Discussion
Although there have been many studies of the prognostic value of biomarkers in patients with established ARDS,16 17 there are relatively few studies of the diagnostic value of plasma biomarkers in ARDS. The primary goal of this study was to derive and validate a plasma biomarker panel for diagnosis of ARDS in adult patients with severe traumatic injuries. We tested 11 biomarkers of various aspects of the pathophysiology of ARDS including biomarkers of inflammation, lung epithelial injury, endothelial injury and coagulation. To minimize overfitting and maximize the potential for rapid bedside application in the future, this panel was narrowed to the top two performing biomarkers and then validated in two independent patient cohorts. The two-biomarker panel of Ang-2 and RAGE performed similarly across the three cohorts and significantly outperformed clinical diagnosis.
Although it has been reported that ARDS is underdiagnosed and undertreated,3 7 8 18 the current study underscores the potential magnitude of this problem. In a detailed review of all history and progress notes for each patient in the derivation cohort, we found that ARDS was largely undiagnosed; clinician recognition had a sensitivity of only 31% for the presence of ARDS, with an AUC of 0.55. Thus, although performance of the two-biomarker panel is only in the moderate range for a diagnostic test, when the performance of the two-biomarker panel is compared with clinician recognition of ARDS, there is clear value. Since timely diagnosis and adherence to low tidal volume ventilation decreases ICU mortality,3 utilization of this simple biomarker panel could expedite diagnosis and treatment of ARDS in severe trauma, leading to improved clinical outcomes. In addition, application of the two-biomarker panel could facilitate identification of patients for inclusion in clinical trials of new therapies for trauma-associated ARDS.
Although we tested biomarkers of many aspects of the pathophysiology of ARDS including inflammation, activation of fibrotic pathways, dysregulated coagulation and a biomarker of increased intravascular volume, the top two performing biomarkers that make up the final two-marker panel are biomarkers of lung epithelial injury (RAGE) and endothelial injury (Ang-2). Both lung epithelial injury and endothelial injury are key features of ARDS that have been well documented in both experimental and clinical acute lung injury, lending biologic plausibility to the findings. Lung epithelial injury is a pathophysiologic hallmark of ARDS19 that is evident both pathologically20 and in functional assays of alveolar epithelial transport function.21 RAGE is highly expressed on the type I alveolar epithelium22; release of RAGE into the airspace and circulation is a biomarker of lung epithelial injury in rodent,22 human experimental23 and clinical studies.24 In patients at risk for ARDS from sepsis, biomarkers of lung epithelial injury including RAGE, SP-D and CC16 are strongly associated with the diagnosis of ARDS,9 suggesting that biomarkers of lung epithelial injury may be useful for diagnosis of ARDS in patients with a variety of underlying risk factors beyond just patients with severe traumatic injuries.
Injury to the microvascular endothelium is also a pathophysiologic hallmark of ARDS.2 Several biomarkers of endothelial injury have previously been associated with development of ARDS including VWF25 and Ang-2. Ang-2, an endothelial growth factor and potent mediator of vascular permeability and endothelial injury, was recently found to be highly predictive of ARDS among patients presenting to the emergency department who were at risk for, but did not yet have, ARDS.10 This study did not include patients with traumatic injuries. The current study extends prior findings to patients with traumatic injuries and suggests that endothelial injury is a key pathophysiologic feature of trauma-induced ARDS that can be used to aid clinical diagnosis.
This study has several strengths. First, because of the large size of the derivation cohort, we were able to test a large number of potential biomarkers in the derivation cohort, and thus the study included candidate biomarkers of diverse aspects of the pathophysiology of ARDS. Second, all three of the cohorts that were used had dedicated ARDS phenotyping done by the study authors, including two physician review of all chest radiographs and clinical data, insuring the validity of the gold standard ARDS diagnosis for this study. Finally, validation of the biomarker panel in two independent cohorts enhances the external validity of the findings.
There are also some limitations. Due to differences in how the three cohorts were phenotyped for ARDS in the three parent studies, each cohort used slightly different definitions for cases and controls. This might, in part, explain why the biomarker panel performance varied somewhat between cohorts. In addition, the gender cohort was a case–control cohort, and the performance of the biomarker panel in this group may be an overestimate of panel performance due to patient selection. As noted above, the overall performance of the two-biomarker panel was only in the moderate range, although biomarkers significantly outperformed clinical diagnosis. Finally, since the studies were limited to patients with severe traumatic injuries, the findings cannot be generalized to other patient populations.
In summary, a two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in patients with severe traumatic injuries. If validated prospectively, clinical application of this model could improve both diagnosis and timely treatment of ARDS.