Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome

Abstract

Introduction: The aim of this study was to investigate the kinetics of immunoglobulin M (IgM) during the different stages of sepsis.

Methods: In this prospective multicenter study, blood sampling for IgM measurement was done within the first 24 hours from diagnosis in 332 critically ill patients; in 83 patients this was repeated upon progression to more severe stages. Among these 83 patients, 30 patients with severe sepsis progressed into shock and IgM was monitored daily for seven consecutive days. Peripheral blood mononuclear cells (PBMCs) were isolated from 55 patients and stimulated for IgM production.

Results: Serum IgM was decreased in septic shock compared to patients with systemic inflammatory response syndrome (SIRS) and patients with severe sepsis. Paired comparisons at distinct time points of the sepsis course showed that IgM was decreased only when patients deteriorated from severe sepsis to septic shock. Serial measurements in these patients, beginning from the early start of vasopressors, showed that the distribution of IgM over time was significantly greater for survivors than for non-survivors. Production of IgM by PBMCs was significantly lower at all stages of sepsis compared with healthy controls.

Conclusions: Specific changes of circulating IgM occur when patients with severe sepsis progress into septic shock. The distribution of IgM is lower among non-survivors.

Figure 1

Study flow chart. Ig, immunoglobulin; MODS, multiple organ dysfunction syndrome; SIRS, systemic inflammatory response syndrome.

Figure 2

Circulating immunoglobulin M (IgM) at various stages of severity. IgM levels were measured in serum within the first 24 hours from diagnosis of systemic inflammatory response syndrome (SIRS) (n= 41), of sepsis (n= 100), of severe sepsis (n= 113) and of septic shock (n= 78). Serum IgM levels for healthy volunteers (n= 35) are also provided. Circles denote outliers. P values of comparisons with patients with septic shock after Mann-Whitney U test and correction for multiple comparisons are provided.

Figure 3

Changes of circulating immunoglobulin M (IgM) upon worsening of sepsis. IgM was measured: in panel (A) in 13 patients within the first 24 hours from diagnosis of sepsis and repeated within the first 24 hours of worsening into severe sepsis; in panel (B) in 16 patients within the first 24 hours from diagnosis of sepsis and repeated within the first 24 hours of worsening into septic shock; in panel (C) in 49 patients within the first 24 hours from diagnosis of severe sepsis and repeated within the first 24 hours of worsening into septic shock; and in panel (D) in 5 patients within the first 24 hours from diagnosis of septic shock and repeated within the first 24 hours of worsening into multiple organ dysfunction. P values of paired comparisons by the Wilcoxon rank sum test are shown. NS, non-significant.

Figure 4

Kinetics of immunoglobulin M (IgM) upon progression to shock. Thirty patients with severe sepsis progressed into septic shock. Serum IgM was measured immediately after start of vasopressors (day 0) until day 6. Results are presented separately for survivors (S) and for non-survivors (NS). The area under the curve of IgM of survivors (AUC_S) and of non-survivors (AUC_NS) is provided. In panel (A) S and NS are distinguished based on their outcome after 28 days; in panel (B) S and NS are distinguished based on their outcome at hospital discharge. The P values of comparisons between AUC_S and AUC_NS by Student’s t test are also given. CI, confidence interval.

Figure 5

Production of immunoglobulin M (IgM) by mononuclear cells. Peripheral blood mononuclear cells (PBMCs) were isolated from 21 healthy volunteers, 24 patients with sepsis, 20 patients with severe sepsis and 11 patients with septic shock. PBMCs were stimulated with phytohemmaglutin (PHA) that is a selective lymphocyte agonist. Concentrations of IgM, panel (A) and of tumor necrosis factor alpha (TNFα), panel (B) were measured in supernatants. P values refer to comparisons with the respective production from PBMCs of healthy volunteers by the Kruskal-Wallis test after correction by Bonferroni. Production of IgM and of TNFα was below the limit of detection in supernatants of unstimulated PBMCs. Panel (C) shows the percentage of patients with IgM in supernatants above the limit of detection. P values of the indicated comparisons by the X² test are provided.