Advances in the management of sepsis and the understanding of key immunologic defects

Abstract

Anesthesiologists are increasingly confronting the difficult problem of caring for patients with sepsis in the operating room and in the intensive care unit. Sepsis occurs in more than 750,000 patients in the United States annually and is responsible for more than 210,000 deaths. Approximately 40% of all intensive care unit patients have sepsis on admission to the intensive care unit or experience sepsis during their stay in the intensive care unit. There have been significant advances in the understanding of the pathophysiology of the disorder and its treatment. Although deaths attributable to sepsis remain stubbornly high, new treatment algorithms have led to a reduction in overall mortality. Thus, it is important for anesthesiologists and critical care practitioners to be aware of these new therapeutic regimens. The goal of this review is to include practical points on important advances in the treatment of sepsis and provide a vision of future immunotherapeutic approaches.

Figure 1. Immunoinflammatory response of three hypothetical patients with sepsis

The individual immune response in sepsis is determined by many factors including pathogen virulence characteristics, size of the bacterial inoculum, patient comorbidities, etc. The initial immune response is hyperinflammatory but the response rapidly progresses to hypoinflammatory. In the healthy individual who develops meningococcemia, there is a robust hyperinflammatory response. Death may occur rapidly due to a hyperinflammatory state and, antiinflammatory treatments may improve survival. If infection resolves, there is only a minimal hypoimmune state. In the elderly patient with malnutrition who develops diverticulitis, the initial response is limited and, if the infection persists, a prolonged hypoinflammatory response develops followed by recovery or death. In the patient with diabetes, chronic renal failure, and pneumonia, the initial response is blunted and there is a prolonged depression of immune function. (Modified with permission from N Eng J Med 2003; 348:138–50)

Figure 2. Sepsis-induced loss of immune effector cells

Sepsis causes a profound depletion of cells of the innate and adaptive immune system. As shown in the color photomicrographs, sepsis induces a major loss of B cells, CD4⁺ T cells, and follicular dendritic cells in spleens from patient with sepsis compared to spleens removed from critically-ill non-septic patients. Magnification is 200×. (Modified with permission from Nat Rev Immunol 2006; 6:813–22)

Figure 3. Temporal Changes in CD8 T cell surface markers correlates with severity of organ failure

Blood was obtained daily from a patient with sepsis and the percentage of CD8 T cells that expressed positive costimulatory cell surface markers CD28 or OX-40 (CD134) was quantitated via flow cytometry. In order to relate the flow cytometric findings to the patient’s clinical course, the severity of organ failure assessment (Sequential Organ Failure Assessment) score was calculated and is depicted on the right hand vertical axis. Note that as the patients’ Sequential Organ Failure Assessment score increases (higher Sequential Organ Failure Assessment score equates to worsened organ failure) there appears to be an inverse relationship with expression of CD28 and OX-40. Decreased expression of these two cell activation markers may translate into a less effective T cell mediated response. Quantitation of cell surface expression of these and similar molecules may serve as “biomarkers” to allow the physician to tract the activity of the sepsis and determine if the patient is entering a hypoimmune phase of the disorder.

Figure 4. Potential Immunotherapeutic Approach to Sepsis

Two novel approaches to sepsis include use of the immunomodulatory molecules IL-7 and anti-PD-1. IL-7 acts on CD4 and CD8 T cells to block sepsis-induced apoptosis and to cause cell proliferation. IL-7 also enables CD4 and CD8 T cells to respond to the pathogens and produce important cytokines such as interferon-γ which activate macrophages. IL-7 also improves the ability of lymphocytes to traffic to the site of infection and thereby assist in pathogen killing. Anti-PD-1 antibody is able to act on CD4 and CD8 T cells that have become inactivated or “exhausted” to restore their ability to respond to the infection. The activated lymphocytes are able to produce interferon-γ assist in pathogen killing. IL-7 = interleukin 7; IL-7R = interleukin 7 receptor; IFN-γ = interferon – gamma; PMN = polymorphonuclear leukocyte; PD-1 = programmed cell death -1.