Intravenous immunoglobulins for treating patients with severe sepsis and septic shock

Sepsis is the inflammatory response of the body to severe infection, which can be caused by a variety of micro-organisms including bacteria, viruses and fungi. Signs of sepsis include fever, hypothermia, rapid heart rate and respiration; and a laboratory finding of increased or decreased white blood cell count. Deaths as a result of sepsis and septic shock remain high despite giving antibiotics, especially if the functions of a persons's vital organs such as the lungs, heart and kidneys are affected. Several studies have looked into other agents than antibiotics to help the body fight the effects of sepsis. Intravenous immunoglobulin preparations contain antibodies that help the body to neutralize bacterial toxins. There are two types of preparations. These are polyclonal immunoglobulins that contain several antibodies directed at endotoxin and inflammatory mediators, and monoclonal immunoglobulins which target a specific inflammatory mediator or antigen. Intravenous immunoglobulins are blood products, specifically pooled sera derived from human donor blood.

For this updated Cochrane review, we searched the medical literature databases to January 2012. We included 43 randomized controlled trials (RCTs); 25 were RCTs of polyclonal intravenous immunoglobulins (IVIGs) with 17 in adults (1958 participants) and eight in newborn infants (3831 participants) including a large polyclonal IVIG trial on infants with sepsis that was published in 2011. The remaining 18 trials (a total of 13,413 participants) were of monoclonal antibodies. Both standard and immunoglobulin M (IgM)-enriched polyclonal immunoglobulins decreased the number of deaths in adults but not in infants. However, no reductions in adult deaths were seen with polyclonal IVIG using high quality trials only. Among newborn infants with sepsis, there is definitive evidence that standard polyclonal IVIG does not reduce the number of deaths. In the monoclonal immunoglobulin trials, anti-endotoxin antibodies showed no benefit while the anti-cytokines showed a very small reduction in deaths among adults with sepsis.

The polyclonal immunoglobulin trials in adults were small compared to the trials of monoclonal agents. The reduction in deaths observed with polyclonal IgM-enriched preparations as add-on therapy for sepsis needs to be confirmed in large studies that use high quality methods.

Authors' conclusions: 

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.

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Background: 

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.

Objectives: 

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.

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

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.

Main results: 

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).

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