What is the role of intravenous immunoglobulin (IVIG) in the treatment of sepsis?

Role of Intravenous Immunoglobulin (IVIG) in Sepsis

IVIG should not be routinely used in the treatment of sepsis or septic shock, as current evidence does not support its general use for reducing mortality or improving outcomes. 1

Evidence Against Routine Use

• The Surviving Sepsis Campaign international guidelines explicitly recommend against the routine use of IVIG in children with septic shock or other sepsis-associated organ dysfunction (weak recommendation, low quality of evidence) 1
• Similar recommendations exist for adult patients with sepsis, with the 2016 Surviving Sepsis Campaign guidelines not supporting routine IVIG therapy 1
• A large randomized controlled trial (n=624) in adult patients found no mortality benefit with IVIG treatment 1
• The Score-based Immunoglobulin G Therapy of Patients with Sepsis (SBITS) study, a phase III multicenter trial with 653 patients, demonstrated that IVIG at a total dose of 0.9 g/kg body weight did not reduce 28-day mortality in patients with score-defined severe sepsis 2
• A recent retrospective study of patients with sepsis caused by extensively drug-resistant pathogens found no significant difference in 30-day mortality between patients receiving IVIG alongside standard treatment versus standard treatment alone (71.4% vs. 77.3%, P=.886) 3

Specific Populations That May Benefit

Despite the general recommendation against routine use, certain patient populations may potentially benefit from IVIG therapy:

• Patients with toxic shock syndrome, especially those with streptococcal etiology 1
• Patients with necrotizing fasciitis, although evidence in adults does not consistently support this use 1
• Patients with primary humoral immunodeficiencies or immunocompromised patients with documented low immunoglobulin levels 1
• Patients with hyperinflammation or immunosuppression may potentially benefit from IgM- and IgA-enriched immunoglobulin (Pentaglobin), though definitive evidence is lacking 4

IgM-Enriched vs. Standard IVIG

• Some meta-analyses have suggested a stronger benefit with IgM-enriched IVIG preparations compared to standard IVIG preparations 1
• A meta-analysis of 18 RCTs indicated that IVIG might reduce mortality risk in septic patients, with a trend favoring immunoglobulin preparations enriched with IgA and IgM (IgGAM) compared with preparations containing only IgG 1
• A 2019 meta-analysis with trial sequential analysis suggested that IgM-enriched immunoglobulin may be associated with reduced mortality in adult septic patients, though the certainty of evidence was low 5

Limitations of Current Evidence

• Considerable heterogeneity exists among studies in terms of:

  • IVIG dosing regimens 1
  • Types of immunoglobulin preparations used 1
  • Control interventions (placebo or albumin) 1
  • Study quality and risk of bias 1

• When only high-quality studies with low risk of bias are considered, the mortality benefit of IVIG is not demonstrated 1

Clinical Approach

For clinicians considering IVIG in sepsis:

1. Do not use IVIG routinely in patients with sepsis or septic shock 1

2. Consider IVIG only in specific circumstances:

   • Toxic shock syndrome, particularly streptococcal 1
   • Patients with known immunoglobulin deficiencies 1
   • As part of clinical trials or research protocols

3. If using IVIG in selected cases, consider:

   • For patients with hyperinflammation: Initial bolus at 0.6 mL/kg/h for 6h followed by maintenance rate of 0.2 mL/kg/h for ≥72h 4
   • For immunosuppressed patients: More conservative dosing at 0.2 mL/kg/h for ≥72h without initial bolus 4

Common Pitfalls

• Relying on lower quality studies that show benefit while ignoring high-quality studies showing no benefit 1
• Using IVIG as a routine intervention for all sepsis patients rather than targeting specific subpopulations who might benefit 1
• Failing to consider the cost-effectiveness of IVIG therapy, which has not been well-established 6
• Overlooking batch-to-batch variability in IVIG preparations, which can affect biologic activity 1