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Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia

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Abstract

Purpose

Excessive activation of the endothelium is associated with adverse outcomes in patients with systemic infections. Endothelium-associated peptides, such as endothelin-1 (ET-1), correlate closely with endothelial activation, and therefore serve as surrogate biomarkers. Our aim was to investigate precursor peptides of endothelin-1 (proET1) on admission and during follow-up on days 3, 5 and 7 in a prospective cohort of 925 patients with community-acquired pneumonia.

Methods

We investigated the association of initial and follow-up proET1 and other prohormone levels with 30-day mortality and ICU admission in proportional Cox regression models with time-varying covariates adjusted for the pneumonia-severity-index (PSI), and calculated reclassification statistics.

Results

The mortality rate and ICU admission rate were 5.4% (95% CI 3.9–6.8%) and 9.0% (95% CI 7.1–10.8%). ProET1 levels on admission and changes from baseline to day 3 were significant mortality predictors with adjusted hazard ratios of 10.5 (95% CI 2.9–38.6) and 28.4 (95% CI 7.0–115.1). Initial proET1 levels improved the PSI in reclassification statistics (net reclassification improvement of 0.29, p < 0.0001) and in c-statistics (from 0.79 to 0.83, p < 0.01). Changes of proET1 on day 3 improved the c-statistic of the combined model of PSI and initial proET1 from 0.80 to 0.85 (p < 0.01) and reclassification tables demonstrated a significant improvement (net reclassification improvement 0.44, p < 0.0001). Similar significant results were found for the risk for ICU admission.

Conclusions

In community-acquired pneumonia, ET-1 precursor peptides on admission and changes from baseline to day 3 were independent predictors for mortality and ICU admission, and significantly improved the PSI. If verified in intervention studies, monitoring of proET1 may be helpful for endothelium targeting therapies and for risk stratification complementary to other prohormones.

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Abbreviations

ADH:

Antidiuretic hormone

ADM:

Adrenomedullin

ANP:

Atrial-natriuretic peptide

ATS:

American Thoracic Society

AUC:

Area under the receiver operating characteristic curve

CAP:

Community-acquired pneumonia

CI:

Confidence interval

ET1:

Endothelin1

HR:

Hazard ratio

ICU:

Intensive care unit

IDI:

Integrated discrimination improvement

IQR:

Interquartile ranges

NRI:

Net reclassification improvement

PSI:

Pneumonia Severity Index

PCT:

Procalcitonin

ROC:

Receiver operating characteristic curve

TRACE:

Time-resolved amplified cryptate emission

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Acknowledgments

We thank Prof. E.Orav for very helpful scientific discussions. We are grateful to the Data Safety and Monitoring Board, namely A. P. Perruchoud, S. Harbarth and A. Azzola for continuous supervision of this trial and all local physicians, the nursing staff, the patients and their relatives who participated in this study. Especially, we thank the staff of the emergency room, medical clinics and central laboratories of the University Hospital Basel, the Cantonal Hospitals Liestal, Aarau, Luzern and Muensterlingen and the “Buergerspital” Solothurn for their very helpful assistance, patience and technical support. We thank other members of the ProHOSP Study Group for their important help during the study. The initial trial was supported by grant SNF 3200BO-116177/1 from the Swiss National Science Foundation. Dr. Schuetz was supported by a research grant from the Swiss Foundation for Grants in Biology and Medicine (Schweizerische Stiftung für medizinisch-biologische Stipendien, SSMBS, PASMP3-127684/1). Dr. Christ-Crain was supported by a grant of the Swiss National Science Foundation (PP00P3-12346).

Conflict of interest

No commercial sponsor had any involvement in design and conduct of this study, namely collection, management, analysis, and interpretation of the data; and preparation, decision to submit, review, or approval of the manuscript. PS, MCC and BM received support from BRAHMS to attend meetings and fulfilled speaking engagements. BM has served as a consultant and received research support. All other authors declare that they have no competing interests.

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Authors and Affiliations

  1. Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA

    Philipp Schuetz

  2. Department of Internal Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, Basel, Switzerland

    Mirjam Christ-Crain

  3. Medical University Clinic, Kantonsspital Liestal, Liestal, Switzerland

    Werner Zimmerli

  4. Medical University Clinic, Kantonsspital Aarau, Aarau, Switzerland

    Beat Mueller

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  1. Philipp Schuetz
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  2. Mirjam Christ-Crain
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  4. Beat Mueller
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Corresponding author

Correspondence to Philipp Schuetz.

Additional information

Members of the ProHOSP Study Group are listed in the appendix.

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Appendix

Appendix

The ProHOSP Study group included the following persons: Ursula Schild, RN, Katharina Regez, RN, Rita Bossart, RN, Robert Thomann, MD, Claudine Falconnier, MD, Marcel Wolbers, PHD, Stefanie Neidert, MD, Thomas Fricker, MD, Claudine Blum, MD, Ronald Schoenenberger, MD, Christoph Henzen, MD, Thomas Bregenzer, MD, Claus Hoess, MD, Martin Krause, MD, Heiner C. Bucher, MD, Fabian Mueller, Jeannine Haeuptle, Roya Zarbosky, Rico Fiumefreddo, Melanie Wieland, RN, Charly Nusbaumer, MD, Andres Christ, MD, Roland Bingisser, MD, Kristian Schneider, RN, Brigitte Walz, PhD, Verena Briner, MD, Dieter Conen, MD, Andreas Huber, MD, Jody Staehelin, MD, Aarau, Chantal Bruehlhardt, RN, Ruth Luginbuehl, RN, Agnes Muehlemann, PhD, Ineke Lambinon and Max Zueger, MD.

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Schuetz, P., Christ-Crain, M., Zimmerli, W. et al. Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia. Intensive Care Med 37, 970–980 (2011). https://doi.org/10.1007/s00134-011-2208-2

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