Increased indoleamine-2,3-dioxygenase activity is associated with poor clinical outcome in adults hospitalized with influenza in the INSIGHT FLU003Plus study
Pett SL., Kunisaki KM., Wentworth D., Griffin TJ., Kalomenidis I., Nahra R., Sanchez RM., Hodgson SW., Ruxrungtham K., Dwyer D., Davey RT., Wendt CH., Lundgren J., Jansson P., Pearson M., Aagaard B., Hudson F., Bennet R., Pacciarini F., Angus B., Paton N., Collaco Moraes Y., Cooper D., Emery S., Courtney-Rogers D., Robson R., Gordin F., Sanchez A., Standridge B., Vjecha M., Moricz A., Delfino M., Belloso W., Losso M., Tillmann K., Touloumi G., Gioukari V., Anagnostou O., La Rosa A., Saenz MJ., Lopez P., Herrero P., Portas B., Kaewon P., Ubolyam S., Brekke K., Campbell M., Denning E., DuChene A., Engen N., George M., Harrison M., Neaton JD., Nelson R., Quan SF., Schultz T., Baxter J., Brown S., Hoover M., Beigel J., Dewar R., Gover E., McConnell R., Metcalf J., Natarajan V., Rehman T., Voell J., Dwyer DE., Kok J., Uyeki T., Munroe D., Paez A., Bertrand M., Temesgen Z., Rizza S., Wolfe C., Carbonneau J., Novak R., Schwarber M., Polenakovik H., Clark L., Patil N., Riska P., Omotosho J., Faber L., Markowitz N., Glesby M., Ham K., Parenti D., Simon G., Coburn P., Freiberg M., Koerbel G., Dharan N., Paez-Quinde M., Gunter J., Beilke M., Lu Z., Gunderson E., Baker J.
Background. Indoleamine-2,3-dioxygenase (IDO) mediated tryptophan (TRP) depletion has antimicrobial and immuno-regulatory effects. Increased kynurenine (KYN)-to-TRP (KT) ratios, reflecting increased IDO activity, have been associated with poorer outcomes from several infections. Methods. We performed a case-control (1:2; age and sex matched) analysis of adults hospitalized with influenza A(H1N1) pdm09 with protocol-defined disease progression (died/transferred to ICU/mechanical ventilation) after enrollment (cases) or survived without progression (controls) over 60 days of follow-up. Conditional logistic regression was used to analyze the relationship between baseline KT ratio and other metabolites and disease progression. Results. We included 32 cases and 64 controls with a median age of 52 years; 41% were female, and the median durations of influenza symptoms prior to hospitalization were 8 and 6 days for cases and controls, respectively (P = .04). Median baseline KT ratios were 2-fold higher in cases (0.24 mM/M; IQR, 0.13-0.40) than controls (0.12; IQR, 0.09-0.17; P ≤ .001). When divided into tertiles, 59% of cases vs 20% of controls had KT ratios in the highest tertile (0.21-0.84 mM/M). When adjusted for symptom duration, the odds ratio for disease progression for those in the highest vs lowest tertiles of KT ratio was 9.94 (95% CI, 2.25-43.90). Conclusions. High KT ratio was associated with poor outcome in adults hospitalized with influenza A(H1N1)pdm09. The clinical utility of this biomarker in this setting merits further exploration.