Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia

Philipp Schuetz, Daiana Stolz, Beat Mueller, Nils G Morgenthaler, Joachim Struck, Christian Mueller, Roland Bingisser, Michael Tamm, Mirjam Christ-Crain, Philipp Schuetz, Daiana Stolz, Beat Mueller, Nils G Morgenthaler, Joachim Struck, Christian Mueller, Roland Bingisser, Michael Tamm, Mirjam Christ-Crain

Abstract

Background: Circulating levels of endothelin-1 are increased in sepsis and correlate with severity of disease. A rapid and easy immunoassay has been developed to measure the more stable ET-1 precursor peptides proET-1. The objective of this study was to assess the diagnostic and prognostic value of proET-1 in a prospective cohort of mainly septic patients with community-acquired pneumonia.

Methods: We evaluated 281 consecutive patients with community acquired pneumonia. Serum proET-1 plasma levels were measured using a new sandwich immunoassay.

Results: ProET-1 levels exhibited a gradual increase depending on the clinical severity of pneumonia as assessed by the pneumonia severity index (PSI) and the CURB65 scores (p < 0.001 and p < 0.01). The diagnostic accuracy to predict bacteraemia of procalcitonin (AUC 0.84 [95% 0.74-0.93]) was superior than C-reactive protein (AUC 0.67 [95%CI 0.56-0.78]) and leukocyte count (AUC 0.66 [95%CI 0.55-0.78]) and in the range of proET-1(AUC of 0.77 [95%CI 0.67-0.86]). ProET-1 levels on admission were increased in patients with adverse medical outcomes including death and need for ICU admission. ROC curve analysis to predict the risk for mortality showed a prognostic accuracy of proET-1 (AUC 0.64 [95%CI 0.53-0.74]), which was higher than C-reactive protein (AUC 0.51 [95%CI 0.41-0.61]) and leukocyte count (AUC 0.55 [95%CI 0.44-0.65]) and within the range of the clinical severity scores (PSI AUC 0.69 [95%CI 0.61-0.76] and CURB65 0.67 [95%CI 0.57-0.77]) and procalcitonin (AUC 0.59 [95% 0.51-0.67]). ProET-1 determination improved significantly the prognostic accuracy of the CURB65 score (AUC of the combined model 0.69 [95%CI 0.59-0.79]). In a multivariate logistic regression model, only proET1 and the clinical severity scores were independent predictors for death and for the need for ICU admission.

Conclusion: In community-acquired pneumonia, ET-1 precursor peptides correlate with disease severity and are independent predictors for mortality and ICU admission. If confirmed in future studies, proET-1 levels may become another helpful tool for risk stratification and management of patients with community-acquired pneumonia.

Trial registration: ISRCTN04176397.

Figures

Figure 1
Figure 1
ProET-1 levels on admission and during/after recovery after 42 days [IQR 35–53]. Data are shown as box plots.
Figure 2
Figure 2
ProET-1 levels increase according to disease severity as represented by the PSI (Pneumonia Severity Index).
Figure 3
Figure 3
ProET-1 levels increase according to disease severity as represented by the CURB65 score (Confusion – Urea – Respiration rate – Blood pressure – Age 65).
Figure 4
Figure 4
ProET-1 levels in survivors and nonsurvivors.
Figure 5
Figure 5
ProET-1 levels in patients with and without an adverse medical outcome including death and/or need for ICU admission.
Figure 6
Figure 6
Kaplan Meier Survival curves showing the incidence of death in patients with proET-1 levels above and below 94 pmol/L. P = log rank test.
Figure 7
Figure 7
Kaplan Meier Survival curves showing the incidence of adverse medical outcome including death and/or ICU admission in patients with proET-1 levels above and below 94 pmol/L. P = log rank test.

References

    1. Wanecek M, Weitzberg E, Rudehill A, Oldner A. The endothelin system in septic and endotoxin shock. Eur J Pharmacol. 2000;407:1–15. doi: 10.1016/S0014-2999(00)00675-0.
    1. Shah R. Endothelins in health and disease. Eur J Intern Med. 2007;18:272–282. doi: 10.1016/j.ejim.2007.04.002.
    1. Hemsen A, Modin A, Weitzberg E. Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone. Crit Care Med. 1996;24:1530–1536. doi: 10.1097/00003246-199609000-00017.
    1. Brauner JS, Rohde LE, Clausell N. Circulating endothelin-1 and tumor necrosis factor-alpha: early predictors of mortality in patients with septic shock. Intensive Care Med. 2000;26:305–313. doi: 10.1007/s001340051154.
    1. Tschaikowsky K, Sagner S, Lehnert N, Kaul M, Ritter J. Endothelin in septic patients: effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med. 2000;28:1854–1860. doi: 10.1097/00003246-200006000-00028.
    1. Wanecek M, Oldner A, Sundin P, Alving K, Weitzberg E, Rudehill A. Effects on haemodynamics by selective endothelin ET(B) receptor and combined endothelin ET(A)/ET(B) receptor antagonism during endotoxin shock. Eur J Pharmacol. 1999;386:235–245. doi: 10.1016/S0014-2999(99)00774-8.
    1. Krejci V, Hiltebrand LB, Erni D, Sigurdsson GH. Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock. Crit Care Med. 2003;31:203–210. doi: 10.1097/00003246-200301000-00031.
    1. Oldner A, Wanecek M, Goiny M, Weitzberg E, Rudehill A, Alving K, Sollevi A. The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock. Gut. 1998;42:696–702.
    1. Iskit AB, Senel I, Sokmensuer C, Guc MO. Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock. Eur J Pharmacol. 2004;506:83–88. doi: 10.1016/j.ejphar.2004.10.038.
    1. Struck J, Morgenthaler NG, Bergmann A. Proteolytic processing pattern of the endothelin-1 precursor in vivo. Peptides. 2005.
    1. Papassotiriou J, Morgenthaler NG, Struck J, Alonso C, Bergmann A. Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem. 2006;52:1144–1151. doi: 10.1373/clinchem.2005.065581.
    1. Schuetz P, Christ-Crain M, Morgenthaler NG, Struck J, Bergmann A, Muller B. Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium. 2007;14:345–351. doi: 10.1080/10623320701678326.
    1. Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, Zimmerli W, Harbarth S, Tamm M, Muller B. Procalcitonin Guidance of Antibiotic Therapy in Community-acquired Pneumonia: A Randomized Trial. Am J Respir Crit Care Med. 2006;174:84–93. doi: 10.1164/rccm.200512-1922OC.
    1. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243–250. doi: 10.1056/NEJM199701233360402.
    1. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377–382. doi: 10.1136/thorax.58.5.377.
    1. Niederman MS, Bass JB, Jr, Campbell GD, Fein AM, Grossman RF, Mandell LA, Marrie TJ, Sarosi GA, Torres A, Yu VL. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. American Thoracic Society. Medical Section of the American Lung Association. Am Rev Respir Dis. 1993;148:1418–1426.
    1. Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, Fine MJ. Causes of death for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med. 2002;162:1059–1064. doi: 10.1001/archinte.162.9.1059.
    1. Grandel U, Grimminger F. Endothelial responses to bacterial toxins in sepsis. Crit Rev Immunol. 2003;23:267–299. doi: 10.1615/CritRevImmunol.v23.i4.20.
    1. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–876. doi: 10.1146/annurev.pharmtox.41.1.851.
    1. Sanai L, Haynes WG, MacKenzie A, Grant IS, Webb DJ. Endothelin production in sepsis and the adult respiratory distress syndrome. Intensive Care Med. 1996;22:52–56. doi: 10.1007/BF01728331.
    1. Voerman HJ, Stehouwer CD, van Kamp GJ, Strack van Schijndel RJ, Groeneveld AB, Thijs LG. Plasma endothelin levels are increased during septic shock. Crit Care Med. 1992;20:1097–1101. doi: 10.1097/00003246-199208000-00005.
    1. Prat C, Dominguez J, Andreo F, Blanco S, Pallares A, Cuchillo F, Ramil C, Ruiz-Manzano J, Ausina V. Procalcitonin and neopterin correlation with aetiology and severity of pneumonia. J Infect. 2006;52:169–177. doi: 10.1016/j.jinf.2005.05.019.
    1. Masia M, Gutierrez F, Shum C, Padilla S, Navarro JC, Flores E, Hernandez I. Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index. Chest. 2005;128:2223–2229. doi: 10.1378/chest.128.4.2223.
    1. Ahlborg G, Weitzberg E, Lundberg JM. Circulating endothelin-1 reduces splanchnic and renal blood flow and splanchnic glucose production in humans. J Appl Physiol. 1995;79:141–145.
    1. Weitzberg E. Circulatory responses to endothelin-1 and nitric oxide with special reference to endotoxin shock and nitric oxide inhalation. Acta Physiol Scand Suppl. 1993;611:1–72.
    1. Weitzberg E, Lundberg JM, Rudehill A. Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock. 1991;33:222–227.
    1. Ramalho FS, Fernandez-Monteiro I, Rosello-Catafau J, Peralta C. Hepatic microcirculatory failure. Acta Cir Bras. 2006;21:48–53.
    1. Marshall JC. Biomarkers of Sepsis. Curr Infect Dis Rep. 2006;8:351–357. doi: 10.1007/s11908-006-0045-1.
    1. Vincent JL, Wendon J, Groeneveld J, Marshall JC, Streat S, Carlet J. The PIRO concept: O is for organ dysfunction. Crit Care. 2003;7:260–264. doi: 10.1186/cc2196.
    1. Wanecek M, Weitzberg E, Alving K, Rudehill A, Oldner A. Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. Acta Anaesthesiol Scand. 2001;45:1262–1270. doi: 10.1034/j.1399-6576.2001.451015.x.
    1. Weitzberg E, Hemsen A, Rudehill A, Modin A, Wanecek M, Lundberg JM. Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. Br J Pharmacol. 1996;118:617–626.
    1. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, Tamm M, Struck J, Bergmann A, Muller B. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397] Crit Care. 2006;10:R96. doi: 10.1186/cc4443.
    1. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9:R816–824. doi: 10.1186/cc3885.
    1. Christ-Crain M, Morgenthaler NG, Struck J, Bergmann A, Mueller B. Copeptin in critically ill patients – an observational study. Endocrine Society Boston, USA. 2006.
    1. Mueller B, Morgenthaler NG, Stolz D, Schuetz P, Mueller C, Bingisser R, Bergmann A, Tamm M, Christ-Crain M. Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest. 2007.
    1. Mueller B, Sueess E, Schuetz P, Mueller C, Bingisser R, Bergmann A, Stolz D, Tamm M, Morgenthaler NG, Christ-Carin M. Circulating levels of Pro-Atrial Natriuretic Peptide in Lower Respiratory Tract Infections. J Int Med. 2006.
    1. Mueller C, Laule-Kilian K, Frana B, Rodriguez D, Scholer A, Schindler C, Perruchoud AP. Use of B-type natriuretic peptide in the management of acute dyspnea in patients with pulmonary disease. Am Heart J. 2006;151:471–477. doi: 10.1016/j.ahj.2005.03.036.
    1. Mueller C, Laule-Kilian K, Scholer A, Perruchoud AP. B-type natriuretic peptide for risk stratification in community-acquired pneumonia. J Intern Med. 2005;258:391–393. doi: 10.1111/j.1365-2796.2005.01540.x.

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