Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome

Abstract

Objectives: To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research.

Design: Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar.

Measurements and main results: Sepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit "a persistent inflammation-immunosuppression and catabolism syndrome," and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory.

Conclusions: Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.

Figure 1. Model of PICS

Early deaths from acute MOF secondary to the acute hyper-inflammatory phase of sepsis have declined with implementation of best clinical practice guidelines, primarily early detection and rapid initiation of supportive care [9-12]. Following the simultaneous inflammatory and immunosuppressive responses patient may return to a homeostatic immune state leading to a rapid recovery, or develop CCI and PICS resulting from protein catabolism, cachexia and secondary infections. Following a prolonged hospitalization, 35% of patients are sent to skilled nursing and long-term acute care facilities [14, 16]. A multitude of these patients fails to ever recover and suffer an indolent death with three-year mortality of 71% [20, 28]. Modified from [28]. Abbreviations: MOF – multiple organ failure; SIRS – systemic inflammatory response syndrome; CARS – compensatory anti-inflammatory response syndrome; PICS – persistent immune suppression inflammation and catabolism syndrome; LTAC – Long term acute care facility.

Figure 2. Role of MDSCs in Severe Sepsis/Septic Shock Patients

A. Under normal physiologic conditions, immature myeloid cells (IMC) differentiate into granulocytes, monocytes/macrophages and dendritic cells; however, in the septic patient, the inflammatory milieu is altered and maturation is impaired. B. Severe sepsis/septic shock results in a cascade of signaling molecules, including but not limited to IL-6, IL-10, IL-12, dsRNA, INF-γ, VEGF, G-CSF, GM-CSF, LPS, SCF, IL-1β, IL-13, IL-17, S100A8/9, prostaglandins, SAA, and CCL2 [49, 50, 101, 102]. As a result, IMCs remain as MDSCs at the expense of differentiation into mature myeloid cell populations. While this causes a decreased number of mature myeloid cells, it more importantly leads to the production of large numbers of MDSCs, which act through several mechanisms to promote inflammation and global suppression of adaptive immune function. C. MDSCs deplete L-arginine via ARG1 and iNOS [56, 57]. In the absence of adequate L-arginine T-cell function is altered, intracellular signaling is impaired, and T-cells undergo apoptosis [57]. D. MDSCs produce increased ROS which combine with the byproduct of iNOS, NO to produce peroxynitrites [49]. The resulting peroxynitrite nitrosylates several cell surface proteins, including the z-chain of T-cell receptors, resulting in decreased T-cell responsiveness [103]. Nitrosylation of cysteine residues results in altered IL-2 signaling [104]. Additionally, IL-2 mRNA stability is affected by NO [104]. E. Monocytic MDSCs cause polarization of macrophages towards a type II phenotype via IL-10 and TGF-β production [53]. Additionally, NK cell suppression is mediated by ROS [105]. F. Direct contact of monocytic MDSCs via CD40 receptors results in induction of T_reg cells [106]. Production of IL-10 by MDSC has been associated with induction of T_reg cells that produce IL-10 [58]. G. Upregulation of PD-L1 and other checkpoint inhibitors in MDSC leads to T-cell apoptosis [100].

Figure 3. Sepsis, Emergency Myelopoiesis, MDSC expansion and the development of CCI and PICS

Sepsis results in a self-stimulating cycle. Initially, sepsis leads to emergency myelopoiesis and MDSC expansion [52]. While MDSC expansion has proven to be of early benefit, prolonged MDSC expansion leads to immunosuppression, chronic inflammation and features of CCI [61]. These patients advance to PICS suffering from manageable organ failure, ongoing protein catabolism, poor nutrition, cachexia, poor wound healing in addition to persistent inflammation and immune suppression [28]. Patients with CCI and PICS have increased susceptibility to secondary or nosocomial infections, which reestablish inflammation, and the cycle repeats.