HHE Sponsored supplement: Sepsis | Page 13

mechanism by which, in the face of a second encounter with the same challenge, the response is more rapid and more effective. 27 In septic patients an early increase in leukocytes is observed at the expense of PMN cells. Lymphocytes are markedly decreased in sepsis at the expense of CD4 + T cells and B cells. 28,29 After the onset of sepsis, an increased expression of co-inhibitory markers such as PD-1 and cytotoxic antigen-4 (CTLA-4) lymphocytes is detected in both T cells and in experimental models of sepsis. Increased activity of regulatory T cells (Treg), which are immunosuppressive cells, has been described. 31 CD8+ T cells are considered effector cytotoxic cells. They decrease in patients with septic shock. 32 B lymphocytes produce antibodies that can neutralise microorganisms by opsonization and activate complement proteins to eliminate bacteria by phagocytosis. Patients with septic shock have decreased levels of B lymphocytes in blood. 33 Pro-inflammation vs anti-inflammation Patients who survive the initial inflammatory response develop a reactive anti-inflammatory response to counteract the effects of the cytokines that have been released and to decrease their synthesis, until a balance that will allow the body to effectively fight the infection has been reached. 34 The predominance of one or the other is directly related to the concentration of TH1 or TH2, in turn related to the presence of IL-2 and IL-4, respectively. 35,36 The reactive anti-inflammatory response is based on the release of specific inhibitory cytokines and soluble receptors of pro- inflammatory cytokines: 37 IL-1 receptor antagonists (IL-1RA) and TNF; TGF-b; IL-4, IL-6, IL-10, IL-11 and IL-13; specific receptors for IL-4, IL-6, IL-10, IL-11 and IL-13. A deep and sustained anti-inflammatory response can induce a state of profound immunosuppressionin the patient, and even to anergy. 38 This ‘immune paralysis’ leaves the majoroty of sepsis patients at the mercy of commonplace nosocomial infections (Figure 2). Cellular alterations and organ failure: the ‘motor of sepsis’ During the past 30 years, the link (pivotal element) between the described alterations and the associated organ dysfunction have been investigated. 39 The exact mechanism is unknown but the following pathogenic factors have been suggested: • Tissue ischaemia: During sepsis, there is a state of peripheral hypoperfusion from the initial onset, in which there is a marked hypovolaemia, vascular regulationdisturbances and cardiac dysfunction that contribute to tissue hypoperfusion. 40 • Cytopathic lesions and mitochondrial dysfunction: Inflammatory mediators can directly alter cellular function by altering mitochondrial function and thereby the transport of electrons. This results in impairment of aerobic metabolism due to poor use of available oxygen, which significantly affects oxidative phosphorylation and induces cytotoxicity. 41,42 In addition, damaged mitochondria can trigger cell death pathways through the release of mitochondrial cytochrome C43. The importance 13 HHE 2018 | hospitalhealthcare.com of mitochondrial dysfunction during sepsis is evidenced by the observations that cellular ATP levels correlate with survival in human and experimental models of sepsis. 44,45 • Apoptosis: Programmed cell death has special relevance in cellular regeneration, and is extremely altered in sepsis. There are several ways in which apoptosis is involved in immunosuppression including depletion of key effector cells in both innate and adaptive immunity. 46 Treatment of T lymphocytes with apoptotic cells induces the release of anti- inflammatory cytokines, including IL-10 and TGFb, which can induce a state of anergy or a change of TH1 to TH2 phenotype. Inflammatory mediators can delay the apoptosis of macrophages and polynuclear neutrophils and on the contrary increase the apoptosis of lymphocytes and dendritic cells in addition in certain parenchymal and endothelial and epithelial cells. Patients with septic shock have increased levels of PD-1 and PD-L1 in their monocytes and T lymphocytes. 47 Studies have shown that increased regulation of PD-L1 in granulocytes results in enhanced lymphocyte apoptosis. 48 • Immunosuppression: Immunosuppression is accompanied by an increased incidence of sepsis. 49 It is also shown that there is a period of immunosuppression that can reach anergy and the inability to respond to another episode of infection after a period of excess inflammation. 50 The sepsis-induced immunosuppression affects both the cellular effectors of the innate immune system and those of the adaptive immune system. In these patients, nosocomial infections have a worse evolution and there is an increase in mortality. 51 • Hyperinflammation (‘cytokine storm’): In some patients, especially in the young, there is an excessive systemic activation characterised by a surge of inflammatory cytokines such as IL-1, TNF, and IL-17, in a relatively short period of time. 35 • Microcirculation: alteration of the microcirculation is fundamental in sepsis; its regulation is affected and produces functional arteriovenous shunts that, in conjunction with the formation of micro-thrombi in the capillaries, explain tissue hypo-perfusion, hypoxia and cellular dysfunction, and the development of organ dysfunction. 39 The relationship between systemic haemodynamics and microcirculation in septic shock is dynamic. At an early stage, microcirculatory abnormalities are sensitive to flow and tend to improve with the optimisation of systemic haemodynamics. Later on, the pathophysiological mechanisms are more complex and the alterations are independent. 53 • The endothelium and glycocalyx: the vascular endothelium regulates the movement of blood componenets to the tissues and plays a crucial role in the development of sepsis. 53–55 The synthesis of nitric oxide 56 and adrenomedullin 57,58 determines the vascular tone and a large part of the haemodynamic alterations of those with sepsis. The glycocalyx also expresses immune receptors (DAMP and PAMP) that can activate inflammatory pathways, alter vascular permeability and activate coagulation. 59 The glycocalyx of the endothelial cells is altered during sepsis, thereby triggering a significant desquamation. 60 This degradation of