Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset

Abstract

There is considerable biological and physiological heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a subgroup of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Nontargeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were conducted to find discriminant metabolites. Seven-hundred and sixty unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared with edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This "high metabolite" endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biological heterogeneity among ARDS patients who meet standard clinical and physiological criteria for ARDS.

Evolution of ARDS biomarkers: Will metabolomics be the answer?

“…The group compared their findings with Calfee et al's results (14); however, because of lack of plasma samples a conclusion was not possible (54). The study could not differentiate between patients with ARDS and hydrostatic pulmonary edema controls (54). Pathway analysis of the 235 significant metabolites revealed a statistically significant overrepresentation of a single pathway (alanine, aspartate, and glutamate metabolism).…”

“…The study identified 6 patients with "hypermetabolic subtype" ARDS (6/16, 38%) mostly caused by nonpulmonary sepsis who had higher levels of 235 metabolites and were different from the rest of the patients with ARDS (10/16, 62%). The group compared their findings with Calfee et al's results (14); however, because of lack of plasma samples a conclusion was not possible (54). The study could not differentiate between patients with ARDS and hydrostatic pulmonary edema controls (54).…”

“…Rogers et al sought to prove ARDS metabolic heterogeneity and hypothesized the presence of a subset of ARDS with a distinct metabolic profile (54). They compared the edema fluid of 16 patients with ARDS and 13 controls with hydrostatic pulmonary edema using untargeted metabolomics (ultrahighperformance liquid chromatography-tandem mass spectrometry for basic species, acidic species, and lipids).…”

ARDS Subphenotypes: Understanding a Heterogeneous Syndrome

“…Meyer et al identified an IL-1RN coding variant that increased risk of developing ARDS in sepsis [31], and Zhu et al found certain micro-RNAs to be risk biomarkers for ARDS among critically ill adults [32], but genomic and transcriptomic subphenotyping of patients with established ARDS remains largely unexplored. In a small cohort of patients with ARDS, Rogers et al found a subset of patients with a distinct metabolic profile with higher levels of numerous metabolites in undiluted pulmonary edema fluid [33]. This "high metabolite" subphenotype was associated with higher mortality but, in part because of the challenges associated with analyzing pulmonary edema fluid, these findings have yet to be reproduced in a larger cohort.…”

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

“…Metabolites are the downstream products of multiple intracellular biomolecules including genes and protein transporters, which enable metabolomics to serve as a remarkable tool that precisely describes "what is happening" within our body [2]. Previous studies have performed metabolomic analysis of plasma, pulmonary edema fluid and bronchoalveolar lavage fluid (BALF) in ARDS patients, preliminarily results revealed a broad range of metabolites that could help in diagnosis and stratify ARDS [3][4][5][6]. However, it is still unknown whether there exist any specific metabolites that not only help in identifying different phenotypes of ARDS but also have a crucial function in the disease process.…”