Development of a metabolome-based respiratory infection prognostic during COVID-19 arrival

In a new respiratory virus pandemic, optimizing allocation of scarce medical resources becomes an urgent challenge. Infection prognosis takes on particular importance when allocating scarce antiviral antibodies and drugs, which are most effective when administered before the onset of severe disease. During arrival of the COVID-19 pandemic to the United States in 2020, we conducted a prognostic biomarker discovery and validation effort based upon metabolomic profiling with a liquid-chromatography-mass spectrometer (LC-MS) type used clinically for rapid toxicology. We obtained urine specimens from 163 patients presenting for evaluation. We obtained LC-MS profiles in the initial cohort and used machine learning methods to define a simplified urine metabolomic signature associated with respiratory failure or death by 90 days. This signature was composed of three metabotypes linked to intestinal microbiome metabolism and anticonvulsant use, with a receiver-operator characteristic area under the curve (ROC AUC) of 89.4%. Blinded application of this signature to the subsequent validation cohort yielded a ROC AUC of 81.2%. A model trained on the two baseline metabotypes present before intubation exhibited similar performance in the validation cohort. This study demonstrates the plausibility and promise of rapid metabolome-based prognostic discovery and validation in the opening wave of a pandemic. The approach used here could be used to inform therapeutic and resource allocation decisions early in a future epidemic.IMPORTANCEIn a new respiratory virus pandemic, the ability to identify patients at greatest risk for severe disease is essential to direct scarce medical resources to those most likely to benefit from them. Tools to predict disease severity are best developed early in a pandemic, but laboratory-based resources to develop these may be limited by available technology and by infection precautions. Here, we show that an accessible metabolic profiling approach could identify a prognostic signature of severe disease in the initial wave of COVID-19, when patients presenting for care often exceeded the available doses of convalescent plasma and remdesivir. In a future pandemic, this approach, alongside efforts to identify clinical disease severity predictors, could improve patient outcomes and facilitate therapeutic trials by identifying individuals at high risk for severe disease.