Edited by: Alexandre Corthay, Oslo University Hospital, Norway
Reviewed by: Akiyoshi Takami, Aichi Medical University, Japan; Andrzej Gorski, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy (PAN), Poland; Charles E. McCall, Wake Forest Baptist Medical Center, United States
Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology
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Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI), defined as ≥14 days requiring intensive care unit (ICU) resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients.
The phenotype of the critically ill patient is evolving. While historically a significant number of these patients would have succumbed to early death, recent diagnostic and therapeutic advances allow many of these patients to survive the acute phase of their disease (
Severe injury or infection leading to CCI and PICS begins with the recognition of alarmins, primarily consisting of microbial products and damaged tissue (
Pattern-recognition receptor pathways for damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). AGEs, advanced glycosylation end products; HMGB, high-mobility group box; ATP, adenosine triphosphate; RNA, ribonucleic acid; DNA, deoxyribonucleic acid; LPS, lipopolysaccharide; RAGE, receptor for advanced glycation end products; NLR, nucleotide-binding oligomerization domain-like receptors; TLR, toll-like receptors; CLR, C-type lectin receptors; RLR, retinoic-acid-inducible gene-I-like receptors; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; TNF, tumor necrosis factor.
Toll-like receptors (TLRs) are the most broadly studied PRRs. To date, 13 different TLRs have been identified in humans and mice, with slight differences in receptor type and function between species. TLR1–TLR9 are functional in both species, but TLR10–13 is not conserved between species. While some TLRs are expressed on the plasma membrane (TLRs 1, 2, 4, 5, and 6) to constantly sample the local environment, others are located within endosomal compartments (TLRs 3, 7, 8, 9, 11, 12, and 13) to sense host danger signals or microbial proteins and nucleic acids (
Pathogen recognition also occurs through C-type lectin receptors (CLRs). CLRs are carbohydrate-binding transmembrane proteins expressed by antigen-presenting cells (APCs). CLRs are able to recognize glycolipids and glycoproteins present on numerous pathogens including bacteria, parasites, fungi, and viruses, as well as on host cells (
Nucleotide-binding oligomerization domain-like receptors are a family of more than 20 cytoplasmic receptors. NOD1 and NOD2 were the first identified NLRs capable of recognizing bacterial peptidoglycan moieties and triggering inflammation by activating nuclear factor (NF)-kB and mitogen-activated protein kinase pathways. Recent studies have demonstrated that NOD2 is also capable of sensing viral ribonucleic acid (RNA) (
Retinoic acid-inducible gene-I-like receptors are cytoplasmic receptors that comprise RIG-I, melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). RIG-I and MDA5 recognize viral double-stranded (ds) RNA and activate the innate immune response (
Finally, RAGE is a transmembrane receptor expressed on human endothelial cells, monocytes, and lymphocytes. RAGE binds to several ligands including advanced glycation end products (AGEs) from aging erythrocytes as well as HMGB1 and S100 proteins. Interactions between AGEs and RAGE on endothelial cells induce oxidative stress and mitochondrial dysfunction leading to tissue injury (
Upon host recognition of PAMPs or DAMPs, PRRs initiate a complex set of downstream signaling events that induce a host-protective response. This includes recruitment and phosphorylation of intracellular intermediates leading in part to the activation of immediate response genes. PRR-signaling pathways are wide ranging and often redundant. For example, the TLR signal transduction employs a Toll/IL-1 receptor domain, which has five adaptor proteins: myeloid differentiation primary response 88 (MyD88), Toll-IL-1 receptor domain containing adaptor protein (TIRAP), Toll-IL-1 receptor domain containing adaptor protein inducing interferon (IFN) β (TRIF), TRIF-related adaptor molecule (TRAM), and sterile-α and armadillo motif containing protein (SARM) (
Pattern-recognition receptors activation and downstream signaling result in both nonspecific and pathogen-specific host cellular responses to prevent or eliminate host stressors, such as microbial infection or tissue damage (
The main immunological functions and products of innate immune cells.
The innate immune system also incorporates cells and systems beyond effector white blood cells. In a further attempt to control local infections or tissue damage, an endothelial cell-target hypercoagulable state occurs with the presumed intent of reducing blood loss and trapping microbial pathogens (
The complement system is a major component of the innate immune system that has the ability to discriminate self from non-self (or damaged/altered self) and eliminate pathogens that might harm the host. The complement system is a complex network of more than 50 proteins in the plasma and on cell surfaces arranged in a system of proteolytic cascades (
Anaphylatoxins (C3a, C4a, and C5a) are the activation products of the effector phase of the complement system. Anaphylatoxins are traditionally reported to have diverse pro-inflammatory effects. This includes smooth muscle contraction, an increased leukocyte chemotaxis, vasodilation, an increased vascular permeability, an improved neutrophil oxidative burst, an enhanced phagocytosis, and an increased release of inflammatory mediators like histamine (
Complement-mediated opsonization plays a major role in phagocyte pathogen recognition. Complement component C3 is cleaved into C3a and C3b by enzymes in all three pathways of complement activation. This cascade results in a conformational change of C3b that allows the covalent association of C3b with the pathogen surface and subsequent cleavage by factor I and its co-factor. Moreover, this conformational rearrangement exposes numerous binding sites for receptors. There are complement C3 receptors including CR1–4 and CRIg that recognize C3b and its fragments. These receptors trigger phagocytosis, promote erythrocyte transportation and clearance, and enhance B cell immunity and regulate T-cell proliferation (
The MAC is the pore-forming terminal assembly of the complement system (C5b–C9), which leads to cell lysis on the surface of bacteria and other targets. The MAC has diverse roles, including the modulation of cell proliferation and the activation of the inflammatory response. A recent study reported that the MAC on a Rab5+ endosome could activate noncanonical pathways for NF-κB activation through intracellular signaling and promote the inflammatory response (
Although the early host response is recognized immediately at the site of infection or tissue injury by resident innate cell populations, the recruitment of additional innate immune cells is almost immediate. Large numbers of mature myeloid cells are released from the BM and are recruited to the site of infection or injury (
Interestingly, developing MPPs do not differentiate equally along myeloid, lymphoid, and erythroid populations. Rather, the cytokine milieu present during infection or tissue damage drives myelopoiesis at the expense of both erythropoiesis and lymphopoiesis (
Severe anemia among critically ill patients is often managed with allogeneic red blood cell transfusion. This can lead to transfusion-related immunomodulation and increased susceptibility to nosocomial infection in a population already with dysfunctional innate and adaptive immune systems (
Many of the myeloid cells in the BM never reach a fully differentiated state. They are released in large numbers as immature myeloid cells. Although they are phenotypically differentiated to granulocyte-like and monocyte-like cells, their cellular function is dissimilar to that of terminally differentiated innate immune effector cells (
The functions of these immature myeloid cells and their role in the sepsis and trauma response are poorly understood (
MDSCs have a strong phagocytic activity, but are poor antigen presenters, and produce increased amounts of pro-ILCs (e.g., TNF-α and MIP-1α/CCL3), superoxides, and nitric oxide (
Among critically ill septic patients, the proportion of circulating MDSCs correlates with the magnitude of the inflammatory response and predicts hospital trajectory and long-term clinical outcomes (
Phagocytosis is a central process in innate immunity that eliminates pathogenic microbial agents and facilitates the presentation of antigens to adaptive immune cells (
To initiate the process of phagocytosis, a direct physical contact between the phagocyte and the target must occur. Residual phagocytes extend membrane protrusions to detect and capture the target (
Phagocytes also play an important role in antigen presentation, and as mentioned previously, DCs are especially relevant to this process (
Regarding toxin and pathogen clearance, the liver is one of the most important organs of host defense. In particular, Kupffer cells (KCs) play a major role in immune surveillance, including pathogen identification as well as antigen presentation (
Apoptosis is a non-lytic and usually immunologically silent form of cell death characterized by cell shrinking, chromatin condensation, and membrane blebbing (
In contrast to apoptosis, necroptosis is a lytic cell death and thought to result in the release of DAMPs, which leads to immune system activation and extensive inflammation like pyroptosis (
Pyroptosis is a lytic form of programmed cell death, which is activated by both the canonical and noncanonical inflammasome. Pyroptosis can be initiated in response to the recognition of PAMPs and DAMPs through PRRs such as NLRs and AIM2 in cytosol. These PRRs form inflammasomes and activate inflammatory caspases that induce pro-ILCs (e.g., IL-1β and IL-18) and pyroptosis. Pyroptosis enhances the inflammatory response through the release of pro-ILCs and improved microbe capture in the phagocyte (
Pyroptosis has features that are distinct from necrosis and apoptosis and have important implications for the innate immune response to trauma and sepsis. Apoptosis describes a highly regulated cell death pathway involving multiple caspases in the relative absence of inflammation, whereas necrosis involves the disintegrations of cell membranes with spillage of DAMPs, cell contents, and cell membrane components into the interstitial space, promoting the inflammatory response (
Host immune responses to pathogens depend on the magnitude of the physiologic insult. Highly virulent pathogens and host immune impairment may potentiate the host’s vulnerability to sepsis. Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection (
Although the activation of the coagulation cascade is protective in reducing the dissemination of invading pathogens through fibrin deposition (
The complement system is activated during sepsis, resulting in increased levels of C3a, C4a, and C5a in plasma (
PMNs exist in three states: resting, primed and activated. PMNs shift from a resting state in the circulation to an activated state at the site of infection
As mentioned above, MDSCs are a heterogeneous population of immature myeloid cells with the common ability to induce immunosuppression. MDSCs are found in healthy individuals at a low amount in peripheral blood (
Myeloid-derived suppressor cell expansion is thought to be primarily mediated by the Janus kinase protein family leading to the activation of transcription 3 (STAT3). Activation is a second step dependent primarily on NF-κB activation through the MyD88 pathway. Several inflammatory mediators, such as IL-6, G-CSF, GM-CSF, and VEGF, are involved in the latter pathway (
Unlike the well-defined role of MDSCs in cancer, the role of MDSCs in sepsis is still controversial. MDSC expansion and immunosuppressive functions are observed in both septic mice and humans (
After sepsis, human MDSC expansion may persist 28 days after the onset of sepsis (
In previous eras, a substantial proportion of patients who survived severe traumatic injury or septic insults were vulnerable to a non-acute death due to multiple organ failure. In modern ICUs, these patients often do not develop multiple organ failure and instead are subjected to the chronic smoldering organ failure of CCI. As previously discussed, DAMPs and PAMPs bind multiple PRRs, including TLRs, CLRs, NLRs, RLRs, and RAGE, with multiple redundant and converging pathways promoting a robust inflammatory response and emergency myelopoiesis, including the expansion and persistence of MDSCs (
Post-sepsis and severe injury patients, particularly CCI patients, often fail to achieve immune homeostasis. Rather than resolving the acute inflammation that accompanies these huge insults, these patients develop chronic low-grade inflammation. In addition to ongoing inflammation, these patients experience immune suppression and lean muscle wasting of prolonged duration. Collectively, this constellation of features has been coined PICS, or the persistent inflammation immunosuppression and catabolism syndrome (
A similar term that has been described is a series of conditions seen in survivors of ICU hospitalization, “post-intensive care syndrome” (
Recent work shows that patients who develop CCI after sepsis (i.e., patients with ICU LOSs of ≥14 days and ongoing organ dysfunction) exhibit persistent elevations in markers of inflammation out to 28 days after sepsis onset, including IL-6 and IL-8 (
Although these cytokines and protein biomarkers serve as signatures for PICS, the detailed mechanisms leading to this persistent inflammation, immune suppression, and catabolism have yet to be elucidated. The discovery of the underlying mechanisms will undoubtedly require further studies, including additional genomic and proteomic analyses, as well as the creation of murine models of PICS, which are currently underway (
The number of aged individuals around the world is dramatically rising (
Severe infection and severe injury illustrate the contribution of aging to poor outcomes. For example, sepsis is primarily a disease of the elderly. While the frequency of hospitalizations with sepsis for patients aged 18–49 years has barely changed from 2000 to 2007, the frequency of hospitalization with sepsis for patients aged 50–64 years has increased and has risen dramatically for patients aged 65 years or greater (
When regarding the poor outcomes of elderly patients after critical illness, one must consider the prevalence of chronic disease in the elderly and how modern medicine allows individuals with severe chronic diseases to survive into old age (
Immunosenescence in hematopoietic stem cells (HSCs), innate, and adaptive immune cells.
Inflammaging, defined as a low-grade chronic systemic inflammation established during physiological aging, contributes to all the above conditions seen in the elderly (
In murine models, both trauma and sepsis induce a rapid release of mature and immature myeloid cell populations from the BM in response to endogenous and exogenous danger signals (
Many analogies can be made among cancer, aging, and PICS patients. This includes the host innate immune system in each of these conditions. If one asks, “what induces a state of persistent inflammation, immunosuppression and catabolism, as well as being associated with frailty and poor outcomes?” the answer could be cancer, aging, or critical illness. Thus, it is not surprising that all three are related. Both the elderly and cancer patients are more likely to become septic and develop critical illness with poor outcomes (
It is not surprising that cancer patients have an immune environment similar to that of the aged and the CCI population and that this immune status is thought to engender poor outcomes. Cancer patients have persistent antigen exposure and protracted inflammation which eventually lead to pathological effects on host-protective immunity as well as tissue wasting and cellular apoptosis (
Similarities and redundancies in the pathophysiology of patients with sepsis, cancer, and advanced age.
Regulation of the hematopoietic response to stress is an integral part of innate immunity (
Sepsis is associated with alterations in immune effector cells including defects in antigen presentation, quantitative and qualitative alternation in neutrophils, defective NK cell-mediated immunity, defective T and B cell-mediated immunity, relative increases in regulatory T cells (Tregs), an increased expression of PD-1/PD-L1, decreased immunoglobulin levels, hypercytokinemia, and complement consumption. Immune-modulatory therapies for sepsis are now being investigated, with a focus on the restoration of immune system homeostasis. Agents under consideration include leukocyte growth factors (e.g., granulocyte macrophage colony-stimulating factor and G-CSF) (
The loss of lean body mass is one of the clinical characteristics of CCI patients. A prolonged low-grade inflammation in muscle may lead to catabolism and myonecrosis that result in the loss of lean body mass (
Candidate therapies for nutritional therapy in CCI include arginine, leucine, and anabolic adjuncts. The use of arginine in sepsis is controversial because arginine serves as an intracellular substrate for nitric oxide, which may cause pathologic vasodilation. However, the upregulation of arginase-1 in MDSCs has been observed following trauma and sepsis (
Finally, there has been an increasing interest in the functional status and health-related QOL in CCI patients. Early ICU-based exercise and rehabilitation programs have been associated with a reduction in the duration of mechanical ventilation and ICU LOS, as well as improved physical function (
Since the 1980s, it has been hypothesized that dysregulated crosstalk among the epithelium, immune system, and gut microbiota leads to the development of sepsis and multiple organ failure. In the last decade, a number of studies have produced valuable insights into the pathophysiologic mechanisms responsible for these phenomena (
In sepsis, several changes occur in gut physiology and immunity, including loss of gut motility, increased bowel wall permeability, and apoptosis of intestinal epithelium due to extrinsic factors (e.g., antibiotics, opiates, and parental and enteral nutrition) and intrinsic factors (e.g., inflammation and increased bowel wall permeability). These changes may result in the alternation of the microbiota composition (
However, high-level evidence and recommendations regarding therapeutic modulation of gut microbiota for septic patients are lacking. Several candidate therapies are under investigation, including pro/pre/synbiotics (
The use of big data in medicine has been rapidly evolving. This approach has the potential to provide researchers and clinicians with the information necessary to practice precision medicine tailored to individual patients. For this purpose, there are many databases such as The Human Genome Project (available from:
Big data is particularly useful in the translational research approach to sepsis due to the heterogeneity of sepsis populations, the limited utility of individual biomarkers, and the wide variability in the duration and severity of illness prior to presentation. For the same reasons, genomic, metabolomic, and transcriptomic markers may be of great value in generating prognostic models and identifying optimal candidates for tailored therapies (
Following remarkable advances in our understanding of the pathophysiology and natural history of trauma and sepsis, two major targets for improving outcomes remain: early death and indolent death attributable to CCI and PICS. A better understanding of the pathophysiologic mechanisms responsible for CCI and PICS may allow for the identification of novel management strategies and therapeutic targets. Future research should continue to investigate anti-inflammatory agents, immune modulators, gut microbiota support, as well as nutritional and exercise therapy. These should all be guided by validated prognostic models, hopefully taking advantage of novel “big data” datasets, to identify patients for whom these approaches will yield the greatest benefits. Retrospective “community” big data can also be used to identify appropriate biomarkers, surrogate outcomes, and putative research approaches. Randomized clinical trials, using biomarker-driven adaptive study design, are also more rapidly moving potential therapeutics into the clinical setting.
HH, TL, RH, SR, JS, and PE drafted the manuscript. MH, BW, EM, AB, SL, AM, SB, HT, HU, FM, LM, and PE provided critical revisions. All authors made substantial contributions to the conception and design of the work, approved the submitted version of the manuscript, and agree to be accountable for all aspects of the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank all clinicians and support staff of the Sepsis and Critical Illness Research Center at UF Shands Health engaged in ongoing sepsis and inflammation research.