Sepsis and septic shock

Abstract

For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.

Figure 1. Cell-surface and intracellular receptors that are responsible for the recognition of microbial products and endogenous danger signals (alarmins)

Sepsis is initiated upon host recognition of pathogen- associated molecular patterns (PAMPs) and is characterized by the activation of inflammatory signalling pathways. A large number of cell-associated and intracellular receptors are available to detect PAMPs or damage-associated molecular patterns (DAMPs), a few examples of which are illustrated here. PAMPs and DAMPs can be microbial and host glycoproteins, lipoproteins and nucleic acids. The associated pattern- recognition receptors include Toll-like receptors (TLRs), C-type lectin domain family 7 member A (dectin 1) and C-type lectin domain family 6 member A (dectin 2). At least ten different TLRs are known, and in many cases they exist as either homodimers or heterodimers. Once activated, the ensuing signalling pathways generally converge towards interferon regulatory factor (IRF) signalling and nuclear factor-κB (NF-κB). IRF is responsible for type I interferon (IFN) production. NF-κB and activator protein 1 (AP-1) signalling are predominately responsible for the early activation of inflammatory genes, such as TNF, IL1 and those encoding endothelial cell-surface molecules. CARD9, caspase recruitment domain-containing protein 9; dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; FcRγ, Fcγ receptor; HMGB1, high-mobility group protein B1; iE-DAP, d-glutamyl-meso-diaminopimelic acid; LGP2, laboratory of genetics and physiology 2 (also known as DHX58); LPL, lipoprotein lipase; LPS, lipopolysaccharide; LY96, lymphocyte antigen 96; MAPK, mitogen- activated protein kinase; MCG, mannose-containing glycoprotein; MDA5, melanoma differentiation-associated protein 5 (also known as IFIH1); MDP, muramyl dipeptide; MCL, mannose-capped lipoarabinomannan; Mincle, also known as CLEC4E; MYD88, myeloid differentiation primary response protein 88; NIK, NF-κB-inducing kinase (also known as MAP3K14); NOD, nucleotide-binding oligomerization domain; RAF1, RAF proto-oncogene serine/threonine-protein kinase; RAGE, advanced glycosylation end product-specific receptor; RIG-I, retinoic acid-inducible gene 1 protein (also known as DDX58); ssRNA, single-stranded RNA; STING, stimulator of interferon genes protein; SYK, spleen tyrosine kinase; TDM, trehalose-6,6′-dimycolate; TICAM1, TIR domain-containing adaptor molecule 1.

Figure 2. Current conceptual model of outcomes of sepsis

Originally conceived by Bone et al. in the 1990s, the current model of the clinical trajectory that patients traverse in sepsis has evolved to reflect the concurrent inflammatory and immunosuppressive responses, and the observation that fewer patients are dying in the early period owing to earlier recognition and better implementation of best clinical practices. Successful resuscitation is occurring more frequently and the patients recover sufficiently to be discharged from the intensive care unit and hospital (blue lines). Some patients experience a pronounced early inflammatory response to the pathogen or danger signals, leading to multiple organ failure and death (red line). Other patients survive the early inflammatory response but experience chronic critical illness (green lines) that is characterized by persistent inflammation, immunosuppression and catabolism syndrome (PICS); reactivation of latent viral infections; nosocomial infections; and long-term functional and cognitive declines. DAMP, damage-associated molecular pattern; DC, dendritic cell; MDSC, myeloid-derived suppressor cell; NO, nitric oxide; ROS, reactive oxygen species; T_H2, T helper 2.

Figure 3. The late immunosuppressive effects of sepsis

After the transitory acute inflammatory response, sepsis results in an immunocompromised state. Immunosuppressive immature polymorphonuclear leukocytes (PMNs) and myeloid-derived suppressor cells (MDSCs) mobilize from the bone marrow and monocyte differentiation skews to the production of M2 macrophages (which decrease inflammation and promote tissue repair). Although these responses can be considered normal, if the source of infection is not controlled, the continued responses rapidly become pathological and lead to chronic immune suppression. Together, immature PMNs, MDSCs and M2 macrophages produce anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β (TGFβ). Professional antigen-presenting cells, including dendritic cells and macrophages, reduce the expression of the activating major histocompatibility complex (MHC) class II molecule human leukocyte antigen-antigen D related (HLA-DR). T cells and stromal cells upregulate negative co-stimulatory molecules, including programmed death protein 1 (PD1) and programmed death ligand 1 (PDL1), respectively, to drive the expansion of regulatory T (T_reg) cells and anergic (unresponsive) T cells. Follicular dendritic cells, B cells and T cells undergo apoptosis, further abrogating the immune response. TCR, T cell receptor; T_H2, T helper 2.

Figure 4. Changes in the vascular endothelium in response to inflammatory stimuli during sepsis

a | The resting vascular endothelium in its natural anticoagulant state. b | Sepsis produces profound changes that convert the endothelium to a procoagulant state. This disrupted endothelium expedites the loss of fluid through disengaged tight junctions and expedites the recruitment, attachment and extravasation of inflammatory cells through the endothelium. Activation of the coagulation cascade potentiates inflammation and completes a vicious cycle in which inflammation induces and exacerbates coagualopathies and endothelial injury. ESL1, E-selectin ligand 1; ICAM1, intercellular adhesion molecule 1; LFA1, lymphocyte function-associated antigen 1; MPO, myeloperoxidase; NO, nitric oxide; PAF, platelet- activating factor; PAI-1, plasminogen activator inhibitor 1; PGI₂, prostaglandin I₂; PMN, polymorphonuclear leukocyte; PSGL1, P-selectin ligand 1; ROS, reactive oxygen species; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; t-PA, tissue plasminogen activator; TXA₂, thromboxane A₂; VE, vascular endothelial.

Figure 5. Interaction between coagulation and inflammation

Microorganisms and damage -associated molecular patterns (DAMPs), as well as complement activation and the release of inflammatory cytokines or mediators, can initiate the coagulation cascade (involving the coagulation factors designated here as ‘F’ followed by the requisite Roman numeral). Primarily through the upregulation of procoagulant proteins such as tissue factor (TF), excessive fibrin deposition and reduced plasmin activity lead to thrombus and fibrin deposition and microcirculatory defects. The system is self-activating as complement activation and the exposure of myeloid and endothelial cells to microbial products and inflammatory cytokines increase the expression of TF. Products of complement activation, such as C3a and C5a, induce platelet-activating factor (PAF; not shown) and inflammatory cytokines. Cytokines, PAF and thrombi can also damage the endothelium, exposing collagen fibres and activating von Willebrand factor (vWF), which further increases TF expression and inflammatory cytokine production. Although not shown here, inflammatory cytokines also decrease the expression of the fibrinolytic pathway, by increasing plasminogen activator inhibitor 1 (PAI-1) activity and decreasing plasmin activity. DIC, disseminated intravascular coagulation; MBL, mannose-binding lectin.