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Erythropoietic dysfunction after trauma and critical illness is associated with anemia, persistent inflammation, increased hematopoietic progenitor cell mobilization from the bone marrow, and reduced erythroid progenitor growth. Yet the duration and reversibility of these postinjury bone marrow changes remain unknown. This study sought to determine whether removal of chronic postinjury stress could induce improvements in erythroid progenitor growth.Sprague-Dawley rats (n = 8-11/group) were assigned to the following: naïve, lung contusion and hemorrhagic shock, lung contusion and hemorrhagic shock plus daily chronic stress for 7 days followed by 7 days of routine handling to allow recovery (lung contusion and hemorrhagic shock + chronic stress 7), or lung contusion and hemorrhagic shock plus chronic stress for 14 days (lung contusion and hemorrhagic shock + chronic stress 14). Circulating CD117Compared to lung contusion and hemorrhagic shock + chronic stress 14, lung contusion and hemorrhagic shock + chronic stress 7 rodents had improved hemoglobin (8% ± 10% increase vs 6% ± 10% decrease) with fewer mobilized erythroid progenitors (898 × vs 1,524 cells), lower granulocyte-colony stimulating factor levels (3.1 ± 1.1 × pg/mL vs 5.9 ± 1.8 pg/mL), and improved erythroid progenitor growth. Cessation of stress had no impact on erythroid transcription factors GATA-1, GATA-2, LMO2, or KLF1.Improvements in erythroid progenitor growth and reduced hematopoietic progenitor cell mobilization were seen 7 days after cessation of chronic stress and were associated with an improvement in hemoglobin. Early bone marrow erythropoietic functional recovery may result from resolution of hematopoietic progenitor mobilization rather than upregulation of pro-erythroid transcription factors. This study suggests that postinjury anemia is reversible and has the potential to improve with the cessation of stress.

Background: To determine whether degree of anemia at sepsis onset is predictive of inflammatory cytokine trajectory, erythropoietin response, and recovery. Patients and Methods: Critically ill patients with sepsis were stratified into three groups based on initial hemoglobin (Hgb): Hgb 10 g/dL (mild). Granulocyte colony stimulating factor (G-CSF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), erythropoietin (EPO), and Zubrod scores were measured serially. Results: Thirty-four percent had severe anemia (Hgb, 7.2 ± 0.7g/dL), 35% had moderate anemia (Hgb, 9.1 ± 0.6g/dL), and 31% had mild anemia (Hgb, 11.3 ± 1.1g/dL). All groups experienced persistently high EPO levels without resolution of anemia. IFN-γ and CRP was persistently elevated in all groups. At three, six, and 12 months, the severe anemia group had higher Zubrod scores. Conclusions: Degree of anemia at sepsis onset was not associated with a difference in proinflammatory cytokine trajectory but was associated with a worse functional outcome. Despite initial elevated EPO levels, it did not correlate with resolution of anemia.

Sepsis is currently defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The skeletal muscle system is among the host organ systems compromised by sepsis. The resulting neuromuscular dysfunction and impaired regenerative capacity defines sepsis-induced myopathy and manifests as atrophy, loss of strength, and hindered regeneration after injury. These outcomes delay recovery from critical illness and confer increased vulnerability to morbidity and mortality. The mechanisms underlying sepsis-induced myopathy, including the potential contribution of peripheral organs, remain largely unexplored. The gut microbiome is an immunological and homeostatic entity that interacts with and controls end-organ function, including the skeletal muscle system. Sepsis induces alterations in the gut microbiota composition, which is globally termed a state of "dysbiosis" for the host compared to baseline microbiota composition. In this review, we critically evaluate existing evidence and potential mechanisms linking sepsis-induced myopathy with gut microbiota dysbiosis.

Background Proinflammatory and immunomodulatory adipokines are linked to inflammation in critically ill patients but are poorly studied after injury. We hypothesized that trauma would induce systemic adipokine release and influence erythroid suppression. Methods Blood and bone marrow (BM) were collected from trauma patients (ISS > 15, n = 90) and compared to patients undergoing elective hip replacement (n = 37). Plasma adipokine levels were measured, and BM was assayed for adipokine transcription and erythroid progenitor growth potential. Differences were detected using t-tests and correlations using simple linear regression. Results Trauma patients exhibited decreased adiponectin (1.8* vs 3.4 mg/mL) and increased leptin (7.8* vs 4.6 ng/mL) and resistin (3.1* vs 2.5 ng/mL), with sex- and age-specific differences. They also showed increased BM visfatin transcription. Adipokine transcription negatively correlated with erythroid progenitor growth. Conclusion Adipose tissue activity is linked to inflammatory responses after injury, with variability by age and sex. Bone marrow adipose tissue may influence erythroid recovery after trauma.

The management of patients with symptomatic rectal masses can be challenging and is further complicated in cases of advanced age, comorbidities, prior surgeries, and acute hemorrhage. In this report, we describe a patient who presented with massive hemorrhage from a 7 cm low rectal tumor with subsequent cardiac arrest. After return of spontaneous circulation, emergent pelvic angiography identified extensive tumor enhancement and blush off the anterior division of the right internal iliac artery from multiple parasitized vessels. The right internal iliac artery was embolized with multiple microcoils to decrease the tumor blood supply and slow the rate of bleeding. The patient was then taken directly from the angiography suite to radiation oncology for planning CT, and within several hours, underwent his first session of radiation. In conjunction with angioembolization, short-course radiation therapy can be an effective treatment modality for advanced bleeding rectal tumors not amenable to surgical resection.

Background The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics. Methods Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects. Results Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization. Conclusion This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.

Background Severe trauma is associated with severe systemic inflammation and neuroendocrine activation that is associated with erythroid progenitor growth suppression and refractory anemia. Although distinct transcriptional profiles have been detected in numerous tissue types after trauma, no study has yet characterized this within the bone marrow. This study sought to identify a unique bone marrow transcriptomic response following trauma. Methods In a prospective observational cohort study, bone marrow was obtained from severely injured trauma patients with a hip or femur fracture (n = 52), elective hip replacement patients (n = 33) and healthy controls (n = 11). RNA was isolated from bone marrow using a Purelink RNA mini kit. Direct quantification of mRNA copies was performed by NanoString Technologies on a custom gene panel. Results Trauma patients displayed an upregulation of genes encoding receptors known to have inhibitory downstream effects on erythropoiesis, including ferroportin, interleukin-6 (IL-6) receptor, transforming growth factor-beta (TGF-β) receptor, and IL-10, as well as genes involved in innate immunity including toll-like receptor 4 (TLR4)-mediated signaling factors. In contrast, hip replacement patients had downregulated transcription of IL-1β, IL-6, TGF-β, tumor necrosis factor alpha (TNFα), and the HAMP gene with no change in TLR4-mediated signaling factors. Conclusions A unique transcriptomic response within the bone marrow was identified following severe trauma compared to elective hip replacement. These transcriptomic differences were related to the innate immune response as well as known inhibitors of erythropoiesis. Although confined to just one time point, this differential transcriptional response may be linked to refractory anemia and inflammation after injury.

Objective To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. Background Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. Methods PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. Results CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). Conclusions Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.

BackgroundWith the successful implementation of the Surviving Sepsis Campaign guidelines, post-sepsis in-hospital mortality to sepsis continues to decrease. Those who acutely survive surgical sepsis will either rapidly recover or develop a chronic critical illness (CCI). CCI is associated with adverse long-term outcomes and 1-year mortality. Although the pathobiology of CCI remains undefined, emerging evidence suggests a post-sepsis state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, as well as downstream leukocyte dysfunction. Our goal was to use single-cell RNA sequencing (scRNA-seq) to perform a detailed transcriptomic analysis of lymphoid-derived leukocytes to better understand the pathology of late sepsis.MethodsA mixture of whole blood myeloid-enriched and Ficoll-enriched peripheral blood mononuclear cells from four late septic patients (post-sepsis day 14-21) and five healthy subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq).ResultsWe identified unique transcriptomic patterns for multiple circulating immune cell subtypes, including B- and CD4+, CD8+, activated CD4+ and activated CD8+ T-lymphocytes, as well as natural killer (NK), NKT, and plasmacytoid dendritic cells in late sepsis patients. Analysis demonstrated that the circulating lymphoid cells maintained a transcriptome reflecting immunosuppression and low-grade inflammation. We also identified transcriptomic differences between patients with bacterial versus fungal sepsis, such as greater expression of cytotoxic genes among CD8+ T-lymphocytes in late bacterial sepsis.ConclusionCirculating non-myeloid cells display a unique transcriptomic pattern late after sepsis. Non-myeloid leukocytes in particular reveal a host endotype of inflammation, immunosuppression, and dysfunction, suggesting a role for precision medicine-guided immunomodulatory therapy.

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p &lt, 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

BACKGROUND After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC microRNA (miR) responses of old and young mice in a clinically relevant model of severe trauma and shock. METHODS C57BL/6 adult male mice aged 8 to 12 weeks (young) and 18 to 24 months (old) underwent multiple injuries and hemorrhagic shock (polytrauma [PT]) that engenders the equivalent of major trauma (Injury Severity Score, >15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. MicroRNA expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT-PNA mice at 24 and 48 hours postinjury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts. RESULTS MicroRNA expression significantly differed among all experimental conditions (p < 0.05), except for old-naive versus old-injured (PT or PT-PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs. 2.2%, p = 0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT-PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis. CONCLUSION The miR expression pattern in BM HSPCs after PT (+/-PNA) is dissimilar in old versus young adult mice. In the acute postinjury phase, old adult mice are unable to mount a robust miR HSPC response. Hematopoietic stem and progenitor cell miR expression in old PT mice reflects a diminished functional status and a blunted capacity for terminal differentiation of myeloid cells.

Implementation of protocolized surveillance, diagnosis, and management of septic patients, and of surgical sepsis patients in particular, is shown to result in significantly increased numbers of patients surviving their initial hospitalization. Currently, most surgical sepsis patients will rapidly recover from sepsis; however, many patients will not rapidly recover, but instead will go on to develop chronic critical illness (CCI) and experience dismal long-term outcomes. The elderly and comorbid patient is highly susceptible to death or CCI after sepsis. Here, we review aspects of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) endotype to explain the underlying pathobiology of a dysregulated immune system in sepsis survivors who develop CCI; then, we explore targets for immunomodulatory therapy.

Hematopoietic stem/progenitor cells (HSPC) have both unique and common responses following hemorrhage, injury, and sepsis. HSPCs from different lineages have a distinctive response to these "stress" signals. Inflammation, via the production of inflammatory factors, including cytokines, hormones, and interferons, has been demonstrated to impact the differentiation and function of HSPCs. In response to injury, hemorrhagic shock, and sepsis, cellular phenotypic changes and altered function occur, demonstrating the rapid response and potential adaptability of bone marrow hematopoietic cells. In this review, we summarize the pathophysiology of emergency myelopoiesis and the role of myeloid-derived suppressor cells, impaired erythropoiesis, as well as the mobilization of HSPCs from the bone marrow. Finally, we discuss potential therapeutic options to optimize HSPC function after severe trauma or infection.

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.