Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.
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ABSTRACT:
SUBMITTER: Darden DB
PROVIDER: S-EPMC8348105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There are sparse clinical data addressing the persistence of disordered coagulation in sepsis and its role in chronic critical illness. Coagulopathy in the absence of anticoagulant therapy and/or liver disease can be highly variable in sepsis, but it tends to be prolonged in patients in the intensive care unit with a length of stay greater than 14 days. These coagulation abnormalities tend to precede multisystem organ failure and persistence of these coagulation derangements can predict 28-day mortality. The studies evaluated in this review consistently link sepsis-associated coagulopathy to poor long-term outcomes and indicate that disordered coagulation is associated with unfavorable outcomes in chronic critical illness. However, the causative mechanism and the definitive link remain unclear. Longer follow-up and more granular data will be required to fully understand coagulopathy in the context of chronic critical illness.
| S-EPMC7570228 | biostudies-literature
Project description:BackgroundBiomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis.MethodsIn this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis.ResultsBio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better.ConclusionsAdmission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.
| S-EPMC7641835 | biostudies-literature
Project description:BackgroundAlthough early survival from sepsis has improved with timely resuscitation and source control, survivors frequently experience persistent inflammation and develop chronic critical illness. We examined whether increased copy number of endogenous alarmins, mitochondrial DNA, and nuclear DNA are associated with the early "genomic storm" in blood leukocytes and the development of chronic critical illness in hospitalized patients with surgical sepsis.MethodsA prospective, observational, cohort study of critically ill septic patients was performed at a United States tertiary health care center. Blood samples were obtained at multiple time points after the onset of sepsis. Droplet Digital polymerase chain reaction (Bio-Rad Laboratories, Hercules, CA) was performed to quantify RHO (nuclear DNA) and MT-CO2 (mitochondrial DNA) copies in plasma. Leukocyte transcriptomic expression of 63 genes was also measured in whole blood.ResultsWe enrolled 112 patients with surgical sepsis. Two experienced early death, 69 recovered rapidly, and 41 developed chronic critical illness. Both mitochondrial DNA and nuclear DNA copy number were increased in all sepsis survivors, but early nuclear DNA, and not mitochondrial DNA, copy number was further increased in patients who developed chronic critical illness. Cell-free DNA copy number was associated with in-hospital but not long-term (180-day and 365-day) mortality and were only weakly correlated with leukocyte transcriptomics.ConclusionIncreased cell-free DNA copy number persists in survivors of sepsis but is not strongly associated with leukocyte transcriptomics. Nuclear DNA but not mitochondrial DNA copy number is associated with adverse, short-term, clinical trajectories and outcomes.
| S-EPMC7028489 | biostudies-literature
Project description:ObjectivesTo provide an appraisal of the evolving paradigms in the pathophysiology of sepsis and propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research.DesignLiterature search using PubMed, MEDLINE, EMBASE, and Google Scholar.Measurements and main resultsSepsis remains one of the most debilitating and expensive illnesses, and its prevalence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness, rarely fully recover, and often experience an indolent death. Patients with chronic critical illness often exhibit "a persistent inflammation-immunosuppression and catabolism syndrome," and it is proposed here that this state of persisting inflammation, immunosuppression and catabolism contributes to many of these adverse clinical outcomes. The underlying cause of inflammation-immunosuppression and catabolism syndrome is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function, and expansion of immature myeloid-derived suppressor cells are all contributory.ConclusionsAlthough newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with chronic critical illness and persistent inflammation-immunosuppression and catabolism syndrome may require a more complementary approach.
| S-EPMC5243156 | biostudies-literature
Project description:Background and aimsDown-regulation of miR-150 was recently linked to inflammation and bacterial infection. Furthermore, reduced serum levels of miR-150 were reported from a small cohort of patients with sepsis. We thus aimed at evaluating the diagnostic and prognostic value of miR-150 serum levels in patients with critically illness and sepsis.MethodsmiR-150 serum levels were analyzed in a cohort of 223 critically ill patients of which 138 fulfilled sepsis criteria and compared to 76 healthy controls. Results were correlated with clinical data and extensive sets of routine and experimental biomarkers.ResultsMeasurements of miR-150 serum concentrations revealed only slightly reduced miR-150 serum levels in critically ill patients compared to healthy controls. Furthermore miR-150 levels did not significantly differ in critically ill patients with our without sepsis, indicating that miR-150 serum levels are not suitable for diagnostic establishment of sepsis. However, serum levels of miR-150 correlated with hepatic or renal dysfunction. Low miR-150 serum levels were associated with an unfavorable prognosis of patients, since low miR-150 serum levels predicted mortality with high diagnostic accuracy compared with established clinical scores and biomarkers.ConclusionReduced miR-150 serum concentrations are associated with an unfavorable outcome in patients with critical illness, independent of the presence of sepsis. Besides a possible pathogenic role of miR-150 in critical illness, our study indicates a potential use of circulating miRNAs as a prognostic rather than diagnostic marker in critically ill patients.
| S-EPMC3555785 | biostudies-literature
Project description:BackgroundPatients who survive critical illness suffer from a significant physical disability. The impact of rehabilitation strategies on health-related quality of life is inconsistent, with population heterogeneity cited as one potential confounder. This secondary analysis aimed to (1) examine trajectories of functional recovery in critically ill patients to delineate sub-phenotypes and (2) to assess differences between these cohorts in both clinical characteristics and clinimetric properties of physical function assessment tools.MethodsTwo hundred ninety-one adult sepsis survivors were followed-up for 24 months by telephone interviews. Physical function was assessed using the Physical Component Score (PCS) of the Short Form-36 Questionnaire (SF-36) and Activities of Daily Living and the Extra Short Musculoskeletal Function Assessment (XSFMA-F/B). Longitudinal trajectories were clustered by factor analysis. Logistical regression analyses were applied to patient characteristics potentially determining cluster allocation. Responsiveness, floor and ceiling effects and concurrent validity were assessed within clusters.ResultsOne hundred fifty-nine patients completed 24 months of follow-up, presenting overall low PCS scores. Two distinct sub-cohorts were identified, exhibiting complete recovery or persistent impairment. A third sub-cohort could not be classified into either trajectory. Age, education level and number of co-morbidities were independent determinants of poor recovery (AUROC 0.743 ((95%CI 0.659-0.826), p < 0.001). Those with complete recovery trajectories demonstrated high levels of ceiling effects in physical function (PF) (15%), role physical (RP) (45%) and body pain (BP) (57%) domains of the SF-36. Those with persistent impairment demonstrated high levels of floor effects in the same domains: PF (21%), RP (71%) and BP (12%). The PF domain demonstrated high responsiveness between ICU discharge and at 6 months and was predictive of a persistent impairment trajectory (AUROC 0.859 (95%CI 0.804-0.914), p < 0.001).ConclusionsWithin sepsis survivors, two distinct recovery trajectories of physical recovery were demonstrated. Older patients with more co-morbidities and lower educational achievements were more likely to have a persistent physical impairment trajectory. In regard to trajectory prediction, the PF score of the SF-36 was more responsive than the PCS and could be considered for primary outcomes. Future trials should consider adaptive trial designs that can deal with non-responders or sub-cohort specific outcome measures more effectively.
| S-EPMC7517819 | biostudies-literature
Project description:ObjectivesThis study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness.DesignSingle-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes.SettingTwo surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center.PatientsAdult critically ill patients that survived 14 days or longer after sepsis onset.InterventionsNone.Measurements and main resultsBaseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures.ConclusionsSurgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.
| S-EPMC6422682 | biostudies-literature
Project description:BACKGROUND:Many sepsis survivors develop chronic critical illness (CCI) and are assumed to be immunosuppressed, but there is limited clinical evidence to support this. We sought to determine whether the incidence of secondary infections and immunosuppressive biomarker profiles of patients with CCI differ from those with rapid recovery (RAP) after sepsis. METHODS:This prospective observational study evaluated 88 critically ill patients with sepsis and 20 healthy controls. Cohorts were defined based on clinical trajectory (early death, RAP, or CCI), whereas immunosuppression was clinically determined by the presence of a postsepsis secondary infection. Serial blood samples were collected for absolute lymphocyte counts (ALCs), monocytic human leukocyte antigen-DR (mHLA-DR) expression, and plasma-soluble programmed death-ligand 1 (sPD-L1) concentrations. RESULTS:Of the 88 patients with sepsis, 3 (3%) died within 14 days of sepsis onset, 50 (57%) experienced RAP, and 35 (40%) developed CCI. Compared with RAP patients, CCI patients exhibited a higher incidence and overall number of infections adjusted for hospital length of stay. ALC and mHLA-DR levels were dramatically reduced at the time of sepsis diagnosis when compared with healthy controls, whereas sPD-L1 concentrations were significantly elevated. There were no differences between RAP and CCI patients in ALC, sPD-L1, or mHLA-DR at the time of diagnosis or within 24?h after sepsis diagnosis. However, in contrast to the RAP group, CCI patients failed to exhibit any trend toward restoration of normal values of ALC, HLA-DR, and sPD-L1. CONCLUSIONS:Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.
| S-EPMC5809297 | biostudies-literature
Project description:BackgroundAs hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes.MethodsReview of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis.ResultsOf the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p < 0.05).ConclusionOver 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.
| S-EPMC7731616 | biostudies-literature
Project description: Not available
| S-EPMC7972647 | biostudies-literature