A Pathophysiological Insight into Sepsis and Its Correlation with Postmortem Diagnosis

Abstract

Background: Sepsis is among the leading causes of death worldwide and is the focus of a great deal of attention from policymakers and caregivers. However, sepsis poses significant challenges from a clinical point of view regarding its early detection and the best organization of sepsis care. Furthermore, we do not yet have reliable tools for measuring the incidence of sepsis. Methods based on analyses of insurance claims are unreliable, and postmortem diagnosis is still challenging since autopsy findings are often nonspecific.

Aim: The objective of this review is to assess the state of our knowledge of the molecular and biohumoral mechanisms of sepsis and to correlate them with our postmortem diagnosis ability.

Conclusion: The diagnosis of sepsis-related deaths is an illustrative example of the reciprocal value of autopsy both for clinicians and for pathologists. A complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insults, is mandatory to illuminate the exact cause of death. This would help clinicians to compare pre- and postmortem findings and to reliably measure the incidence of sepsis.

Figure 1

Schematic of events associated with major mediators of cytokine cascade on initiation of sepsis. The release of a large amount of pathogen and damage associated molecular patterns (PAMPs and DAMPs) from invading microorganisms and/or damaged host tissue, respectively, results in the overstimulation of pattern-recognition receptors (PRRs) of immune cells. This process activates an inflammatory cascade in which large amounts of cytokines are released into the body. Macrophages and endothelial cells are then hyperactivated by the unusually large quantity of circulating cytokines. The activation of macrophages and endothelial cells results in the release of more cytokines, exacerbating the inflammatory response. The profound proinflammatory response is counteracted by certain anti-inflammatory cytokines, including IL-10, transforming growth factor-β (TGF-β), and IL-4, which attempt to restore immunological equilibrium.

Figure 2

A schematic representing the involvement of different organs in sepsis. During sepsis large amounts of inflammatory mediators are found within the bloodstream. They can act on different organs and induce tissue injury that in turn will favour further production of inflammatory mediators. Cross talk between the different organs and tissues is further mediated by the local delivery of mediators that can amplify or limit the inflammatory response (MIF, macrophage migration inhibitory factor; NO, nitric oxide; ROS, reactive oxygen species; RNS, reactive nitrogen species; VCAM-1, vascular adhesion molecule-1; and ICAM-1, intercellular adhesion molecule-1).

Figure 3

A schematic representing microvesicles (MVs) functions. MVs are released in the extracellular environment through a membrane reorganization and blebbing process following cell activation or apoptosis. They contribute to the spread of inflammatory and prothrombotic vascular status and they may affect smooth muscle tissue through adhesion molecules (E-selectin, ICAM, and VCAM) activation of nuclear factor κB and the expression of inducible nitric oxide synthase and cyclooxygenase-2, with an increase in nitric oxide (NO) and vasodilator prostanoids, leading to arterial hyporeactivity.