Increased indoleamine-2,3-dioxygenase activity is associated with poor clinical outcome in adults hospitalized with influenza in the INSIGHT FLU003Plus study

Sarah L. Pett, Ken M. Kunisaki, Deborah Wentworth, Timothy J. Griffin, Ioannis Kalomenidis, Raquel Nahra, Rocio Montejano Sanchez, Shane W. Hodgson, Kiat Ruxrungtham, Dominic Dwyer, R. T. Davey, Chris H. Wendt, J. Lundgren, P. Jansson, M. Pearson, B. Aagaard, F. Hudson, R. Bennet, F. Pacciarini, B. AngusN. Paton, Y. Collaco Moraes, D. Cooper, S. Pett, S. Emery, D. Courtney-Rogers, R. Robson, F. Gordin, A. Sanchez, B. Standridge, M. Vjecha, A. Moricz, M. Delfino, W. Belloso, M. Losso, K. Tillmann, G. Touloumi, V. Gioukari, O. Anagnostou, A. La Rosa, M. J. Saenz, P. Lopez, P. Herrero, B. Portas, A. Avihingsanon, K. Ruxrungtham, P. Kaewon, E. Denning, N. Engen, J. D. Neaton, For the INSIGHT FLU003 Plus Study Group

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4 Scopus citations

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.

Original languageEnglish (US)
Article numberofx228
JournalOpen Forum Infectious Diseases
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2018

Bibliographical note

Funding Information:
Potential conflicts of interest. The views expressed in this article are those of the authors and do not reflect the views of the US Government, the National Institutes of Health, the Department of Veterans Affairs, the funders, or any of the authors’ affiliated academic institutions. Sarah L. Pett: grants from the University of Minnesota to support the conduct of the trial at the FLU003Plus sites under the jurisdiction of the University of New South Wales; funding from the University of New South Wales to conduct the FLU003Plus trial at the clinical site. Ken Kunisaki: protected research time was provided by the Department of Veterans Affairs Office of Research and Development. Deborah Wentworth: none. Timothy Griffin: none. Ioannis Kalomenidis: none. Raquel Nahra: none. Rocio Montejano Sanchez: none. Shane Hodgson: none. Kiat Ruxrungtham: protected research time was provided by the Department of Medicine, The Faculty of Medicine, Chulalongkorn University, Thailand. Chris Wendt: protected research time was provided by the Department of Veterans Affairs Office of Research and Development. Dominic Dwyer: funding from the University of New South Wales to support the conduct of the FLU003Plus clinical trial at the clinical site. Richard Davey: funding from the University of Minnesota to support the conduct of the FLU003Plus clinical trial at the clinical site. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Funding Information:
Financial support. The INSIGHT FLU studies are funded under a Subcontract award 13XS134 under Leidos Biomed’s Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.

Publisher Copyright:
© The Author(s) 2018.

Keywords

  • Indoleamine-2,3-dioxygenase
  • Influenza
  • Kynurenine
  • Outcome
  • Tryptophan

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