People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden.
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ABSTRACT:
SUBMITTER: Cillo AR
PROVIDER: S-EPMC8636386 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There remains an urgent need to delinate immune cell states that contribute to mortality in critially ill COVID-19 patients. To better understand determinants of mortality, we performed high dimensional profiling of blood and respiratory samples from critially ill COVID-19 patients. Single-cell RNAseq based characterization of peripheral immune states reveal distinct expression profiles that were predictive of COVID-19 mortality. Temporal analysis revealed a that persistently elevated levels of inflammatory monocyte signatures and persistent interferon signaling preceeded concerted upregulation of inflammatory cytokines. Interrogation of lower respiratory tract saples revelaed that infected myeliod cells upregulated CXCL10, and elevated levels of CXCL10 in plasma were associated with a high risk of death. Overall, our data suggest a pivotal role for myeloid cell states in severe COVID-19 and may faciliate discovery of new diagnostics and therapeutics.
2021-12-08 | GSE180578 | GEO
Project description:People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden
| PRJNA748731 | ENA
Project description:Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood.To characterize and define mechanisms of peripheral blood neutrophil (PBN) dysfunction in critically ill patients. To determine whether the inflamed lung contributes additional phagocytic impairment.Prospective collection of blood and bronchoalveolar lavage fluid from patients with suspected ventilator-associated pneumonia and from age- and sex-matched volunteers; laboratory analysis of neutrophil functions.Seventy-two patients and 21 volunteers were included. Phagocytic capacity of PBNs was 36% lower in patients than in volunteers (P < 0.0001). From several biologically plausible candidates only activated complement was significantly associated with impaired PBN phagocytosis (P < 0.0001). Phagocytosis was negatively correlated with serum C3a and positively correlated with expression of C5a receptor type 1 (CD88) on PBNs. C5a recapitulated impaired PBN phagocytosis and significantly down-regulated CD88 expression in vitro. C5a-mediated phagocytic impairment was prevented by blocking either CD88 or phosphoinositide 3-kinase, and completely reversed by granulocyte-macrophage colony-stimulating factor. C5a also impaired killing of Pseudomonas aeruginosa by, and migration of, PBNs, indicating that effects were not restricted to phagocytosis. Bronchoalveolar lavage fluid leukocytes from patients also demonstrated significantly impaired function, and lavage supernatant reduced phagocytosis in healthy neutrophils by 43% (P = 0.0001). However, lavage fluid did not affect CD88 expression and lavage-mediated impairment of phagocytosis was not blocked by anti-CD88 antibody.Critically ill patients have significant dysfunction of PBNs, which is mediated predominantly by activated complement. Further, profound complement-independent neutrophil dysfunction occurs in the inflamed lung.
| S-EPMC2948533 | biostudies-other
Project description:BACKGROUND:During critical illness in humans, the effects of caloric restriction on the inflammatory response are not well understood. The aim of this study is to examine the associations of caloric restriction, inflammatory response profiles and outcomes in critically ill patients. METHODS:This is a sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998). Serum samples were collected on study days 1, 3, 5, 7 and 14 and analyzed for a panel of 29 cytokines. We used principal component analysis to convert possibly correlated variables (cytokine levels) into a limited number of linearly uncorrelated variables (principal components). We constructed repeated measures mixed linear models to assess whether permissive underfeeding compared to standard feeding was associated with difference cytokine levels over time. RESULTS:A total of 72 critically ill patients were enrolled in this study (permissive underfeeding n = 36 and standard feeding n = 36). Principal component analysis identified 6 components that were responsible for 78% of the total variance. When adjusted to principal components, permissive underfeeding was not associated with 90-day mortality (adjusted odds ratio 1.75, 95% confidence interval 0.44, 6.95, p = 0.43) or with incident renal replacement therapy. The cytokines did not differ with time between permissive underfeeding and standard feeding groups. CONCLUSIONS:The association of permissive underfeeding compared to standard feeding with mortality was not influenced by the inflammatory profile. Permissive underfeeding compared to standard feeding was not associated with differences in the serum levels of cytokines in critically ill patients.
| S-EPMC6322779 | biostudies-literature
Project description: Not available
| S-EPMC6513027 | biostudies-literature
Project description:Coronavirus disease (COVID)-19, as a result of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has been the direct cause of over 2.2 million deaths worldwide. A timely coordinated host-immune response represents the leading driver for restraining SARS-CoV-2 infection. Indeed, several studies have described dysregulated immunity as the crucial determinant for critical illness and the failure of viral control. Improved understanding and management of COVID-19 could greatly reduce the mortality and morbidity caused by SARS-CoV-2. One aspect of the immune response that has to date been understudied is whether lipid mediator production is dysregulated in critically ill patients. In the present study, plasma from COVID-19 patients with either severe disease and those that were critically ill was collected and lipid mediator profiles were determined using liquid chromatography tandem mass spectrometry. Results from these studies indicated that plasma concentrations of both pro-inflammatory and pro-resolving lipid mediator were reduced in critically ill patients when compared with those with severe disease. Furthermore, plasma concentrations of a select group of mediators that included the specialized pro-resolving mediators (SPM) Resolvin (Rv) D1 and RvE4 were diagnostic of disease severity. Interestingly, peripheral blood SPM concentrations were also linked with outcome in critically ill patients, where we observed reduced overall concentrations of these mediators in those patients that did not survive. Together the present findings establish a link between plasma lipid mediators and disease severity in patients with COVID-19 and indicate that plasma SPM concentrations may be linked with survival in these patients.
| S-EPMC8389414 | biostudies-literature
Project description: Not available
| S-EPMC6373621 | biostudies-literature
Project description:Background: Outcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by viral control and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. Methods: Patients admitted to an intensive care unit (ICU) with documented COVID-19 were prospectively included and IFIH1 rs1990760 genotypes determined. Peripheral blood gene expression, cell populations and immune mediators were measured during the first day after ICU admission before steroid therapy. Peripheral blood mononuclear cells from healthy volunteers were exposed ex-vivo to an MDA5 agonist and dexamethasone, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone therapy as factors. Findings: 237 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a decrease in expression of inflammation-related pathways, an anti-inflammatory cell profile and a decrease in pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist ex-vivo showed an increase in FOXO3 and IL6 when dexamethasone was added. All patients with the TT variant not treated with steroids (n=14) survived their ICU stay (HR 2.49 95% confidence interval 1.29 – 4.79). Dexamethasone therapy in this subgroup (N=50) delayed ICU discharge and increased hospital mortality (HR 2.19, 95% confidence interval 1.01 – 4.87) and serum IL-6 concentrations. Interpretation: COVID-19 ICU patients with the IFIH1 rs1990760 TT variant show an ameliorated inflammatory response that results in better outcomes than CC/CT variants. Dexamethasone can reverse this anti-inflammatory phenotype, worsening the outcome. Funding: Instituto de Salud Carlos III.
2021-07-03 | GSE168400 | GEO
Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator
2015-10-24 | E-GEOD-74224 | biostudies-arrayexpress
Project description:To identify the relationships between advance directive status, demographic characteristics and decisional burden (role stress and depressive symptoms) of surrogate decision-makers (SDMs) of patients with chronic critical illness.Although the prevalence of advance directives among Americans has increased, SDMs are ultimately responsible for complex medical decisions of the chronically critically ill patient. Decisional burden has lasting psychological effects on SDMs. There is insufficient evidence on the influence of advance directives on the decisional burden of surrogate decision-makers of patients with chronic critical illness.The study was a secondary data analysis of cross-sectional data. Data were obtained from 489 surrogate decision-makers of chronically critically ill patients at two academic medical centres in Northeast Ohio, United States, between September 2005-May 2008.Data were collected using demographic forms and questionnaires. A single-item measure of role stress and the Center for Epidemiological Studies Depression (CESD) scale were used to capture the SDM's decisional burden. Descriptive statistics, t-tests, chi-square and path analyses were performed.Surrogate decision-makers who were nonwhite, with low socioeconomic status and low education level were less likely to have advance directive documentation for their chronically critically ill patient. The presence of an advance directive mitigates the decisional burden by directly reducing the SDM's role stress and indirectly lessening the severity of depressive symptoms.Most SDMs of chronically critically ill patients will not have the benefit of knowing the patient's preferences for life-sustaining therapies and consequently be at risk of increased decisional burden.Study results are clinically useful for patient education on the influence of advance directives. Patients may be informed that SDMs without advance directives are at risk of increased decisional burden and will require decisional support to facilitate patient-centred decision-making.
| S-EPMC5573593 | biostudies-other