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Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study

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Abstract

Background/Introduction

Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine. An increase of its activity is associated with severity in patients with pneumonia. In chronic obstructive pulmonary disease (COPD) patients, an elevation of serotonin has been reported. Experimental models showed that cigarette smoke inhibits monoamine oxidase (MAO) leading to higher levels of serotonin. We investigated the prognostic ability of tryptophan, serotonin, kynurenine, IDO, and tryptophan hydroxylase (TPH) to predict short- and long-term outcomes in patients with a COPD exacerbation.

Methods

We measured tryptophan, serotonin, and kynurenine on admission plasma samples in patients with a COPD exacerbation from a previous trial by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). IDO and TPH were calculated as ratios of kynurenine over tryptophan, and serotonin over tryptophan, respectively. We studied their association with parameters measured in clinical routine at emergency department admission representing inflammation (C-reactive protein [CRP]), infection (procalcitonin [PCT]), oxygenation (SpO2), as well as patients' clinical outcome, confirmed by structured phone interviews.

Results

Mortality in the 149 included patients was 53.7% within six years of follow-up. While IDO activity showed strong positive correlations, tryptophan was negatively correlated with CRP and PCT. For 30-day adverse outcome defined as death and/or intensive care unit (ICU) admission, a multivariate regression analysis adjusted for age and comorbidities found strong associations for IDO activity (adjusted odds ratios of 31.4 (95%CI 1.1–857), p = 0.041) and TPH (adjusted odds ratios 27.0 (95%CI 2.2–327), p = 0.010). TPH also showed a significant association with mortality at 18 months, (hazard ratio 2.61 (95%CI 1.2–5.8), p = 0.020).

Conclusion

In hospitalized patients with a COPD exacerbation, higher IDO and TPH activities independently predicted adverse short-term outcomes and TPH levels were also predictive of 18-month mortality. Whether therapeutic modulation of the serotonin pathway has positive effects on outcome needs further investigation.

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Abbreviations

AUC:

Area under curve

CAP:

Community-acquired pneumonia

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disease

CRP:

C-reactive protein

ED:

Emergency department

HR:

Hazard ratio

ICU:

Intensive care unit

IDO:

Indoleamine 2,3-dioxygenase

IQR:

Interquartile range

KYN:

Kynurenine

MAO:

Monoamine oxidase

OR:

Odds ratio

PCT:

Procalcitonin

SpO2 :

Oxygen saturation

SSRI:

Selective serotonin re-uptake inhibitor

TDO:

Tryptophan 2,3-dioxygenase

TPH:

Tryptophan hydroxylase

TRP:

Tryptophan

5-HT:

Serotonin (5-hydroxytryptamine)

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Acknowledgements

We are thankful for all patients, patients’ relatives, and all local general practitioners who participated in this study. In particular, we thank the emergency department, medical clinic, and central laboratory staff of the University Hospital Basel and the Cantonal Hospitals Aarau, Liestal, Lucerne, and Muensterlingen, and the ‘Buergerspital’ Solothurn for their assistance and technical support. Finally, we acknowledge our ProHOSP Study Group for their important support.

Author Contributions

PS, MC-C, and BM created concept and design, wrote the protocol, and initiated the initial ProHOSP study. MM and PS drafted the present manuscript and performed the statistical analyses. CS, AH, and LB performed laboratory measurements of p180-Kit. All authors contributed to the data acquisition, interpretation, and drafting of the analyses, critical review for important content, and final approval of the manuscript. PS had full access to all data and takes responsibility for the accuracy of the data analysis and the integrity of the work.

The ProHOSP Study Group included: U. Schild, K. Regez, R. Bossart, C. Blum, M. Wolbers, S. Neidert, I. Suter, H.C. Bucher, F. Mueller, A. Chaudry, J. Haeuptle, R. Zarbosky, R. Fiumefreddo, M. Wieland, C. Nussbaumer, A. Christ, R. Bingisser, and K. Schneider (University Hospital Basel, Basel, Switzerland); T. Bregenzer, D. Conen, A. Huber, and J. Staehelin (Kantonsspital Aarau, Aarau, Switzerland); W. Zimmerli, C. Falconnier, and C. Bruehlhardt (Kantonsspital Baselland, Liestal, Switzerland); C. Henzen and V. Briner (Kantonsspital Luzern, Luzern, Switzerland); T. Fricker, C. Hoess, M. Krause, I. Lambinon, and M. Zueger (Kantonsspital Muensterlingen, Muensterlingen, Switzerland); and R. Thomann, R. Schoenenberger, and R. Luginbuehl (Buergerspital Solothurn, Solothurn, Switzerland).

Funding

This study was supported in part by the Swiss National Science Foundation (SNSF Professorship, PP00P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). The initial trial was funded by the Swiss National Science Foundation (Grant SNF 3200BO-116177/1), Santé Suisse, the Gottfried and Julia Bangerter-Rhyner Foundation and BRAHMS Biomarkers.

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Authors and Affiliations

  1. Medical University Department, Kantonsspital Aarau, Medical faculty, University of Basel, Tellstrasse, 5001, Aarau and Basel, Switzerland

    Marc A. Meier, Manuel Ottiger, Alaadin Vögeli, Beat Mueller & Philipp Schuetz

  2. Department of Laboratory Medicine, Kantonsspital Aarau, Aarau, Switzerland

    Christian Steuer, Luca Bernasconi & Andreas Huber

  3. Medical Department, Buergerspital Solothurn, Solothurn, Switzerland

    Robert Thomann

  4. Medical University Department, University Hospital Basel, Basel, Switzerland

    Mirjam Christ-Crain

  5. Medical Department, Kantonsspital Luzern, Lucerne, Switzerland

    Christoph Henzen

  6. Medical Department, Kantonsspital Muensterlingen, Muensterlingen, Switzerland

    Claus Hoess

  7. Medical University Department, Kantonsspital Baselland, Liestal, Switzerland

    Werner Zimmerli

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  1. Marc A. Meier
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  2. Manuel Ottiger
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  13. Philipp Schuetz
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Corresponding author

Correspondence to Philipp Schuetz.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in this study.

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Meier, M.A., Ottiger, M., Vögeli, A. et al. Activation of the Serotonin Pathway is Associated with Poor Outcome in COPD Exacerbation: Results of a Long-Term Cohort Study. Lung 195, 303–311 (2017). https://doi.org/10.1007/s00408-017-0004-7

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  • DOI: https://doi.org/10.1007/s00408-017-0004-7

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