The release of hormones from the adrenal gland is vital in acute and chronic illnesses such as chronic obstructive pulmonary disease (COPD) involving recurrent exacerbations. Using a metabolomic approach, we aim to investigate associations of different adrenal hormone metabolites with short- and long-term mortality in COPD patients.
We prospectively followed 172 COPD patients (median age 75 years, 62% male) from a previous Swiss multicenter trial. At baseline, we measured levels of a comprehensive spectrum of adrenal hormone metabolites, including glucocorticoid, mineralocorticoid and androgen hormones by liquid chromatography coupled with tandem mass spectrometry (MS). We calculated Cox regression models adjusted for gender, age, comorbidities and previous corticosteroid therapy.
Mortality was 6.4% after 30 days and increased to 61.6% after 6 years. Higher initial androgen hormones predicted lower long-term mortality with significant results for dehydroepiandrosterone (DHEA) [adjusted hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70–0.98; p=0.026] and dehydroepiandrosterone sulfate (DHEA-S) (adjusted HR, 0.68; 95% CI, 0.50–0.91; p=0.009). An activation of stress hormones (particularly cortisol and cortisone) showed a time-dependent effect with higher levels pointing towards higher mortality at short term, but lower mortality at long term. Activation of the mineralocorticoid axis tended to be associated with increased short-term mortality (adjusted HR of aldosterone, 2.76; 95% CI, 0.79–9.65; p=0.111).
Independent of age, gender, corticosteroid exposure and exacerbation type, adrenal hormones are associated with mortality at short and long term in patients with COPD exacerbation with different time-dependent effects of glucocorticoids, androgens and mineralocorticoids. A better physiopathological understanding of the causality of these effects may have therapeutic implications.
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, 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; Chantal Bruehlhardt, RN; Ruth Luginbuehl, RN; Agnes Muehlemann, PhD; Ineke Lambinon; Werner Zimmerli, MD; and Max Zueger, MD.
Author contributions: MCC, BM and PS created concept and design, wrote the protocol and initiated the initial ProHOSP study. SZ and PS drafted the present manuscript and performed statistical analyses. CS and AH performed laboratory measurements of glucocorticoids. All authors contributed to the data acquisition, interpretation and drafting of the analyses, as well as to critical review for important intellectual content, and final approval of the manuscript. PS had full access to all data in the present study and takes responsibility for the integrity of the work and the accuracy of the data analyses.
Availability of data and material: The data sets used and analyzed during the present study are available from the corresponding author on reasonable request.
Research funding: This study was supported in part by the Swiss National Science Foundation (SNSF Professorship, Funder ID: 10.13039/501100001711, 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 (Funder ID: 10.13039/501100001711, grant SNF 3200BO-116177/1), Santé Suisse, the Gottfried and Julia Bangerter-Rhyner Foundation.
Employment or leadership: None declared.
Honorarium: None declared.
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. Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology 2016;21:14–23.10.1111/resp.12660Search in Google Scholar
2. Burney P, Jarvis D, Perez-Padilla R. The global burden of chronic respiratory disease in adults. Int J Tuberc Lung Dis 2015;19:10–20.10.5588/ijtld.14.0446Search in Google Scholar
3. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370:765–73.10.1016/S0140-6736(07)61380-4Search in Google Scholar
4. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–128.10.1016/S0140-6736(12)61728-0Search in Google Scholar
5. Wacker ME, Jorres RA, Schulz H, Heinrich J, Karrasch S, Karch A, et al. Direct and indirect costs of COPD and its comorbidities: results from the German COSYCONET study. Respir Med 2016;111:39–46.10.1016/j.rmed.2015.12.001Search in Google Scholar PubMed
6. Nickler M, Ottiger M, Steuer C, Huber A, Anderson JB, Müller B, et al. Systematic review regarding metabolic profiling for improved pathophysiological understanding of disease and outcome prediction in respiratory infections. Respir Res 2015;16:125.10.1186/s12931-015-0283-6Search in Google Scholar PubMed PubMed Central
7. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351–62.10.1056/NEJM199505183322008Search in Google Scholar PubMed
8. Christ-Crain M, Stolz D, Jutla S, Couppis O, Muller C, Bingisser R, et al. Free and total cortisol levels as predictors of severity and outcome in community-acquired pneumonia. Am J Respir Crit Care Med 2007;176:913–20.10.1164/rccm.200702-307OCSearch in Google Scholar PubMed
9. Kolditz M, Halank M, Schulte-Hubbert B, Hoffken G. Adrenal function is related to prognosis in moderate community-acquired pneumonia. Eur Respir J 2010;36:615–21.10.1183/09031936.00191709Search in Google Scholar PubMed
10. Kolditz M, Hoffken G, Martus P, Rohde G, Schutte H, Bals R, et al. Serum cortisol predicts death and critical disease independently of CRB-65 score in community-acquired pneumonia: a prospective observational cohort study. BMC Infect Dis 2012;12:90.10.1186/1471-2334-12-90Search in Google Scholar PubMed PubMed Central
11. Cortes-Puch I, Hicks CW, Sun J, Solomon SB, Eichacker PQ, Sweeney DA, et al. Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia. Am J Physiol Endocrinol Metab 2014;307:E994–1008.10.1152/ajpendo.00345.2014Search in Google Scholar PubMed PubMed Central
12. Vassiliadi DA, Dimopoulou I, Tzanela M, Douka E, Livaditi O, Orfanos SE, et al. Longitudinal assessment of adrenal function in the early and prolonged phases of critical illness in septic patients: relations to cytokine levels and outcome. J Clin Endocrinol Metab 2014;99:4471–80.10.1210/jc.2014-2619Search in Google Scholar PubMed
13. Nickler M, Ottiger M, Steuer C, Kutz A, Christ-Crain M, Zimmerli W, et al. Time-dependent association of glucocorticoids with adverse outcome in community-acquired pneumonia: a 6-year prospective cohort study. Crit Care 2017;21:72.10.1186/s13054-017-1656-7Search in Google Scholar PubMed PubMed Central
14. Moraes RB, Friedman G, Viana MV, Tonietto T, Saltz H, Czepielewski MA. Aldosterone secretion in patients with septic shock: a prospective study. Arq Bras Endocrinol Metabol 2013;57:636–41.10.1590/S0004-27302013000800009Search in Google Scholar
15. Ohlsson C, Labrie F, Barrett-Connor E, Karlsson MK, Ljunggren O, Vandenput L, et al. Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men. J Clin Endocrinol Metab 2010;95:4406–14.10.1210/jc.2010-0760Search in Google Scholar PubMed
16. Ohlsson C, Vandenput L, Tivesten A. DHEA and mortality: what is the nature of the association? J Steroid Biochem Mol Biol 2015;145:248–53.10.1016/j.jsbmb.2014.03.006Search in Google Scholar PubMed
17. Barrett-Connor E, Khaw KT, Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986;315:1519–24.10.1056/NEJM198612113152405Search in Google Scholar PubMed
18. Berr C, Lafont S, Debuire B, Dartigues JF, Baulieu EE. Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study. Proc Natl Acad Sci USA 1996;93:13410–5.10.1073/pnas.93.23.13410Search in Google Scholar PubMed PubMed Central
19. Trivedi DP, Khaw KT. Dehydroepiandrosterone sulfate and mortality in elderly men and women. J Clin Endocrinol Metab 2001;86:4171–7.10.1210/jcem.86.9.7838Search in Google Scholar PubMed
20. Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, et al. Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study. Arch Intern Med 2007;167:2249–54.10.1001/archinte.167.20.2249Search in Google Scholar PubMed PubMed Central
21. Beishuizen A, Thijs LG, Vermes I. Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care 2002;6:434–8.10.1186/cc1530Search in Google Scholar PubMed PubMed Central
22. Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, Allolio B, et al. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab 2006;91:2548–54.10.1210/jc.2005-2258Search in Google Scholar PubMed
23. Mueller C, Blum CA, Trummler M, Stolz D, Bingisser R, Mueller C, et al. Association of adrenal function and disease severity in community-acquired pneumonia. PLoS One 2014;9:e99518.10.1371/journal.pone.0099518Search in Google Scholar PubMed PubMed Central
24. Schuetz P, Leuppi JD, Bingisser R, Bodmer M, Briel M, Drescher T, et al. Prospective analysis of adrenal function in patients with acute exacerbations of COPD: the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial. Eur J Endocrinol 2015;173:19–27.10.1530/EJE-15-0182Search in Google Scholar PubMed
25. 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
26. 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
27. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–55.10.1164/rccm.200703-456SOSearch in Google Scholar PubMed
28. Steuer C, Schutz P, Bernasconi L, Huber AR. Simultaneous determination of phosphatidylcholine-derived quaternary ammonium compounds by a LC-MS/MS method in human blood plasma, serum and urine samples. J Chromatogr B Analyt Technol Biomed Life Sci 2016;1008:206–11.10.1016/j.jchromb.2015.12.002Search in Google Scholar PubMed
29. Crisafulli E, Guerrero M, Menendez R, Huerta A, Martinez R, Gimeno A, et al. Inhaled corticosteroids do not influence the early inflammatory response and clinical presentation of hospitalized subjects with COPD exacerbation. Respir Care 2014;59:1550–9.10.4187/respcare.03036Search in Google Scholar PubMed
30. Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:1207–14.10.1164/rccm.200709-1356OCSearch in Google Scholar PubMed
31. Fischli S, Jenni S, Allemann S, Zwahlen M, Diem P, Christ ER, et al. Dehydroepiandrosterone sulfate in the assessment of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 2008;93:539–42.10.1210/jc.2007-1780Search in Google Scholar PubMed
32. Schmitz D, Kobbe P, Wegner A, Hammes F, Oberbeck R. Dehydroepiandrosterone during sepsis: does the timing of administration influence the effectiveness. J Surg Res 2010;163:e73–7.10.1016/j.jss.2010.05.017Search in Google Scholar PubMed
33. Dumas de La Roque E, Savineau JP, Metivier AC, Billes MA, Kraemer JP, Doutreleau S, et al. Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study. Ann Endocrinol (Paris) 2012;73:20–5.10.1016/j.ando.2011.12.005Search in Google Scholar PubMed
34. Spiga F, Lightman SL. Dynamics of adrenal glucocorticoid steroidogenesis in health and disease. Mol Cell Endocrinol 2015;408:227–34.10.1016/j.mce.2015.02.005Search in Google Scholar PubMed
35. Van den Berghe G, de Zegher F, Bouillon R. Clinical review 95: acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–34.Search in Google Scholar
36. Van den Berghe GH. Acute and prolonged critical illness are two distinct neuroendocrine paradigms. Verh K Acad Geneeskd Belg 1998;60:487–518; discussion-20.Search in Google Scholar
37. Bartanusz V, Corneille MG, Sordo S, Gildea M, Michalek JE, Nair PV, et al. Diurnal salivary cortisol measurement in the neurosurgical-surgical intensive care unit in critically ill acute trauma patients. J Clin Neurosci 2014;21:2150–4.10.1016/j.jocn.2014.04.018Search in Google Scholar PubMed
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2017-0873).
©2018 Walter de Gruyter GmbH, Berlin/Boston