David J. Lederer, MD, MS

Transcription

1 COPD: Definition Chronic Obstructive Pulmonary Disease Chronic airflow obstruction due to chronic bronchitis and/or pulmonary emphysema David J. Lederer, MD, MS Associate Medical Director, Lung Transplant Program Columbia University College of Physicians and Surgeons New York Presbyterian Lung Transplant and ILD Programs Chronic Bronchitis Pulmonary Emphysema Definition persistent cough and sputum production for at least three months in at least two consecutive years Submucosal gland hyperplasia Airway edema Mucus plugging and airways fibrosis Destruction of acinar walls Physiologic effects Loss of radial traction on airways Increased lung compliance Consequences Hyperinflation Airflow obstruction Risk Factors for COPD Centrilobular emphysema - Smoking-related - Upper lobe predominant Particulate exposure Tobacco smoke Occupational dusts Indoor air pollution (biomass fuel combustion) Genes Alpha-1 anti-trypsin (SERPINA1) Panlobular emphysema - alpha-1 antitrypsin deficiency - Lower lobe (basilar) or diffuse Contributing factors Older age Male gender Low socioeconomic status Poor nutrition

2 Case: I m winded What is the next step? A 52 year old women with no medical history presents to your office with dyspnea with household chores for the past few months. She has a 60 cigarette packyear history and reports a smoker s cough for the past 5 years without change. She continues to smoke 10 cigarettes per day. No chest pain or edema. Breath sounds are quiet. No crackles, rhonchi, or wheezing. No edema or clubbing. 1. Alpha-1 anti-trypsin level 2. Chest CT scan (without contrast) 3. Spirometry with and without bronchodilator 4. Echocardiography Chest x-ray shows hyperinflation. You suspect COPD Spirometry results Diagnosis of COPD Causes of Airflow Obstruction Symptoms Airflow obstruction COPD Upper airway obstruction Lower airway obstruction COPD Asthma Bronchiectasis (e.g., cystic fibrosis) Large airway obstruction Tumor, stenosis, foreign body aspiration, et al. Bronchiolitis Pulmonary edema Carcinoid syndrome Airflow obstruction = FEV 1 /FVC ratio < 0.70

3 Clinical Presentation of COPD 10% of adults > 40 have COPD 24 million adults with COPD 50% undiagnosed Common symptoms Cough with sputum production (chronic bronchitis) Exertional dyspnea Muscular wasting During an exacerbation Change in sputum quantity, color, or consistency Wheezing Increased dyspnea Physical Exam in COPD Early disease = normal exam Common findings Increased anteroposterior chest diameter Barrel chest Bilaterally diminished breath sounds Skeletal muscle atrophy During an exacerbation Wheezing Rhonchi Cyanosis Spirometry is the BEST test for diagnosis and staging of COPD Stage FEV 1 /FVC FEV 1 ABG I: Mild >80% predicted Any II: Moderate 50 to 79% Any III: Severe 30 to 49% < 0.70 IV: Very Severe PaO 2 >60 mm Hg, and PaCO 2 <50 mm Hg PaO 2 < 60 mm Hg 30 to 49% or PaCO 2 > 50 mm Hg <30% Any What other diagnostic test should be performed? 1. Alpha-1-anti-trypsin level 2. Chest CT scan without contrast 3. Chest CT scan with contrast 4. Echocardiography α1-antitrypsin (AAT) Deficiency Autosomal co-dominant disorder caused by mutation in the SERPINA1 gene Phenotypes classified by migration in isoelectric ph gradient from A to Z (slowest migration) Case 1 Control Case 2 Paper electrophoresis of patient serum AAT alleles Allele Groups Examples Defect Normal Deficiency M X (Glu363Lys) S (Glu264Val) Z (Glu342Lys) M malton (Phe52del) None Intracellular degradation or accumulation Null Tyr160X No mrna or protein Laurell and Eriksson Dysfunctional M mineral springs Met358Arg Defective inhibition of elastase Stoller JK and Aboussouan LS. Lancet 2005.

4 AAT genotypes and emphysema risk α1-antitrypsin (AAT) deficiency Genotype Prevalence A1AT Serum Concentration Risk of Emphysema MM 91% mg/dl Background MS 6% mg/dl Background MZ 3% mg/dl Background SS 0.1% mg/dl Background SZ 0.1% mg/dl 20-50% ZZ 0.02% mg/dl % Stoller JK and Aboussouan LS. Lancet % of COPD pts have severe A1AD 59,000 Americans Only 10,000 are receiving replacement therapy All patients with COPD should be tested (serum level and/or phenotype) AAT is a serine protease inhibitor inhibits trypsin Inhibits neutrophil elastase Panlobular emphysema Younger pts with basilar emphysema Can also cause liver disease Treatment Intravenous pooled plasma α1-antitrypsin May slow the decline in lung function What is the next step? Management by COPD stage 1. Short-acting beta-agonist + tiotropium 2. Short-acting beta-agonist + inhaled corticosteroid 3. Short-acting beta-agonist + oral prednisone 4. Smoking cessation Stage FEV 1 Consider I: Mild >80% Risk factor reduction Influenza/pneumococcal vaccination Short acting inhaled β2 agonists II: Moderate 50 to 79% Long acting inhaled bronchodilators Pulmonary rehabilitation III: Severe 30 to 49% Inhaled corticosteroids (if wheezing or repeated exacerbations) IV: Very Severe <30%* Long term oxygen therapy Surgical therapy Non pharmacologic approaches to smoking cessation Behavioral counseling 5 A s & 5 R s Telephone based Computer program based Text messaging Group based therapy ASK ADVISE Brief Strategies to Help the Patient Willing to Quit Smoking Identify smokers at every visit Strongly urge all users to quit Alternative therapies Acupuncture less effective than nicotine replacement. Meta analyses suggest no effect Hypnosis meta analysis found insufficient data Financial incentives $750 works! ASSESS ASSIST ARRANGE Determine willingness to quit Aid the patient in quitting Schedule follow-up contact

5 Five R s for smokers who are unwilling to quit Intervention Encourage the patient to Examples Relevance Indicate why quitting is personally relevant Disease state or risk Family/kids Risks Identify negative health effects of tobacco use See next slide Rewards Roadblocks Repetition Identify benefits of tobacco cessation Identify barriers to quitting while you note elements of treatment to address those barriers Improved health Save money Smell better (!) Setting an example Reduced wrinkles Withdrawal symptoms Weight gain Depression Enjoyment of tobacco Risks of tobacco use Timing Risk Acute Dyspnea, cough, wheeze Asthma exacerbation Pregnancy harm Long term Atherosclerosis (acute MI, CVA, PAD) Cancer (lung, oral/pharyngeal/esophageal, pancreas bladder, cervix) COPD Environmental Spouses Lung cancer Heart disease Children More likely to smoke Low birth weight & SIDS Asthma/respiratory infections Smokers who are ready to quit Set a quit date (typically within 2 weeks) Build support by telling family/friends Remove all tobacco products TOTAL ABSTINENCE Be available to the patient Pharmacotherapy Pharmacologic therapies for tobacco cessation Agent Usage 6 month abstinenc e rate Nicotine replacement 25% Nicotine polacrilex (gum) 2 4mg piece every 1 2 hrs x 8 12 wks Nicotine lozenges 1 2mg every hour Nasal nicotine spray 0.5 mg each nare hourly x 3 6 months Nicotine inhaler 6 16 cartridges/day x 3 6 months Transdermal nicotine patch 16 24hrs/day x8 weeks Oral medication Buproprion 150mg x 3 days, then 300mg daily for 24% up to 6 months Varenicline See next slide 33% Varenicline Orally available partial agonist at the α4β2 subunit of the nicotinic acetylcholine receptor Effects Stimulates nicotinic receptor (reduces withdrawal) Block nicotine from binding (reduces reward) Increases the odds of quitting three fold 33% 6 month quit rate Use: 0.5mg daily x 3 days, then 0.5 mg BID for 4 days, then 1mg BID for 11 more weeks. Quit smoking 1 weeks after initiating varenicline Successful quitters at 12 weeks should continue for 12 more weeks Nausea Headache Insomnia Abnormal dreams Varenicline Side Effects FDA Black box warning (2009) Depression Suicidal thoughts and actions FDA safety announcement (2011) Small increased risk of cardiovascular adverse events in patients with cardiovascular disease

6 Suggested approach to smoking cessation Use the 5 A s Dual approach Counseling Pharmacologic therapy Varenicline most effective May be combined with nicotine replacement Tailor therapy to the individual Comorbidities Preferences What treatment should be given? 1. Short-acting beta-agonist + tiotropium 2. Short-acting beta-agonist + inhaled corticosteroid 3. Short-acting beta-agonist + oral prednisone 4. Short-acting beta-agonist alone Selected Inhaled Medications for COPD Drug Class Drug Trade Names Use Short-acting β2- agonist (SABA) Long-acting β2- agonist (LABA) Short-acting anti-cholinergic Long-acting anti-cholinergic Albuterol Pirbuterol Levalbuterol Salmeterol Formoterol Arformoterol Ipratropium Ventolin Maxair Xopenex Serevent Foradil Brovana Atrovent Symptom relief Controller Symptom relief (slower than SABA) Tiotropium Spiriva Controller SABA/Anticholinergic Albuterol/Ipratropium Combivent Symptom relief Glucocorticoid LABA/Glucocorticoid Budesonide Fluticasone Mometasone Triamcinalone Becolmethasone Formoterol/Budesonide Salmeterol/Fluticasone Pulmicort Flovent Asmanex Azmacort Beclovent, Vanceril Symbicort Advair Controller Controller Management by COPD stage Stage FEV 1 Consider I: Mild >80% Risk factor reduction Influenza/pneumococcal vaccination Short acting inhaled β2 agonists II: Moderate 50 to 79% Long acting inhaled bronchodilators Pulmonary rehabilitation III: Severe 30 to 49% Inhaled corticosteroids (if wheezing or repeated exacerbations) IV: Very Severe <30%* Long term oxygen therapy Surgical therapy *You should be familiar with all of the Drug Classes and with the drugs in green font UPLIFT: Primary endpoint UPLIFT: COPD exacerbation Tashkin et al. NEJM 2008; 359: Tashkin et al. NEJM 2008; 359:

7 UPLIFT: Survival UPLIFT: Other benefits Decreased risk of respiratory failure RR 0.69 (95% CI 0.52 to 0.92) Decreased risk of serious cardiac events RR 0.84 (95% CI 0.93 to 0.98) Tashkin et al. NEJM 2008; 359: Tashkin et al. NEJM 2008; 359: Meta-analysis: CV events and anti-cholinergics Case - continued Over the next two years Three hospitalizations for acute exacerbations FEV 1 declines to 40% predicted Started on supplemental oxygen with exercise Initiates pulmonary rehabilitation Singh, S. et al. JAMA 2008;300: What additional treatment should be considered? 1. Lung transplantation 2. Theophylline 3. Long-term oral corticosteroids 4. Inhaled corticosteroids COPD Classification Stage FEV 1 % Add treatment Stage I: Mild > 80% Smoking cessation Vaccination Short-acting bronchodilators Long-acting bronchodilator Stage II: Moderate 50 to 79% Pulmonary rehabilitation Stage III: Severe 30 to 49% Inhaled glucocorticoids Stage IV: Very severe <30% Supplemental oxygen Surgical management GOLD guidelines:

8 TORCH: Primary endpoint TORCH: Acute Exacerbations p value Calverley et al. NEJM 2007;356: Calverley et al. NEJM 2007;356: TORCH: Adverse events Side effects of inhaled medications β2-agonists Tremor Tachycardia Hypokalemia LABA: Increased risk of severe exacerbation and asthma death? FDA recommends using LABAs only in combination with other controller therapy (such as inhaled corticosteroids Anti-cholinergics Dry mouth Cardiovascular events appear not be a concern with the formulation of tiotropium available in the US Inhaled glucocorticoids Oropharyngeal thrush (gargle & rinse to prevent) Cataracts Osteoporosis Increased risk of pneumonia in COPD pts? Calverley et al. NEJM 2007;356: Roflumilast: PDE-4 inhibitor Oral phosphodiesterase-4 (PDE4) inhibitor FDA-approved to decrease exacerbation rate in patients with chronic bronchitis, severe airflow limitation, and a history of exacerbations Mechanisms Decreases airway inflammation Promotes airway smooth muscle relaxation Clinical Effects Improved FEV1 Decreases exacerbation rate Side effects Diarrhea Weight loss Hasn t been studied in combination with ICS Azithromycin for COPD Placebo-controlled RCT of 1,577 adults with COPD Azithromycin 250mg daily Benefits Decreased acute exacerbation rate Improved quality-of-life Concerns Hearing decrements more common (25% vs. 20%)?effect on microbial resistance Cardiovascular risk in a recent (non-copd) study Albert et al. NEJM 2011; 365:689-98

9 Long term oxygen therapy Surgery for COPD: LVRS Indicated for chronic hypoxemia PaO 2 < 55 mm Hg (SpO 2 < 88%) PaO mm Hg (SpO 2 < 89%) with one of the following: Hematocrit > 55% Cor pulmonale Dependent edema Improves Survival Pulmonary hemodynamics Exercise capacity Resect 25% of each lung Highly selected candidates Upper lobe predominant emphysema Low exercise capacity (by cardiopulmonary exercise testing) High risk candidates FEV1 < 20% predicted + DLCO < 20% predicted FEV1 < 20% predicted + homogeneous emphysema Improves symptoms, exercise capacity, QOL, survival Surgery for COPD: Lung Transplantation COPD: Acute exacerbation Replacement of one or both lungs with lungs from a deceased donor Highly selected candidates FEV1 < 20-25% Absence of extrapulmonary disease Benefits Improved survival only for some (not proven) Improved quality-of-life Improved exercise capacity 50% mortality at 5 years Increased sputum quantity, thickness, and/or change in color Often with systemic signs of infection, dyspnea Management Short-acting beta-agonists and anti-cholinergics Oxygen therapy, if indicated Systemic antibiotics Systemic corticosteroids (2 week taper) Non-invasive positive pressure ventilation For acute alveolar hypoventilation (hypercapnia) Improves dyspnea and decreases length-of-stay COPD: Summary of Therapies Summary Drug Symptoms FEV1 acute exacerbation rate mortality Short-acting beta-agonist X X Long-acting beta-agonist X X X Ipratropium X X Tiotropium X X X Inhaled corticosteroids X X X Azithromycin X Long-term oxygen therapy X X Alpha-1 replacement Lung volume reduction surgery X X X Lung transplantation X X X No therapy has been proven to change the rate of FEV1 decline over time Diagnosis Spirometry Management for all patients Smoking cessation influenza/pneumococcal vaccination! Test for alpha-1-anti-trypsin deficiency Pharmacotherapy based on FEV 1 Tiotropium for FEV1 < 80% Inhaled corticosteroids for FEV1<50% If recurrent exacerbations Inhaled long-acting beta-agonist if still symptomatic Consider Supplemental oxygen Referral for surgical therapies