Sepsis: evolving concepts and challenges

Abstract

Sepsis remains a major cause of morbidity and mortality worldwide, with increased burden in low- and middle-resource settings. The role of the inflammatory response in the pathogenesis of the syndrome has supported the modern concept of sepsis. Nevertheless, a definition of sepsis and the criteria for its recognition is a continuous process, which reflects the growing knowledge of its mechanisms and the success and failure of diagnostic and therapeutic interventions. Here we review the evolving concepts of sepsis, from the "systemic inflammatory response syndrome triggered by infection" (Sepsis-1) to "a severe, potentially fatal, organic dysfunction caused by an inadequate or dysregulated host response to infection" (Sepsis-3). We focused in the pathophysiology behind the concept and the criteria for recognition and diagnosis of sepsis. A major challenge in evaluating the host response in sepsis is to characterize what is protective and what is harmful, and we discuss that, at least in part, the apparent dysregulated host response may be an effort to adapt to a hostile environment. The new criteria for recognition and diagnosis of sepsis were derived from robust databases, restricted, however, to developed countries. Since then, the criteria have been supported in different clinical settings and in different economic and epidemiological contexts, but still raise discussion regarding their use for the identification versus the prognostication of the septic patient. Clinicians should not be restricted to definition criteria when evaluating patients with infection and should wisely use the broad array of information obtained by rigorous clinical observation.

Figure 1. Sequential steps of sepsis pathogenesis and organ dysfunction. I, Infection: pyelonephritis in a patient with septic shock. II, Sepsis-induced endothelial changes leading to organ dysfunction; IIa, Schematic endothelial changes; IIb, Renal microcirculation: sepsis-induced injury to the endothelium, microcirculation and tubular cells. Adapted with permission from Springer-Nature (89) Copyright 2018; IIc, Alveolus-capillary changes during the acute phase of acute lung injury and acute respiratory distress syndrome. From (90) Copyright 2000. Reprinted with permission from Massachusetts Medical Society. III, Organ dysfunction: radiographic findings in a septic patient with progressive lung injury and acute respiratory distress syndrome.

Figure 2. Similarities in monocyte functions observed in lipopolysaccharide (LPS)-induced tolerance and in septic patients evaluated at a cellular level by flow cytometry. Left panels represent modulated functions in LPS-tolerized monocytes: upper panels: reduced tumor necrosis factor (TNF)-α and interleukin (IL)-6 detection; middle panels: increased or preserved reactive oxygen species (ROS) generation; lower panel: preserved phagocytosis of S. aureus. Right panels represent modulated functions in monocytes from septic patients: upper panels: reduced TNF-α and IL-6 detection; middle panels: increased ROS and NO generation; lower panel: preserved phagocytosis of E. coli. Adapted from (42,49,50). Reproduction licenses available at creativecommons.org/licenses/by/4.0/.

Figure 3. Modulation of monocytes/macrophages response during sepsis. I, In the initial infectious process, microorganisms and their products (pathogen-associated molecular patterns, such as lipopolysaccharide) are recognized by innate immune cells, such as macrophages through pattern recognition receptors, triggering intracellular inflammatory response pathways. II, Amplification of the inflammatory and immune response occurs through the synthesis of inflammatory mediators and cell-to-cell contact. Activated macrophages use glycolysis as a source of energy and biosynthetic intermediates to carry out its effectors' functions. III, Monocytes/macrophages reduce the production of inflammatory cytokines and the efficiency of T cell activation, while they retain the ability to phagocytose and kill microorganisms through the generation of ROS and nitric oxide (NO). IV, Resolution or immunosuppression. This phase represents the return to homeostasis and clinical recovery or, in a complicated course, the lack of an inflammatory response leads to immunosuppression, persistence of organ dysfunction, and emergence of new or recrudescent infections. Panel I adapted from (12) with permission. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer. Please contact permissions@lww.com for further information.