catabolism?

41 Is Persistent Critical Illness a Syndrome of Ongoing Inflammation/Immunosuppression/Catabolism? McKenzie K. Hollen, Philip A. Efron, and Scott C. Brakenridge

INTRODUCTION The standard host response to infection can be overly robust and effectually cause an auto-destructive state of systemic inflammatory response syndrome (SIRS) that leads to multiple organ dysfunction (MODS), refractory shock, and fulminant death.1 Due in part to advances in intensive care and organ support, mortality among critically ill septic patients has declined, especially among those receiving aggressive resuscitation and organ support.2 For example, very few surgical intensive care unit (ICU) patients with sepsis now die from refractory shock, and mortality in this group has dropped from historical rates of 40%–50% to as low as 13% in those that survive the first 48 hours.3,4 Instead, a new clinical phenotype, termed chronic critical illness (CCI), has emerged. CCI patients experience extended stays in the ICU, develop persistent, low-grade organ dysfunction, and have poor long-term survival rates.3 CCI patients extensively utilize resources, accrue significant personal and hospital financial burdens, and are frequently discharged to long-term acute care facilities (LTAC) or skilled nursing facilities (SNFs) where they endure further cognitive disabilities, rapid accelerated aging, frailty, and sepsis recidivism requiring rehospitalization.1 CCI is characterized by a number of immunosuppressive and inflammatory phenotypes. These patients often exhibit: • persistent inflammation (elevated C-reactive proteins, interleukin-6 [IL-6], and interleukin-8 [IL-8]) • myeloid derived suppressor cell (MDSC) expansion •� immunosuppression � ����������������� (latent �������� viral ������ reactivation ������������� and ���� in��� creased secondary infections), and • protein catabolism with muscle wasting.1 Researchers and physicians have investigated mechanisms that might drive these clinical abnormalities. The combination has been termed the persistent inflammation immunosuppression and catabolism syndrome (PICS). It is hoped that this formulation will lead to the identification of mechanistic causes for increased late morbidity and mortality in patients with sepsis and will uncover testable approaches to therapy (Fig. 41.1).1

EVIDENCE THAT PERSISTENT CRITICAL ILLNESS IS A SYNDROME OF ONGOING INFLAMMATION, IMMUNOSUPPRESSION, AND CATABOLISM Three clinical trajectories have emerged following sepsis (Fig. 41.2). A 3-year prospective observational cohort study evaluated surgical ICU (SICU) patients with sepsis for the development of CCI (14 days of intensive care unit resource utilization with persistent organ dysfunction).4 Of the patients studied, only 6% that survived the first 48 hours died within 14 days. Forty-six percent of patients experienced rapid recovery (that is, recovery within 14 days). However, a striking 49% survived but failed to recover with the 14-day window, thus meeting our criteria for CCI. Of the patients who developed CCI, .60% died within six months.1,4 The patients with CCI that died within this time frame exhibited the following characteristics: 1. persistent inflammation as evidenced by elevated plasma concentrations of cytokines and 2. elevated immunosuppressive proteins, i.e., soluble programmed death ligand 1(sPD-L1) and IL-10.4 Seventy percent of RAP patients were discharged to their home or rehabilitation facilities. Of CCI patients who survived to discharge, nearly two thirds were discharged to LTACs, SNFs, inpatient hospitals, or hospice.4 According to a number of developed health-related quality of life, physical function and performance indices (EuroQol-5D, the Short Physical Performance Battery, and the ECOG/WHO/Zubrod Scale), long-term follow-up demonstrated that CCI patients reported poorer quality of life and greater functional incapacities compared to patients who experienced rapid recovery.4 Additionally, PICS has been observed in critical illness arising from disorders other than sepsis. A retrospective cohort study determined that severe acute pancreatitis patients with prolonged ICU stays were associated with a high morbidity of PICS and reported poorer long-term quality of life.5 A study addressing long-term mortality in burn survivors demonstrated that, when compared to matched controls, survival from the acute phase of burn injury was associated 285

286

SECTION 7 

Persistent Critical Illness Three clinical trajectories Pro-inflammatory

Early death MOF Chronic critical illness Organ dysfunction SIRS

Anti-inflammatory

Sepsis

Persistent kidney injury

Persistent inflammation

Genomic storm

Immunosuppression

Rapid recovery Immune Homeostasis

Catabolism

Lymphopenia and sPDL-1, nosocomial infections

Muscle wasting and cachexia PICS

Discharge to home

IL-6 and IL-8, MDSC expansion

Discharge to LTAC Profound disabilities 40% indolent death

Time 2 days 14 days 6 mo. 1 yr. Fig. 41.1  ​Proposed hypothesis for persistent inflammation, immunosuppression, and catabolism syndrome (PICS). LTAC, long-term acute care facilities; MDSC, myeloid-derived suppressor cell; SIRS, systemic inflammatory response syndrome; sPDL-1, soluble programmed death ligand-1. (Redrawn from Hawkins RB, Raymond SL, Stortz JA, et al. Chronic critical illness and the persistent inflammation, immunosuppression, and catabolism syndrome. Front Immunol. 2018;9:1511.)

1.0 RAP

Survival probability

0.8 0.6

CCI

0.4 0.2

Early death

0.0 0

50

100 Days

150

Fig. 41.2  ​Six-month sepsis mortality of patients with chronic critical illness (CCI) (n 5 71) and those who experienced rapid recovery (RAP) (n 5 66). (Redrawn from Stortz JA, Mira JC, Raymond SL, et al. Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients. J Trauma Acute Care Surg. 2018;84[2]:342-349.)

with an increased incidence of cognitive disabilities and greater long-term mortality.6 In addition, severe burn patients demonstrated a sustained elevation of serum cytokines that persisted for up to 3 years.7 These patients also experienced systemic and skeletal muscle hypermetabolism that was associated with insulin resistance, oxidative stress, cytosolic protein degradation, and mitochondrial stress—hypothesized to be contributors of muscle catabolism postburn.8 In summary, an increase in survival from these high acuity insults has unmasked a new phenotype—that of PICS. It is believed that these patients enter a cyclic and persistent but chronically manageable syndrome of organ dysfunction.

This new phenotype is associated with a high likelihood of discharge to long-term care facilities, poor functional outcomes, and high post-ICU discharge mortality rates.9

THE SELF-PERPETUATING CYCLE OF PICS Recent data permit the construction of a model that explains the development of CCI. Accumulating data suggest that CCI is a product of three concurrent, interacting cycles being driven by, and also contributing to the perpetuation of both systemic and local end-organ inflammation (Fig. 41.3), muscle wasting, emergency myelopoiesis and organ injury.1 Subsequent to source control and antimicrobial coverage, it is thought that PICS is propagated by sustained release of alarmins and danger-associated molecular pattern (DAMP) molecule signaling from damaged organs. This contributes to a self-perpetuating cycle of “pathophysiologic alterations” driven by chronic low-grade inflammation (elevated serum concentration of interleukin-6), dysfunctional emergency myelopoiesis, catabolism (maladaptive metabolic changes in lipid, carbohydrate, and protein metabolism), compromised host immunity (lymphocyte dysfunction and decreased function of antigen presenting cells), and conti­ nued organ injury.1

INFLAMMATION/IMMUNOSUPPRESSION Biopsy-driven studies in CCI patients with burn injury demonstrate defective mitochondrial biogenesis and myocyte necrosis associated with leukocyte infiltration.10 These findings suggest that persistent inflammation causes mitochondrial and skeletal muscle injury, releasing breakdown products

CHAPTER 41

287

DAMPs

Oxidative phosphorylation

Metabolic reprogamming Emergency myelopoiesis

Organ injury

MDSCs

Aerobic glycolysis

PAMPs

Nosocomial/ opportunistic infections

Immune suppression

Inflammation Fig. 41.3  ​The self-perpetuating cycle of immune dyscrasia, organ injury, dysfunctional metabolic adaptations, and myelodysplasia driving chronic critical illness (CCI). (Redrawn from Hawkins RB, Raymond SL, Stortz JA, et al. Chronic critical illness and the persistent inflammation, immunosuppression, and catabolism syndrome. Front Immunol. 2018;9:1511.)

(alarmins) that exacerbate inflammation and continue the vicious cycle. Alarmins, endogenous molecules that signal cell and tissue damage, are of particular interest in the perpetration of persistent inflammation. Two different types are recognized by the pattern-recognition receptors on immune and parenchymal cells that modulate inflammation: exogenous pathogen-associated molecular patterns (PAMPs) of microbial origin and DAMPs from injured organs and inflammatory cells.11 PAMPs involved in the initiation of sepsis arise from the inciting infection while additional PAMPs that are involved in the pathogenesis of CCI likely arise from nosocomial infections and latent virus reactivation.12 In burn injury, a number of DAMPs are released from skeletal muscle. These include mitochondrial DAMPs (mitoDAMPs) such as mitochondrial DNA (mtDNA), HMGB1, and transcription factor A, mitochondrial (TFAM) that stimulate the release of additional breakdown products that add to ongoing inflammation.1 It is also thought that the kidney and skeletal muscle wasting contribute to the expansion of endogenous DAMPs.1 PAMPs and DAMPs can bind to multiple receptors, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and can complement retinoic acid-inducible gene (RIG)-like receptors and mannose-binding lectin or scavenger receptors.13,14 PAMPs and DAMPs can activate multiple signaling pathways in a variety of cell types.13,14 Current paradigms describing the immune response following high acuity events like severe trauma, sepsis, burns, and pancreatitis postulate that inflammation cooccurs with antiinflammation and immunosuppression (Fig. 41.4).4,9,13,15,16 Immunosuppression in CCI would explain the subclinical reactivation of latent viruses and the high incidence of secondary bacterial infections. During PICS, both myeloid and lymphoid cells are recruited and both pro- and anti-inflammatory

cytokines, reactive oxygen species, and reactive nitrogen species proliferate in conjunction with increased T-cell apoptosis (due in part to the upregulation of PD-L1 and inadequate L-arginine) and tissue wasting.17,18 The host’s immune system develops multiple innate immune deficiencies such as myeloid derived stem cell (MDSC) expansion, increased T-regulatory cells (Tregs) and M2 macrophages, T-cell exhaustion, and decreased dendritic cell function.18 Evidence of a state of immunosuppression includes increased circulating levels of immunosuppressive mediators such as IL-10 and TGF-B, as well as an increased expression of T-cell inhibitory ligands such as PD-L1, and decreased expression of the major histocompatibility complex (e.g., HLA-DR) by monocytes and antigen presenting cells.2,12,16,18

EMERGENCY MYELOPOIESIS Sepsis and other major insults induce an expansion of myeloid lineage cells.19,20 This acute response likely represents an adaptive, evolutionarily-conserved acute response to injury or infection. However, among patients with prolonged critical illness, the response appears to become chronic and detrimental. This “emergency myelopoiesis” occurs at the expense of lymphopoiesis and erythropoiesis, promoting lymphopenia and anemia. Additionally, cytokines and chemokines are released in conjunction with adrenergic stimulation. These mediators promote the release of myeloid populations from bone marrow and secondary lymphoid tissues.1,21,22 Most hematopoietic stem cells (HSCs) are relatively quiescent, participating in routine immune and hematologic homeostasis. In response to stress, HSCs are upregulated as part of the normal physiologic innate immune response and enter the cell cycle to differentiate and become active. This process,

288

SECTION 7 

Persistent Critical Illness miRNA, erythropoietin

Dy sf

e

MDSCs

anti-PDL1, erythropoietin, Flt3L, nicotinamide riboside

PICS

ad

HSCs Co

tin r uo wg in f u s l o n l a m m a ti o

n

Chronic condition • Aging • Cancer • Kidney disease

nal myelo po ctio i un

is es

Acute insult • Burn • Pancreatitis • Sepsis • Trauma

Death

Exercise, propanolol, nutrition, antiinflammatory medication, anabolics

CCI

Fig. 41.4  ​Depiction of Myelodysplasia of persistent inflammation, immunosuppression and catabolism syndrome. CCI, chronic critical illness; HSC, hematopoietic stem cell; MDSC, myeloid derived suppressor cell. (Redrawn from Efron PA, Mohr AM, Bihorac A, et al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164[2]:178-184.)

“emergency myelopoiesis,” repopulates innate immune effector cells after acute insult; however, the preferential differentiation of myeloid cells occurs at the expense of lymphopoiesis and erythropoiesis, placing patients at increased risks of anemia and secondary infections following acute physiologic insult.9 Additionally, emergency myelopoiesis is modulated by various redundant pathways incorporating growth factors, cytokines and mesenchymal cells, and this process blocks the differentiation of immature myeloid cells into mature innate immune effector cells. Consequently, a heterogeneous population of myeloid-derived suppressor cells expands. MDSCs have the capability to affect nearly every cell involved in host innate and adaptive immunity.9 Though the distinct roles of MDSCs are still widely unknown, they are believed to emerge as part of the physiologic response to sepsis and trauma to help decrease inflammation through immunosuppression, without eliminating all protective innate immunity.9,23,24 The persistence of this population of cells has been clinically associated with poor outcomes in sepsis patients.19,25 One of the characteristic functions of MDSCS appears to be the suppression of the function and proliferation of T lymphocytes. MDSCs also secrete antiinflammatory cytokines, IL-10 and TGF-b, which polarize differentiating macrophages into type II macrophages, in turn, upregulating Tregs. Additionally, MDSCs deplete L-arginine via arginase 1 and inducible nitric oxide synthase (iNOS), which consequently antagonizes clonal expansion, impairs intracellular signaling, and induces T-cell apoptosis. MDSCs produce reactive oxygen species, which, in conjunction with the nitric oxide byproducts of iNOS, produce peroxynitrites that nitrosylate cell surface proteins on lymphocytes and decrease T-cell responsiveness and alter IL-2 signaling.9,26 MDSCs have been shown to persistently increase in circulation after clinical sepsis or septic shock in the SICU, and their appearance is a biomarker for

nosocomial infections, prolonged hospital stays, increased mortality, and poor functional status at discharge.19

ORGAN INJURY Additionally, many organs are damaged by critical illness, but the kidney is thought to be particularly vulnerable in CCI.1 A retrospective analysis validated acute kidney injury (AKI; as defined by RIFLE or KDIGO criteria) as a predictor of mortality and adverse outcomes in surgical sepsis, and determined the kidney to be the most frequently injured organ in sepsis.27 The strong associations between sepsis and AKI/chronic kidney disease (CKD) implement the critical importance of the kidney in long-term outcomes and survival following sepsis and critical illness.1 The kidney is host to a number of immune cells (dendritic cells (DC), macrophages, and lymphocytes) and expresses a large number TLRs.28 During CCI, immunosuppressive MDSCs and DAMPs infiltrate the kidney and expose renal dendritic cells and lymph nodes to antigens and pathogens that are continuously processed by the nephrons.29 Importantly, the kidneys filter the entire blood volume more than 30 times per day effectively exposing renal DCs and lymph nodes to these DAMPs and pathogenic antigens more than any other organ.28–30

CATABOLISM IN CCI Skeletal muscle constitutes the largest protein reservoir in the body and, in cancer and other chronic inflammatory diseases, is subject to catabolism with lean muscle wasting.9 This depletion is also evident in CCI. Historically, cachexia in ICU patients has been attributed to a normal macro-endocrine and cytokine driven stress response.10,31 Biopsy-driven studies on CCI have shown the increase in breakdown products, relative to synthesis products, that result in a net catabolic state.32

CHAPTER 41

Despite early administration of enteral nutrition, persistent catabolism and sarcopenia have been observed in critically-ill patients, and cross-sectional area reduction of the rectus femoris muscle was associated with multiple organ failure and inflammation.32 Recent studies have demonstrated that patients who develop CCI following sepsis have decreased levels of albumin and insulin-like growth factor-binding protein 3 and elevated urinary 3-methylhistidine to creatinine ratios, suggestive of a persistent catabolic state.4,26 Long-term, prospective follow-up studies on CCI have demonstrated a correlation between loss of lean muscle mass and functional disabilities, breakdown of myofibrillar protein, decreased protein synthesis, increased mitochondrial dysfunction, and the increased release of potential proinflammatory degradation products.1,32,33 These changes are thought to produce systemic inflammatory responses and release DAMPs and exogenous alarmins during skeletal muscle damage or wasting, as previously described. It is likely that dysfunctions in substrate utilization further complicate the cycle of reciprocal catabolism and inflammation.9 The complexity of this disease will undoubtedly require a multifactorial approach to treatment that includes, but is not limited to supplemented nutrition and physical exercise.

TREATMENT AND THERAPY Considering that PICS is a complex pathophysiological response to a pro-inflammatory insult on the host’s immunity, there is likely no monotherapeutic solution to address all aspects of the persistent inflammation, immunosuppression, and catabolism. However, because the underlying PICS pathophysiology is characteristic of a myelodysplastic disease, immunomodulation therapies should be incorporated to counter the chronic and acute responses to trauma and sepsis.9 Propranolol and oxandrolone have been show to benefit pediatric burn patients; however, more studies are needed to study the effects with adult CCI patients.

AUTHORS’ RECOMMENDATIONS • A growing number of ICU patients are plagued by chronic critical illness • CCI is thought to be initiated by alarmin-triggered genomic storm, persistent organ dysfunction, and skeletal muscle wasting • Pro-inflammatory expansion of myeloid derived suppressor cells occurs in conjunction with immunosuppression • Adequate nutrition and physical rehabilitation are insufficient to treat persistent catabolism and muscle wasting because substrate utilization is likely involved in this catabolic state • Future immunopathology research may be directed toward inflammation, immune stimulation, epigenetic modifications, and stem cell administration.34 • Propranolol and oxandrolone have been shown to benefit pediatric burn patients; however, more studies are needed to study the effects with adult CCI patients.

289

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18. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J Med. 2014;371(4):380-383. 19. 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. Ann Surg. 2017;265(4):827-834. 20. Guirgis FW, Brakenridge S, Sutchu S, et al. The long-term burden of severe sepsis and septic shock. J Trauma Acute Care Surg. 2016;81(3):525-532. 21. Cosentino M, Marino F, Maestroni GJ. Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives. Front Cell Neurosci. 2015;9:302. 22. Hasan S, Mosier MJ, Szilagyi A, Gamelli RL, Muthumalaiappan K. Discrete b-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia. Surgery. 2017;162(4):901-916. 23. Cuenca AG, Delano MJ, Kelly-Scumpia KM, et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011;17:281-292. 24. Goldszmid RS, Dzutsev A, Trinchieri G. Host immune response to infection and cancer: unexpected commonalities. Cell Host Microbe. 2014;15(3):295-305. 25. Uhel F, Azzaoui I, Grégoire M, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in patients with sepsis. Am J Respir Crit Care Med. 2017; 196(3):315-327.

26. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysio­­ logy, chronic critical illness, and persistent inflammationimmunosuppression and catabolism syndrome. Crit Care Med. 2017;45(2):253-262. 27. White LE, Hassoun HT, Bihorac A, et al. Acute kidney injury is surprisingly common and a powerful predictor of mortality in surgical sepsis. J Trauma Acute Care Surg. 2013;75(3): 432-438. 28. Kurts C, Panzer U, Anders H-J, Rees AJ. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol. 2013;13(10):738-753. 29. Tryggvason K, Wartiovaara J. How does the kidney filter plasma? Physiology. 2005;20(2):96-101. 30. Mulay SR, Kulkarni OP, Rupanagudi KV, et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1b secretion. J Clin Invest. 2012;123(1):236-246. 31. Yoshida T, Delafontaine P. Mechanisms of cachexia in chronic disease states. Am J Med Sci. 2015;350(4):250-256. 32. Puthucheary Z, Harridge S, Hart N. Skeletal muscle dysfunction in critical care: Wasting, weakness, and rehabilitation strategies. Crit Care Med. 2010;38(10 Suppl):S676-S682. 33. Batt J, Santos CCD, Cameron JI, Herridge MS. Intensive care unit–acquired weakness. Am J Respir Crit Care Med. 2013;187(3):238-246. 34. van der Poll T, van de Veerdonk FL. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407-420.

e1 Abstract: A dysfunctional innate immune response to injury or infection often leads to sepsis, multiple organ failure, and fulminant death. As treatment of the critically ill patient has improved significantly over the past two decades, many high acuity patients in intensive care units (ICU) survive in a state of chronic critical illness (CCI)—characterized by high resource utilization, prolonged ICU stay, incapacitating functional outcomes, and dismal long-term survival. These patients are described by many different terms, including but not limited to, “Post-Sepsis Syndrome” and “Post Intensive Care Unit Syndrome.” However, these terms describe a clinical phenotype and do not necessarily describe or lend insight into

the pathophysiology of these patients. The Persistent Inflammation, Immunosuppression, and Catabolism Syndrome, which will be delineated as PICS in this chapter, has been hypothesized as an important driver of CCI patient outcomes. The self-perpetuating and persistent cycle of inflammation is induced by the release of endogenous alarmins and dangerassociated molecular patterns (DAMPs). As the incidence of CCI cases continues to escalate, a better understanding of the mechanisms driving PICS and propagating CCI is necessary. Keywords: catabolism, chronic critical illness, emergency myelopoiesis, immunosuppression, inflammation, organ injury