Neurotrauma Biomarkers in Patients With Acute Respiratory Distress Syndrome

Abstract RATIONALE: The lung-brain axis has emerged as a significant area of clinical importance with central nervous system and respiratory system injuries demonstrating bi-directional impact. Unfortunately, effective therapeutics for addressing this pathological cross talk remains an unmet need, due in part to the absence of reliable biomarkers that reflect the severity of lung-brain axis disruption. We assessed specific biomarkers in subjects with traumatic brain injury (TBI), a major public health concern affecting 1.4million Americans annually, and subjects with Acute Respiratory Distress Syndrome (ARDS), a life-threatening inflammatory lung injury responsible for more than 10% of ICU admissions each year with a 30-40% mortality. METHODS: Serum collected from TBI subjects (n=63, ∼47y/o, ∼20hr post), ARDS (n=39, ∼52y/o, ∼ day 1), and healthy patients (n=40, ∼50y/o) was analyzed via Meso Scale Discovery ELISA for inflammatory biomarkers (eNAMPT, IL-6, PSGL-1, ANG-2, IL-1β, IL-1RA, TNF-α, S100A8) and neurotrauma biomarkers (Glial fibrillary acidic protein [GFAP], Neuro filament light chain [NFL], Tau). Outliers were removed via ROUT analysis; results were analyzed utilizing Mann-Whitney, Kruskal-Wallis w/ Dunn, and Receiver Operating Characteristic (ROC) Curve analysis. RESULTS: All biomarkers were significantly elevated in TBI patients compared to controls except for PSGL-1 (4xeNAMPT, 21x IL-6, 2x Ang-2, 13x IL-1β,3x IL-1RA, 2x TNF-α, 3x S100A8, 136xGFAP, 9x NFL, 9x Tau). ARDS patients demonstrated significantly elevated levels of all biomarkers compared to controls except for GFAP (8x eNAMPT, 12x IL-6, 5xAng-2, 13x IL-1β, 6x IL-1RA, 1.3xPSGL-1, 3x TNF-α, 3x S100A8, 11x NFL, 5xTau). Comparing ARDS to TBI, IL-6 was significantly higher in TBI subjects (2x)whereas eNAMPT, TNF-α, and Ang-2 were all significantly elevated (2x) in ARDS. GFAP was significantly elevated only in TBI. CONCLUSIONS: The elevations in inflammatory biomarkers in TBI- and ARDS-exposed subjects without neuro trauma reflect shared activation of innate immunity consistent with the observation that 25% of TBI patients develop lung injury (including ARDS) supporting lung brain axis disruption. GFAP appears to be a TBI-specific biomarker with the elevations in NFL and Tau in ARDS subjects potentially reflecting peripheral neurological damage without lung brain axis disruption. Longitudinal studies of well-phenotyped TBI and ARDS subjects are needed to disclose the integrated inflammatory responses and the value of inflammatory biomarker testing to detect bidirectional injuries.