Severe Hospitalization-Requiring Viral Infection With Influenza or COVID-19: Metabolic Pathway Analysis

Influenza and SARS-CoV-2 can cause severe respiratory failure, but the metabolic pathways that lead to clinical deterioration are not fully uncovered. Tryptophan catabolism has been linked to disease progression and adverse outcomes. We aimed to find out whether the link between tryptophan catabolism and disease progression is shared by the 2 viral infections and, in an exploratory manner, to assess other metabolic pathways.

Adults hospitalized due to influenza or SARS-CoV-2 from 3 prospective studies were pooled in a nested case-control study design. Cases were defined by disease progression: an increase in oxygen supplementation, intensive care unit admission, or death within 28 days. Cases were matched 1:2 to nonprogressors by pathogen and initial disease severity. We tested associations of plasma kynurenine, tryptophan, and the kynurenine/tryptophan ratio with disease progression. Metabolic profiles were investigated by unsupervised clustering-based, pathway-resolved methods.

We included 303 patients hospitalized with influenza or SARS-CoV-2. Higher levels of kynurenine and higher kynurenine/tryptophan ratios were associated with disease progression (odds ratio per log₂ increase [95% CI], 1.81 [1.21-2.70] and 1.89 [1.26-2.84], respectively) independent of pathogen. Two metabolite modules were associated with disease progression. One module contained multiple amino acids, including kynurenine and 10 other tryptophan catabolism metabolites. The other module contained mainly lipids and xenobiotics.

Several groups of metabolites were associated with disease progression independent of the pathogen. This indicates that biological mechanisms related to disease severity are shared in influenza and COVID-19. These mechanisms could be used for risk stratification of patients for potential disease-modifying treatments.