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Open Forum Infect Dis
. 2026 Jun 23;13(6):ofag316.
doi: 10.1093/ofid/ofag316. eCollection 2026 Jun.
Severe Hospitalization-Requiring Viral Infection With Influenza or COVID-19: Metabolic Pathway Analysis
Kirstine K Rasmussen 1 , Wendy Bannister 1 , Theis Itenov 2 3 , Melissa Skeans 4 , Sarah L Pett 5 , Christine Wendt 6 7 , Ken M Kunisaki 6 7 , Gail Matthews 8 9 , Alexander Jordan 10 , Charlotte Suppli Ulrik 3 11 , Therese Lapperre 12 , Rasmus Dahlin Bojesen 13 , Uffe Bodtger 14 , Emma E Ilett 1 15 , Thomas Benfield 11 , Pradeesh Sivapalan 3 10 , Daniel D Murray 1 , Jens-Ulrik Stæhr Jensen 3 10
Affiliations
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: SARS-CoV-2; influenza; kynurenine; metabolomics; tryptophan.
. 2026 Jun 23;13(6):ofag316.
doi: 10.1093/ofid/ofag316. eCollection 2026 Jun.
Severe Hospitalization-Requiring Viral Infection With Influenza or COVID-19: Metabolic Pathway Analysis
Kirstine K Rasmussen 1 , Wendy Bannister 1 , Theis Itenov 2 3 , Melissa Skeans 4 , Sarah L Pett 5 , Christine Wendt 6 7 , Ken M Kunisaki 6 7 , Gail Matthews 8 9 , Alexander Jordan 10 , Charlotte Suppli Ulrik 3 11 , Therese Lapperre 12 , Rasmus Dahlin Bojesen 13 , Uffe Bodtger 14 , Emma E Ilett 1 15 , Thomas Benfield 11 , Pradeesh Sivapalan 3 10 , Daniel D Murray 1 , Jens-Ulrik Stæhr Jensen 3 10
Affiliations
- PMID: 42344786
- PMCID: PMC13288296
- DOI: 10.1093/ofid/ofag316
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: SARS-CoV-2; influenza; kynurenine; metabolomics; tryptophan.