The persistent inflammation, immunosuppression, and catabolism syndrome 10 years later

Abstract

With the implementation of new intensive care unit (ICU) therapies in the 1970s, multiple organ failure (MOF) emerged as a fulminant inflammatory phenotype leading to early ICU death. Over the ensuing decades, with fundamental advances in care, this syndrome has evolved into a lingering phenotype of chronic critical illness (CCI) leading to indolent late post-hospital discharge death. In 2012, the University of Florida (UF) Sepsis Critical Illness Research Center (SCIRC) coined the term Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) to provide a mechanistic framework to study CCI in surgical patients. This was followed by a decade of research into PICS-CCI in surgical ICU patients in order to define the epidemiology, dysregulated immunity, and long-term outcomes after sepsis. Other focused studies were performed in trauma ICU patients and emergency department sepsis patients. Early deaths were surprisingly low (4%); 63% experienced rapid recovery. Unfortunately, 33% progressed to CCI, of which 79% had a poor post-discharge disposition and 41% were dead within one year. These patients had biomarker evidence of PICS, and these biomarkers enhanced clinical prediction models for dismal one-year outcomes. Emergency myelopoiesis appears to play a central role in the observed persistent immune dysregulation that characterizes PICS-CCI. Older patients were especially vulnerable. Disturbingly, over half of the older CCI patients were dead within one year and older CCI survivors remained severely disabled. Although CCI is less frequent (20%) after major trauma, PICS appears to be a valid concept. This review will specifically detail the epidemiology of CCI, PICS biomarkers, effect of site of infection, acute kidney injury, effect on older patients, dysfunctional high-density lipoproteins, sarcopenia/cachexia, emergency myelopoiesis, dysregulated erythropoiesis, and potential therapeutic interventions.

Figure 1:

Timeline of evolving epidemiology of multiple organ failure (MOF). The upper portion (a) depicts the major advances in care from 1970 through early 2010s and the lower portion depicts the resulting series of predominant clinical presentations (or phenotypes) that emerged over these four decades. The bottom of the figure (b) lists corresponding research topics that have been pursued. ICU, intensive care unit; TPN, total parenteral nutrition; IAI, intra-abdominal infection; PAC, pulmonary artery catheter; CT, computerized tomographic; IR, interventional radiology; ATLS, advanced trauma life support; ACS, abdominal compartment syndrome; SIRS/CARS, systemic inflammatory response syndrome/compensatory anti-inflammatory response syndrome; TIC, trauma-induced coagulopathy; MTPs, massive transfusion protocols; FAST, focused abdominal sonography of trauma; SOPs, standard operating procedures; PICS-CCI, persistent inflammation, immunosuppression catabolism syndrome-chronic critical illness; VO₂, oxygen consumption; PMN, neutrophil; IEDs, immune-enhancing diets; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; CTAA, chronic trauma-associated anemia. Adapted from Moore FA, Moore EE, Billiar TR, Vodovotz Y, Banerjee A, Moldawer LL. The role of NIGMS P50 sponsored team science in our understanding of multiple organ failure. J Trauma Acute Care Surg. 2017;83(3):520–531. Copyright© 2017 Lippincott Williams.

Figure 2:

Bone marrow changes associated with the clinical trajectories of sepsis. BM, bone marrow; EMVs, exosomes and microvesicles; PICS, persistent inflammation-immunosuppression and catabolism syndrome; LTAC, long-term acute care; MOF, multiple organ failure; SIRS, systemic inflammatory response syndrome; HSCs, hematopoietic stem cells; Tregs, regulatory T-cells; sPDL-1, soluble programmed death-ligand 1; MDSC, myeloid-derived suppressor cells. Adapted from: Rincon JC, Efron PA, Moldawer LL. Immunopathology of chronic critical illness in sepsis survivors: Role of abnormal myelopoiesis. J Leukoc Biol. 2022; 112(6):1525–34. Copyright© 2022 Society for Leukocyte Biology.

Figure 3:

Comparison of outcomes over 1-year after sepsis for CCI versus RAP sepsis cohorts. (A) One-year mortality probability and (B) Twelve-month Zubrod scores. Data presented as mean ± standard error with statistical significance set at p < 0.05. Adapted from: Brakenridge SC, Efron PA, Cox MC, Stortz JA, Hawkins RB, Ghita G, et al. Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes. Ann Surg. 2019; 270(3):502–10. Copyright© 2019 Wolters Kluwer Health, Inc.

Figure 3:

Comparison of outcomes over 1-year after sepsis for CCI versus RAP sepsis cohorts. (A) One-year mortality probability and (B) Twelve-month Zubrod scores. Data presented as mean ± standard error with statistical significance set at p < 0.05. Adapted from: Brakenridge SC, Efron PA, Cox MC, Stortz JA, Hawkins RB, Ghita G, et al. Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes. Ann Surg. 2019; 270(3):502–10. Copyright© 2019 Wolters Kluwer Health, Inc.

Figure 4:

Area under the receiver operator curve (AUC) for MLR prediction models for Zubrod 4/5 (reflecting dismal long-term outcomes) at day 7 with clinical variables without biomarkers (AUC=0.80) and with biomarkers (AUC=0.88). Adapted from: Darden DB, Brakenridge SC, Efron PA, Ghita GL, Brumback B, Mohr AM, et al. Biomarker Evidence of the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS) in Chronic Critical Illness (CCI) after Surgical Sepsis. Ann Surg 2021;274(4):664–73. Copyright© 2021 Wolters Kluwer Health, Inc.

Figure 5:

Comparisons of selected biomarkers. The left panel shows data for older (≥ 65 yrs) vs younger (≤ 45 yrs) patients and the right panel shows data for older CCI vs older RAP patients. A) shows increased interleukin-6 (IL-6) reflecting inflammation; B) shows increased soluble programmed death ligand 1 (sPDL-1) reflecting immunosuppression; C) shows increased glucagon-like peptide 1 (GLP-1) reflecting stress metabolism; D) decreased albumin catabolism. Perforated line represents biomarker levels in matched control subjects. Shaded area represents published normal reference ranges. Data presented as median (25% and 75%) with statistical significance set at p < 0.05. Adapted from Mankowski RT, Anton SD, Ghita GL, Brumback B, Darden DB, Bihorac A, et al. Older adults demonstrate biomarker evidence of the persistent inflammation, immunosuppression and catabolism syndrome (PICS) after sepsis. J Gerontol A Biol Sci Med Sci. 2022; 77(1):188–96. Copyright© 2022 Oxford University Press.

Figure 6:

The pathophysiology of chronic trauma associated anemia: Systemic inflammation, neuroendocrine activation, and allogenic blood product transfusions propagate iron dysregulation, mobilization of hematopoietic progenitors to injured tissues, and suppression of erythroid progenitor growth (NE: norepinephrine, IL-6: interleukin 6, G-CSF: granulocyte colony-stimulating factor, EPO: erythropoietin, EPO-R: erythropoietin receptor, TfR: transferrin receptor, CSF1/2-R: colony-stimulating factor 1 receptor and colony-stimulating factor 2 receptor). Reprinted with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. Originally published by Loftus TJ, Mira JC, Miller ES, Kannan KB, Plazas JM, Delitto D, Stortz JA, Hagen JE, Parvateneni HK, Sadasivan KK, Brakenridge SC, Moore FA, Moldawer LL, Efron PA, Mohr AM. 2018. The Postinjury Inflammatory State and the Bone Marrow Response to Anemia. Am J Respir Crit Care Med. Volume 198, pages 629–638. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.