COPD. Topics for discussion. Clinical implications COPD. Genes and COPD: when to test for alpha-1- antitrypsin deficiency

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1 Advances in Internal Medicine 2007 James K. Brown, M. D. Pulmonary and Critical Care Medicine Section, Department of Veterans Affairs Medical Center, San Francisco Topics for discussion Screening for genetic abnormalities Inhaled bronchodilators Short-acting Long-acting Inhaled corticosteroids Alone Combined with long-acting beta-agonists Treatment of exacerbations Antibiotics Systemic corticosteroids Non-invasive ventilation Confounding diagnoses Lung volume reduction surgery Genes and : when to test for alpha-1- antitrypsin deficiency Early onset dyspnea from prior to 50 years Prominent family history of early-onset Lower lobe-predominant emphysema Unexplained cirrhosis or HCC in a patient Early-onset : Risks to 1 st -degree relatives who smoke Goal: to assess the risk to relatives of those with early-onset for airflow obstruction and chronic bronchitis. Methods: Probands: 44 patients with severe, early-onset - FEV1 < 40% predicted - age < 53 years - absence of alpha-1-antitrypsin deficiency - all cigarette smokers or ex-smokers Study subjects: 204 first-degree and 45 second-degree relatives of early-onset probands. Controls: smokers or ex-smokers matched with early-onset probands for smoking, age, and sex. Silverman EK et al. Am J Respir Crit Care Med 1998; 157: Early-onset : Risks to 1 st -degree relatives who smoke Clinical implications Patients with early-onset should be identified. Definition: onset of dyspnea that limits ADL from prior to age 50. First-degree relatives should be counseled regarding their extra risk of lung disease from cigarette smoking. Silverman EK et al. Am J Respir Crit Care Med 1998; 157:

2 severity stages: 2003 GOLD Guidelines Stage Characteristics 0: At Risk Normal spirometry Symptoms of chronic bronchitis (cough and sputum) is a heterogeneous disease I: Mild FEV1/FVC<70%; FEV1>80% predicted With or without symptoms II: Moderate III: Severe IV: Very Severe FEV1/FVC<70%; 50%<FEV1<80% predicted With or without symptoms FEV1/FVC<70%; 30%<FEV1<50% predicted With or without symptoms FEV1/FVC<70%; FEV1<30% predicted or FEV1<50% predicted plus chronic respiratory failure Reilly J. Proc Am Thor Soc 3: , 2006 Bronchodilators in stable Bronchodilators are central to symptom management of. No agent has been shown to modify the long-term decline in lung function. Inhaled therapy always is preferred. Bronchodilators may be prescribed on an asneeded or regular basis to reduce symptoms. Regular treatment with long-acting inhaled bronchodilators is more convenient than with short-acting agents, but also more expensive. From GOLD Guidelines, 2003 Effects of Susceptibility, Smoking, and Smoking Cessation on Normal Age-Dependent Decline in FEV1 Effects of smoking cessation on age-dependent FEV1 decline LUNG HEALTH STUDY Fletcher CM et al, 1977 Anthonisen et al, Am J Respir Crit Care Med 2002; 166:

3 Bronchodilators in stable Duration and Administration of Inhaled Bronchodilators Bronchodilators are central to symptom management of. No agent has been shown to modify the long-term decline in lung function. Inhaled therapy always is preferred. Bronchodilators may be prescribed on an asneeded or regular basis to reduce symptoms. Regular treatment with long-acting inhaled bronchodilators is more convenient than with short-acting agents, but also more expensive. From GOLD Guidelines, 2003 Sutherland, ER et al. NEJM 2004;350: Sites of action of bronchodilators in airways Effects of Ipratropium (inhibitor of muscarinic cholinergic receptors) and Metaproterenol (beta-adrenergic agonist) on FEV1 in chronic stable Non-selective muscarinic antagonists (iptratroprium) mediators Beta-2-adrenergic agonists (albuterol) Inflammatory cell Structures of ipratropium and tioproprium bromide When should we be using tiotropium? In stage II - IV (moderate -> very severe) patients that benefit symptomatically from bronchodilators; AND When tiotropium is preferred over long-acting betaagonists because of: - tachycardia or tremor from beta-agonists; - strong preference for once-daily administration schedule.

4 Some unanswered questions about longacting bronchodilators for - are the once-daily administration schedule or other features of tiotropium worth the increased expense over long-acting beta-adrenergic agonists (LABA s) - should we be using tiotropium in combination with LABA, and if so, in which patients? - are there clinically important non-bronchodilator actions of these agents, such as antiinflammatory effects? Definition is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. GOLD Guidelines. Am J Respir Crit Care Med 2001; 163: NORMAL RESPIRATORY BRONCHIOLE RESPIRATORY BRONCHIOLE IN : -Decreased tethering of alveolar septae -Inflamed, thickened airway wall -Luminal plugs of mucous and inflammatory cells pathogenesis: potential relationships to asthma Differences in Inflammation and its Consequences: Asthma and ASTHMA Allergens Cigarette smoke Y Y Y Smokers Asthma I. requires co-occurrence of asthma and smoking Ep cells Mast cell Alv macrophage Ep cells Smokers with Asthma Asthmatic Bronchitis or II. and asthma are distinct diseases with occasional co-occurrence Reversible CD4+ cell Eosinophil (Th2) Bronchoconstriction AHR Airflow Limitation CD8+ cell (Tc1) Neutrophil Small airway narrowing Alveolar destruction Irreversible

5 Decline in FEV1 in Patients on Inhaled Triamcinolone vs. Placebo Inhaled corticosteroids in stable : results of 4 RCT s Inhaled corticosteroids in stable : results of 3 recent RCT s Copenhagen EUROSCOP ISOLDE LHS Patients (n) Mean entry FEV1 (l) Active smokers (%) Exclusion criteria Asthma Yes Yes Yes No BD response Yes Yes Yes No Prednisone response Yes ND Done - but did not ND exclude responders Treatment Budesonide - (800 μg/day) - Budesonide Fluticasone 1 μg/day TAM 1200 ug/day Outcomes FEV1 Initial effect Not seen Yes - small Yes - small Not seen (3-6 months) Rate of decline (3 years) No effect No effect No effect No effect Exacerbations No effect Not reported 33% reduction Reduced Quality of life Not reported Not reported Mild beneficial effect Not measured Inhaled corticosteroids do not alter the accelerated agedependent decline in FEV1 in chronic stable NEJM 2000; 343: Inhaled Corticosteroids in Potential mechanisms for interactions between LABA and inhaled corticosteroids Consider in patients with: moderate or severe (FEV1< 50% predicted) plus frequent exacerbations (> 3 in past 3 years) OR: features suggesting concurrent asthma or atopy - unusual degree of BD reversibility on PFT testing; - background or FH suggestive of asthma or atopy; - eosinophilia. Weigh the risks. Barnes PJ et al. EurRespirJ.25: 1084, 2005 TORCH ( Towards a Revolution in Health ) Trial TORCH Trial: Results Patients: 6112 with Current smokers 43% FEV1 1.1 L (44% predicted) Exclusion: >10% FEV1 or FVC improvement with bronchodilator on PFT s Treatments: for 3 years [after 2-week run-in when ICS, LABA excluded in all patients] Placebo Fluticasone 50 μg BID Salmeterol 500 μg BID Fluticasone + Salmeterol BID Endpoints: Primary: mortality Secondary: health status, FEV1, # exacerbations N Engl J Med 356: , 2007 N Engl J Med 2007;356:

6 TORCH Trial Criticisms - Relatively high rates of withdrawal of study subjects - Increased pneumonia rates in subjects receiving fluticasone - Lack of cost-benefit analysis - No information as to whether benefit was the same in active smokers versus non-smokers/sustained quitters? Implications - Not completely clear! - For now: when the indication for inhaled corticosteroids is: moderate or severe (FEV1< 50% predicted) plus frequent exacerbations (> 3 in past 3 years) then consider adding a long-acting beta agonist Exacerbation: Definition An event in the natural course of the disease characterized by a change in the patient s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying. exacerbations: importance of infections Bacteria (40-50%) Common - Streptococcus pneumoniae - Hemophilus influenzae - Moraxella catarrhalis Rare - Pseudomonas aeroginosa (severe, bronchiectasis, recent hospitalizations, multiple recent courses of antibiotics) Viruses (30%) - rhinoviruses, influenza, parainfluenza, respiratory syncytial virus Atypical bacteria (5%) - Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella species exacerbations: evidence for effectiveness of antibiotics Meta-analysis of 9 placebo-controlled studies in 1995 indicated small but significant benefit. Since those studies, bacterial antimicrobial resistance has emerged. Beneficial effects of antibiotics have occurred particularly in patients with: FEV1 < 50% co-morbid conditions > 3 exacerbations in previous year A few recent studies have demonstrated benefits of using more advanced generation antibiotics though benefits have been subtle (e.g. times to next exacerbation, need for further courses of antibiotics). Sethi S. et al. Infect Dis Clin N Am 18: , 2004 Algorithm for antibiotic treatment of exacerbations Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, and Morgan NA. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999; 340: Goal: to evaluate the efficacy of systemic glucocorticoids for exacerbations. Sethi S. et al. Infect Dis Clin N Am 18: , 2004 Methods: 221 patients with exacerbations, > 30 pack years, age > 50 years, and baseline FEV1 < 1.5 or unmeasureable. Exclusions: asthma, use of systemic glucocorticoids within past month. Treatments (3 groups): - 8-week group: MP 125 mg iv q 6h x 3 days, then prednisone slow taper (60 mg on days 4-7, 40 mg days 8-11, 20 mg days 12-43, 10 mg days 44-50, and 5 mg days 51-57). - 2-week group: MP 125 mg iv q 6h x 3 days, then prednisone rapid taper (60 mg on days 4-7, 40 mg days 8-11, and 20 mg days 12-15). - placebo.

7 Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, and Morgan NA. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999; 340: Exacerbations: Beneficial Effects of Systemic Corticosteroids on FEV1 Recovery Methods (cont): Universal treatments: antibiotics x 7 days, inhaled beta-agonists and ipratropium bromide. Endpoints: Primary endpoint: treatment failure = death, intubation, re-admission, and/or intensification of pharmacologic therapy. Secondary endpoints: rate of improvement in FEV1, length of hospital stay. Niewoehner DE et al, NEJM 1999; 340: Exacerbations: Beneficial Effects of Systemic Corticosteroids on Treatment Failure Niewoehner DE et al, NEJM 1999; 340: Treatment of exacerbations with high-dose systemic corticosteroids: summary Beneficial Effects of NIPPV in Severe Exacerbations High doses (iv or oral) provide modest benefit in: increasing rate of rise in FEV1 reducing length of hospital stay No demonstrated benefits in: re-intubation rates mortality Duration of administration should be < 2 weeks Keenan, S. P. et. al. Ann Intern Med 2003;138:

8 Beneficial Effects of NIPPV in Severe Exacerbations exacerbations : are we missing pulmonary emboli? Keenan, S. P. et. al. Ann Intern Med 2003;138: Tillie-Leblond, I. et. al. Ann Intern Med 2006;144: Predictors of pulmonary embolism in patients with exacerbations Dyspnea without increased sputum volume/purulence, fever, or previous URI GOLD stage I severity (54%) Malignant disease (43%) Previous PE or DVT (25%) Decrease in arterial pco 2 by > 5 mm Hg Favorable and unfavorable predictors of beneficial response to LVRS Favorable Unfavorable Clinical Age < 75 y. Age > 75 y. Predominant emphysema. Predominant bronchitis. Off cigarettes > 6 months. Co-morbid conditions Severe dyspnea despite increasing surgical risk. maximal medical treatment Pulmonary hypertension including rehabilitation. PA syst >45 mmhg PA mean>35 mmhg. Severe obesity or cachexia. Previous thoracic procedure. Pleurodesis. Tillie-Leblond, I. et. al. Ann Intern Med 2006;144: From Martinez FJ. Chest Surgical Clinics North America 13: , 2003 Favorable and unfavorable predictors of beneficial response to LVRS - 2 LVRS: Which patients will benefit? Favorable Physiologic FEV1< 45% (post bd) RV>150%. TLC>100%. PaO2>45 mm Hg PaCO2<60 mm Hg Unfavorable NETT Research Group. Patients at high risk of death after lungvolume-reduction surgery. NEJM 345: , Radiologic Severe emphysema with Homogeneous and diffuse upper lung field predominance. emphysema. NETT Research Group. A randomized trial comparing lung-volumereduction surgery with medical therapy for severe emphysema. NEJM 348: , From Martinez FJ. Chest Surgical Clinics North America 13: , 2003

9 NETT: Identification of subgroup with high surgical risk FEV1 <20% predicted and Either diffusing capacity < 20% predicted or homogeneous pattern of emphysema NETT Research Group. NEJM 345: , 2001 NETT Research Group. NEJM 348: , 2003 NETT: Measurement of exercise capacity to predict benefit from surgery Incremental exercise test on bicycle ergometer. Starting with no-load pedaling, 5-10 watt increments every 3 minutes. Patient breathing 30% O 2 throughout. Low maximum exercise capacity defined as <40% predicted maximum value: Women: 25 watts Men: 40 watts.

10 Benefit from emphysema surgery in patient with upper lobe bullae Exercise Date FEV1/FVC Dsb Duration O2 requirement 1/99 0.8/ lpm 4/99(postrehab) 0.8/ lpm 8/99(postsurgery) 1.5/ RA 12/99 1.7/ RA 5/00 1.1/ RA 11/00 1.2/ /01 1.2/ RA Emphysema surgery: when to think of it? For lung volume reduction surgery: Measure PFT s Consider if FEV1 < 45%, TLC >100%, RV >150% Exclude if FEV1 < 20% predicted and DLCO < 20% predicted Perform high resolution chest CT scan Consider if emphysema is predominant in upper-lung fields with at least partial sparing of lower lobes Refer for incremental pulmonary exercise testing Presence of large bullous emphysema Topics for discussion Screening for genetic abnormalities Inhaled bronchodilators Short-acting Long-acting Inhaled corticosteroids Alone Combined with long-acting beta-agonists Treatment of exacerbations Antibiotics Systemic corticosteroids Non-invasive ventilation Confounding diagnoses Lung volume reduction surgery