Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation

Abstract

Sepsis is a leading cause of death worldwide. After initial trials modulating the hyperinflammatory phase of sepsis failed, generations of researchers have focused on evaluating hypo-inflammatory immune phenotypes. The main goal has been to develop prognostic biomarkers and therapies to reduce organ dysfunction, nosocomial infection, and death. The depressed host defense in sepsis has been characterized by broad cellular reprogramming including lymphocyte exhaustion, apoptosis, and depressed cytokine responses. Despite major advances in this field, our understanding of the dynamics of the septic host response and the balance of inflammatory and anti-inflammatory cellular programs remains limited. This review aims to summarize the epidemiology of nosocomial infections and characteristic immune responses associated with sepsis, as well as immunostimulatory therapies currently under clinical investigation.

Keywords: SIRS; compensatory anti-inflammatory response; immunostimulation; immunosuppression; nosocomial infection; priming; sepsis.

Figure 1

Revised model of inflammation in sepsis. The traditional biphasic model of sepsis (19) plots the immune system on a timeline with an initial hyperinflammatory cytokine storm followed by hypoinflammatory immune paralysis. However, clinical evidence does not support well-demarcated immune phases. In this revised model, the initial immune response to sepsis is a continuous mix of pro- and anti-inflammatory processes that lead to specific immune reprogramming. These programs include persistently pro- or anti-inflammatory and primed responses. The duration and magnitude of each inflammatory program is likely result of many determining factors.

Figure 2

Conceptual model of the compartmentalization and heterogeneity of sepsis. This conceptual model is derived from studies in experimental sepsis that have demonstrated tissue-specific inflammatory responses. In this model, acute sepsis in one compartment (abdomen) leads to specific and dynamic changes in proximal (blood) and distal (lungs) compartments. Assessment of the immune response by ex vivo stimulation assays (second hit) may then reveal the predominant cellular program. In this case, each compartment responds differently to secondary stimulation based on the severity and composition of the preceding inflammatory insult.

Figure 3

Clinical phases of sepsis and factors influencing outcome. The clinical course of sepsis is characterized by accelerated progression in severity of illness leading to the development of clinical sepsis. The outcome of each clinical phase of sepsis is influenced by multiple factors. The pre-sepsis phase is influenced primarily by the baseline functional state of the patient. Pre-sepsis functionality directly affects the course of acute sepsis including onset, magnitude and duration. Furthermore, properties inherent to the type of sepsis and exposures occurring during management of acute sepsis continue to affect outcome. Recovery follows and is largely dependent on the severity of prior phases, though continued exposure to the healthcare system places patients at risk for nosocomial complications. Throughout each phase the specific immune program is heterogenous and influences outcome.

Figure 4

Cellular and molecular mechanisms of immune reprogramming in sepsis. TLR, toll-like receptor; miRNA, microRNA; PAMP, pathogen associated molecular pattern; DAMP, damage associated molecular pattern; PRR, pathogen recognition receptor; MDSC, myeloid derived suppressor cell; T-reg, regulator T-cell; mHLA-DR, monocyte Human Leukocyte Antigen-DR.