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Licensed Unlicensed Requires Authentication Published by De Gruyter April 21, 2016

Prospective evaluation of biomarkers for prediction of quality of life in community-acquired pneumonia

  • Manuela Nickler , Daniela Schaffner , Mirjam Christ-Crain , Manuel Ottiger , Robert Thomann , Claus Hoess , Christoph Henzen , Beat Mueller and Philipp Schuetz EMAIL logo



Most clinical research investigated prognostic biomarkers for their ability to predict cardiovascular events or mortality. It is unknown whether biomarkers allow prediction of quality of life (QoL) after survival of the acute event. Herein, we investigated the prognostic potential of well-established inflammatory/cardiovascular blood biomarkers including white blood cells (WBC), C-reactive protein (CRP), procalcitonin (PCT), pro-adrenomedullin (proADM) and pro-atrial natriuretic peptide (proANP) in regard to a decline in QoL in a well-defined cohort of patients with community-acquired pneumonia (CAP).


Within this secondary analysis including 753 patients with a final inpatient diagnosis of CAP from a multicenter trial, we investigated associations between admission biomarker levels and decline in QoL assessed by the EQ-5D health questionnaire from admission to day 30 and after 6 years.


Admission proADM and proANP levels significantly predicted decline of the weighted EQ-5D index after 30 days (n=753) with adjusted odds ratios (ORs) of 2.0 ([95% CI 1.1–3.8]; p=0.027) and 3.7 ([95% CI 2.2–6.0]; p<0.001). Results for 6-year outcomes (n=349) were similar with ORs of 3.3 ([95% CI 1.3–8.3]; p=0.012) and 6.2 ([95% CI 2.7–14.2]; p<0.001). The markers were associated with most of the different QoL dimensions including mobility, self-care, and usual activities, but not pain/discomfort and to a lesser degree anxiety/depression and the visual analogue scale (VAS). Initial WBC, PCT and CRP values did not well predict QoL at any time point.


ProADM and proANP accurately predict short- and long-term decline in QoL across most dimensions in CAP patients. It will be interesting to reveal underlying physiopathology in future studies.

Corresponding author: Prof Dr. med. Philipp Schuetz, MD, MPH, Division of General Internal and Emergency Medicine, University Department of Medicine, Kantonsspital Aarau, Tellstrasse, 5001 Aarau, Switzerland, Phone: +41 (0)62 838 4141, Fax: +41 (0)62 838 4100
aManuela Nickler and Daniela Schaffner contributed equally to this work.


We are grateful to 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. In particular, we thank all patients, their relatives and all local general practitioners who participated in this study. Finally, we acknowledge the ProHOSP Study Group for their important support. 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, Thomas Bregenzer, MD, Claus Hoess, MD, Heiner C. Bucher, MD, Fabian Mueller, Jeannine Haeuptle, Roya Zarbosky, Rico Fiumefreddo, MD, 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, Werner Zimmerli, MD, and Max Zueger, MD.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: The main sources of funding for the investigator-initiated ProHOSP study were the Swiss National Science Foundation (grant SNF 3200BO-116177/1), Santé Suisse and the Gottfried and Julia Bangerter-Rhyner Foundation.

  3. Employment or leadership: MC-C, BM and PS have received grants from B·R·A·H·M·S/Thermo and bioMérieux; in addition, BM has served as a consultant to these companies. None of the other authors has any relevant industrial relationships.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


1. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: final data for 2005. Natl Vital Stat Rep 2008;56:1–120.Search in Google Scholar

2. Brown PD, Lerner SA. Community-acquired pneumonia. Lancet 1998;352:1295–302.10.1016/S0140-6736(98)02239-9Search in Google Scholar

3. File TM. Community-acquired pneumonia. Lancet 2003;362:1991–2001.10.1016/S0140-6736(03)15021-0Search in Google Scholar

4. Menendez R, Torres A, Zalacain R, Aspa J, Martin Villasclaras JJ, Borderias L, et al. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax 2004;59:960–5.10.1136/thx.2003.017756Search in Google Scholar PubMed PubMed Central

5. Almirall J, Bolibar I, Vidal J, Sauca G, Coll P, Niklasson B, et al. Epidemiology of community-acquired pneumonia in adults: a population-based study. Eur Respir J 2000;15:757–63.10.1034/j.1399-3003.2000.15d21.xSearch in Google Scholar PubMed

6. Alan M, Grolimund E, Kutz A, Christ-Crain M, Thomann R, Falconnier C, et al. Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study. J Intern Med 2015;278:174–84.10.1111/joim.12341Search in Google Scholar PubMed

7. Restrepo MI, Faverio P, Anzueto A. Long-term prognosis in community-acquired pneumonia. Curr Opin Infect Dis 2013;26:151–8.10.1097/QCO.0b013e32835ebc6dSearch in Google Scholar PubMed PubMed Central

8. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007;167:1655–63.10.1001/archinte.167.15.1655Search in Google Scholar PubMed PubMed Central

9. Guertler C, Wirz B, Christ-Crain M, Zimmerli W, Mueller B, Schuetz P. Inflammatory responses predict long-term mortality risk in community-acquired pneumonia. Eur Respir J 2011;37:1439–46.10.1183/09031936.00121510Search in Google Scholar PubMed

10. Schuetz P, Suter-Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B, et al. Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J 2011;37:384–92.10.1183/09031936.00035610Search in Google Scholar PubMed

11. Suter-Widmer I, Christ-Crain M, Zimmerli W, Albrich W, Mueller B, Schuetz P, et al. Predictors for length of hospital stay in patients with community-acquired pneumonia: results from a Swiss multicenter study. BMC Pulm Med 2012;12:21.10.1186/1471-2466-12-21Search in Google Scholar PubMed PubMed Central

12. Corrales-Medina VF, Alvarez KN, Weissfeld LA, Angus DC, Chirinos JA, Chang CC, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. J Am Med Assoc 2015;313:264–74.10.1001/jama.2014.18229Search in Google Scholar PubMed PubMed Central

13. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243–50.10.1056/NEJM199701233360402Search in Google Scholar PubMed

14. Zhydkov A, Christ-Crain M, Thomann R, Hoess C, Henzen C, Werner Z, et al. Utility of procalcitonin, C-reactive protein and white blood cells alone and in combination for the prediction of clinical outcomes in community-acquired pneumonia. Clin Chem Lab Med 2015;53:559–66.10.1515/cclm-2014-0456Search in Google Scholar PubMed

15. Schuetz P, Hausfater P, Amin D, Amin A, Haubitz S, Faessler L, et al. Biomarkers from distinct biological pathways improve early risk stratification in medical emergency patients: the multinational, prospective, observational TRIAGE study. Crit Care 2015;19:377.10.1186/s13054-015-1098-zSearch in Google Scholar PubMed PubMed Central

16. Kutz A, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Prognostic value of procalcitonin in respiratory tract infections across clinical settings. Crit Care 2015;19:74.10.1186/s13054-015-0792-1Search in Google Scholar PubMed PubMed Central

17. Grolimund E, Kutz A, Marlowe RJ, Vogeli A, Alan M, Christ-Crain M, et al. Long-term prognosis in COPD exacerbation: role of biomarkers, clinical variables and exacerbation type. COPD 2015;12:295–305.10.3109/15412555.2014.949002Search in Google Scholar PubMed

18. Debiane L, Hachem RY, Al Wohoush I, Shomali W, Bahu RR, Jiang Y, et al. The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer*. Crit Care Med 2014;42:2500–7.10.1097/CCM.0000000000000526Search in Google Scholar PubMed

19. Schuetz P, Maurer P, Punjabi V, Desai A, Amin DN, Gluck E. Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients. Crit Care 2013;17:R115.10.1186/cc12787Search in Google Scholar PubMed PubMed Central

20. Schuetz P, Litke A, Albrich WC, Mueller B. Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia. Curr Opin Infect Dis 2013;26:159–67.10.1097/QCO.0b013e32835d0becSearch in Google Scholar PubMed

21. Suberviola B, Castellanos-Ortega A, Llorca J, Ortiz F, Iglesias D, Prieto B. Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia. Swiss Med Wkly 2012;142:w13542.10.4414/smw.2012.13542Search in Google Scholar PubMed

22. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care 2006;10:R96.10.1186/cc4955Search in Google Scholar PubMed PubMed Central

23. Huang DT, Angus DC, Kellum JA, Pugh NA, Weissfeld LA, Struck J, et al. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest 2009;136:823–31.10.1378/chest.08-1981Search in Google Scholar PubMed PubMed Central

24. Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T, et al. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: Results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med 2010;182:1426–34.10.1164/rccm.201003-0415OCSearch in Google Scholar PubMed

25. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care 2010;14:R106.10.1186/cc9055Search in Google Scholar PubMed PubMed Central

26. Albrich WC, Dusemund F, Ruegger K, Christ-Crain M, Zimmerli W, Bregenzer T, et al. Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC Infect Dis 2011;11:112.10.1186/1471-2334-11-112Search in Google Scholar PubMed PubMed Central

27. Bello S, Lasierra AB, Minchole E, Fandos S, Ruiz MA, Vera E, et al. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J 2012;39:1144–55.10.1183/09031936.00080411Search in Google Scholar PubMed

28. Renaud B, Schuetz P, Claessens YE, Labarere J, Albrich W, Mueller B. Proadrenomedullin improves Risk of Early Admission to ICU score for predicting early severe community-acquired pneumonia. Chest 2012;142:1447–54.10.1378/chest.11-2574Search in Google Scholar PubMed

29. Courtais C, Kuster N, Dupuy AM, Folschveiller M, Jreige R, Bargnoux AS, et al. Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. Am J Emerg Med 2013;31:215–21.10.1016/j.ajem.2012.07.017Search in Google Scholar PubMed

30. Gordo-Remartinez S, Calderon-Moreno M, Fernandez-Herranz J, Castuera-Gil A, Gallego-Alonso-Colmenares M, Puertas-Lopez C, et al. Usefulness of midregional proadrenomedullin to predict poor outcome in patients with community acquired pneumonia. PLoS One 2015;10:e0125212.10.1371/journal.pone.0125212Search in Google Scholar PubMed PubMed Central

31. Kruger S, Ewig S, Kunde J, Hartmann O, Suttorp N, Welte T, et al. Pro-atrial natriuretic peptide and pro-vasopressin for predicting short-term and long-term survival in community-acquired pneumonia: results from the German Competence Network CAPNETZ. Thorax 2010;65:208–14.10.1136/thx.2009.121178Search in Google Scholar PubMed

32. Kruger S, Papassotiriou J, Marre R, Richter K, Schumann C, von Baum H, et al. Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired pneumonia: results from the German competence network CAPNETZ. Intensive Care Med 2007;33:2069–78.10.1007/s00134-007-0895-5Search in Google Scholar PubMed

33. Muller B, Suess E, Schuetz P, Muller C, Bingisser R, Bergmann A, et al. Circulating levels of pro-atrial natriuretic peptide in lower respiratory tract infections. J Intern Med 2006;260:568–76.10.1111/j.1365-2796.2006.01722.xSearch in Google Scholar PubMed

34. Haeuptle J, Zaborsky R, Fiumefreddo R, Trampuz A, Steffen I, Frei R, et al. Prognostic value of procalcitonin in Legionella pneumonia. Eur J Clin Microbiol Infect Dis 2009;28:55–60.10.1007/s10096-008-0592-5Search in Google Scholar PubMed

35. Kruger S, Ewig S, Marre R, Papassotiriou J, Richter K, von Baum H, et al. Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes. Eur Respir J 2008;31:349–55.10.1183/09031936.00054507Search in Google Scholar PubMed

36. Muller B, Harbarth S, Stolz D, Bingisser R, Mueller C, Leuppi J, et al. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis 2007;7:10.10.1186/1471-2334-7-10Search in Google Scholar PubMed PubMed Central

37. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. J Am Med Assoc 2009;302:1059–66.10.1001/jama.2009.1297Search in Google Scholar PubMed

38. Schuetz P, Christ-Crain M, Wolbers M, Schild U, Thomann R, Falconnier C, et al. Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial. BMC Health Serv Res 2007;7:102.10.1186/1472-6963-7-102Search in Google Scholar PubMed PubMed Central

39. Gonzales R, Sande MA. Uncomplicated acute bronchitis. Ann Intern Med 2000;133:981–91.10.7326/0003-4819-133-12-200012190-00014Search in Google Scholar PubMed

40. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730–54.10.1164/ajrccm.163.7.at1010Search in Google Scholar PubMed

41. Woodhead M, Blasi F, Ewig S, Huchon G, Ieven M, Ortqvist A, et al. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J 2005;26:1138–80.10.1183/09031936.05.00055705Search in Google Scholar PubMed

42. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27–72.10.1086/511159Search in Google Scholar

43. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004;25:1369–72.10.1016/j.peptides.2004.06.019Search in Google Scholar

44. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 2005;51:1823–9.10.1373/clinchem.2005.051110Search in Google Scholar

45. Morgenthaler NG, Struck J, Thomas B, Bergmann A. Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 2004;50:234–6.10.1373/clinchem.2003.021204Search in Google Scholar

46. Schrag A, Selai C, Jahanshahi M, Quinn NP. The EQ-5D–a generic quality of life measure-is a useful instrument to measure quality of life in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 2000;69:67–73.10.1136/jnnp.69.1.67Search in Google Scholar

47. EuroQol G. EuroQol–a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.10.1016/0168-8510(90)90421-9Search in Google Scholar

48. Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53–72.10.1016/0168-8510(96)00822-6Search in Google Scholar

49. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005;43:203–20.10.1097/00005650-200503000-00003Search in Google Scholar

50. Kitamura K, Kangawa K, Kojima M, Ichiki Y, Matsuo H, Eto T. Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor. FEBS Lett 1994;338:306–10.10.1016/0014-5793(94)80289-0Search in Google Scholar

51. Temmesfeld-Wollbruck B, Hocke AC, Suttorp N, Hippenstiel S. Adrenomedullin and endothelial barrier function. Thromb Haemost 2007;98:944–51.10.1160/TH07-02-0128Search in Google Scholar PubMed

52. Hao SL, Yu ZH, Qi BS, Luo JZ, Wang WP. The antifibrosis effect of adrenomedullin in human lung fibroblasts. Exp Lung Res 2011;37:615–26.10.3109/01902148.2011.623823Search in Google Scholar

53. Marinoni E, Pacioni K, Sambuchini A, Moscarini M, Letizia C, DI Iorio R. Regulation by hypoxia of adrenomedullin output and expression in human trophoblast cells. Eur J Obstet Gynecol Reprod Biol 2011;154:146–50.10.1016/j.ejogrb.2010.10.013Search in Google Scholar

54. Martinez A, Miller MJ, Unsworth EJ, Siegfried JM, Cuttitta F. Expression of adrenomedullin in normal human lung and in pulmonary tumors. Endocrinology 1995;136:4099–105.10.1210/endo.136.9.7649118Search in Google Scholar

55. Eto T. A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. Peptides 2001;22:1693–711.10.1016/S0196-9781(01)00513-7Search in Google Scholar

56. Linscheid P, Seboek D, Zulewski H, Keller U, Muller B. Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology 2005;146:2699–708.10.1210/en.2004-1424Search in Google Scholar PubMed

57. Stolz D, Kostikas K, Blasi F, Boersma W, Milenkovic B, Lacoma A, et al. Adrenomedullin refines mortality prediction by the BODE index in COPD: the “BODE-A” index. Eur Respir J 2014;43:397–408.10.1183/09031936.00058713Search in Google Scholar PubMed

58. Pfeil U, Aslam M, Paddenberg R, Quanz K, Chang CL, Park JI, et al. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability. Am J Physiol Lung Cell Mol Physiol 2009;297:L837–45.10.1152/ajplung.90608.2008Search in Google Scholar PubMed PubMed Central

59. Di Paola R, Talero E, Galuppo M, Mazzon E, Bramanti P, Motilva V, et al. Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis. Respir Res 2011;12:41.10.1186/1465-9921-12-41Search in Google Scholar PubMed PubMed Central

60. Qi JG, Ding YG, Tang CS, Du JB. Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats. Peptides 2007;28:910–9.10.1016/j.peptides.2006.12.008Search in Google Scholar PubMed

61. Haviv M, Haver E, Lichtstein D, Hurvitz H, Klar A. Atrial natriuretic peptide in children with pneumonia. Pediatr Pulmonol 2005;40:306–9.10.1002/ppul.20233Search in Google Scholar PubMed

62. Vesely DL. Atrial natriuretic peptide prohormone gene expression: hormones and diseases that upregulate its expression. IUBMB Life 2002;53:153–9.10.1080/15216540212336Search in Google Scholar PubMed

63. Aiura K, Ueda M, Endo M, Kitajima M. Circulating concentrations and physiologic role of atrial natriuretic peptide during endotoxic shock in the rat. Crit Care Med 1995;23:1898–906.10.1097/00003246-199511000-00017Search in Google Scholar PubMed

Received: 2016-1-1
Accepted: 2016-3-10
Published Online: 2016-4-21
Published in Print: 2016-11-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

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