Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

Abstract

Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.

Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock

“…Ig has many immunomodulatory effects including neutralising endotoxins, stimulating opsonic and bactericidal activity, reducing pro-inflammatory mediators and increasing anti-inflammatory mediators [6]. Moreover, patients with hypogammaglobulinemia have a high incidence of infections, and a high proportion of patients with severe sepsis and septic shock have low serum levels of Ig, which seems to be associated with a significantly higher mortality rate [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”

“…Immunoglobulin (Ig) preparations are a promising treatment option owing to their pleiotropic effects on bacteria and the host response to infection. The mechanism of action for Ig therapy is likely multifaceted and could include direct antibacterial and anti-endotoxin activities; reducing the expression of inflammatory mediators or directly scavenging these molecules; and other complex immunomodulatory effects [6]. Clinically, the serum Ig concentrations are generally low in patients with septic shock, and the level and kinetics of serum Ig are related to patient outcome [7,8].…”

Emerging therapies for the treatment of sepsis

“…The suggested mechanisms by which immunoglobulins may have beneficial effects in sepsis include roles in pathogen recognition and clearance, scavenging of toxins, and nonapoptotic and antiapoptotic immune cell effects [18]. Multiple small trials have assessed their potential role, but meta-analyses have given conflicting results, although in general, there does not seem to be any benefit of intravenous immunoglobulin administration when results are limited to high-quality studies [19].…”

Immunomodulation in sepsis-why blunting the response doesn't work?

“…2e4 Intravenous immunoglobulin use has been proposed as an adjunctive treatment of postoperative sepsis not only to neutralize bacterial toxins (endotoxin and exotoxin) and to increase serum bactericidal action but also for modulation of cytokine release and its immunomodulatory effect. 5 Immunomodulatory and anti-inflammatory mechanisms of immunoglobulins may reflect the involvement of several biological pathways, including a) decrease in the production of proinflammatory cytokines, b) suppression or neutralization of autoantibodies, c) down-regulation of adhesion molecules and chemokines, d) neutralization of superantigens and e) activated complement components and f) modulation of maturation and function of dendritic cells. 6 Intravenous immunoglobulins have been used with mixed results in postoperative sepsis and in this issue of the Journal Tagami et al (2015) provide another important jigsaw to the picture.…”