Biological and Clinical Factors contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

Abstract

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. Exploratory studies evaluating the impact of COVID-19 infection on the plasma metabolome have been performed, often with small numbers of patients, and with or without relevant control data; however, determining the impact of biological and clinical variables remains critical to understanding potential markers of disease severity and progression. The present large study, including relevant controls, sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831), testing positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on 831 plasma samples from acutely ill patients while in the emergency department, at admission, and during hospitalization. We then performed additional lipidomics analyses of the 60 subjects with the lowest and highest body mass index, either COVID-19 positive or negative. Omics data were correlated to detailed data on patient characteristics and clinical laboratory assays measuring coagulation, hematology and chemistry analytes. Significant changes in arginine/proline/citrulline, tryptophan/indole/kynurenine, fatty acid and acyl-carnitine metabolism emerged as highly relevant markers of disease severity, progression and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half yielding ~ 78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for follow-up mechanistic studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19

“…Y-axis indicates peak areas for each selected analyte, as determined by UHPLC-MS. Statistically-significant differences exist between controls (CinC) and patients (PinP) in the levels of tryptophan and anthranilate. Plasma exchanges cause strong significant differences in anthranilate levels and the ratio tryptophan-kynurenine (Trp/Kyn) in all groups, a marker of COVID-19 disease severity and mortality in previous studies (27).…”

Reprogramming of red blood cell metabolism in Zika virus–infected donors

“…This suggests potentially increased activity of heme dioxygenases, since these enzymes catalyze the oxidation of tryptophan to N‐formylkynurenine (kynurenine precursor and the first, rate‐limiting step in tryptophan catabolism) 60 . Notably, the products of tryptophan metabolism—in particular, elevated levels of kynurenine—have been proposed as prognostic for disease severity and outcomes in Dengue hemorrhagic fever 61 and SARS‐CoV‐2 62,63 ; thus, these observations could support a possible metabolic hallmark of disease due to viral infection, due to the activation of the cGAS/STING‐interferon/indole 2,3‐dioxygenase axis (rate‐limiting enzyme of the kynurenine pathway) 64 …”

“…These metabolites are regulated by the rate‐limiting step of this pathway, which is catalyzed by indole 2,3‐dioxygenase (IDO1). IDO1 is controlled by interferon signaling—critical in antiviral responses; therefore, it is interesting to consider that this signature—also noted for coronaviruses like SARS‐CoV‐2 22,62,63 —is likely not unique to flaviviruses but instead could be considered a general feature of viral infection. Of note, excess copies of interferon receptors due to Trisomy 21 in Down syndrome 97 corresponds to the basal activation of this pathway and increases severity of cognitive deficit and worse outcomes upon SARS‐CoV‐2 infection in this population 98 .…”

“…Additional caveats of the present study include insufficient clinical information regarding subject blood group classifications (correlated with disease severity for some viral infection, like COVID‐19 62 ), lack of availability of other hematological parameters (MCV, Hct, etc., all factors affected in subjects suffering from other viral infections that affect iron metabolism and/or erythropoiesis, such as SARS‐CoV‐2 62 ), disease severity and stage (symptoms reported were relativity mild, and a larger cohort is needed to subdivide donors according to symptoms presented), biological variables such as ethnicity, and other possible comorbidities. Although preliminary attempts were made to determine the impact of ZIKV infection on RBCs as a function of sex and age, these were insufficiently powered.…”

Combined Oral Contraceptive Treatment Does Not Alter the Gut Microbiome but Affects Amino Acid Metabolism in Sera of Obese Girls With Polycystic Ovary Syndrome

“…Detailed methods have been published previously. (Nemkov et al, 2019;D'Alessandro et al, 2021) Briefly, a volume of There were no statistical differences in α-diversity between groups. Shannon diversity, Shannon evenness, and richness (Sobs) (measures of α-diversity) were calculated using rarefaction and compared across groups using linear models adjusting for batch effects.…”