Dataset Information

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

ABSTRACT:

Background

Matrix metalloproteinase-3 (MMP-3) is a proteolytic enzyme involved in acute respiratory distress syndrome (ARDS) pathophysiology that may serve as a lung-specific biomarker in ARDS.

Methods

This study was a secondary biomarker analysis of a subset of Albuterol for the Treatment of Acute Lung Injury (ALTA) trial patients to determine the prognostic value of MMP-3. Plasma sample MMP-3 was measured by enzyme-linked immunosorbent assay. The primary outcome was the area under the receiver operating characteristic (AUROC) of MMP-3 at day 3 for the prediction of 90-day mortality.

Results

A total of 100 unique patient samples were evaluated and the AUROC analysis of day three MMP-3 showed an AUROC of 0.77 for the prediction of 90-day mortality (95% confidence interval: 0.67-0.87), corresponding to a sensitivity of 92% and specificity of 63% and an optimal cutoff value of 18.4 ng/mL. Patients in the high MMP-3 group (≥ 18.4 ng/mL) showed higher mortality compared to the non-elevated MMP-3 group (< 18.4 ng/mL) (47% vs. 4%, p < 0.001). A positive difference in day zero and day three MMP-3 concentration was predictive of mortality with an AUROC of 0.74 correlating to 73% sensitivity, 81% specificity, and an optimal cutoff value of + 9.5 ng/mL.

Conclusions

Day three MMP-3 concentration and difference in day zero and three MMP-3 concentrations demonstrated acceptable AUROCs for predicting 90-day mortality with a cut-point of 18.4 ng/mL and + 9.5 ng/mL, respectively. These results suggest a prognostic role of MMP-3 in ARDS.

SUBMITTER: Jones TW

PROVIDER: S-EPMC10286483 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

Jones Timothy W TW Almuntashiri Sultan S Chase Aaron A Alhumaid Abdullah A Somanath Payaningal R PR Sikora Andrea A Zhang Duo D

Respiratory research 20230622 1

<h4>Background</h4>Matrix metalloproteinase-3 (MMP-3) is a proteolytic enzyme involved in acute respiratory distress syndrome (ARDS) pathophysiology that may serve as a lung-specific biomarker in ARDS.<h4>Methods</h4>This study was a secondary biomarker analysis of a subset of Albuterol for the Treatment of Acute Lung Injury (ALTA) trial patients to determine the prognostic value of MMP-3. Plasma sample MMP-3 was measured by enzyme-linked immunosorbent assay. The primary outcome was the area und ...[more]

PMID: 37349704

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Project description:RationaleMMPs (Matrix metalloproteinases) and their endogenous tissue inhibitors may contribute to lung injury through extracellular matrix degradation and modulation of inflammation and fibrosis.ObjectivesTo test for an association between MMP pathway proteins and inflammation, endothelial dysfunction, and clinical outcomes.MethodsWe measured MMPs in plasma collected on acute respiratory distress syndrome (ARDS) Day 1 from 235 children at five hospitals between 2008 and 2017. We used latent class analysis to identify patients with distinct MMP profiles and then associated those profiles with markers of inflammation (IL-1RA, -6, -8, -10, and -18; macrophage inflammatory protein-1α and -1β; tumor necrosis factor-α and -R2), endothelial injury (angiopoietin-2, von Willebrand factor, soluble thrombomodulin), impaired oxygenation (PaO2/FiO2 [P/F] ratio, oxygenation index), morbidity, and mortality.Measurements and main resultsIn geographically distinct derivation and validation cohorts, approximately one-third of patients demonstrated an MMP profile characterized by elevated MMP-1, -2, -3, -7, and -8 and tissue inhibitor of metalloproteinase-1 and -2; and depressed active and total MMP-9. This MMP profile was associated with multiple markers of inflammation, endothelial injury, and impaired oxygenation on Day 1 of ARDS, and conferred fourfold increased odds of mortality or severe morbidity independent of the P/F ratio and other confounders (95% confidence interval, 2.1-7.6; P < 0.001). Logistic regression using both the P/F ratio and MMP profiles was superior to the P/F ratio alone in prognosticating mortality or severe morbidity (area under the receiver operating characteristic curve, 0.75; 95% confidence interval, 0.68-0.82 vs. area under the receiver operating characteristic curve, 0.66; 95% confidence interval, 0.58-0.73; P = 0.009).ConclusionsPediatric patients with ARDS have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.

Project description:ObjectivesCirculating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown.DesignWe performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome.SettingLarge academic tertiary-care PICU.PatientsIntubated children meeting Berlin criteria for acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsWe enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome.ConclusionsPlasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

Project description:The optimal method to assess fluid overload in acute respiratory distress syndrome is not known, and current techniques have limitations. Plasma volume status has emerged as a noninvasive method to assess volume status and is defined as the percentage alteration from ideal plasma volume. We hypothesized that plasma volume status would suggest the presence of significant excess volume and therefore correlate with mortality in acute respiratory distress syndrome.Design and settingThis is a retrospective cohort study of subjects enrolled in four previously completed National Heart Lung and Blood Institute-sponsored acute respiratory distress syndrome trials, using data from the National Institutes of Health Biologic Specimen and Data Repository Information Coordinating Center repository.PatientsStudy subjects included 3,165 patients with acute respiratory distress syndrome previously enrolled in National Heart Lung and Blood Institute-sponsored acute respiratory distress syndrome trials.Measurements and main resultsThe exposure variable of interest was plasma volume status, calculated as the percentage alteration of actual plasma volume calculated on the basis of weight and hematocrit using sex-specific constants. We performed Kaplan-Meier survival analysis and univariable and adjusted Cox proportional hazard models to determine the association of plasma volume status with 60-day mortality. The median age of subjects was 52 years (interquartile range, 40-63 yr). Median plasma volume status was 5.9% (interquartile range, -2.4% to 13.6%), and overall, 68% of subjects had positive plasma volume status suggesting plasma volume higher than ideal plasma volume. In adjusted models, plasma volume status greater than median was associated with 38% greater risk for mortality (hazard ratio, 1.38; 95% CI, 1.20-1.59; p < 0.001). Each interquartile range increase in plasma volume status was associated with greater mortality in adjusted models (hazard ratio, 1.24 per interquartile range increase; 95% CI, 1.13-1.36; p < 0.001). Plasma volume status greater than median was associated with fewer ventilator-free days (18 vs 19 d; p = 0.0026) and ICU-free days (15 vs 17 d; p = 0.0001).ConclusionsPlasma volume status is independently associated with mortality, ICU-free days, and ventilator-free days among subjects with acute respiratory distress syndrome. Plasma volume status could be considered for risk-stratification and to direct therapy, particularly fluid management.

Project description:Sepsis-associated acute respiratory distress syndrome (ARDS) is a life-threatening condition in critical care medicine for which there is a substantial need for early prognostic biomarkers of outcome. The present study seeks to link plasma renin levels and 30-day mortality in sepsis-associated ARDS patients treated at our institution. The Registry of Critical Illness (RoCI) prospectively enrolled patients from the intensive care units (ICU) within a single academic medical center, and a convenience sample of patients with sepsis-associated ARDS was analyzed from this cohort. This study was approved by the Mass General Brigham Institutional Review Boards (IRB) as part of the RoCI, and all procedures performed were in accordance with the ethical standards of the institutional board. From April 2012 to February 2019, a cohort of 32 adult sepsis-associated ARDS patients with 500 µL of plasma samples available on Day 0 and Day 3 of their ICU stay were enrolled. Renin levels were measured twice, on Day 0 and Day 3 via the direct renin enzyme-linked immunosorbent assay (ELISA EIA-525) by DRG diagnostics. Day 0 and Day 3 renin were statistically evaluated via logistic regression to predict 30-day mortality. Direct renin levels of 64 samples were assayed from 32 sepsis-associated ARDS patients (50% male; mean ± SD, 55 ± 13.8 years old). The 30-day hospital mortality rate was 59.4%. Patients who died within 30 days of admission were more likely to have an elevated Day 3 Renin (Odds ratio [OR] = 6, 95% CI 1.25-28.84) and have received vasopressors (OR = 13.33, 95% CI 1.43-123.95). Adjusting for vasopressor use as a proxy for septic shock status, patients with an Elevated Day 3 Renin had a 6.85 (95% CI 1.07-43.75) greater odds of death than those with Low-Normal Day 3 Renin. Patients with sustained Elevated Renin levels from Day 0 to Day 3 had the highest risk of death in a 30-day window. In this study, we found that renin may be a novel biomarker that has prognostic value for patients with sepsis-associated ARDS. Future studies evaluating renin levels in patients with sepsis-associated ARDS are needed to validate these findings.

Project description:BackgroundThere is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model.MethodsMetabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder.ResultsThe metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS.ConclusionIncreased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.Trial registrationChinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4.

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Dataset Information

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

Background

Methods

Results

Conclusions

Publications

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

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