Log in | Register

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

Philipp Schuetz| Mirjam Christ-Crain| Werner Zimmerli| Beat Mueller
Original
Volume 37, Issue 6 / June , 2011

Pages 970 - 980

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.

Keywords

References

  1. Lee WL, Slutsky AS (2010) Sepsis and endothelial permeability. N Engl J Med 363:689–691
    • View reference on PubMed
    • View reference on publisher's website
  2. Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101:3765–3777
    • View reference on PubMed
    • View reference on publisher's website
  3. Shah R (2007) Endothelins in health and disease. Eur J Int Med 18:272–282
    • View reference on publisher's website
  4. Wanecek M, Weitzberg E, Rudehill A, Oldner A (2000) The endothelin system in septic and endotoxin shock. Eur J Pharmacol 407:1–15
    • View reference on PubMed
    • View reference on publisher's website
  5. Aird WC (2008) Endothelium in health and disease. Pharmacol Rep 60:139–143
    • View reference on PubMed
  6. Hemsen A, Modin A, Weitzberg E (1996) Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone. Crit Care Med 24:1530–1536
    • View reference on PubMed
    • View reference on publisher's website
  7. Brauner JS, Rohde LE, Clausell N (2000) Circulating endothelin-1 and tumor necrosis factor-alpha: early predictors of mortality in patients with septic shock. Intensive Care Med 26:305–313
  8. Tschaikowsky K, Sagner S, Lehnert N, Kaul M, Ritter J (2000) Endothelin in septic patients: effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med 28:1854–1860
    • View reference on PubMed
    • View reference on publisher's website
  9. Wanecek M, Oldner A, Sundin P, Alving K, Weitzberg E, Rudehill A (1999) Effects on haemodynamics by selective endothelin ET(B) receptor and combined endothelin ET(A)/ET(B) receptor antagonism during endotoxin shock. Eur J Pharmacol 386:235–245
    • View reference on PubMed
    • View reference on publisher's website
  10. Krejci V, Hiltebrand LB, Erni D, Sigurdsson GH (2003) Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock. Crit Care Med 31:203–210
    • View reference on PubMed
    • View reference on publisher's website
  11. Oldner A, Wanecek M, Goiny M, Weitzberg E, Rudehill A, Alving K, Sollevi A (1998) The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock. Gut 42:696–702
    • View reference on PubMed
    • View reference on publisher's website
  12. Iskit AB, Senel I, Sokmensuer C, Guc MO (2004) Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock. Eur J Pharmacol 506:83–88
    • View reference on PubMed
    • View reference on publisher's website
  13. Wanecek M, Weitzberg E, Alving K, Rudehill A, Oldner A (2001) Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. Acta Anaesthesiol Scand 45:1262–1270
    • View reference on PubMed
    • View reference on publisher's website
  14. Weitzberg E, Hemsen A, Rudehill A, Modin A, Wanecek M, Lundberg JM (1996) Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. Br J Pharmacol 118:617–626
    • View reference on PubMed
  15. Struck J, Morgenthaler NG, Bergmann A (2005) Proteolytic processing pattern of the endothelin-1 precursor in vivo. Peptides 26:2482–2486
    • View reference on PubMed
    • View reference on publisher's website
  16. Papassotiriou J, Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 52:1144–1151
    • View reference on PubMed
    • View reference on publisher's website
  17. Schuetz P, Christ-Crain M, Morgenthaler N, Struck J, Bergmann A, Müller B (2007) Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium 14:345–351
    • View reference on PubMed
    • View reference on publisher's website
  18. Schuetz P, Stolz D, Mueller B, Morgenthaler NG, Struck J, Mueller C, Bingisser R, Tamm M, Christ-Crain M (2008) Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia. BMC Infect Dis 8:22
    • View reference on PubMed
    • View reference on publisher's website
  19. Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T (2010) Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia. Am J Respir Crit Care Med 182:1426–1434
    • View reference on PubMed
    • View reference on publisher's website
  20. Samransamruajkit R, Moonviriyakit K, Vanapongtipagorn P, Prapphal N, Deerojanawong J, Poovorawan Y (2002) Plasma endothelin-1 in infants and young children with acute bronchiolitis and viral pneumonia. Asian Pac J Allergy Immunol 20:229–234
    • View reference on PubMed
  21. Ando T, Ogawa K, Yamaki K, Hara M, Takagi K (1996) Plasma concentrations of atrial, brain, and C-type natriuretic peptides and endothelin-1 in patients with chronic respiratory diseases. Chest 110:462–468
    • View reference on PubMed
    • View reference on publisher's website
  22. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B (2009) Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 302:1059–1066
    • View reference on PubMed
    • View reference on publisher's website
  23. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Morgenthaler NG, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B (2010) Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care (London, England) 14:R106
    • View reference on publisher's website
  24. Vazquez M, Jockers K, Christ-Crain M, Zimmerli W, Muller B, Schuetz P (2010) MR-pro-atrial natriuretic peptide (MR-proANP) predicts short- and long-term outcomes in respiratory tract infections: a prospective validation study. Int J Cardiol [Epub ahead of print]
  25. Schuetz P, Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B (2010) Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J 37:384–392
    • View reference on PubMed
    • View reference on publisher's website
  26. Schuetz P, Christ-Crain M, Wolbers M, Schild U, Thomann R, Falconnier C, Widmer I, Neidert S, Blum CA, Schonenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Muller B (2007) Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial. BMC Health Serv Res 7:102
    • View reference on PubMed
    • View reference on publisher's website
  27. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72
    • View reference on PubMed
    • View reference on publisher's website
  28. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, Dean N, File T, Fine MJ, Gross PA, Martinez F, Marrie TJ, Plouffe JF, Ramirez J, Sarosi GA, Torres A, Wilson R, Yu VL (2001) Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 163:1730–1754
    • View reference on PubMed
  29. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN (1997) A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243–250
    • View reference on PubMed
    • View reference on publisher's website
  30. Struck J, Morgenthaler NG, Bergmann A (2005) Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients. Peptides 26:2500–2504
    • View reference on PubMed
    • View reference on publisher's website
  31. Morgenthaler NG, Struck J, Alonso C, Bergmann A (2005) Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 51:1823–1829
    • View reference on PubMed
    • View reference on publisher's website
  32. Struck J, Tao C, Morgenthaler NG, Bergmann A (2004) Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 25:1369–1372
    • View reference on PubMed
    • View reference on publisher's website
  33. Morgenthaler NG, Struck J, Thomas B, Bergmann A (2004) Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 50:234–236
    • View reference on PubMed
    • View reference on publisher's website
  34. Cook NR (2008) Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem 54:17–23
    • View reference on PubMed
    • View reference on publisher's website
  35. Grambsch PM, Therneau TM, Fleming TR (1995) Diagnostic plots to reveal functional form for covariates in multiplicative intensity models. Biometrics 51:1469–1482
    • View reference on PubMed
    • View reference on publisher's website
  36. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172 discussion 207–112
    • View reference on PubMed
    • View reference on publisher's website
  37. Grandel U, Grimminger F (2003) Endothelial responses to bacterial toxins in sepsis. Crit Rev Immunol 23:267–299
    • View reference on PubMed
    • View reference on publisher's website
  38. Kedzierski RM, Yanagisawa M (2001) Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 41:851–876
    • View reference on PubMed
    • View reference on publisher's website
  39. Sanai L, Haynes WG, MacKenzie A, Grant IS, Webb DJ (1996) Endothelin production in sepsis and the adult respiratory distress syndrome. Intensive Care Med 22:52–56
  40. Voerman HJ, Stehouwer CD, van Kamp GJ, Strack van Schijndel RJ, Groeneveld AB, Thijs LG (1992) Plasma endothelin levels are increased during septic shock. Crit Care Med 20:1097–1101
    • View reference on PubMed
    • View reference on publisher's website
  41. File TM Jr, Marrie TJ (2010) Burden of community-acquired pneumonia in North American adults. Postgrad Med 122:130–141
    • View reference on PubMed
    • View reference on publisher's website
  42. Fine MJ, Hough LJ, Medsger AR, Li YH, Ricci EM, Singer DE, Marrie TJ, Coley CM, Walsh MB, Karpf M, Lahive KC, Kapoor WN (1997) The hospital admission decision for patients with community-acquired pneumonia. Results from the pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med 157:36–44
    • View reference on PubMed
    • View reference on publisher's website
  43. Schuetz P, Koller M, Christ-Crain M, Steyerberg E, Stolz D, Muller C, Bucher HC, Bingisser R, Tamm M, Muller B (2008) Predicting mortality with pneumonia severity scores: importance of model recalibration to local settings. Epidemiol Infect 136:1628–1637
    • View reference on PubMed
    • View reference on publisher's website
  44. Schuetz P, Christ-Crain M, Muller B (2009) Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype? Swiss Med Wkly 139:318–326
    • View reference on PubMed
  45. Albertini M, Clement MG, Hussain SN (2003) Role of endothelin ETA receptors in sepsis-induced mortality, vascular leakage, and tissue injury in rats. Eur J Pharmacol 474:129–135
    • View reference on PubMed
    • View reference on publisher's website
  46. Antonelli M, Azoulay E, Bonten M, Chastre J, Citerio G, Conti G, De Backer D, Lemaire F, Gerlach H, Hedenstierna G, Joannidis M, Macrae D, Mancebo J, Maggiore SM, Mebazaa A, Preiser JC, Pugin J, Wernerman J, Zhang H (2010) Year in review in Intensive Care Medicine 2009: I. Pneumonia and infections, sepsis, outcome, acute renal failure and acid base, nutrition and glycaemic control. Intensive Care Med 36:196–209
  47. Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, De Backer D, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Macrae D, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C (2007) Year in review in Intensive Care Medicine, 2006. II. Infections and sepsis, haemodynamics, elderly, invasive and noninvasive mechanical ventilation, weaning, ARDS. Intensive Care Med 33:214–229
  48. Sligl WI, Majumdar SR, Marrie TJ (2009) Triaging severe pneumonia: what is the “score” on prediction rules? Crit Care Med 37:3166–3168
    • View reference on PubMed
    • View reference on publisher's website
  49. Leone M, Boutiere B, Camoin-Jau L, Albanese J, Horschowsky N, Mege JL, Martin C, Dignat-George F (2002) Systemic endothelial activation is greater in septic than in traumatic-hemorrhagic shock but does not correlate with endothelial activation in skin biopsies. Crit Care Med 30:808–814
    • View reference on PubMed
    • View reference on publisher's website

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement