Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000075.xml
Semin Respir Crit Care Med 2015; 36(04): 478-490
DOI: 10.1055/s-0035-1555609
DOI: 10.1055/s-0035-1555609
The Promise of Observational Studies (ECLIPSE, SPIROMICS, and COPDGene) in Achieving the Goal of Personalized Treatment of Chronic Obstructive Pulmonary Disease
Further Information
Publication History
Publication Date:
03 August 2015 (online)
Abstract
Personalized medicine is based on the concept that individuals differ from one another. Chronic obstructive pulmonary disease (COPD) is particularly in need of a personalized medicine strategy. However, while the COPD population is characterized by a marked degree of heterogeneity at the etiologic, mechanistic, physiologic, and clinical levels, efforts to cluster COPD patients into meaningful groups that can guide therapy have been limited. Three large observational studies—the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE), the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS), and COPDGene—are underway and/or being analyzed. These studies have accumulated a uniquely rich set of clinical and biological data on relatively large cohorts of patients who have already influenced the way in which COPD is viewed. These studies have great potential to advance understanding of COPD so that the goal of personalized treatment can be pursued.
-
References
- 1 Global Strategy for Diagnosis and Management of COPD. 2015. www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html
- 2 Shapiro SD, Reilly JJJ, Rennard SI. Chronic bronchitis and emphysema. In: Mason RJ, Martin TR, King Jr TE, Schraufnagel DE, Murray JF, Nadel JA, , eds. Textbook of Respiratory Medicine, 5th ed. Philadelphia, PA: Saunders; 2010: 919-967
- 3 Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013; 5: CD007891
- 4 Rabe KF, Fabbri LM, Vogelmeier C , et al. Seasonal distribution of COPD exacerbations in the Prevention of Exacerbations with Tiotropium in COPD trial. Chest 2013; 143 (3) 711-719
- 5 Rennard SI, Calverley PM, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res 2011; 12: 18
- 6 Camargo Jr CA, Budinger GR, Escobar GJ , et al. Promotion of lung health: NHLBI workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc 2014; 11 (Suppl. 03) S125-S138
- 7 Drummond MB, Buist AS, Crapo JD, Wise RA, Rennard SI. Chronic obstructive pulmonary disease: Nhlbi workshop on the primary prevention of chronic lung diseases. Ann Am Thorac Soc 2014; 11 (Suppl. 03) S154-S160
- 8 Rennard SI, Drummond MB. Early COPD: definition, evaluation and prevention. Lancet 2015; 385: 1778-1788
- 9 Rennard SI, Vestbo J. Natural histories of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5 (9) 878-883
- 10 Agusti A, Calverley PM, Celli B , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010; 11: 122
- 11 Vestbo J, Anderson W, Coxson HO , et al; ECLIPSE investigators. Evaluation of COPD longitudinally to identify predictive surrogate end-points (eclipse). Eur Respir J 2008; 31 (4) 869-873
- 12 Regan EA, Hokanson JE, Murphy JR , et al. Genetic epidemiology of COPD (COPDGene) study design. COPD 2010; 7 (1) 32-43
- 13 Couper D, LaVange LM, Han M , et al; SPIROMICS Research Group. Design of the subpopulations and intermediate outcomes in COPD study (spiromics). Thorax 2014; 69 (5) 491-494
- 14 Fletcher C, Peto R, Tinker C, Speizer F. The Natural History of Chronic Bronchitis and Emphysema. New York: Oxford University Press; 1976
- 15 Vestbo J, Edwards LD, Scanlon PD , et al; ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011; 365 (13) 1184-1192
- 16 Tashkin DP, Li N, Halpin D , et al. Annual rates of change in pre- vs. post-bronchodilator FEV1 and FVC over 4 years in moderate to very severe COPD. Respir Med 2013; 107 (12) 1904-1911
- 17 Rennard SI, Locantore N, Delafont B , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints. Identification of five chronic obstructive pulmonary disease subgroups with different prognoses in the eclipse cohort using cluster analysis. Ann Am Thorac Soc 2015; 12 (3) 303-312
- 18 Everitt B, Landau S, Leese M, Stahl D. Cluster Analysis. Hoboken, NJ: John Wiley and Sons; 2011
- 19 Castaldi PJ, Dy J, Ross J , et al. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax 2014; 69 (5) 415-422
- 20 Lee JH, Cho MH, McDonald ML , et al; COPDGene Investigators. Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene. Respir Med 2014; 108 (10) 1469-1480
- 21 Wan ES, Castaldi PJ, Cho MH , et al; COPDGene Investigators. Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene. Respir Res 2014; 15: 89
- 22 Pistolesi M, Camiciottoli G, Paoletti M , et al. Identification of a predominant COPD phenotype in clinical practice. Respir Med 2008; 102 (3) 367-376
- 23 Garcia-Aymerich J, Gómez FP, Benet M , et al; PAC-COPD Study Group. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax 2011; 66 (5) 430-437
- 24 Burgel PR, Paillasseur JL, Caillaud D , et al; Initiatives BPCO Scientific Committee. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J 2010; 36 (3) 531-539
- 25 Burgel PR, Paillasseur JL, Peene B , et al. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS ONE 2012; 7 (12) e51048
- 26 Burgel PR, Roche N, Paillasseur JL , et al; INITIATIVES BPCO Scientific Committee. Clinical COPD phenotypes identified by cluster analysis: validation with mortality. Eur Respir J 2012; 40 (2) 495-496
- 27 Vanfleteren LE, Spruit MA, Groenen M , et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187 (7) 728-735
- 28 Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2000; 160 (11) 1683-1689
- 29 Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007; 370 (9589) 765-773
- 30 Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 1977; 115 (2) 195-205
- 31 Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15%. Lancet 2006; 367 (9518) 1216-1219
- 32 Tashkin DP, Detels R, Simmons M , et al. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am J Respir Crit Care Med 1994; 149 (5) 1209-1217
- 33 Downs SH, Schindler C, Liu LJ , et al; SAPALDIA Team. Reduced exposure to PM10 and attenuated age-related decline in lung function. N Engl J Med 2007; 357 (23) 2338-2347
- 34 Rice MB, Ljungman PL, Wilker EH , et al. Long-term exposure to traffic emissions and fine particulate matter and lung function decline in the Framingham heart study. Am J Respir Crit Care Med 2015; 191 (6) 656-664
- 35 Rice MB, Ljungman PL, Wilker EH , et al. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013; 188 (11) 1351-1357
- 36 Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009; 374 (9691) 733-743
- 37 Camp PG, Ramirez-Venegas A, Sansores RH , et al. COPD phenotypes in biomass smoke- versus tobacco smoke-exposed Mexican women. Eur Respir J 2014; 43 (3) 725-734
- 38 Ramírez-Venegas A, Sansores RH, Quintana-Carrillo RH , et al. FEV1 decline in patients with chronic obstructive pulmonary disease associated with biomass exposure. Am J Respir Crit Care Med 2014; 190 (9) 996-1002
- 39 Kauffmann F, Drouet D, Lellouch J, Brille D. Twelve years spirometric changes among Paris area workers. Int J Epidemiol 1979; 8 (3) 201-212
- 40 Marchetti N, Garshick E, Kinney GL , et al; COPDGene Investigators. Association between occupational exposure and lung function, respiratory symptoms, and high-resolution computed tomography imaging in COPDGene. Am J Respir Crit Care Med 2014; 190 (7) 756-762
- 41 Kim V, Davey A, Comellas AP , et al; COPDGene® Investigators. Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir Res 2014; 15: 52
- 42 Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70 (3) 171-179
- 43 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339 (17) 1194-1200
- 44 Ulrik CS, Backer V. Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma. Eur Respir J 1999; 14 (4) 892-896
- 45 Wang X, Mensinga TT, Schouten JP, Rijcken B, Weiss ST. Determinants of maximally attained level of pulmonary function. Am J Respir Crit Care Med 2004; 169 (8) 941-949
- 46 Sexton P, Black P, Wu L , et al. Fixed airflow obstruction among nonsmokers with asthma: a case-comparison study. J Asthma 2013; 50 (6) 606-612
- 47 Asthma, COPD and asthma-COPD overlap syndrome (ACOS). 2015. http://www.goldcopd.org/asthma-copd-overlap.html
- 48 Hardin M, Silverman EK, Barr RG , et al; COPDGene Investigators. The clinical features of the overlap between COPD and asthma. Respir Res 2011; 12: 127
- 49 Braman SS. The chronic obstructive pulmonary disease-asthma overlap syndrome. Allergy Asthma Proc 2015; 36 (1) 11-18
- 50 Swanney MP, Ruppel G, Enright PL , et al. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax 2008; 63 (12) 1046-1051
- 51 Mohamed Hoesein FA, Zanen P, Lammers JW. Lower limit of normal or FEV1/FVC < 0.70 in diagnosing COPD: an evidence-based review. Respir Med 2011; 105 (6) 907-915
- 52 Gina Report, Global Strategy for Asthma Management and Prevention. 2015. www.ginasthma.org/documents/4
- 53 Diaz AA, Hardin ME, Come CE , et al; COPDGene Investigators. Childhood-onset asthma in smokers. association between CT measures of airway size, lung function, and chronic airflow obstruction. Ann Am Thorac Soc 2014; 11 (9) 1371-1378
- 54 Woodruff PG. Subtypes of asthma defined by epithelial cell expression of messenger RNA and microRNA. Ann Am Thorac Soc 2013; 10 (Suppl): S186-S189
- 55 Bhakta NR, Erle DJ. IL-17 and “TH2-high” asthma: Adding fuel to the fire?. J Allergy Clin Immunol 2014; 134 (5) 1187-1188
- 56 Irvin C, Zafar I, Good J , et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol 2014; 134 (5) 1175-1186.e7
- 57 Hinks TS, Zhou X, Staples KJ , et al. Innate and adaptive T cells in asthmatic patients: Relationship to severity and disease mechanisms. J Allergy Clin Immunol 2015;
- 58 Kanemitsu Y, Ito I, Niimi A , et al. Osteopontin and periostin are associated with a 20-year decline of pulmonary function in patients with asthma. Am J Respir Crit Care Med 2014; 190 (4) 472-474
- 59 Bhakta NR, Solberg OD, Nguyen CP , et al. A qPCR-based metric of Th2 airway inflammation in asthma. Clin Transl Allergy 2013; 3 (1) 24
- 60 Diamant Z, Tufvesson E, Bjermer L. Which biomarkers are effective for identifying Th2-driven inflammation in asthma?. Curr Allergy Asthma Rep 2013; 13 (5) 477-486
- 61 Christenson SA, Steiling K, van den Berge M , et al. Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 191 (7) 758-766
- 62 Carolan BJ, Hughes G, Morrow J , et al. The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes. Respir Res 2014; 15: 127
- 63 Tager IB, Segal MR, Speizer FE, Weiss ST. The natural history of forced expiratory volumes. Effect of cigarette smoking and respiratory symptoms. Am Rev Respir Dis 1988; 138 (4) 837-849
- 64 Sherrill DL, Lebowitz MD, Knudson RJ, Burrows B. Continuous longitudinal regression equations for pulmonary function measures. Eur Respir J 1992; 5 (4) 452-462
- 65 Barker DJP, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991; 303 (6804) 671-675
- 66 Kotecha SJ, Edwards MO, Watkins WJ , et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax 2013; 68 (8) 760-766
- 67 Beyer D, Mitfessel H, Gillissen A. Maternal smoking promotes chronic obstructive lung disease in the offspring as adults. Eur J Med Res 2009; 14 (Suppl. 04) 27-31
- 68 Svanes C, Omenaas E, Jarvis D, Chinn S, Gulsvik A, Burney P. Parental smoking in childhood and adult obstructive lung disease: results from the European Community Respiratory Health Survey. Thorax 2004; 59 (4) 295-302
- 69 Vollsæter M, Røksund OD, Eide GE, Markestad T, Halvorsen T. Lung function after preterm birth: development from mid-childhood to adulthood. Thorax 2013; 68 (8) 767-776
- 70 Gold DR, Wang X, Wypij D, Speizer FE, Ware JH, Dockery DW. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996; 335 (13) 931-937
- 71 Wang X, Wypij D, Gold DR , et al. A longitudinal study of the effects of parental smoking on pulmonary function in children 6-18 years. Am J Respir Crit Care Med 1994; 149 (6) 1420-1425
- 72 Wright RJ, Brunst KJ. Programming of respiratory health in childhood: influence of outdoor air pollution. Curr Opin Pediatr 2013; 25 (2) 232-239
- 73 Kabesch M, Adcock IM. Epigenetics in asthma and COPD. Biochimie 2012; 94 (11) 2231-2241
- 74 Qiu W, Baccarelli A, Carey VJ , et al. Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function. Am J Respir Crit Care Med 2012; 185 (4) 373-381
- 75 Basma H, Gunji Y, Iwasawa S , et al. Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells. Am J Physiol Lung Cell Mol Physiol 2014; 306 (6) L552-L565
- 76 Gough J, Wentworth JE. Thin sections of entire organs mounted on paper. Harvey Lect 1957– 1959; 53: 182-185
- 77 Leopold JG, Gough J. The centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax 1957; 12 (3) 219-235
- 78 Anderson Jr AE, Hernandez JA, Eckert P, Foraker AG. Emphysema in lung macrosections correlated with smoking habits. Science 1964; 144 (3621) 1025-1026
- 79 Barr RG, Berkowitz EA, Bigazzi F , et al; COPDGene CT Workshop Group. A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation. COPD 2012; 9 (2) 151-159
- 80 Castaldi PJ, San José Estépar R, Mendoza CS , et al. Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers. Am J Respir Crit Care Med 2013; 188 (9) 1083-1090
- 81 Castaldi PJ, Cho MH, San José Estépar R , et al; COPDGene Investigators. Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns. Am J Respir Crit Care Med 2014; 190 (4) 399-409
- 82 Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med 2004; 170 (11) 1172-1178
- 83 Ito I, Nagai S, Handa T , et al. Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema. Am J Respir Crit Care Med 2005; 172 (11) 1378-1382
- 84 DeMeo DL, Hersh CP, Hoffman EA , et al. Genetic determinants of emphysema distribution in the national emphysema treatment trial. Am J Respir Crit Care Med 2007; 176 (1) 42-48
- 85 Fishman A, Martinez F, Naunheim K , et al; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348 (21) 2059-2073
- 86 Jones PW, Rames AD. Tesra (treatment of emphysema with a selective retinoid agonist) study results. Am J Respir Crit Care Med 2011; 183: A6418
- 87 Schroeder JD, McKenzie AS, Zach JA , et al. Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease. AJR Am J Roentgenol 2013; 201 (3) W460-70
- 88 Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of α-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 2010; 11: 136
- 89 Coxson HO, Dirksen A, Edwards LD , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study. Lancet Respir Med 2013; 1 (2) 129-136
- 90 Galbán CJ, Han MK, Boes JL , et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012; 18 (11) 1711-1715
- 91 Boes JL, Hoff BA, Bule M , et al. Parametric response mapping monitors temporal changes on lung CT scans in the subpopulations and intermediate outcome measures in COPD Study (SPIROMICS). Acad Radiol 2015; 22 (2) 186-194
- 92 Christenson SA, Brandsma CA, Campbell JD , et al. miR-638 regulates gene expression networks associated with emphysematous lung destruction. Genome Med 2013; 5 (12) 114
- 93 Campbell JD, McDonough JE, Zeskind JE , et al. A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Med 2012; 4 (8) 67
- 94 Coxson HO. Quantitative chest tomography in COPD research: chairman's summary. Proc Am Thorac Soc 2008; 5 (9) 874-877
- 95 Wells JM, Washko GR, Han MK , et al; COPDGene Investigators; ECLIPSE Study Investigators. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012; 367 (10) 913-921
- 96 Jaramillo JD, Wilson C, Stinson DJ , et al; the COPDGene Investigators. Reduced bone density and vertebral fractures in smokers: men and COPD patients at increased risk. Ann Am Thorac Soc 2015;
- 97 Romme EA, Murchison JT, Edwards LD , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study Investigators. CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes. J Bone Miner Res 2013; 28 (6) 1369-1377
- 98 Budoff MJ, Nasir K, Kinney GL , et al. Coronary artery and thoracic calcium on noncontrast thoracic CT scans: comparison of ungated and gated examinations in patients from the COPD Gene cohort. J Cardiovasc Comput Tomogr 2011; 5 (2) 113-118
- 99 Williams MC, Murchison JT, Edwards LD , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. Thorax 2014; 69 (8) 718-723
- 100 Diaz AA, Zhou L, Young TP , et al; ECLIPSE investigators. Chest CT measures of muscle and adipose tissue in COPD: gender-based differences in content and in relationships with blood biomarkers. Acad Radiol 2014; 21 (10) 1255-1261
- 101 McDonald ML, Diaz AA, Ross JC , et al. Quantitative computed tomography measures of pectoralis muscle area and disease severity in chronic obstructive pulmonary disease. A cross-sectional study. Ann Am Thorac Soc 2014; 11 (3) 326-334
- 102 O'Neal WK, Anderson W, Basta PV , et al; SPIROMICS Investigators. Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study. J Transl Med 2014; 12: 9
- 103 Agustí A, Edwards LD, Rennard SI , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012; 7 (5) e37483
- 104 Mahler DA, Huang S, Tabrizi M, Bell GM. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 2004; 126 (3) 926-934
- 105 Polkey MI, Spruit MA, Edwards LD , et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study Investigators. Six-minute-walk test in chronic obstructive pulmonary disease: minimal clinically important difference for death or hospitalization. Am J Respir Crit Care Med 2013; 187 (4) 382-386
- 106 Doyle TJ, Washko GR, Fernandez IE , et al; COPDGene Investigators. Interstitial lung abnormalities and reduced exercise capacity. Am J Respir Crit Care Med 2012; 185 (7) 756-762
- 107 Friedman M, Witek TJ, Serby CW, Flanders J, Menjoge SS, Wilson JD. Combination bronchodilator therapy is associated with a reduction in exacerbations. Am J Respir Crit Care Med 1996; 153: A126
- 108 Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320 (7245) 1297-1303
- 109 Hurst JR, Vestbo J, Anzueto A , 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) 1128-1138
- 110 Mannino DM, Tal-Singer R, Lomas DA , et al. Plasma fibrinogen as a biomarker for mortality and hospitalized exacerbations in people with copd. Chronic Obstr Pulm Dis (Miami) 2015; 2 (1) 23-34
- 111 Han MK, Kazerooni EA, Lynch DA , et al; COPDGene Investigators. Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011; 261 (1) 274-282
- 112 Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106 (2) 196-204
- 113 Aaron SD, Vandemheen KL, Maltais F , et al. TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial. Thorax 2013; 68 (2) 142-148
- 114 Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S ; EXACT-PRO Study Group. Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J Respir Crit Care Med 2011; 183 (3) 323-329
- 115 Coursol S, Fan LM, Le Stunff H, Spiegel S, Gilroy S, Assmann SM. Sphingolipid signalling in Arabidopsis guard cells involves heterotrimeric G proteins. Nature 2003; 423 (6940) 651-654
- 116 Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1 (6077) 1645-1648