Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study
Authors: Pett Sarah L , Kunisaki Ken M , Wentworth Deborah , Griffin Timothy J , Kalomenidis Ioannis , Nahra Raquel , Montejano Sanchez Rocio , Hodgson Shane W , Ruxrungtham Kiat , Dwyer Dominic , Davey Richard T , Wendt Chris H ,   INSIGHT FLU003 Plus Study Group, 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 
Published: January 2019

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.