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

Abstract

Rationale: Using 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.

Methods: LCA 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.

Results: A 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.

Conclusion: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

Keywords: ARDS; critical care; cytokine biology.

Figure 1.

Overview of the cohorts and their subsets used for analysis in the study.

Figure 2.. Standardized values for continuous class-defining variables used in the latent class models. The variables are sorted from left to right in descending order for the highest values in the Hyperinflammatory subphenotype. Standardized values were calculated by assigning the mean of the variables as 0 and standard deviation as 1. 2A VALID Cohort (AECC Definition). 2B VALID Cohort (AECC Definition with Trauma patients excluded). 2C VALID Cohort (AECC Definition).

BMI: body mass index, SBP: systolic blood pressure, ICAM-1: intercellular adhesion molecule-1, IL-6: interleukin 6, IL-8: interleukin 8, PAI-1: plasminogen activator inhibitor-1, PEEP: positive end-expiratory pressure, sTNFr1: tumor necrosis factor receptor-1, VE: minute ventilation, VT: tidal volume, WBC: white blood cell count, RR = Respiratory Rate, HR = Heart Rate.

Figure 3.. Comparison of substance abuse and selected co-morbidities between subphenotypes. 3A: Alcohol abuse and current smoking status. 3B: Chronic liver disease and diabetes.

P-values are derived using Chi-squared test. * Denotes statistically significant value.

Figure 4.. Receiver operating characteristic (ROC) curves for the parsimonious classifier models in the three VALID cohorts: AECC (n = 624), No trauma (n = 452) and Berlin (n = 500) Cohorts. 4A: ROC curves for the 3-variable model (interleukin-8, serum bicarbonate and protein c). 4B: ROC curves for the 4-variable model (interleukin-8, serum bicarbonate, protein c and vasopressor-use).

AUC: Area under the curve.

Figure 5.. Comparison of differences in novel plasma biomarkers between subphenotypes. 5A: Matrix metalloproteinases. 5B: Chemokines). 5C: Markers of endothelial injury. 5D: Markers of epithelial injury.

MIP = Macrophage Inflammatory Protein; RAGE = Receptor for Advanced Glycation Endproducts. Protein P-values are derived using Wilcoxon-rank test.