Development of a Biomarker Mortality Risk Model in Acute Respiratory Distress Syndrome

Christian Bime; Nancy Casanova; Radu C. Oita; Juliet Ndukum; Heather Lynn; Sara M. Camp; Yves Lussier; Ivo Abraham; Darrick Carter; Edmund J. Miller; Armand Mekontso-Dessap; Charles A. Downs; Joe G. N. Garcia


Crit Care. 2019;23(410) 

In This Article

Abstract and Introduction


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.


Acute respiratory distress syndrome (ARDS) is a devastatingly-intense inflammatory lung disorder characterized by severe respiratory failure requiring mechanical ventilation with a high mortality rate of 30–40%.[1] ARDS exhibits clinical and biological heterogeneity with respiratory and multi-organ system failure in response to diverse inciting stimuli. For example, in the USA, sepsis and pneumonia are the major inducers of ARDS, whereas in India, ARDS occurs in response to various tropical infections (malaria, miliary tuberculosis, dengue infections, etc.).[2] The clinical and radiographic diagnostic criteria for ARDS are relatively imprecise.[3] Diagnostic uncertainty in ARDS further exacerbates disease heterogeneity and is a potential source of bias in conducting clinical trials. Consequently, the development of novel therapies in ARDS has been extremely challenging and contributes to the abysmal track record of Phase II/III ARDS clinical trials.[4] Scoring systems in critically ill patients such as the APACHE II score[5] or the lung injury severity score[6] successfully link to patient outcomes but fail to provide consistent and accurate predictive estimates of the risk of death in patient populations with a specific disease process. General severity scores lack specificity by failing to distinguish sepsis, ARDS, or acute kidney injury and are not significantly different between ARDS survivors and non-survivors.[7] Furthermore, general severity scores do not have pathophysiologic input and, therefore, are unlikely to guide personalized therapies. Attempts to characterize predictors of death in ARDS by developing a prognostic index[8] remain controversial and have not yet been replicated or validated. Thus, there is a compelling unmet medical need to identify clinical and/or biochemical disease-specific parameters that risk-stratify patients for both accurate prognostication and clinical trial purposes. Stratification of ARDS patients with reliable biomarkers predictive of mortality would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new clinical interventions.[9,10]

We and others have used "omic" approaches and translational systems biology methods to identify a panel of plasma protein biomarkers with diverse biological mechanisms that suggest a possible association with ARDS mortality.[11–22] The objective of the current study was to utilize plasma protein biomarkers to derive a prognostic model for predicting ARDS patients least likely to survive to 28 days. We used latent class analysis and predictive analytics on eight plasma biomarkers collected from a well-phenotyped combined ARDS cohort. Biomarkers included cytokine-chemokines (interleukin-6 [IL-6], interleukin-8 [IL-8], interleukin-1 beta [IL-1B], and interleukin-1 receptor antagonist [IL-1RA]), dual-functioning cytozymes, i.e., cytokine/intracellular enzymes (macrophage migration inhibitory factor [MIF], nicotinamide phosphoribosyltransferase [eNAMPT]) and vascular injury markers (sphingosine 1-phosphate receptor 3 [S1PR3], angiopoietin-2 [Ang-2]). These analyses utilizing complementary analytical approaches, latent class analysis, classification and regression tree (CART) analysis, and rank aggregation were consistent and allowed the identification of six biomarkers that were most predictive of ARDS mortality.