Sepsis/Acute Kidney InjuryA randomized trial of Mycobacterium w in severe sepsis
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.
Section snippets
Study design
This was a randomized, double-blind, 2–parallel arm, comparative controlled prospective study to assess the efficacy of Mw in combination with standard therapy in patients with severe sepsis. The study protocol was approved by the Institute Ethics Committee, and a written informed consent was obtained from all patients or their next of kin.
Setting
The study was conducted in the respiratory intensive care unit (RICU) of this Institute. All patients with suspected gram-negative sepsis admitted in the
Results
There were 278 admissions during the study period, of which 50 patients were enrolled in this study. The baseline parameters were similar in the 2 groups (Table 1). The study population comprised predominantly of male subjects. Patients in the Mw group were younger than the control arm, albeit not statistically significant. The Mw group had lower hemoglobin and platelet count, and higher baseline SOFA scores than the control group (Table 1). Sepsis of unknown origin followed by
Discussion
The use of Mw in combination with standard care did not reduce 28-day mortality in patients with severe sepsis. Nevertheless, we found a significant reduction in the ICU and hospital length of stay, days spent on mechanical ventilator, lesser incidence of secondary bacterial infection, and reduction in the delta SOFA score.
In an in vitro study, it was demonstrated that Mw can restore immunity in mice infested with Leishmania by its TLR4 agonist activity through involvement of the MyD88 pathway.
Acknowledgements
Council of Scientific & Industrial research (CSIR): New Millenium Indian Technology Leadership Initiative (NMITLI) program.
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Conflicts of interest- none, financial disclosures- none.