Acute respiratory distress syndrome phenotyping and latent class analysis, first steps toward precision medicine in critical care illness?

Abstract Background There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. Methods This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. Results From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04). Conclusions An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.

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Identification of three classes of acute respiratory distress syndrome using latent class analysis

PeerJ ◽

10.7717/peerj.4592 ◽

2018 ◽

Vol 6 ◽

pp. e4592 ◽

Cited By ~ 3

Author(s):

Zhongheng Zhang

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Latent Class Analysis ◽

Fluid Balance ◽

Latent Class ◽

Distress Syndrome ◽

Class Analysis ◽

Class 1

Acute respiratory distress syndrome (ARDS) is a highly heterogeneous syndrome that can exhibit significant differences in the underlying causes, leading to different responses to treatment. It is required to identify subtypes of ARDS to guideline clinical treatment and trial design. The study aimed to identify subtypes of ARDS using latent class analysis (LCA). The study was a secondary analysis of the EDEN study, which was a randomized, controlled, multicenter trial conducted from January 2, 2008 to April 12, 2011. The primary study endpoint was death through 90-day follow up. LCA was performed incorporating variables on day 0 before randomization. The number of classes was chosen by a bootstrapped likelihood ratio test, Bayesian information criterion and the number of patients in each class. A total of 943 patients were enrolled in the study, including 219 (23.2%) non-survivors and 724 (76.8%) survivors. The LCA identified three classes of ARDS. Class 1 (hemodynamically unstable type) had significantly higher mortality rate (p = 0.003) than class 2 (intermediate type) and 3 (stable type) through 90 days follow up. There was significant interaction between cumulative fluid balance and the class (p = 0.02). While more fluid balance was beneficial for class 1, it was harmful for class 2 and 3. In conclusion, the study identified three classes of ARDS, which showed different clinical presentations, responses to fluid therapy and prognosis. The classification system used simple clinical variables and could help to design ARDS trials in the future.

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Latent class analysis to predict intensive care outcomes in Acute Respiratory Distress Syndrome: a proposal of two pulmonary phenotypes

Critical Care ◽

10.1186/s13054-021-03578-6 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Pedro D. Wendel Garcia ◽

Alessio Caccioppola ◽

Silvia Coppola ◽

Tommaso Pozzi ◽

Arianna Ciabattoni ◽

...

Keyword(s):

Computed Tomography ◽

Acute Respiratory Distress Syndrome ◽

Gas Exchange ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Latent Class Analysis ◽

Latent Class ◽

Distress Syndrome ◽

Respiratory Mechanics ◽

Class Analysis

Abstract Background Acute respiratory distress syndrome remains a heterogeneous syndrome for clinicians and researchers difficulting successful tailoring of interventions and trials. To this moment, phenotyping of this syndrome has been approached by means of inflammatory laboratory panels. Nevertheless, the systemic and inflammatory expression of acute respiratory distress syndrome might not reflect its respiratory mechanics and gas exchange. Methods Retrospective analysis of a prospective cohort of two hundred thirty-eight patients consecutively admitted patients under mechanical ventilation presenting with acute respiratory distress syndrome. All patients received standardized monitoring of clinical variables, respiratory mechanics and computed tomography scans at predefined PEEP levels. Employing latent class analysis, an unsupervised structural equation modelling method, on respiratory mechanics, gas-exchange and computed tomography-derived gas- and tissue-volumes at a PEEP level of 5cmH2O, distinct pulmonary phenotypes of acute respiratory distress syndrome were identified. Results Latent class analysis was applied to 54 respiratory mechanics, gas-exchange and CT-derived gas- and tissue-volume variables, and a two-class model identified as best fitting. Phenotype 1 (non-recruitable) presented lower respiratory system elastance, alveolar dead space and amount of potentially recruitable lung volume than phenotype 2 (recruitable). Phenotype 2 (recruitable) responded with an increase in ventilated lung tissue, compliance and PaO2/FiO2 ratio (p < 0.001), in addition to a decrease in alveolar dead space (p < 0.001), to a standardized recruitment manoeuvre. Patients belonging to phenotype 2 (recruitable) presented a higher intensive care mortality (hazard ratio 2.9, 95% confidence interval 1.7–2.7, p = 0.001). Conclusions The present study identifies two ARDS phenotypes based on respiratory mechanics, gas-exchange and computed tomography-derived gas- and tissue-volumes. These phenotypes are characterized by distinctly diverse responses to a standardized recruitment manoeuvre and by a diverging mortality. Given multicentre validation, the simple and rapid identification of these pulmonary phenotypes could facilitate enrichment of future prospective clinical trials addressing mechanical ventilation strategies in ARDS.

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Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study

Thorax ◽

10.1136/thoraxjnl-2021-217158 ◽

2021 ◽

pp. thoraxjnl-2021-217158

Author(s):

Pratik Sinha ◽

Kevin L Delucchi ◽

Yue Chen ◽

Hanjing Zhuo ◽

Jason Abbott ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Lung Injury ◽

Matrix Metalloproteinase ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Latent Class Analysis ◽

Latent Class ◽

Distress Syndrome ◽

Class Analysis ◽

Early Assessment

RationaleUsing latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.MethodsLCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.ResultsA 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described ‘hyperinflammatory’ subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92–0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.ConclusionPreviously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

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Acute Respiratory Distress Syndrome Phenotypes

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-1684049 ◽

2019 ◽

Vol 40 (01) ◽

pp. 019-030 ◽

Cited By ~ 13

Author(s):

John Reilly ◽

Carolyn Calfee ◽

Jason Christie

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Precision Medicine ◽

Latent Class ◽

Distress Syndrome ◽

Randomized Controlled ◽

Focal Pattern ◽

Definition Of ◽

Made In

AbstractThe acute respiratory distress syndrome (ARDS) phenotype was first described over 50 years ago and since that time significant progress has been made in understanding the biologic processes underlying the syndrome. Despite this improved understanding, no pharmacologic therapies aimed at the underlying biology have been proven effective in ARDS. Increasingly, ARDS has been recognized as a heterogeneous syndrome characterized by subphenotypes with distinct clinical, radiographic, and biologic differences, distinct outcomes, and potentially distinct responses to therapy. The Berlin Definition of ARDS specifies three severity classifications: mild, moderate, and severe based on the PaO2 to FiO2 ratio. Two randomized controlled trials have demonstrated a potential benefit to prone positioning and neuromuscular blockade in moderate to severe phenotypes of ARDS only. Precipitating risk factor, direct versus indirect lung injury, and timing of ARDS onset can determine other clinical phenotypes of ARDS after admission. Radiographic phenotypes of ARDS have been described based on a diffuse versus focal pattern of infiltrates on chest imaging. Finally and most promisingly, biologic subphenotypes or endotypes have increasingly been identified using plasma biomarkers, genetics, and unbiased approaches such as latent class analysis. The potential of precision medicine lies in identifying novel therapeutics aimed at ARDS biology and the subpopulation within ARDS most likely to respond. In this review, we discuss the challenges and approaches to subphenotype ARDS into clinical, radiologic, severity, and biologic phenotypes with an eye toward the future of precision medicine in critical care.

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