Are Asthma and COPD Two Faces of a Similar Process? Towards a new taxonomy of airways diseases

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Published on February 20, 2014

Author: Grupomenarini



Barcelona-Boston Lung Conference

Ian D Pavord Professor of Respiratory Medicine University of Oxford Are Asthma and COPD Two Faces of a Similar Process? Towards a new taxonomy of airways diseases

Plan • Asthma and COPD: is the sub-division helpful? • Is it better to describe rather than categorise? • Eosinophilic airway inflammation in COPD • Development of fixed airflow obstruction (‘COPD’) in asthma • Could the mechanisms leading to the development of fixed airflow obstruction in asthma be similar to those resulting in COPD in a smoker?

Features of asthma Features of COPD Features of asthma Features of COPD The various types of airway diseases should not be considered as separate diseases but as one disease, the components of which are influenced by host (genetic) and environmental factors. Postma DS, Boezen HM. Chest 2004; 126: 96s-109s Orie, NG

Why we should all be Dutch • Community studies have shown that 6% of patients with asthma and 5% of patients with COPD responding to a survey would be eligible for key, opinion forming clinical trials in these conditions1,2 • A common reason for exclusion is presence of features normally associated with the other condition • Labels suggest exclusivity and inhibit full description • Physiological classification overemphasises this aspect of the disease • This has inhibited major conceptual advances and new drug discovery. 1Travers 2Travers et al. Thorax 2007;62:219-223; et al. Resp Med 2007;101:1313-20

Don’t get hung up on the diagnosis FENO (ppb) 78 20ppb Prednisolone xxxxxxxxxxxxxxxxxxxxx Cough and sputum xxxxxxxxxxxxx COPD Asthma Predicted PEF

The A to E of potential causes for persistent morbidity in patients with airway disease • • • • • Airway hyperresponsiveness Bronchitis Cough reflex hypersensitivity Damage Extra-pulmonary factors Pavord & Wardlaw. Clin Exp Allergy 2010

Airway hyperresponsiveness • Responsible for many day-to-day symptoms • Exaggerated response to constrictor stimuli, bronchodilator responsive airflow obstruction, short-term variable airflow obstruction, deep breath-induced bronchodilation • Most closely linked to mast cell-airway smooth muscle interactions • Current treatments usually suppresses but not completely

Bronchitis • Eosinophilic or neutrophilic • Bronchodilator unresponsive, corticosteroid responsive airflow obstruction, less short-term variable airflow obstruction, deep breath-induced bronchoconstriction • Most closely linked to exacerbations, particularly when associated with acute inflammation in patients with A and D • Current treatments usually suppress eosinophilic bronchitis effectively; some patients require oral prednisolone • Neutrophilic bronchitis is corticosteroid resistant

Mechanisms of airflow limitation FENO (ppb) 78 20ppb Prednisolone xxxxxxxxxxxxxxxxxxxxx Cough and sputum xxxxxxxxxxxxx B Predicted PEF D A

Sputum eosinophil counts in COPD Sputum eosinophils (%) 100 30 10 3 1 0.3 0 Asthma COPD Normal Brightling et al. Lancet 2000;356:1480-85; Green et al. Thorax 2002; 57:875-879

Baseline characteristics by tertiles of sputum eosinophil count in patients with COPD Eosinophil count <1.3 (22) 1.3-4.5 (23) >4.5 (22) Male 13 13 15 Age 68 (42-82) 66 (49-83) 64 (47-78) FEV1 1.16 (0.03) 1.11 (0.09) 0.96 (0.08) FEV1 BD 1.21 (0.1) 1.15 (0.09) 0.98 (0.08) Pack years 33 (4.1) 35 (2.5) 37 (4.3) 7 7 6 FBC Eo (x109/l) 0.12 (0.02) 0.22 (0.04) 0.17 (0.02) CRQ Total 3.92 (0.25) 4.04 (0.19) 4.08 (0.25) Atopic Brightling et al. Lancet 2000;356:1480-85

Response to prednisolone by tertile 0.25 ** 0.20 D FEV1 (l) 0.15 0.10 0.05 0.00 -0.05 Brightling et al. Lancet 2000;356:1480-85 <1.3 1.3-4.5 >4.5 Eosinophil count **p<0.01

Severe exacerbations (n) Sputum eosinophil directed steroid treatment in asthma and COPD 120 100 BTS guidelines (n=37) 6 patients admitted 80 60 35 40 20 *p=0.01 Sputum guided (n=37) 1 patient admitted 0 0 Admissions (n) 109* Asthma 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Green et al, Lancet 2002; 360: 1715-21 COPD 20 Traditional n=20 15 10 Sputum n=8* 5 *p=0.037 0 0 2 4 6 Time (months) 8 12 Siva et al. Eur Respir J 2007; 29:906-913

Mepolizumab (anti-IL-5). Effect on severe exacerbations Haldar et al. NEJM 2009;360:973-84 Pavord et al. Lancet 2012;380:651-9.

Is there a role for Mepolizumab in eosinophilic COPD? DFEV1 after salbutamol (ml) Exacerbations/pt/year Mepo Placebo <50 50 to 150 >150 1.3 1.7 2.6 3.8 3.6 2.4 p-value 0.02 0.11 0.85 • 95 patients in DREAM study would have been eligible for most recent COPD trials if they had smoked for a few more years • Patients with symptom onset >40 years, a smoking history, a post-bronchodilator FEV1 <80% predicted and FEV1/FVC <0.7 had a 61% reduction in exacerbations, compared to 48% in total population Haldar et al. NEJM 2009;360:973-84 Pavord et al. Lancet 2012;380:651-9.

Exacerbation: inflammatory phenotypes • 145 patients with COPD followed for 1 year; 182 exacerbations characterised • Three inflammatory patterns: bacterial (55%), viral (29%) and eosinophilic (28%) • Associated with characteristic and largely predictable sputum and blood cytokine patterns • A blood eosinophilia is a good marker of eosinophilic exacerbations • Eosinophilic exacerbations are associated with a more rapid and complete response to steroids • Bacterial and eosinophilic exacerbations almost never coexist • Exacerbation patterns tend to be consistent within patients Bafadhel et al. Am J Respir Crit Care Med 2011;184:662-71

Eosinophilic exacerbations: bad but treatable Sp Eos >3% treated with prednisolone Sp Eos <3% treated with placebo Sp Eos <3% treated with prednisolone Bafadhel M et al. Am J Respir Crit Care Med 2012;186:48-55

Phenotype-specific management of COPD exacerbations 14 excluded; 11 did not fulfil inclusion criteria, 3 other co-morbidity 170 patients screened for eligibility of biomarker observation study 156 patients entered biomarker observation study 115 patients completed biomarker observation study 13 died, 7 withdrew, 21 other comorbidity 167 patients screened for eligibility into biomarker intervention study 164 entered into biomarker intervention study (94 from biomarker observation study) At exacerbation 55 patients randomised to biomarker treatment arm 54 patients randomised to standard treatment arm 80 exacerbation events 86 exacerbation events ≤ 2% 42 exacerbations received Placebo + antibiotics 1 treatment failure 1 died, 2 withdrew > 2% ≤ 2% 44 exacerbations received Prednisolone + antibiotics 3 treatment failures 39 exacerbations received Prednisolone + antibiotics 6 treatment failures > 2% 41 exacerbations received Prednisolone + antibiotics 4 treatment failures Bafadhel et al. Am J Respir Crit Care Med 2012; 186:48-55

Fixed airflow obstruction in asthma • • • • Seen in patients with severe childhood asthma Also in a subgroup of adult onset disease; association with smoking Associated with neutrophilic and eosinophilic airway inflammation Clinical, physiological and radiological evidence of small and large airway damage (remodelling) • Related to frequency of asthma attacks, particularly in untreated disease • One attack/year caused 30 ml excess loss in FEV1/year FEV1 Asthma Smoking Early onset Severe asthma Asthma or Smoking Asthma and Smoking Age Bai et al. Eur Resp J 2007;30:452-56 Lange et al. NEJM 1998;339:1194-1200

Why does airway disease become severe? Mild atopic asthma Severe, refractory asthma Severe COPD Mild smokers bronchitis • • • • Large airway inflammation Homogeneous (eosinophilic, neutrophilic) Little damage Responsive to intervention (inhaled steroids, smoking cessation) • • • • Large and small airway inflammation Heterogeneous; increased neutrophils Damage++ Unresponsive to intervention (inhaled steroids, smoking cessation)

Multiple ‘hits’ and the airway • Amplification of inflammatory response • More distal, neutrophil predominant response • More airway damage • Corticosteroid resistance • Worse clinical consequences Pavord et al. ERJ 2006;27:884-888

Multiple ‘hits’ and airway disease: examples • Enhanced allergen response after viral infection or after exposure to pollutants • Increased decline in FEV1 in smokers and asthmatics with occupational coal dust exposure • Increased decline in FEV1 and airway damage in patients sensitised and colonised/infected with aspergillus • Chronic viral/bacterial infection in COPD and asthma

Multiple ‘hits’ and airway disease

Multiple ‘hits’ and airway disease

Smoking and asthma • • • • Increased symptoms and exacerbations Sputum neutrophilia More rapid decline in FEV1 Poor response to inhaled and oral corticosteroids Chalmers et al Thorax 2002;57:226-30

Smoking cessation and asthma control • • • • 10 quitters vs 11 continued smokers Improved FEV1 and ACQ in quitters Reduced sputum neutrophils (-29% at 6 weeks) Increased cutaneous vasoconstrictor response to topical steroid 1 3 6 Weeks abstinence Chaudhuri et al. AJRCCM 2006;174:127-133

Aspergillus sensitisation is associated with impaired lung function P<0.0001 P<0.05 Positive culture Logistic regression for Sputum Af culture – Af sensitisation p = 0.004, Age = p= 0.076 Fairs et al. Am J Respir Crit Care Med 2010;182:1362-68 Negative culture

Anti-fungal treatment in aspergillusassociated asthma Denning et al. AJRCCM 2009;179:11-18

Macrolides and severe airway disease COPD Asthma 16 Clarithromycin 14 Placebo #P<0.05 IL-8 ng/mL 12 10 8 6 *# 4 2 0 Albert et al. NEJM 2011;365:689-98 Neutrophil Elastase ng/mL Baseline 2000 1800 1600 1400 1200 1000 800 600 400 200 0 After treatment Treatment withdrawn Clarithromycin Placebo # Baseline After treatment Treatment withdrawn Simpson et al. AJRCCM 2008;177:148–155

Conclusions • “Asthma” is an important cause of “COPD” • An important number of patients classified as having COPD are receiving sub-optimal treatment with corticosteroids • Common features are potentially responsible for evolution of mild to severe disease • Multiple inflammatory „hits‟ may be one such factor • Recognition of potential hits might lead to effective management approaches

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