphylactoid systemic reactions, renal dysfunction, and aseptic meningitis syndrome 1

Immediate Management Algorithm

For Mild to Moderate Fever (Grade 1-2)

1. Stop or slow the infusion rate immediately 1
2. Administer symptomatic treatment:
   • Acetaminophen (paracetamol) for fever 1
   • Antihistamines if urticaria or pruritus present 1
3. Once symptoms resolve, restart the infusion at half the previous rate 1
4. Gradually titrate the rate upward as tolerated 1
5. Monitor vital signs closely during and after resumption 2

For Severe Reactions (Grade 3-4)

1. Immediately discontinue the infusion 1
2. Administer aggressive symptomatic treatment:
   • Epinephrine 0.01 mg/kg of 1:1000 solution (maximum 0.3-0.5 mg) for anaphylaxis 3
   • Oxygen supplementation 1
   • IV antihistamines 1
   • IV corticosteroids 1
   • Cardiorespiratory support as needed 1
3. Fluid resuscitation with normal saline 1-2 L IV at 5-10 mL/kg in the first 5 minutes for hypotension 3
4. Transfer to intensive care if respiratory failure or cardiovascular instability develops 4
5. Do not attempt to restart the infusion 1

Premedication Considerations for Future Infusions

• If a prior infusion reaction occurred, premedicate before the next dose with acetaminophen, antihistamines, and corticosteroids 1
• For patients with recurrent mild reactions, consider premedication with corticosteroids (methylprednisolone 1 g) plus antihistamines 1
• Premedication may reduce but does not eliminate the risk of infusion reactions 5

Critical Distinction: Fever vs. IVIG Resistance

In Kawasaki Disease Context

• Fever during the infusion itself is an infusion reaction, not IVIG resistance 6
• IVIG resistance is defined as persistent or recrudescent fever ≥36 hours after completing the initial 2 g/kg IVIG infusion 6
• A new rash without fever does not constitute IVIG resistance 6
• Do not administer additional IVIG doses based solely on fever during the infusion—manage as an infusion reaction first 6

Infusion Rate and Prevention Strategies

• Most adverse reactions are associated with fast infusion rates 2
• Symptoms typically subside when the rate of infusion is reduced 2
• Slow infusion rate and good hydration prevent most adverse effects including renal failure, thromboembolic events, and aseptic meningitis 5
• In a large series, adverse effects occurred in 24-36% of patients after high-dose IVIG, with most being mild and transient 5

Common Pitfalls to Avoid

• Do not confuse fever during infusion with IVIG resistance—the latter requires fever ≥36 hours after completion 6
• Do not restart the full infusion at the original rate after a reaction; always resume at half the previous rate 1
• Do not assume all fever is benign—monitor for signs of anaphylaxis including hypotension, respiratory distress, and altered consciousness 1, 3
• Do not delay epinephrine administration in suspected anaphylaxis, as delayed treatment increases risk of poor outcomes 3
• Ensure adequate hydration before and during infusion to prevent renal complications, especially with sucrose-stabilized products 5

Observation Period After Reaction

• After treatment of an anaphylactic reaction, observe the patient for several hours due to the risk of biphasic reactions 1
• Biphasic reactions are more likely in patients who present initially with severe symptoms 1
• For severe reactions requiring epinephrine, assessment in an emergency department is essential to determine whether additional interventions are needed 3