Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock

Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010.

To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008.

We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock.

Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation.

We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97).

Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.