Persistent Inflammation, Immunosuppression and Catabolism Syndrome

Abstract

Following advances in critical care, in-hospital multiple organ failure-related mortality is declining. Consequently, incidence of chronic critical illness is increasing. These patients linger in the intensive care unit, have high resource utilization, and poor long-term outcomes. Within this population, the authors propose that a substantial subset of patients have a new phenotype: persistent inflammation, immunosuppression, and catabolism syndrome. There is evidence that myelodysplasia with expansion of myeloid-derived suppressor cells, innate and adaptive immune suppression, and protein catabolism with malnutrition are major contributors. Optimal care of these patients will require novel multimodality interventions.

Keywords: Cachexia; Chronic critical illness; Multiple organ failure; Myeloid-derived suppressor cells; PICS; Sepsis; Shock; Trauma.

Figure 1. Evolution of MOF

MOF evolves over 40 years as does the clinical and surgical management of shock states. Paradigms to explain the developing phenotypes are adopted and discarded. We propose that PICS is the predominant phenotype resulting from CCI.

Figure 2. PICS paradigm

Following a major inflammatory insult (trauma, sepsis, burns, acute pancreatitis, etc) there is a simultaneous inflammatory and immunosuppressive response. Early deaths from acute MOF are now rare due to early recognition of shock and rapid implementation of supportive care thorough effective application of EBM and SOPs. Survivors may progress through two pathways: 1) patients readily return to immune homeostasis and achieve a rapid recovery; 2) patients smolder in the ICU with CCI and develop chronic inflammation, suppression of adaptive immunity, ongoing protein catabolism with cachectic wasting, and suffer from recurrent nosocomial infections. These patients often suffer from PICS, many of which fail to achieve functional independence, are discharged to LTACs, have and extremely poor quality of life, and ultimately succumb to an indolent death. Adapted from Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care. The journal of trauma and acute care surgery. Jun 2012 72(6):1491–1501. Abbreviations: MOF – multiple organ failure; SIRS – systemic inflammatory response syndrome; CARS – compensatory anti-inflammatory response syndrome; CCI – Chronic Critical Illness; ICU – Intensive Care Unit; PICS – persistent immune suppression inflammation and catabolism syndrome;

Figure 3. MDSCs in PICS

Characterization of MDSCs (CD33⁺CD11b⁺HLA⁻DR^−/low) in 72 trauma and surgical ICU patients with severe sepsis/septic shock. A) After sepsis onset, circulating MDSCs expand early and are persistently elevated by a significant margin over the first 28 days when compared to healthy controls. B & C) The commonly observed high ratio of monocytic/granulocytic MDSCs seen in healthy subjects is reversed in patients with severe sepsis/septic shock. From Mathias B, Delmas AL, Ozrazgat-Baslanti T, et al. Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Annals of surgery. May 9 2016 *p<0.05 when compared to HC subjects # p<0.05 when compared to SS/SS patients at 12 hours.

Figure 4. MDSCs and ICU mortality/length of stay

Increase in circulating MDSCs correlates with early mortality and prolonged length of stay. MDSC expansion was more significant in patients with early mortality (<14days) than in patients who survived >14 days at both 12 hours and 24 hours after sepsis onset. MDSC levels then decline until death. In patients with a prolonged ICU stay (>14days), MDSCs are significantly elevated at 7 days and 14days when compared to patients with and ICU length of stay of <14 days. From Mathias B, Delmas AL, Ozrazgat-Baslanti T, et al. Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Annals of surgery. May 9 2016 *p<0.05 when compared to patients with ICU LOS <14 days #p<0.05 when compared to patients with ICU LOS ≥14 days

Figure 5. The PICS cycle

PICS can be represented as a recurring, vicious cycle. First, the inciting inflammatory event stimulates an emergency myelopoietic response. While the ensuing expansion of MDSC can be protective, prolonged expansion promotes suppression of adaptive immunity and chronic inflammation. Following this initial response, the patient may convalesce or progress to CCI. In a subset of CCI patients PICS develops and is characterized by manageable organ dysfunction, ongoing inflammation and immune suppression, protein catabolism, muscle wasting, and unmet nutritional needs. This predisposes the patient for recurrent infections and recidivism of this cycle. Modified from Mira et al (in press).