Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials.
BACKGROUND
Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder.


METHODS
We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort.


RESULTS
We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<0·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=0·049 for mortality, p=0·018 for ventilator-free days, p=0·003 for organ-failure-free days).


CONCLUSIONS
We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials.


BACKGROUND
National Institutes of Health.
Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA. Electronic address: carolyn.calfee@ucsf.edu.
Carolyn S
CS
Calfee
Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
Kevin
K
Delucchi
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Vermont, Burlington, VT, USA.
Polly E
PE
Parsons
Department of Medicine, Pulmonary and Critical Care Medicine Unit, Massachusetts General Hospital, Boston, MA, USA; Biostatistics Unit, Massachusetts General Hospital, Boston, MA, USA.
B Taylor
BT
Thompson
Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt, University, Nashville, TN, USA.
Lorraine B
LB
Ware
Departments of Medicine and Anesthesia, Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, San Francisco, CA, USA.
Michael A
MA
Matthay
D018806:APACHE; D000328:Adult; D000368:Aged; D001639:Bicarbonates / Q000097:blood; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010641:Phenotype; D012121:Respiration, Artificial / Q000379:methods / Q000706:statistics & numerical data; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000145:classification* / Q000401:mortality / Q000628:therapy; D018805:Sepsis / Q000453:epidemiology; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
D001639:Bicarbonates; D015415:Biomarkers; D018836:Inflammation Mediators; D014662:Vasoconstrictor Agents