Modes of (Inter)Actions of Polyvalent Immunoglobulins: Nonclinical and Clinical Research in Severe Bacterial Infections

In severe bacterial infections, endotoxin- and exotoxin-induced inflammation and tissue damage, combined with the consequent excessive production of inflammatory mediators by neutrophils, may result in sepsis, septic shock, organ failure, and possibly death. Evidence suggests that supplementation with polyvalent intravenous (IV) immunoglobulin (Ig) preparations, such as standard IVIg or IgM/IgA-enriched Ig preparations, could be an additional treatment option. However, their use in severe bacterial infections like sepsis and septic shock is still a matter of debate. This review summarizes the diverse beneficial mechanisms of (inter)actions of Igs with pathogens and the host. Support for these mechanisms comes from numerous nonclinical studies, complemented by clinical research in adult patients with sepsis, septic shock, and other severe infectious diseases. Depending on Ig type, timepoint of administration, patient population, and dose, the pathogen- and host-induced inflammatory responses are modulated by the combined (inter)actions of polyvalent IgM, IgA, and IgG, with pathogens, and particularly with the host's neutrophil and complement pathways. However, while nonclinical and clinical studies suggest potential benefits of Ig therapy, clinical evidence remains heterogeneous, and trials with low risk of bias have not consistently demonstrated a definitive survival benefit. A deeper understanding of the conditions under which Ig treatment benefits patients with severe bacterial infections will help select patients most likely to profit from Ig treatment and achieve better outcomes.