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Open Forum Infect Dis. 2017 Oct 25;5(1):ofx228. doi: 10.1093/ofid/ofx228. eCollection 2018 Jan.

Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study.

Collaborators (195)

Lundgren J, Jansson P, Pearson M, Aagaard B, Hudson F, Bennet R, Pacciarini F, Angus B, Paton N, Collaco Moraes Y, Cooper D, Pett S, 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, Avihingsanon A, Ruxrungtham K, 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, Wentworth D, Baxter J, Brown S, Hoover M, Beigel J, Davey RT Jr., 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, Baxter J, Coburn P, Freiberg M, Koerbel G, Dharan N, Paez-Quinde M, Gunter J, Beilke M, Lu Z, Gunderson E, Baker J, Koletar S, Harber H, Hurt C, Marcus C, Allen M, Cummins S, Uslan D, Bonam T, Paez A, Santiago F, States D, Gardner E, DeHovitz J, Holman S, Watson V, Nixon D, Dwyer D, Kabir M, Pett S, Kilkenny F, Elliott J, Garlick J, McBride J, Richmond S, Barcan L, Sanchez M, Lopardo G, Barcelona L, Bonvehi P, Temporiti ER, Losso M, Macias L, Laplume H, Daciuk L, Warley E, Tavella S, Fernandez Cruz E, Paño J, Estrada V, Lopetegui P, Gimenez Julvez T, Ryan P, Sanz Moreno J, Knobel H, Soriano V, Dalmau D, Dockrell D, Angus B, Price D, Newport M, Chadwick D, Østergaard L, Yehdego Y, Pedersen C, Hergens L, Joensen Z, Aagaard B, Kronborg G, Collins P, Nielsen H, Gerstoft J, Baadegaard B, Koulouris N, Antoniadou A, Protopappas K, Polixronopoulos V, Diamantea F, Sambatakou H, Mariolis I, Vassilopoulos N, Gerogiannis A, Pinedo Ramirez Y, Cornelio Mauricio E, Vega Bazalar J, Castillo Cordova R, Fãtkenhuerer G, Thomas E, Bergmann F, Fõllmer U, Rockstroh J, Englehardt A, Stephan C, Thomas E, Bogner J, Brockmeyer N, Klinker H, Chetchotisakd P, Jumpimai T, Avihingsanon A, Ruxrungtham K, Clumeck N, Kameya K, Chu MY, Wu TC, Horban A, Bakowska E, Burgmann H, Tobudic S, Maagaard A, Wolff M, Allendes G.

Author information

Medical Research Council Clinical Trials Unit (MRC CTU), Institute of Clinical Trials and Methodology, University College London, UK.
Clinical Research Group, Infections and Population Health, UCL, London, UK.
Kirby Institute, University of New South Wales, Kensington, Australia.
Minneapolis VA Health Care System, Minneapolis, Minnesota.
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
Division of Biostatistics, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota.
1st Department of Critical Care and Pulmonary Medicine, University of Athens School of Medicine, Evangelismos General Hospital, Athens, Greece.
Cooper University Hospital, Division of Infectious Disease, Camden, New Jersey.
Hospital La Paz, Madrid, Spain.
HIV-NAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand.
Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Institute of Clinical Pathology and Medical Research, Pathology West and NSW Health Pathology, Westmead Hospital and University of Sydney, Westmead, Australia.
National National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.



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.


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.


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).


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.

ClinicalTrialsgov Identifier:



indoleamine-2,3-dioxygenase; influenza; kynurenine; outcome; tryptophan

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