What are the potential side effects of immunoglobulin (Ig) therapy and how can they be managed?

Immunoglobulin Side Effects and Management

Immediate/Infusion-Related Reactions (Most Common)

The most common side effects of immunoglobulin therapy are mild, transient, infusion-related reactions including headache, fever, chills, nausea, myalgia, flushing, chest discomfort, and blood pressure changes, occurring in 24-36% of patients, which typically respond to slowing or temporarily stopping the infusion. 1, 2, 3, 4

Common Immediate Side Effects:

• Headache is the most frequently reported adverse effect 1, 2, 3
• Fever, chills, and malaise occur commonly during or immediately after infusion 2, 3, 4
• Flushing, myalgia, and fatigue are transient and mild 1, 2, 3
• Nausea, vomiting, and diarrhea may occur during infusion 2, 3, 4
• Chest tightness, dyspnea, and back pain can develop during administration 3, 4
• Blood pressure changes (hypertension or hypotension) and tachycardia are possible 2, 3, 5

Management of Immediate Reactions:

• Slow or temporarily discontinue the infusion when mild symptoms develop 3, 4
• Administer symptomatic therapy: analgesics for headache, antihistamines for flushing, NSAIDs for myalgia 3, 5
• Use glucocorticoids for more severe reactions 3
• Resume infusion at a slower rate once symptoms resolve 1, 3

Anaphylaxis (Rare but Life-Threatening)

Anaphylactic reactions, though rare, represent the most serious immediate complication, occurring predominantly in IgA-deficient patients, and require immediate discontinuation of infusion with intramuscular epinephrine 0.2-0.5 mg in the lateral thigh. 6, 7, 8, 3

Recognition and Management:

• Stop the infusion immediately and maintain IV access 8
• Administer epinephrine 0.01 mg/kg IM (maximum 0.5 mg) in the lateral thigh, repeating every 5-15 minutes if needed 7, 8
• Provide oxygen and aggressive volume resuscitation with normal saline 7, 8
• Give adjuvant therapy: diphenhydramine 50 mg IV and ranitidine 50 mg IV 8
• Administer corticosteroids (methylprednisolone 1-2 mg/kg IV) to prevent biphasic reactions 8
• Monitor for 24 hours after severe reactions due to risk of biphasic response 8

Risk Factors:

• IgA deficiency is the primary risk factor for anaphylaxis 6, 3, 4
• Previous anaphylactic reactions contraindicate future immunoglobulin use 8

Delayed Serious Adverse Effects

Acute Renal Failure

Acute renal failure, usually oliguric and transient, occurs primarily with sucrose-containing products due to osmotic injury, particularly in inadequately hydrated patients. 1, 2, 3, 4

Risk Factors for Renal Complications:

• Pre-existing renal disease increases risk significantly 3, 4
• Dehydration, diabetes mellitus, and advanced age are major risk factors 3, 4
• Hypertension, hyperviscosity, and concurrent nephrotoxic medications elevate risk 3, 4
• Sucrose-containing products cause osmotic injury 1, 3, 4

Prevention and Management:

• Ensure adequate hydration before and during infusion 3, 4, 5
• Use non-sucrose-containing products in high-risk patients 3
• Infuse at low concentration and slow rate 3, 4
• Monitor urine output and kidney function during and after infusion 3

Thromboembolic Events

Thromboembolic complications occur due to hyperviscosity, especially in elderly patients, those with previous thrombotic events, or when receiving high-dose rapid infusions. 1, 2, 3, 4

High-Risk Patients:

• Advanced age is a significant risk factor 3, 4, 5
• Previous thromboembolic disease increases risk substantially 3, 4
• Immobilization or being bedridden elevates thrombotic risk 3, 4
• Diabetes mellitus, hypertension, and dyslipidemia are important risk factors 3, 4
• High-dose IVIg with rapid infusion rate increases hyperviscosity 3, 4

Prevention:

• Maintain slow infusion rate to minimize hyperviscosity 3, 4
• Ensure adequate hydration before and during therapy 3, 4, 5
• Avoid high-dose rapid infusions in high-risk patients 3, 4

Aseptic Meningitis

Aseptic meningitis is a rare delayed complication presenting with severe headache, neck stiffness, photophobia, and fever, typically occurring 6-48 hours after infusion. 7, 1, 2, 3

Management:

• Slow infusion rate and ensure hydration for prevention 3, 4
• Provide supportive care with analgesics and hydration 1, 5
• Symptoms typically resolve spontaneously within days 2, 5

Hemolytic Anemia

Hemolytic anemia can occur, particularly with anti-D immunoglobulin, ranging from mild extravascular hemolysis to severe intravascular hemolysis with disseminated intravascular coagulation. 6, 1, 2, 3

Specific to Anti-D Immunoglobulin:

• Mild extravascular hemolysis is common in Rh(D)-positive children 6
• Rare instances of intravascular hemolysis, DIC, and renal failure have been reported in pediatric patients with comorbidities 6

Transfusion-Related Acute Lung Injury (TRALI)

TRALI is a rare but serious complication presenting with acute respiratory distress, hypoxemia, and bilateral pulmonary infiltrates within 6 hours of infusion. 2

Neurological Complications (When Used for Immune Checkpoint Inhibitor Toxicity)

When immunoglobulin is used to treat neurological immune-related adverse events from checkpoint inhibitors, it may be required for Guillain-Barré syndrome or myasthenia gravis-like symptoms, along with plasmapheresis. 6

• Consider IV immunoglobulin or plasmapheresis for myasthenia and Guillain-Barré syndrome 6
• Withhold checkpoint inhibitors until neurological toxicity is defined 6

Prevention Strategies

Pre-Infusion Assessment:

• Screen for IgA deficiency before first infusion 3, 4
• Assess risk factors: renal disease, thrombotic history, age, diabetes, cardiovascular disease 3, 4
• Ensure adequate hydration in all patients, especially high-risk 3, 4, 5

Infusion Technique:

• Start with slow infusion rate (0.5-1 mg/kg/min initially) 1, 3
• Use low concentration products in high-risk patients 3
• Consider premedication with acetaminophen and antihistamines for patients with previous reactions 1, 5
• Switch from IVIG to subcutaneous immunoglobulin (SCIG) if recurrent infusion reactions occur 2

Monitoring:

• Monitor vital signs during and after infusion 7, 8
• Supervise urine output and kidney function in high-risk patients 3
• Watch for delayed reactions up to 48 hours post-infusion 1, 5

Common Pitfalls to Avoid

• Never delay epinephrine in suspected anaphylaxis while waiting for antihistamines or corticosteroids 8
• Do not confuse vasovagal reaction with anaphylaxis: vasovagal presents with bradycardia and pallor without urticaria, while anaphylaxis causes tachycardia and cutaneous manifestations 8
• Avoid rapid infusion rates in elderly or high-risk patients to prevent thrombotic complications 3, 4
• Do not use sucrose-containing products in patients with renal risk factors 3
• Never assume mild symptoms will not progress: monitor closely and be prepared to stop infusion 1, 3