Combined Plasma and Urinary Metabolomics Uncover Metabolic Perturbations Associated with Severe Respiratory Syncytial Viral Infection and Future Development of Asthma in Infant Patients.

Shao Thing Teoh,John W Winters,Nikita L Vandenbosch,Jeremy W Prokop,Surender Rajasekaran,Sophia Y Lunt,Mara L Leimanis-Laurens,Sarah S Comstock,André S Bachmann

doi:10.3390/metabo12020178

Shao Thing Teoh, John W Winters + Show 7 more

Open Access

https://doi.org/10.3390/metabo12020178

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Abstract

A large percentage of infants develop viral bronchiolitis needing medical intervention and often develop further airway disease such as asthma. To characterize metabolic perturbations in acute respiratory syncytial viral (RSV) bronchiolitis, we compared metabolomic profiles of moderate and severe RSV patients versus sedation controls. RSV patients were classified as moderate or severe based on the need for invasive mechanical ventilation. Whole blood and urine samples were collected at two time points (baseline and 72 h). Plasma and urinary metabolites were extracted in cold methanol and analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and data from the two biofluids were combined for multivariate data analysis. Metabolite profiles were clustered according to severity, characterized by unique metabolic changes in both plasma and urine. Plasma metabolites that correlated with severity included intermediates in the sialic acid biosynthesis, while urinary metabolites included citrate as well as multiple nucleotides. Furthermore, metabolomic profiles were predictive of future development of asthma, with urinary metabolites exhibiting higher predictive power than plasma. These metabolites may offer unique insights into the pathology of RSV bronchiolitis and may be useful in identifying patients at risk for developing asthma.

Highlights

Respiratory syncytial virus (RSV) is a major cause of childhood morbidity across the world and mortality in low to middle income countries [1]
LC-MS/MS has been employed in a number of metabolomic analyses of clinical samples including urinary and serum or plasma [10,11,12,13]; less comprehensive in coverage than untargeted metabolomics, targeted LC-MS/MS has the advantage of increased sensitivity and quantitative performance [14,15], and our established method [16,17,18,19] is capable of profiling a wide range of metabolites including amino acids, phosphorylated compounds in glycolysis and pentose phosphate pathway, organic acids in the tricarboxylic acid (TCA) cycle, as well as intermediates in nucleotide biosynthesis and nucleotide sugar metabolism to detect perturbations within a variety of metabolic pathways
We identified plasma and urinary metabolites correlated with severity of RSV infection, and found urinary metabolites with strong predictive power for future asthma development in RSV patients

Summary

Introduction

Respiratory syncytial virus (RSV) is a major cause of childhood morbidity across the world and mortality in low to middle income countries [1]. Twenty percent of the annual birth cohort develops viral bronchiolitis that requires medical attention [3], and acutely ill patients have been reported to continue having other respiratory problems requiring medical attention throughout their childhood [4]. Metabolomics has been used in a number of studies to identify associations between metabolic changes in biofluids and perturbations to the immune system; for example, altered levels of aromatic amino acids, fatty acids and energy metabolites have been reported to associate with serum inflammatory markers in a number of different medical conditions [6,7,8,9]. We extend our study of the aforementioned cohort by using liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomics to characterize metabolic perturbations associated with RSV severity in plasma and urine of these patients. Since metabolomics are predictive of the development of disease [20], biomarkers identified in this study may have prognostic utility in determining whether severe disease may develop after initial hospitalization

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