Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study
Author:
Pett Sarah L123, Kunisaki Ken M45, Wentworth Deborah6, Griffin Timothy J7, Kalomenidis Ioannis8, Nahra Raquel9, Montejano Sanchez Rocio10, Hodgson Shane W4, Ruxrungtham Kiat1112, Dwyer Dominic13, Davey Richard T14, Wendt Chris H45, 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 M J, 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 J D, Nelson R, Quan S F, Schultz T, Wentworth D, Baxter J, Brown S, Hoover M, Beigel J, Davey R T, Dewar R, Gover E, McConnell R, Metcalf J, Natarajan V, Rehman T, Voell J, Dwyer D E, 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 E R, 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 M Y, Wu T C, Horban A, Bakowska E, Burgmann H, Tobudic S, Maagaard A, Wolff M, Allendes G,
Affiliation:
1. Medical Research Council Clinical Trials Unit (MRC CTU), Institute of Clinical Trials and Methodology, University College London, UK 2. Clinical Research Group, Infections and Population Health, UCL, London, UK 3. Kirby Institute, University of New South Wales, Kensington, Australia 4. Minneapolis VA Health Care System, Minneapolis, Minnesota 5. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 6. Division of Biostatistics, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 7. Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 8. 1st Department of Critical Care and Pulmonary Medicine, University of Athens School of Medicine, Evangelismos General Hospital, Athens, Greece 9. Cooper University Hospital, Division of Infectious Disease, Camden, New Jersey 10. Hospital La Paz, Madrid, Spain 11. HIV-NAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand 12. Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 13. Institute of Clinical Pathology and Medical Research, Pathology West and NSW Health Pathology, Westmead Hospital and University of Sydney, Westmead, Australia 14. National National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Abstract
Abstract
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.
ClinicalTrials.gov Identifier
NCT01056185.
Funder
National Cancer Institute National Institute of Allergy and Infectious Diseases
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Oncology
Cited by
11 articles.
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