医学交流课件：AZ China COPD ATS ERS 2 Russell

1、Nuffield Department of Medicine Recent Advances in COPD: Nuffield Department of Medicine 2 Building bridges in the city of canals Scientific highlights from the 2015 ERS in Amsterdam Golden insights Scientific highlights from the 2016 ATS in San Francisco Nuffield Department of Medicine Respiratory

2、Consultant, Southern Healthcare Senior Researcher, Oxford University Editor of International Journal of COPD r.russellimperial.ac.uk Nuffield Department of Medicine Lymington New Forest Hospital Chest Physician West Hampshire Integrated Respiratory Service Nuffield Department of Medicine Presenter d

3、isclosures: I have no shares in Pharmaceutical companies and do everything I can to hinder tobacco companies Who AstraZeneca Boehringer Ingelheim GlaxoSmithKline Napp Pfizer Teva Sandoz British Lung Foundation Editor Int J COPD What Paid speaker Advisory Boards Clinical Trial Investigator Travel Sup

4、port Support our Patients Increase our Impact Factor! Nuffield Department of Medicine What am I going to cover? GOLD classification High Risk Patients and exacerbations The Role of Eosinophils ACOS Update on Pulmonary Rehab E-Cigarettes Progress is being made in COPD: The world is changing for the b

5、etter 7 COPD is the 3rd largest cause of mortality, responsible for 5% of deaths worldwide However, disease management is improving as shown in large studies over time: Lung function improvements of approximately 23 mL/yr Decreasing annual rate of change of mortality of 0.47% Progress in: smoking ce

6、ssation, better identification of disease and management of symptoms and exacerbations Analysis of 6 landmark COPD studies between 1999 and 2016 Nuffield Department of Medicine At presentation, patients typically show:16 Significant airflow limitation Symptoms of breathlessness Impaired QoL at prese

7、ntation Presentation in later-stage disease Failure to initiate prompt, optimized maintenance therapy Loss of the benefits of early treatment7,8 1. Price D, et al. Prim Care Respir J 2005;14:285293; 2. Mapel DW, et al. Int J Chron Obstruct Pulmon Dis 2011;6:573581; 3. Aisanov Z, et al. Int J Chron O

8、bstruct Pulmon Dis 2012;7:271282; 4. Lindberg A, et al. Respir Med 2006;100:264272; 5. Mapel DW, et al. Chest 2000;117:346S353S; 6. Price D, et al. Prim Care Respir J 2011;20:1522; 7. Wilkinson TM, et al. Am J Respir Crit Care Med 2004;169:12981303; 8. Welte T, et al. Int J Clin Pract 2015;69:336349

9、. Nuffield Department of Medicine 1. Mapel DW, et al. Int J Chron Obstruct Pulmon Dis 2011;6:573581; 2. Price D, et al. Prim Care Respir J 2011;20:1522. Data collected from medical charts and administrative claims in a managed care data repository. COPD diagnosis is often late GOLD 1 GOLD 3 GOLD 4 P

10、atients typically present at GOLD 21 Many remain undiagnosed until they have more severe airflow limitation1,2 Nuffield Department of Medicine FEV1 decline: the traditional view Modified version of the Fletcher and Peto graph showing the decline in FEV1. Fletcher C, Peto R. BMJ 1977;1:16451648. Nuff

11、ield Department of Medicine FEV1 decline: what is really going on? Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012;7:9599. More recent analyses concluded that, in contrast with earlier findings, FEV1 decline was fastest in the early stages of COPD, particularly in GOLD 2 disease FEV1 (% p

12、redicted) Years GOLD 1 (mild) GOLD 2 (moderate) GOLD 3 (severe) GOLD 4 (very severe) 4779 mL/yr 5659 mL/yr 2% overall seems to be the cut off for predicting a positive response Inflammation and infection Airway eosinophilic inflammation seems to be associated with lower systemic inflammation Sputum

13、and blood eosinophils seem to be associated with a lower probability of airway bacterial infection How can eosinophils help to guide treatment in acute exacerbations? 25 Bafadhel M, et al. Eur Respir J 2014;44:789-791. See notes for references 243 randomised 2% eosinophils Prednisolone (n=71) 26% tr

14、eatment failures No prednisolone (n=68) 20% treatment failures 2% eosinophils Prednisolone (n=77) 11% treatment failures No prednisolone (n=27) 66% treatment failures Should treatment be a question of eosinophil levels? Predictive role established in asthma, new evidence now arising for COPD (ATS 20

15、15): Two analyses of large clinical trials show that blood eosinophil levels 2% are associated with fewer COPD exacerbations and a more favourable rate in FEV1 decline in patients whose treatment regimen includes an ICS 26 Pneumonia events Green RH et al. Lancet. 2002;360:1715-21. Bafadhel M et al.

16、Eur Respir J. 2014;44:789-91; Barnes N et al. Am J Respir Crit Care Med 191;2015:A3975; Barnes N et al. Am J Respir Crit Care Med 191;2015:A3976; Bateman ED et al. Am J Respir Crit Care Med 191;2015: A3979; Vogelmeier CF. Oral presentation at ATS 2015 Session C82; Brusselle GG et al. Lancet Respir M

17、ed 2015; published online April 17. /10.1016/S2213-2600(15)00145-9. Analysis of four large trial populations for predictive role of blood eosinophils 27 Barnes N et al. Am J Respir Crit Care Med 191;2015:A3976; Barnes N et al. Am J Respir Crit Care Med 191;2015:A3976. Three trials in

18、cluding patients treated with inhaled therapy containing FP, SAL or the two combined provided a total of 3,045 patients with eosinophil counts Blood eosinophil count 2% range: 57% to 75% Reduction in exacerbation rate with FP/SAL in the 2% subgroup No reduction in 2% subgroup Blood eosinophil count

19、2% associated with response inhaled corticosteroids (vs. placebo) Pre-specified analysis of ISOLDE trial: Do inhaled corticosteroids (ICS) reduce rate of decline of lung function in COPD patients with eosinophil count 2%? Blood eosinophil count was 2% in 68% of patients Baseline blood eosinophil 2%

20、show slower rate of FEV1 decline with ICSs Blood eosinophil % and change in FEV1 from baseline in response to treatment with fluticasone propionate 2%2% ArmChangeDifference P valueChange Differenc e P value Placebo-36.4 ml/year 3.8 ml/year 0.016-27.0 ml/year 37.7 ml/year 0.001 FP 500 g -40.2 ml/year

21、 -64.7 ml/year Eosinophils and ICS Abstract 6944 ATS 2016 29 NO EFFECT ON EXACERBATIONS EFFECT IN THOSE WITH RAISED EOSINOPHIL COUNTS ONLY “ albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with raised eosinop

22、hil counts. The results of prespecified subgroup analysis support further investigation in patients with COPD and eosinophilia”. Eosinophils in COPD: a story with 2 parts At Stable State 25% of patients have an eosinophilia Predict steroid response at 3% level ICS leads to reduced exacerbations Wisd

23、om study demonstrates that ICS should not be withdrawn in those with raised blood Eos At Exacerbation 26% of patients have an eosinophilia 2% Predicts response to Oral Steroids Shorter length of hospital stay Possibly lower Mortality BUT: More readmissions 30 Abstracts: 7720, 5757, 5758, 9510, 6944,

24、 12085, 8534, Nuffield Department of Medicine ACOS: is CHAOS! ACOS the question of overlap syndrome or coincidental morbidity remains controversial 32 Vogelmeier CF. Oral presentation at ATS 2015; GINA Cosentino J et al. Am J Respir Crit Care Med 191;2015: A4451 Abstract. ACOS: Lack of agreement on

25、a definition and diagnostic criteria Frequency of “ACOS” lies between 12% and 56%, depending on the definition used Are ACOS patients asthma or COPD patients that share some similar lung pathologies? Some experts view ACOS as an artificial construct and ask if we apply existing asthma and COPD defin

26、itions with sufficient rigour Hypothesis: As a better future understanding of the underlying pathology, drivers and coincidental lung conditions grows, this may improve categorisation of either asthma or COPD, under consideration of possibly coincidental elements of lung pathology Current guidelines

27、: GINAGOLD approach to diseases of chronic airflow limitation. Diagnostic criteria relatively broad If features of both diseases, initially start on ICS treatment and consider LABA (+/- LAMA) Some clinical concerns have been raised regarding applicability in clinical practice ACOS evaluation by new

28、GOLD classification an analysis from the COPDGene Investigators 33 Study based on the GOLD letter grade, including 385 patients with ACOS* and 620 patients with COPD alone: No significant difference between the two groups for severe or frequent exacerbations Nearly 50% of ACOS patients were GOLD B,

29、indicating a high degree of symptoms Nearly 65% of ACOS patients were GOLD B or D, indicating this as a cohort with a high degree of disease instability and symptomatology GOLD Letter Grade ACOS (n=385) COPD (n=620) P value A 121 (31.43%) 76 (12.26%) 0.0001 B 154 (40.0%) 93 (15.0%) C 10 (2.6%) 47 (7

30、.58%) D 100 (25.97%) 404 (65.16%) Cosentino J et al. Am J Respir Crit Care Med 191;2015: A4451 Abstract. Data taken from Cosentino J et al. Am J Respir Crit Care Med 191;2015: A4451 Abstract. Review Article The AsthmaCOPD Overlap Syndrome Dirkje S. Postma, M.D., Ph.D., and Klaus F. Rabe, M.D., Ph.D.

31、 N Engl J Med Volume 373(13):1241-1249 September 24, 2015 On the basis of information presented in the current review, we believe that it is premature to recommend the designation of ACOS as a disease entity in primary and specialist care Exacerbations: not just a lung thing! 35 Wisnivesky JP et al.

32、 Am J Respir Crit Care Med 191;2015:A2530 Severe AECOPDs requiring hospitalisation associated with significant declines in cognitive function Acute changes in cognition potential barrier to patient- provider communication and effective post-discharge self-management Potentially increases risk for re

33、admissions Prospective, longitudinal multisite study of COPD patients requiring hospitalisation for exacerbation, comparing difference between stable periods vs. COPD-related hospitalisations: n=53 (mean SD: age 657 years; 72% female) Yearly face-to-face interviews for 2 years and during COPD-relate

34、d hospitalisations Global cognitive functioning (MMSE) Cognitive function domains: Speed (Trail Making A tests), Executive functioning (Trail Making B Test), Immediate and delayed recall (New York University Paragraph Recall test), and Word fluency (Animal Naming test) mean in score (units) P value

35、MMSE 1.40.0001 Immediate recall1.10.003 Delayed recall1.60.001 Word fluency1.50.01 Executive functioning 2.3NS Processing speed 1.5NS The pathology of cognitive dysfunction in COPD: White matter is under attack What type of damage is seen? Microstructural damage to white matter Similar in appearance

36、 to micro-vascular brain disease Total macroscopic lesion volume due to an increase in size, rather than number of lesions Where does the damage occur? Confined to the cerebral white matter No evidence of damage in sub-cortical region Not localised to any specific lobe (seen in frontal, temporal, pa

37、rietal, occipital sub-lobar) 36 What are the possible mechanisms? Direct toxic effect on white matter Consequence of micro-vascular disease (most probable) General rather than localised effect What are the consequences? Widespread reduction in neuronal connectivity Disrupted information transfer bet

38、ween cortical regions Slow or no memory recall Spilling C et al. Am J Respir Crit Care Med 191;2015:A6188 Abstract; Spilling C et al. Am J Respir Crit Care Med 191;2015:A6189 Abstract A troika of negative impact: anxiety, depression and cognitive dysfunction Willingness to participate in rehabilitat

39、ion programmes, especially exercise is affected. Goldstein RS. Oral presentation at ATS 2015 Session C8; Meek PM. Oral presentation at ATS 2015 Session C8 37 Depression Tiredness Blunted motivation Anxieties Falling (imbalance, osteoporosis) Dyspnoea Other (non- COPD) Cognitive dysfunction Working memory impaired Visio-spatial memory impaired Cannot