A randomized trial of Mycobacterium w in severe sepsis

Abstract

Purpose

The aim of this study was to evaluate the efficacy of Mycobacterium w (Mw), an immunomodulator in severe sepsis.

Methods

Patients 18 years or older with severe sepsis were randomized within 48 hours of first organ dysfunction to receive either intradermal Mw or saline. The primary end point was 28-day mortality, whereas the secondary end points were ventilator days, intensive care unit (ICU) and hospital length of stay, and delta Sequential Organ Failure Assessment (SOFA) score.

Results

Fifty patients with severe sepsis (25 Mw, 25 control) were included in the study. There were 7 and 8 deaths in the Mw and control groups, respectively (P = 0.51). The days on mechanical ventilator were significantly lesser in the Mw group compared with control (median, 6 vs 9; P = 0.025). The median ICU and hospital length of stay was significantly less in the Mw arm (7 vs 12 days [P = 0.006] and 10 vs 16 [P = 0.007], respectively). The delta SOFA score was significantly higher in the control arm (P = 0.027). There was a higher incidence of secondary bacterial infections in the control group (P = 0.009).

Conclusion

The use of Mw in severe sepsis was associated with significant reduction in days on mechanical ventilation, ICU and hospital length of stay, lower incidence of nosocomial infection, and delta SOFA score.

Introduction

Sepsis accounts for 6% to 30% of all intensive care unit (ICU) admissions with a mortality rate of 10% to 80% depending on the severity [1], [2]. In the last 2 decades, no treatment has been shown to reduce mortality in patients with severe sepsis. Several large trials directed against inflammatory pathway and coagulation cascade have failed to demonstrate any benefit in sepsis [3], [4], [5], [6]. Sepsis represents a complex cascade of events occurring in response to invading microbial agents. Recent evidence suggests that sepsis continuum includes an immune paralytic state, which may play a significant role in sepsis [7]. Lipopolysaccharide, a cell wall component of gram-negative organisms combines with toll-like receptor 4 (TLR4) on the host leukocyte and other immune cells (macrophages, neutrophils, dendritic cells, and natural killer cells). The binding of lipopolysaccharide with TLR4 activates 2 major intracellular pathways, MyD88 pathway, involved in proinflammatory responseand a toll/interleukin-1 (IL-1) receptor domain–containing adaptor protein inducing interferon-β (IFN-β) (TRIF) pathway, leading to production of type 1 IFNs that stem the inflammatory response and cause a state of immune suppression [8], [9], [10].

In a postmortem analysis of 40 patients who died of sepsis, it was demonstrated that significantly reduced levels of cytokine secretion (tumor necrosis factor, IFN-γ, IL-6, and IL-10) occurred at 5 hours by anti-CD3/anti-CD28–stimulated splenocytes. The cytokine secretion was generally less than 10% in sepsis compared with controls and was independent of age, duration of sepsis, corticosteroid use, and nutritional status [7]. The concept of immune suppression in sepsis is further exemplified in a study involving 41 patients with sepsis [11]. In this study, there was a marked reduction in the T cell receptor β chain diversity that was associated with increased mortality and a higher risk of developing nosocomial infection [11]. It has also been demonstrated that there is decreased ex vivo proliferation of Th1 and an increased Th2 immune response [12], [13]. Thus, it seems that sepsis is characterized by an initial “cytokine storm” and a later “immune paralysis.” Modulating this response and overcoming immune paralysis may help in improving the outcome in severe sepsis.

Mycobacterium w (Mw) is a nonpathogenic, rapidly growing atypical mycobacterium classifiable in Runyon group IV. It shares T and B cell determinants with Mycobacterium leprae and Mycobacterium tuberculosis. When heat-inactivated and administered intradermally, Mw is an immune modulator that evokes antigen-specific cell-mediated immunity and augments Th1 type of cross-reactive response [14], [15], [16]. We hypothesized that Mw by its TLR4 agonist activity may help in restoring immunity, thereby improving outcomes in severe sepsis. In this randomized trial, we evaluate the efficacy of Mw in severe sepsis.