Asthma and COPD in older people lumping or splitting? Christine Jenkins Concord Hospital Woolcock Institute of Medical Research

Asthma and COPD in older people lumping or splitting? Christine Jenkins Concord Hospital Woolcock Institute of Medical Research

Concord Hospital

Woolcock Institute of Medical Research

Joe has asthma What the I get Short of breath Joe has COPD

Problems in the classification of airways disease New tools have defined different inflammatory profiles, some are common to asthma and COPD Disparity in clinical, physiologic, and pathologic markers within the spectrum of asthma, suggesting heterogeneity Spectrum of airways disease and a spectrum within types of airways disease Asthma and COPD are multidimensional diseases with generalised systemic aspects (COPD) or focal multisystem aspects (asthma) Marked heterogeneity in physiology, pathology, clinical presentation. Hence 1. Are the current diagnostic labels too simplistic? 2. Are different approaches to treatment required?

Why is it important to consider obstructive airways diseases beyond asthma and COPD? Patients with overlapping asthma and COPD are frequently excluded from clinical trials of treatments for either condition An accurate diagnosis is challenging in day to day practice, especially in older patients There is variability in bronchodilator responsiveness day to day and class to class in COPD, making not fully reversible difficult to define Identifying overlap or mixed disease opens up a more realistic spectrum of management issues and expectations, especially in people with irreversible AO people with AO and partial reversibility

The overlap syndrome of asthma and COPD Gibson & Simpson Thorax 2009 64: 728-735 Asthma = Episodic respiratory symptoms and variable airflow obstruction occurring spontaneously, with treatment or after provocation COPD = Incompletely reversible airflow obstruction Asthma and COPD are not mutually exclusive Overlap syndrome of Asthma and COPD = symptoms of increased variability of airflow and incompletely reversible airflow obstruction When a patient exhibits features of more than one condition, then they have an overlap syndrome

The overlap of airways diseases The ATS 1995 COPD guidelines defined asthma, chronic bronchitis, emphysema, COPD and airflow obstruction Identified 11 distinct syndromes Overlap between two or more conditions made up 6 of these 11 syndromes

Quantitative assessment of airway remodelling using high-resolution CT Nakano, Muller, King; Chest 2002 The relationship between emphysema (LAA, low attenuation areas) and airway wall thickness (WA%) in 94 COPD subjects and 20 smokers (quantitative CT scan analyses). The pattern (ie, phenotype) represented in the right lower quadrant of the graph is similar to the pattern found in patients with severe asthma that is incompletely reversible

Percentage of people with overlap syndrome related to increasing age Soriano JB et al Chest 2003;124:474 81

Airway Remodelling : what is affected? James A, Wenzel S. Clinical relevance of airway remodelling. Eur Respir J 2007;30:134

Cohort study of asthma followed to adulthood Sears et al. NEJM 2003;349:1414

Busselton Height adjusted FEV1 decline male female Subjects who have asthma and smoke have fastest rate of decline

Clinical phenotypes of asthma Haldar et al AJRCCM 2008; 178. pp 218 224 Undertook cluster analysis in asthma subjects in primary care (n = 184) with predominantly mild to moderate disease Compared to a refractory asthma population managed in secondary care (n = 187) Compared differences in asthma outcomes - exacerbation frequency & change in ICS at 12m In a third population of 68 subjects with predominantly refractory asthma, RCT compared a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care Two clusters were common to both asthma populations early-onset atopic and obese, noneosinophilic Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation were specific to refractory asthma early-onset, symptom predominant late-onset, inflammation predominant

Clinical phenotypes of asthma Haldar et al AJRCCM 2008; 178. pp 218 224 Inflammation-guided management was superior for both discordant subgroups a reduction in exacerbation frequency in the inflammationpredominant cluster (3.53 vs. 0.38 exac/pt/yr, P < 0.002) and A dose reduction of ICS in the symptom-predominant cluster (mean difference, 1829 mcg BDP eq/day (95% CI 307 3,349 mcg); P < 0.02 a symptom-led approach would be effective for concordant mild to moderate asthma in primary care for patients with early-onset atopic asthma = benign discordance between these domains is a prevalent characteristic of refractory asthma

Clinical phenotypes of asthma Haldar et al AJRCCM 2008; 178. pp 218 224

Distinct clinical phenotypes of airways disease defined by cluster analysis Weatherall et al Eur Respir J 2009; 34: 812 818 A random population sample of 25 75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and CT Cluster analysis was performed on the subgroup with a complete dataset (n=175) and current respiratory symptoms or obstructive spirometry Five clusters were identified Cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema = an overlap syndrome Cluster 2: features of emphysema alone Cluster 3: atopic asthma with eosinophilic airways inflammation Cluster 4: mild airflow obstruction without other dominant phenotypic features Cluster 5: chronic bronchitis in non-smokers Overlap cluster had most severe disease : worse airflow obstruction, requirement for hospital admission, prescribed treatment and quality of life

Asthma and COPD The old approach to diagnosis and management

GOLD WORKSHOP REPORT 2010 Diagnosis of COPD A diagnosis of COPD should be considered in any patient who has chronic cough, sputum production or dyspnea, and/or a history of exposure to risk factors for the disease. The diagnosis should be confirmed by spirometry The presence of a post-bd FEV1/FVC< 0.7 and an FEV1<80% predicted confirms the presence of airflow limitation that is not fully reversible

Asthma diagnosis = symptoms + variable obstruction To establish the diagnosis of asthma, the clinician must determine that: Episodic symptoms of airflow obstruction are present. Airflow obstruction is at least partially reversible Working definition of asthma a disorder of the airways in which they are prone to narrowing too much and too easily in response to a wide variety of provoking stimuli, causing variable wheeze, chest tightness, cough and breathlessness.

Asthmatic airway Non-asthmatic airway

Antecedents to Obstruction Several routes one outcome

FEV 1 % normal at age 20 Theoretical rates of lung function growth and decline Normal growth, peak and rate of decline Normal growth & peak, accelerated decline Normal growth, premature decline, normal rate Sub-maximal growth & peak, normal rate decline 20 40 60 Age in years

Risk factors for sub maximal peak Intra-uterine ETS Early life RTI Early life ETS Early life biomass fuel smoke exposure Low birth weight Early life pneumonia malnutrition Socio-economic factors Under-treated asthma

Risk factors for accelerated rate of FEV1 decline Smoking Female AHR Age Chronic mucus hypersecretion Reversibility Atopy

Why (I believe) the distinction matters Predicting response to treatment Pulmonary rehab Preparation for future events Prognosis Public health initiatives prevention

Predicting response to treatment

Morning PEF, L/min FEV 1, % predicted b 2 -agonist use Nights/week 5 4 b 2 -agonist use 4 3 Night waking 3 2 2 1 1 0 0 100 500 400 300 90 80 70 Morning PEF Clinic FEV 1 60 0 8 16 24 32 40 48 56 64 72 50 0 8 16 24 32 40 48 56 64 72

Rate ratio for death from asthma Low dose inhaled corticosteroids and the prevention of death from asthma Suissa, Ernst, Benayoun et al. NEJM 2000:343:322-6 2.5 2.0 1.5 93% ICS canisters were BDP 50 mcg/puff 1.0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 No. canisters of ICS per year

Post-bronchodilator FEV1 Effect of fluticasone on FEV1 over 3 years 1.5 1.4 1.3 1.2 * * * p<0.001 * * FP 1mg * Placebo -3 0 3 6 9 121518212427303336 Time (months) 32% reduction in absolute decline in FEV 1 Disease modifying effect Effect maintained over 3 years ISOLDE BMJ May 2000

PEF (L/min) 800 700 600 500 400 300 200 100 0 0 4 8 12 16 20 24 28 32 Weeks from commencement of budesonide Morning pre - BD PEF Evening pre -BD PEF Post-BD PEF

Survival probability Exacerbations and Mortality Soler-Cataluna JJ, et al. Thorax 2005; 60:925 931 1.0 0.8 0.6 A p<0.0002 0.4 0.2 B p=0.069 C p<0.0001 0 n=304 0 10 20 30 40 50 60 Time (months) Prospective study in 304 male patients with stable COPD, recruited 1998 and followed for 5 years Group A: no exacerbations Group B: 1 2 exacerbations Group C: 3 exacerbations

40% 30% 20% 10% 0% ISOLDE results : COPD exacerbations Effect Greatest in Those With Lowest Lung Function (FEV 1 ) 35% 24% <1.25 1.25-1.54 FEV 1 (litres) DEFINITION OF AN EXACERBATION worsening of respiratory symptoms that required treatment with antibiotics, OCS or both; no objective symptom criteria Burge PS et al BMJ May 2000

ICS and risk of pneumonia Ernst et al. AJRCCM 2007;176:162

Rate per 10,000 Rate of patterns of comorbidity in newly diagnosed COPD in primary care 450 400 350 300 250 200 150 100 50 0 Cataracts (0.90) Skin bruises (1.00) Glaucoma (1.29) Angina (1.67) Fractures (1.58) Respiratory infection (2.24) Myocardial infarction (1.75) 0 0.5 1 1.5 2 2.5 3 3.5 4 Relative risk in COPD vs non-copd Osteoporosis (3.14) Pneumonia (16.00) Soriano et al 2005 Rate of medical events in UK General Practice Research Database 1998

Mortality in COPD : Role of co-morbidities Sin D et al ERJ 2006;28:1245 Estimated rate of 30d mortality post hospital D/C in patients with and without COPD National Hospital Discharge Survey, UK 1979-2001

Preparation for Future Events

Process and patterns of care in chronic disease Holman & Lorig BMJ 2000;320:526-7 Ambulatory care threshold Disease severity Medication Diagnosis Self management strategies Primary care threshold Self care threshold Effective self Mx controls progression and avoids crossing thresholds Progression of disease over time

Action Plans

ALF COPD Action Plan

Prognosis

Prognosis after ICU admission Seneff et al JAMA 1995/274:1852-7: Hospital & I year survival of patients admitted to ICU with acute exacerbations of COPD 362 admissions to ICU for COPD exacerbations Overall mortality 24% (12 months) Median survival 224 days Non-respiratory organ dysfunction was the major predictor of hospital mortality & 180 day mortality 167 patients aged > 65, mortality: 30% at D/C 41% at 90 days, 47% at 180 days, 59% at 1 year

A predictive model of hospitalisation and death from COPD Schembri et al Resp Med 2009;103:1461 Prospective observational study 3343 patients with FEV1 < 80% pred and FEV1/FVC < 70% from a clinical network in Tayside, Scotland Data collected during annual visits - spirometry, smoking history, MRC dyspnoea scale, BMI Main outcome measures were hospitalisations and death secondary to COPD Increasing age, low BMI, worsening MRC dyspnoea score, decreased FEV1, and prior respiratory or cardiovascular admission hospitalisation were predictors of poor outcome Influenza vaccination was protective

Prognostic issues for COPD patients need to be discussed Role of bacterial infection in exacerbations Planning for increased dependency Anticipate and manage co-morbidity Anticipating hospital admissions Review for LTOT Discuss choice for ventilatory support End of life decisions / Living will

Summary COPD and Asthma each have a spectrum of causes, manifestations and pathophysiologic stages Common clinical features in these diseases result in some indistinguishable features and overlap syndromes increase with age However, the natural history of each is different and prognosis is affected by pathology Asthma is predominantly an airways disease, while COPD is a mixed airways-parenchymal disease Patients are best served by Acknowledging the importance of symptoms and addressing these Respecting the differing pathologies and outlooks and tailoring treatment accordingly