Immunological Endotyping of Chronic Critical Illness After Severe Sepsis

Abstract

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early “cytokine or genomic storm,” but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed.

A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis

“…Our study highlights that lymphoid populations have a transcriptomic profile more suggestive of immune and metabolic dysfunction than inflammation at 14-21 days post-sepsis. Tlymphocytes had some overexpression of both pro-inflammatory and immunosuppressive genes in late sepsis, but not to the levels seen in myeloid populations (12). In contrast, both pDCs and platelets appear to play an important role in the persistent inflammation seen in chronic sepsis with upregulation of genes for pro-inflammatory cytokines and chemokines.…”

“…Thus, sepsis research is adapting to evaluate long-term outcomes, such as functional status, cognitive status, and one-year morality, as primary outcomes (3,4,57,59,60). Ongoing research suggests that the dismal long-term outcomes experienced by CCI patients are due to a dysregulated immune response that fails to return to homeostasis (5,6,9,11,13), which we have identified as the PICS endotype (12).…”

“…CCI was defined as an ICU length of stay greater than or equal to 14 days with evidence of persistent organ dysfunction, measured using components of the Sequential Organ Failure Assessment (SOFA) score (i.e. cardiovascular SOFA ≥ 1, or score in any other organ system ≥ 2) (3,5,12,17). Patients with an ICU length of stay less than 14 days would also qualify for CCI if they were discharged to another hospital, a long-term acute care facility, or to hospice and demonstrated continuing evidence of organ dysfunction at the time of discharge.…”

“…Although the underlying pathobiology of the CCI phenotype remains unclear, it is understood that CCI can result from a Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) endotype (8)(9)(10)(11)(12). Previous studies indicate that the dismal long-term outcomes experienced by CCI patients are due in part to a failure of the host to return to their pre-sepsis immune status (5,6,9,11,13).…”

Long Noncoding RNA ZFAS1 Protects HK-2 Cells against Sepsis‐Induced Injury through Targeting the miR3723p/PPARα Axis

“…It is mainly caused by pathogenic bacteria and toxins from local infected sites that enter the blood circulation and spread to various tissues and organs and can further develop into multiple organ dysfunction syndromes, septic shock, acute renal failure, etc. [1]. e kidney is the most easily affected target organ in sepsis.…”