Abdominal sepsis patients have a high incidence of chronic critical illness with dismal long-term outcomes

Cox, Michael C.; Brakenridge, Scott C.; Stortz, Julie A.; Hawkins, Russell B.; Darden, Dijoa B.; Ghita, Gabriela; Mohr, Alicia M.; Moldawer, Lyle L.; Efron, Philip A.; Moore, Frederick A.

doi:10.1016/j.amjsurg.2020.07.016

Cited by 18 publications

(32 citation statements)

References 33 publications

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“…Finally, we should consider that not all sepsis is the same-that is, community-versus hospital-acquired, medical versus surgical sepsis or pneumonia versus abdominal sepsis. 45,46 We compared an animal model of surgical sepsis to both human surgical sepsis and community-acquired sepsis in our work. Further studies to compare the genomic response of different murine models of sepsis to specific corresponding types of human sepsis are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…[40][41][42][43][44] Importantly, our collective data illustrate the importance of further evaluating preclinical models of sepsis and emphasizes that with modifications more relevant rodent models can be engendered to achieve better and more appropriate comparisons (as all sepsis is not equivalent). 45,46 There are many possible explanations as to why there have been no interventional therapies, proven successful in murine models of sepsis, translated in clinical trials. First, biomedical research has traditionally used young male mice despite human sepsis population being predominantly older adults with a significant proportion being female.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

et al. 2020

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Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress 2 | EFRON Et al. How to cite this article: Efron PA, Darden DB, Wang Z, et al. Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

et al. 2020

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“…CCI was defined as an ICU length of stay greater than or equal to 14 days with evidence of persistent organ dysfunction, measured using components of the Sequential Organ Failure Assessment (SOFA) score (i.e. cardiovascular SOFA ≥ 1, or score in any other organ system ≥ 2) (3,5,12,17). Patients with an ICU length of stay less than 14 days would also qualify for CCI if they were discharged to another hospital, a long-term acute care facility, or to hospice and demonstrated continuing evidence of organ dysfunction at the time of discharge.…”

Section: Study Design Patient Enrollment and Classificationmentioning

confidence: 99%

A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis

et al. 2021

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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.

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“…CCI is defined in several ways, but an accepted definition in the literature is an individual with a prolonged intensive care unit stay (>14 days) and persistent organ dysfunction ranging from low-grade organ insufficiency to chronic organ failure [ 8 , 9 ]. Patients who develop CCI are more likely to be older males with a greater number of medical comorbidities [ 10 , 11 ]. Importantly, patients who develop CCI continue to consume vast resources long after hospital discharge [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, patients who develop CCI continue to consume vast resources long after hospital discharge [ 12 ]. Additionally, CCI patients have an increased number of secondary infections [ 13 , 14 ] and have poor long-term outcomes that include functional and neurocognitive impairments, increased muscle wasting, and higher 30-day and 1-year mortality [ 5 , 9 , 10 , 15 ]. However, the underlying pathobiology of CCI remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated Immunity and Immunotherapy after Sepsis

Darden

Kelly

Fenner

et al. 2021

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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.

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Abdominal sepsis patients have a high incidence of chronic critical illness with dismal long-term outcomes

Cited by 18 publications

References 33 publications

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis

Dysregulated Immunity and Immunotherapy after Sepsis

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