IgM-enriched Immunoglobulins in Sepsis F. Esen and S. Tugrul Introduction The role of intravenous immunoglobulins (IVIGs) as an adjunctive treatment in sep- sis has been a subject of debate for years. The main critique has been the lack of randomized trials of adequate size showing the effect of IVIGs on outcome. For that reason, many of the guidelines on sepsis have not addressed the use of IVIG treat- ment. Likewise, the Surviving Sepsis Guidelines [1] did not consider the use of immunoglobulins in adult patients with sepsis. As an adjunctive therapy in adults with sepsis, the use of immunoglobulins was first reported in the early 1980s [2], and studies completed through the 1990s were reviewed by the Cochrane collaboration [3]; this began the series of meta-analyses on immunoglobins in sepsis. In the Cochrane review of IVIGs for the treatment of sepsis, IVIGs were reported to significantly reduce mortality in patients with sepsis [3]. However the authors concluded that due to the small size of the trials, the evi- dence was insufficient to support a definitive conclusion. The Cochrane review also included a retrospective subgroup analysis comparing IgM-enriched IVIG with stan- dard polyclonal IgG IVIG. In this subgroup analysis of 11 trials, a post hoc sub-anal- ysis according to the type of IVIG demonstrated a greater reduction in mortality among patients given IgM-enriched immunoglobulin compared with standard immunoglobulin. To date, five newer meta-analyses on the use of polyclonal immu- noglobulins as adjunctive therapy for sepsis have been published [4–8]. Compared with the Cochrane statement, these meta-analysis included more trials and study patients, including the large Score-Based Immunoglobulin G Therapy of patients with Sepsis (SBITS) study [9] using a standard IgG preparation in patients with severe sepsis. The results of each meta-analysis were very similar to the results of the Cochrane meta-analysis, which showed a reduction in mortality with a standard IgG IVIG administration, and a greater risk reduction with an IgM-enriched prepa- ration. In the latest meta-analysis, Kreymann et al. [4] summarized the data for two groups of studies using IgM-enriched IVIG or IgG IVIG. The authors included 8 smaller trials with IgM-enriched immunoglobulins, including 560 adult patients in whom the estimate of the pooled effect on mortality showed a relative risk of 0.66 (a 34 % relative reduction in mortality) with no substantial heterogeneity. The results were even better in neonate trials with 352 patients in 5 studies with a 50 % relative reduction in mortality. The comparison of IgM-enriched IVIG and IgG IVIG showed a strong trend in favor of IgM-enriched treatment both in adults and in neonates. As already reported in the Cochrane meta-analysis [3], these data again confirmed that preparations enriched with IgA and IgM (IgGAM) yielded better results than IgG 102 III