Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins

Abstract

The emergence of infections by multidrug-resistant (MDR) Gram-negative bacteria, which is accompanied by considerable mortality due to inappropriate therapy, led to the investigation of whether adjunctive treatment with one polyclonal IgM-enriched immunoglobulin preparation (IgGAM) would improve outcomes. One hundred patients in Greece with microbiologically confirmed severe infections by MDR Gram-negative bacteria acquired after admission to the Intensive Care Unit and treated with IgGAM were retrospectively analysed from a large prospective multicentre cohort. A similar number of patient comparators well-matched for stage of sepsis, source of infection, appropriateness of antimicrobials and co-morbidities coming from the same cohort were selected. All-cause 28-day mortality was the primary end point; mortality by extensively drug-resistant (XDR) pathogens and time to breakthrough bacteraemia were the secondary end points. Fifty-eight of the comparators and 39 of the IgGAM-treated cases died by day 28 (p 0.011). The OR for death under IgGAM treatment was 0.46 (95% CI 0.26-0.85). Stepwise regression analysis revealed that IgGAM was associated with favourable outcome whereas acute coagulopathy, cardiovascular failure, chronic obstructive pulmonary disease and chronic renal disease were associated with unfavourable outcome. Thirty-nine of 62 comparators (62.9%) were infected by XDR Gram-negative bacteria and died by day 28 compared with 25 of 65 cases treated with IgGAM (38.5%) (p 0.008). Median times to breakthrough bacteraemia were 4 days and 10 days, respectively (p <0.0001). Results favour the use of IgGAM as an adjunct to antimicrobial treatment for the management of septic shock caused by MDR Gram-negative bacteria. A prospective randomized trial is warranted.

The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure

“…Quantification of immunoglobulin levels using nephelometry is a fast test which takes less than 2 h. In turn, the SOFA score has widespread familiarity within the critical care community, making it useful to assess the degree of organ failure extent at ICU admission [7, 17]. In addition, our results provide a scientific rational to evaluate whether IVIG preparations containing IgG, IgA and IgM could be more effective for the treatment of sepsis than those containing exclusively IgG [18–20]. Interestingly, Kreymann KG et al, a meta-analysis in 2007 of all randomized controlled studies published on polyvalent immunoglobulins for treatment of sepsis or septic shock, observed a strong protective trend in favor of an immunoglobulin preparation containing the three major immunoglobulin isotypes [21].…”

Immunoglobulins and sepsis

“…For example, patients with low levels of immunoglobulins with concurrently raised free light chains imply impaired immunoglobulin production which may be a major mechanism contributing to death in sepsis. Interventional cohort studies highlight the potential utility of immunoglobulin therapy in patients with multidrug resistant bacterial infections [14] and in patients with sepsis associated coagulopathy [15], which should be followed through to inform future immunoglobulin trials in sepsis.…”

Clinical, laboratory features and prognosis of children receiving IgM-enriched immunoglobulin (3 days vs. 5 days) as adjuvant treatment for serious infectious disease in pediatric intensive care unit: a retrospective single-center experience (PIGMENT study)

“…21 Results from recent trials and systemic meta-analyses seem more promising with regard to the use of IgM-enriched intravenous immunoglobulin in septic patients. 13,14,22,23 IgM-enriched intravenous immunoglobulin in different dosing schemes has been used in retrospective or prospective studies of adults and newborns, generating different 28-day mortality results. Alejandria et al 24 evaluated seven studies on the use of IgM-enriched intravenous immunoglobulin as an adjuvant therapy in adult patients with bacterial sepsis or septic shock and showed a significant reduction in mortality when compared with placebo or nonintervention.…”