Abstract
Predisposing aetiologies in Acute Respiratory Distress Syndrome (ARDS), perpetuates to heterogeneous clinical course hampering therapeutic response. Therefore, physiological variables need to be identified by stratifying ARDS subphenotypes and endotype, to target ARDS heterogeneity. The present study is stimulated by the fact that the ARDS heterogeneity arises from diverse pathophysiological changes leading to distinct ARDS endotypes characterized by perturbed biological mechanism which can be exploited in terms of metabolic profile by metabolomics. Biological endotypes using (n = 464 patients and controls), mBALF and serum samples were identified by high – resolution NMR spectroscopy from two clinically diagnosed ARDS subtypes grouped under mild, moderate and severe ARDS as subphenotype1and pulmonary and extra – pulmonary ARDS as subphenotype2. The identified mBALF endotypes (isoleucine, leucine, valine, lysine/arginine, tyrosine, threonine) and serum endotypes (proline, glutamate, phenylalanine, valine) in both subphenotypes by statistical analysis were tested for their reproducibility and robustness. By combining metabolic endotypes with clinical based mortality score (APACHE and SOFA) added to their predictive performance as ARDS mortality predictors. Thus, a comprehensive set of mBALF endotypes representing compartmentalized lung milieu and serological endotypes representing systemic markers of ARDS subtypes were validated. The interlinked biological pathway of these disease specific endotype further elucidated their role as candidate biomarker in governing ARDS heterogeneous biology.
Highlights
Distinct physiological differences in these Acute Respiratory Distress Syndrome (ARDS) subtypes[9,10,11]
Metabolomics provides the answer to the paradigm shift of identifying metabolic endotypes that best stratifies ARDS reflecting the underlying difference in biological mechanism due to pathophysiological stimuli, which results in different response to therapeutic intervention and therapies[24,25]
Different degrees of anatomical and physiological derangement add to clinical and biological heterogeneity which requires characterization of disease specific endotype by epidemiological approaches. Both mini Bronchoalveolar lavage fluid (mBALF) and serum has been previously established as an archetype of lung milieu and ailing prognosticator of ARDS19,20,28–31
Summary
Distinct physiological differences in these ARDS subtypes[9,10,11]. ARDS subphenotypes has been grouped as mild, moderate and severe phenotype and pulmonary and extra-pulmonary phenotype based on underlying biology and severity[12]. Endotype specific to the disease subtypes can be correlated to biomarker validation by epidemiological approaches In this respect, small molecular weight metabolites are the endpoint of all the biochemical and physiological process involved in metabolism. We have employed NMR based metabolomics to identify metabolic endotypes, which can serve as biological marker mirroring the patient heterogeneity due to diverse pathophysiological process underlying ARDS subphenotype. To test the physiological difference in these two model n = 464 samples of mini Bronchoalveolar lavage fluid (mBALF) and serum biofluid were collected and subjected to metabolic profiling by NMR Though both these biofluids vary in the mode of collection and biomarker information but together depict comprehensive view of ARDS biology by providing both circulating biomarkers of systemic origin and localized biomarkers of lung milieu. Metabolomics proves to be platform in mapping ARDS heterogeneous biology by determining the predictive endotype
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