Predictors of re-exacerbation after an index exacerbation of chronic obstructive pulmonary disease in the REDUCE randomised clinical trial
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) compromise physical activity and quality of life and contribute significantly to health care costs. Systemic glucocorticoids benefit clinical outcome in AECOPD, and the REDUCE trial demonstrated noninferiority of a 5-day treatment course with prednisone compared with 14 days therapy regarding clinical outcome over 6 months of follow-up. Unexpectedly, we found an inverse correlation between circulating cortisol levels and exacerbation risk during a 6-month follow-up period.
To evaluate whether additional predictors of COPD re-exacerbation can be identified after the index exacerbation in the REDUCE cohort.
Of 314 patients with AECOPD randomised to 5 or 14 days of prednisone treatment, 311 were included in the analysis. Parameters tested as predictors of re-exacerbation were sex, age, smoking status, forced expiratory volume in one second (FEV1), dyspnoea as assessed with the Medical Research Council (MRC) dyspnoea scale, home oxygen therapy, pretreatment with systemic glucocorticoids, pretreatment with antibiotics, duration of hospitalisation, blood pressure, oxygen saturation, admission to the Intensive Care Unit (ICU) and relevant infections in follow-up. The risks for re-exacerbation were estimated by means of logistic regression and Cox proportional hazard models and expressed as odds ratios and hazard ratios, respectively.
After multivariate adjustment, significant predictors at hospital discharge for COPD re-exacerbation during follow-up were: duration of hospital stay >8 days (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.03–2.28); FEV1 <30% predicted (HR 1.76, 95% CI 1.06–2.91); hypertension (HR 2.39, 95% CI 1.04–5.48) and MRC dyspnoea scale (HR 1.61, 95% CI 1.30–2.01, per unit increment). Present cigarette smoking (HR 0.60, 95% CI 0.38–0.92) was negatively associated with re-exacerbation.
In addition to biochemical suppression of the adrenal glands, other standard clinical parameters predict re-exacerbation in patients admitted to the emergency department with AECOPD. (REDUCE trial registration: ISRCTN29646069)
- World Health Report [Internet]. Geneva: World Health Organization; [updated 2014 May; cited 2016 June 19]. Available from: http://www.who.int/mediacentre/factsheets/fs310/en/
- Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 [Internet]. Global strategy for the diagnosis, management and prevention of COPD; [updated 2017; cited 2017 February 5]. Available from: http://goldcopd.org/
- Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al.; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532–55. https://doi.org/10.1164/rccm.200703-456SO
- Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–96. https://doi.org/10.1016/S0140-6736(07)61382-8
- Sykes A, Mallia P, Johnston SL. Diagnosis of pathogens in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(8):642–6. https://doi.org/10.1513/pats.200707-101TH
- Abu Hussein N, Ter Riet G, Schoenenberger L, Bridevaux PO, Chhajed PN, Fitting JW, et al. The ADO index as a predictor of two-year mortality in general practice-based chronic obstructive pulmonary disease cohorts. Respiration. 2014;88(3):208–14. https://doi.org/10.1159/000363770
- Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124(2):459–67. https://doi.org/10.1378/chest.124.2.459
- Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. BMJ. 1959;2(5147):257–66. https://doi.org/10.1136/bmj.2.5147.257
- Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581–6. https://doi.org/10.1136/thx.54.7.581
- Jenkins CR, Celli B, Anderson JA, Ferguson GT, Jones PW, Vestbo J, et al. Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J. 2012;39(1):38–45. https://doi.org/10.1183/09031936.00194610
- Yoshikawa M, Fujita Y, Yamamoto Y, Yamauchi M, Tomoda K, Koyama N, et al. Mini Nutritional Assessment Short-Form predicts exacerbation frequency in patients with chronic obstructive pulmonary disease. Respirology. 2014;19(8):1198–203. https://doi.org/10.1111/resp.12380
- Hallin R, Koivisto-Hursti UK, Lindberg E, Janson C. Nutritional status, dietary energy intake and the risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Respir Med. 2007;101(9):1954–60. https://doi.org/10.1016/j.rmed.2007.04.009
- Jochmann A, Neubauer F, Miedinger D, Schafroth S, Tamm M, Leuppi JD. General practitioner’s adherence to the COPD GOLD guidelines: baseline data of the Swiss COPD Cohort Study. Swiss Med Wkly. 2010;140:w13053.
- Jochmann A, Scherr A, Jochmann DC, Miedinger D, Török SS, Chhajed PN, et al. Impact of adherence to the GOLD guidelines on symptom prevalence, lung function decline and exacerbation rate in the Swiss COPD cohort. Swiss Med Wkly. 2012;142:w13567.
- Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ. 1977;1(6077):1645–8. https://doi.org/10.1136/bmj.1.6077.1645
- Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet. 2009;374(9691):744–55. https://doi.org/10.1016/S0140-6736(09)61342-8
- Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847–52. https://doi.org/10.1136/thorax.57.10.847
- Tanabe N, Muro S, Hirai T, Oguma T, Terada K, Marumo S, et al. Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(12):1653–9. https://doi.org/10.1164/rccm.201009-1535OC
- Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–38. https://doi.org/10.1056/NEJMoa0909883
- Silverman EK. Exacerbations in chronic obstructive pulmonary disease: do they contribute to disease progression? Proc Am Thorac Soc. 2007;4(8):586–90. https://doi.org/10.1513/pats.200706-068TH
- Hurst JR, Donaldson GC, Wilkinson TM, Perera WR, Wedzicha JA. Epidemiological relationships between the common cold and exacerbation frequency in COPD. Eur Respir J. 2005;26(5):846–52. https://doi.org/10.1183/09031936.05.00043405
- Spruit MA, Gosselink R, Troosters T, Kasran A, Gayan-Ramirez G, Bogaerts P, et al. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax. 2003;58(9):752–6. https://doi.org/10.1136/thorax.58.9.752
- Donaldson GC, Wilkinson TM, Hurst JR, Perera WR, Wedzicha JA. Exacerbations and time spent outdoors in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171(5):446–52. https://doi.org/10.1164/rccm.200408-1054OC
- Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R. Physical activity and hospitalization for exacerbation of COPD. Chest. 2006;129(3):536–44. https://doi.org/10.1378/chest.129.3.536
- Seymour JM, Moore L, Jolley CJ, Ward K, Creasey J, Steier JS, et al. Outpatient pulmonary rehabilitation following acute exacerbations of COPD. Thorax. 2010;65(5):423–8. https://doi.org/10.1136/thx.2009.124164
- Yohannes AM, Baldwin RC, Connolly MJ. Depression and anxiety in elderly patients with chronic obstructive pulmonary disease. Age Ageing. 2006;35(5):457–9. https://doi.org/10.1093/ageing/afl011
- Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM, et al. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax. 2006;61(4):284–9. https://doi.org/10.1136/thx.2005.051029
- Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309(21):2223–31. https://doi.org/10.1001/jama.2013.5023
- 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(1):19–27. https://doi.org/10.1530/EJE-15-0182
- Schuetz P, Leuppi JD, Tamm M, Briel M, Bingisser R, Dürring U, et al. Short versus conventional term glucocorticoid therapy in acute exacerbation of chronic obstructive pulmonary disease - the “REDUCE” trial. Swiss Med Wkly. 2010;140:w13109.
- Evans AT, Husain S, Durairaj L, Sadowski LS, Charles-Damte M, Wang Y. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet. 2002;359(9318):1648–54. https://doi.org/10.1016/S0140-6736(02)08597-5
- Kleinbaum DG, Klein M. Survival Analysis. A Self-Learning Text, Third Edition. Springer Series on Statistics for Biology and Health, New York, Springer, 2011.
- Husebø GR, Bakke PS, Aanerud M, Hardie JA, Ueland T, Grønseth R, et al. Predictors of exacerbations in chronic obstructive pulmonary disease--results from the Bergen COPD cohort study. PLoS One. 2014;9(10):e109721. https://doi.org/10.1371/journal.pone.0109721
- Gudmundsson G, Gislason T, Janson C, Lindberg E, Hallin R, Ulrik CS, et al. Risk factors for rehospitalisation in COPD: role of health status, anxiety and depression. Eur Respir J. 2005;26(3):414–9. https://doi.org/10.1183/09031936.05.00078504
- Müllerova H, Maselli DJ, Locantore N, Vestbo J, Hurst JR, Wedzicha JA, et al.; ECLIPSE Investigators. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015;147(4):999–1007. https://doi.org/10.1378/chest.14-0655
- Garcia-Aymerich J, Monsó E, Marrades RM, Escarrabill J, Félez MA, Sunyer J, et al.; EFRAM Investigators. Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation. EFRAM study. Am J Respir Crit Care Med. 2001;164(6):1002–7. https://doi.org/10.1164/ajrccm.164.6.2006012
- Becklake MR, Lalloo U. The ‘healthy smoker’: a phenomenon of health selection? Respiration. 1990;57(3):137–44. https://doi.org/10.1159/000195837
- Eisner MD. Smoking and adult asthma: a healthy smoker effect? Am J Respir Crit Care Med. 2002;165(11):1566–7, author reply 1566–7. https://doi.org/10.1164/ajrccm.165.11.165112
- Melzer AC, Feemster LC, Crothers K, Carson SS, Gillespie SE, Henderson AG, et al.; COPD Outcomes-based Network for Clinical Effectiveness and Research Translation Consortium. Respiratory and Bronchitic Symptoms Predict Intention to Quit Smoking among Current Smokers with, and at Risk for, Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc. 2016;13(9):1490–6. https://doi.org/10.1513/AnnalsATS.201601-075OC
- Troisi RJ, Speizer FE, Rosner B, Trichopoulos D, Willett WC. Cigarette smoking and incidence of chronic bronchitis and asthma in women. Chest. 1995;108(6):1557–61. https://doi.org/10.1378/chest.108.6.1557
- Abu Hussein N, Bridevaux PO, Chhajed PN, Fitting JW, Geiser T, Joos Zellweger L, et al. Factors associated with exacerbation in a general practitioners’-based Swiss chronic obstructive pulmonary disease (COPD) cohort. Eur Respir J. 2014;42(Suppl 57):5102.
- Chandy D, Aronow WS, Banach M. Current perspectives on treatment of hypertensive patients with chronic obstructive pulmonary disease. Integr Blood Press Control. 2013;6:101–9.
- Lindberg A, Larsson LG, Rönmark E, Lundbäck B. Co-morbidity in mild-to-moderate COPD: comparison to normal and restrictive lung function. COPD. 2011;8(6):421–8. https://doi.org/10.3109/15412555.2011.629858
- Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962–9. https://doi.org/10.1183/09031936.00012408
- Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165–85. https://doi.org/10.1183/09031936.00128008
- Bahadori K, FitzGerald JM, Levy RD, Fera T, Swiston J. Risk factors and outcomes associated with chronic obstructive pulmonary disease exacerbations requiring hospitalization. Can Respir J. 2009;16(4):e43–9. https://doi.org/10.1155/2009/179263
- Tsimogianni AM, Papiris SA, Stathopoulos GT, Manali ED, Roussos C, Kotanidou A. Predictors of outcome after exacerbation of chronic obstructive pulmonary disease. J Gen Intern Med. 2009;24(9):1043–8. https://doi.org/10.1007/s11606-009-1061-2
- Ospina MB, Mrklas K, Deuchar L, Rowe BH, Leigh R, Bhutani M, et al. A systematic review of the effectiveness of discharge care bundles for patients with COPD. Thorax. 2017;72(1):31–9. https://doi.org/10.1136/thoraxjnl-2016-208820