What are the adverse effects of intravenous immunoglobulin (IVIG) when used experimentally to treat severe enterovirus-associated pneumonia in critically ill patients?

Side Effects of IVIG in Enterovirus Pneumonia Treatment

IVIG is not recommended for routine use in severe pneumonia or sepsis, including enterovirus-associated cases, and carries significant risks including acute renal failure, thromboembolism, hemolysis, and aseptic meningitis that may outweigh uncertain benefits in this context. 1, 2

Evidence Against Routine Use in Severe Pneumonia/Sepsis

The Surviving Sepsis Campaign explicitly recommends against routine IVIG use in critically ill patients with severe sepsis or septic shock, based on high-quality evidence showing no mortality benefit 1, 2. This applies directly to enterovirus pneumonia patients who are critically ill:

• A large multicenter RCT (n=624) in adults with severe sepsis found no benefit for IVIG 1
• When only high-quality studies with low risk of bias are analyzed, IVIG shows no reduction in mortality (RR 0.97; 95% CI 0.81-1.15) 1
• The 2020 COVID-19 guidelines similarly recommend against routine IVIG use in critically ill adults with viral pneumonia 1

Major Adverse Effects

Acute Renal Failure

This is one of the most serious complications, particularly in critically ill pneumonia patients who often have multiple risk factors:

• Acute renal dysfunction, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis can occur 3
• Risk is highest in patients with pre-existing renal insufficiency, diabetes, age >65, volume depletion, sepsis, or concurrent nephrotoxic drugs 3
• Sucrose-containing products carry higher risk, though non-sucrose formulations can still cause renal injury 4, 5
• Monitor BUN and serum creatinine before infusion and at appropriate intervals; discontinue if renal function deteriorates 3

Thrombotic Complications

Critically ill pneumonia patients are already at elevated thrombotic risk, which IVIG significantly compounds:

• Thrombosis may occur even without known risk factors 3
• Risk factors include advanced age, immobilization, hypercoagulable states, cardiovascular disease, indwelling catheters, and hyperviscosity 3
• Hyperviscosity from hyperproteinemia increases serum viscosity and thrombotic risk 3, 4
• Acute myocardial infarction has been reported, with one study showing 4.7% incidence with certain IVIG products 5
• Assess baseline blood viscosity in high-risk patients (those with cryoglobulins, high triglycerides, or monoclonal gammopathies) 3

Hemolytic Reactions

Passive transfer of blood group antibodies can cause significant hemolysis:

• Acute hemolytic anemia from anti-A, anti-B, or anti-D antibodies in IVIG preparations 3, 4
• Coombs-positive hemolysis may occur, particularly with high-dose therapy 6
• Enhanced erythrocyte sequestration can develop 3

Aseptic Meningitis Syndrome

This typically occurs within hours to 2 days after infusion:

• Symptoms include severe headache, nuchal rigidity, photophobia, fever, nausea, and vomiting 3
• Usually resolves within several days after discontinuation without sequelae 3, 4
• More common with high-dose therapy 4

Anaphylactic/Hypersensitivity Reactions

Particularly dangerous in IgA-deficient patients:

• Severe hypersensitivity with blood pressure drop may occur even in previously tolerant patients 3
• IVIG contains trace IgA (<50 μg/mL); patients with anti-IgA antibodies are at highest risk 3
• Requires immediate discontinuation and appropriate treatment 3

Infusion-Related Reactions

These are the most common but generally mild:

• Headache, flushing, malaise, chest tightness, fever, chills, myalgia, fatigue, dyspnea, back pain, nausea, vomiting, blood pressure changes, tachycardia 4, 7
• Usually respond to slowing or temporarily stopping the infusion 4, 6
• Can be managed with analgesics, NSAIDs, antihistamines, or glucocorticoids in severe cases 4

Pseudohyponatremia

Critical to distinguish from true hyponatremia:

• Hyperproteinemia causes falsely low sodium readings with normal or elevated osmolar gap 3
• Treating as true hyponatremia with fluid restriction can cause volume depletion, increased viscosity, and higher thrombotic risk 3

Risk Mitigation Strategies

For patients in whom IVIG is deemed necessary despite lack of evidence for enterovirus pneumonia:

• Ensure adequate hydration before administration 3, 4
• Use minimum effective dose and slowest practicable infusion rate 3, 4
• Avoid in volume-depleted patients until volume status corrected 3
• Monitor renal function (BUN, creatinine) before and during therapy 3
• Monitor for signs of thrombosis, particularly in high-risk patients 3
• Use low concentration products and slow infusion rates in high-risk patients 4, 7
• Consider non-sucrose-containing products to reduce renal risk 4, 5

Clinical Context for Enterovirus Pneumonia

There is no evidence supporting IVIG efficacy specifically for enterovirus pneumonia, and the guideline recommendations against routine use in severe pneumonia/sepsis apply 1, 2. The risks outlined above are particularly concerning in critically ill patients with respiratory failure who already face:

• Volume depletion from fever and tachypnea
• Potential renal hypoperfusion from shock
• Hypercoagulability from critical illness
• Need for nephrotoxic antimicrobials

The risk-benefit ratio does not favor IVIG use in this experimental indication.