Dysregulated nicotinamide adenine dinucleotide metabolome in patients hospitalized with COVID-19.

Nicotinamide adenine dinucleotide (NAD⁺) depletion has been postulated as a contributor to the severity of COVID-19; however, no study has prospectively characterized NAD⁺ and its metabolites in relation to disease severity in patients with COVID-19. We measured NAD⁺ and its metabolites in 56 hospitalized patients with COVID-19 and in two control groups without COVID-19: (1) 31 age- and sex-matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD⁺ concentrations in COVID-19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1-methylnicotinamide concentrations were significantly higher in patients with COVID-19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age- and sex-matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID-19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2-methyl-2-pyridone-5-carboxamide (2-PY), but not NAD⁺, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD⁺ synthesis as well as degradation, and dysregulation of NAD⁺-dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD⁺ concentrations are modestly reduced in COVID-19; however, NAD⁺ turnover is substantially increased with upregulation of genes involved in both NAD⁺ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity.