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Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

ABSTRACT: 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 < 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.

SUBMITTER: Darden DB

PROVIDER: S-EPMC8348105 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

Darden Dijoia B DB Ghita Gabriela L GL Wang Zhongkai Z Stortz Julie A JA Lopez Maria-Cecilia MC Cox Michael C MC Hawkins Russell B RB Rincon Jaimar C JC Kelly Lauren S LS Fenner Brittany P BP Ozrazgat-Baslanti Tezcan T Leeuwenburgh Christiaan C Bihorac Azra A Loftus Tyler J TJ Moore Frederick A FA Brakenridge Scott C SC Baker Henry V HV Bacher Rhonda R Mohr Alicia M AM Moldawer Lyle L LL Efron Philip A PA

Journal of clinical medicine 20210721 15

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 d ...[more]

PMID: 34361995

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Project description:BackgroundSirtuin 2 (SIRT2) is a conserved deacetylase that participates in the regulation of inflammation in sepsis. In this observational prospective study, we investigated the predictive value of the SIRT2 expression level in the development of chronic critical illness (CCI) in patients with sepsis.MethodsA total of 128 critically ill patients with sepsis or septic shock were enrolled and assigned to the CCI group, rapid recovery (RAP) group, or early death group according to their clinical trajectories. Patients' demographic and clinical information, as well as laboratory data, including C-reactive protein (CRP) level and total lymphocyte counts, were collected. Blood samples were obtained at admission and on days 1, 4, 7, 10, 14, and 21 (days 14 and 21 for the CCI group only). Peripheral blood mononuclear cells were isolated, and SIRT2 expression was measured by real-time polymerase chain reaction. Serum levels of interleukin (IL)-6 and IL-10 were measured by enzyme-linked immunosorbent assay.ResultsOur cohort included 37 CCI and 82 RAP patients, and 9 early death patients, who died within 14 days of intensive care unit (ICU) admission. Compared with the RAP group, CCI patients showed elevated CRP and IL-6 levels throughout the observation period, reflecting a sustained inflammatory response. However, decreases in total lymphocyte count and IL-10 expression in these patients were indicative of immunosuppression. SIRT2 mRNA level was lower in CCI and RAP patients compared with healthy controls at the initial stage of hospitalization, but increased starting on day 4 and continued to increase for the duration of hospitalization. By day 10, SIRT2 expression had almost returned to normal in RAP patients; however, in CCI patients, it continued to increase until the end of the observation period. A receiver-operating characteristic curve analysis showed that the expression level of SIRT2 at 10 days predicts the occurrence of CCI (P<0.05).ConclusionsSIRT2 expression may be a useful marker for identifying sepsis survivors who are at risk of progressing to CCI.

Project description:IntroductionDespite continued improvement in post-sepsis survival, long term morbidity and mortality remain high. Chronic critical illness (CCI), defined as persistent inflammation and organ injury requiring prolonged intensive care, is a harbinger of poor long-term outcomes in sepsis survivors. Current dogma states that sepsis survivors are immunosuppressed, particularly in CCI. Investigation of this immune suppression in heterogeneous immune populations across distinct clinical trajectories and outcomes, along with limited sampling access, is accessible via single-cell RNA sequencing (scRNA-seq).MethodsscRNA-seq analysis was performed on healthy subjects (n=12), acutely septic patients at day 4 ± 1 (n=4), and those defined as rapid recovery (n=4) or CCI (n=5) at day 14-21. Differential gene expression and pathway analyses were performed on peripheral blood lymphocytes at both a population and annotated cell subset level. Cellular function was assessed via enzyme-linked immunosorbent spot (ELISpot), cytokine production analysis, and T-cell proliferation assays on an additional cohort of septic patients (19 healthy, 68 acutely septic, 27 rapid recovery and 20 classified as CCI 14-21 days after sepsis onset).ResultsSepsis survivors that developed CCI exhibited proportional shifts within lymphoid cell populations, with expanded frequency of CD8+ and NK cells. Differential expression and pathway analyses revealed continued activation in T cells and NK cells, with generalized suppression of B-cell function. Both T and NK cell subsets displayed transcriptomic profiles of exhaustion and immunosuppression in CCI, particularly in CD8+ T effector memory (TEM) cells and NK cells. Functional validation of T-cell behavior in an independent cohort demonstrated T cells maintained proliferative responses in vitro yet exhibited a marked loss of cytokine production. IFN-γ production at the acute phase (day 4 ± 1) was significantly reduced in subjects later classified as CCI.DiscussionSepsis patients exhibit unique T-, B-, and NK-cell transcriptional patterns that are both time- and clinical trajectory-dependent. These transcriptomic and pathway differences in sepsis patients that develop CCI are associated with exhaustion in CD8+ TEM cells and NK cells. Understanding the specific immune system patterns of different cell subsets after sepsis at a molecular level will be key to the development of personalized immunotherapy and drug-targeting intervention.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT02276417.

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.

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.

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.

Project description:BackgroundMany 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.MethodsThis 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.ResultsOf 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.ConclusionsSeptic 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.

Dataset Information

Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

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Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

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