Stability of ARDS subphenotypes over time in two randomised controlled trials

Abstract

Rationale: Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are durable over time.

Objective: To determine the stability of ARDS subphenotypes over time.

Methods: Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes.

Measurements and main results: In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment.

Conclusions: ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.

Keywords: acute lung injury; acute respiratory distress syndrome; endotypes; precision medicine; subphenotypes.

Figure 1

Differences in standardised values of each continuous variable by class in the ARMA cohort by day of assessment and latent class. The variables are sorted on the basis of the degree of separation between the classes at day 0, from maximum positive separation at day 0 on the left (ie, class 2 higher than class 1) to maximum negative separation at day 0 on the right (ie, class 2 lower than class 1). The y-axis represents standardised variable values, in which all means are scaled to 0 and SDs to 1. A value of +1 for the standardised variable signifies that the mean value for a given phenotype was one SD higher than the mean value in the cohort as a whole. Mean values are joined by lines to facilitate displaying class profiles. BMI, body mass index; ICAM-1, intercellular adhesion molecule-1; MAP, mean airway pressure; PaCO2, pressure of carbon dioxide in arterial blood; PAI, plasminogen activator inhibitor-1; Plateau, plateau pressure; SBP, systolic blood pressure; SPD, surfactant protein D; TNFr1, tumour necrosis factor receptor-1; VWF, von Willebrand factor.

Figure 2

Differences in standardised values of each continuous variable by class in the ALVEOLI cohort by day of assessment and latent class. The variables are sorted on the basis of the degree of separation between the classes at day 0, from maximum positive separation at day 0 on the left (ie, class 2 higher than class 1) to maximum negative separation at day 0 on the right (ie, class 2 lower than class 1). The y-axis represents standardised variable values, in which all means are scaled to 0 and SDs to 1. A value of +1 for the standardised variable signifies that the mean value for a given phenotype was one SD higher than the mean value in the cohort as a whole. Mean values are joined by lines to facilitate displaying class profiles. BMI, body mass index; HCTL, hematocrit (low); ICAM-1, intercellular adhesion molecule-1; MAP, mean airway pressure; PaCO2, pressure of carbon dioxide in arterial blood; PAI, plasminogen activator inhibitor-1; Plateau, plateau pressure; SBP, systolic blood pressure; SPD, surfactant protein D; TNFr1, tumour necrosis factor receptor-1; VWF, von Willebrand factor.