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1 10:50-11:50am Case Studies in Pulmonary Medicine for the Primary Care Clinician SPEAKERS Timothy J. Scialla, MD Common Shortcuts/Common Misperceptions Smoking + Dyspnea = COPD Hospitalization for cough + wheezing = COPD exacerbation COPD vs Asthma Both diagnosed clinically Deciphered based on history/physical exam Therapies similar ICS + LABA for everyone Overview Diagnosing COPD Focus on spirometry GOLD directed assessment GOLD directed therapeutics Pharmacology (mostly inhalers) Non-pharmacology COPD phenotypes in Primary Care Case #1: 63 year-old female with recurrent bronchitis Friday afternoon visit; covering for your colleague Requests antibiotics before the weekend Reports worsening productive cough in past 2 weeks Thinks she had a mild fever last night Does not want to end up in the ED again Does not want CXR Wants the same antibiotics as last time

2 Case #1: Take More History 22 pack-year smoker Fourth bout of bronchitis in past 2 years Decrease in activities due to frequent shortness of breath Has had a smoker s cough for the past few years, often productive in the morning Mother died of CHF, and father had asthma Consider Chronic Lung Disease COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or history of exposure to risk factors for disease GOLD Guidelines GOLD: 2019 Report. Why is COPD underdiagnosed in Primary care? Symptom increase slowly Belief that most cases occur in men; 57% of cases are women Misdiagnosis with asthma common 10-20% are nonsmokers <50% of PCPs aware of GOLD guidelines Underuse of spirometry Do spirometry to diagnose COPD Tinkelman, DG. J. Asthma Golpe R. Semergen. 2017;43(8): NIH Fact Sheets COPD, 2010

3 Primer of Spirometry Issues getting air OUT of the lungs (Obstruction) Obstruction defined by FEV1/FVC FEV1/FVC steadily declines with aging Natural loss of elasticity Fixed ratio vs lower limit of normal (LLN) Severity of Obstruction Determined by FEV1 (% predicted) FVC Clues about restriction vs. air trapping Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease Classification by Severity (based on post-bronchodilator FEV 1 ) In patients with FEV1/FVC < 0.70 Persistent Airflow Limitation GOLD 1 Mild FEV1 > 80% pred GOLD 2 Moderate 50% < FEV1 < 80% GOLD 3 Severe 30% < FEV1 < 50% GOLD 4 Very Severe FEV1 < 30% Spirometry basics in the clinic Full inhalation at start of test Satisfactory start of exhalation No cough or glottal closure during first second No evidence of leak No evidence of early termination or cutoff No evidence of obstruction of mouthpiece Satisfactory exhalation (at least 6 seconds and/or plateau in the volume-time curve) * Chronic symptoms = cough, sputum, dyspnea. Global Initiative for Chronic Obstructive Lung Disease ( GOLD ). NIH/NHLBI; April 2001, updated July NIH Publication Available at: Adapted from GOLD 2019 report American Thoracic Society. Am J. Respir Crit Care Med. 2005; 152:

4 Common Errors in Interpretation Case #2: 74 year-old with progressive SOB Interpreting a normal result as an obstructive pattern Interpreting a poor effort as a restrictive pattern Diagnosing COPD in the absence of an FEV 1 /FVC ratio <70% Last seen 1 year ago Increasing SOB with activity Productive cough Former smoker (35 pack year/ quit 15 years-ago) Using a SABA 1-2 times per day Undergoes spirometry Case #2: Interpret spirometry results Spirometry Reference Pre Albuterol Pre % Ref Post Albuterol Post % Reference FVC 3.92 L 2.80 L 71% 3.00 L 76% 7 % FEV L 1.34 L 45% 1.40 L 47% 4 % FEV1/FVC 77% 48% 62% 47% 62% 4% %change 1. Moderate Obstruction with response to bronchodilators; COPD excluded due to response 2. Moderate Obstruction without response to bronchodilators; GOLD 2 3. Severe Obstruction without response to bronchodilators; GOLD 3 4. Very Severe Obstruction without response to bronchodilators GOLD 4 Overview Diagnosing COPD Focus on spirometry GOLD directed assessment GOLD directed therapeutics Pharmacology (mostly inhalers) Non-pharmacology COPD phenotypes in Primary Care

5 The refined ABCD assessment tool mmrc (> 2 equates to breathlessness) Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease GOLD 2019 report Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease Exacerbation history Symptoms of COPD Chronic cough Dyspnea Sputum production Acute Exacerbations Episodes of acute worsening Requires hospitalization = severe exacerbation GSK is the copyright holder of the COPD Assessment Test (CAT)

6 Overview Diagnosing COPD Focus on spirometry GOLD directed assessment GOLD directed therapeutics Pharmacology (mostly inhalers) Non-pharmacology COPD phenotypes in Primary Care Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease GOLD 2019 report Natural History of COPD Fletcher C and Peto R. BMJ Pharmacotherapy: Multiple challenges % of Baseline FEV Susceptible smoker Symptoms Disability Age (y) Non-susceptible smoker or nonsmoker Quit at age Cognitive impairment MDIs Most moving parts in administration Improved with spacer DPIs Need adequate inspiratory flow rates (60 L/min) Still multiple step to administer Nebulizer Longer time commitment Need to clean machine No long acting anticholinergic options

7 Pharmacotherapy disclaimer Not disease modifying Mortality Rate of decline in FEV1 Reduce exacerbations Improve quality of life Lots of options MDIs/ DPIs/Nebulizers/Oral Agents Pros/Cons to each Almost universally expensive! Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease GOLD 2019 report Withdrawal of ICS and Exacerbations H Magnussen et al. NEJM 2014; 371: Non-inferiority trial 2485 patients (severe to very severe COPD + 1 AECOPD) All patients received triple inhaler therapy for 6 weeks Tiotropium Handihaler; Fluticasone/Salmeterol (230/25) Withdrawal group (reduced fluticasone every 6 weeks till off) Primary endpoint = Time to first moderate to severe AECOPD during 12 month period Results: HR 1.06 (95% CI, 0.94 to 1.19) with withdrawal compared to glucocorticoid continuation Withdrawal group loss 43mL compared to ICS group Indacaterol Glycopyrronium versus Salmeterol Fluticasone for COPD JA Wedzicha. FLAME trial. NEJM 2016; 374: Non-inferiority trial 3362 patients (COPD w/ FEV % and 1 AECOPD in past year LAMA/LABA (n=1680) vs. ICS/LABA (n=1682) for 52 weeks Primary outcome: Annual rate of ALL AECOPD Results Annual rate ALL AECOPD = 3.59 vs 4.03 (RR = 0.89; p=.003) Mod to Severe AECOPD = 0.98 vs (RR = 0.78; p<.001 LAMA/LABA 62mL larger trough FEV1 compared to ICS/LABA

8 Once-daily single-inhaler triple vs dual therapy in COPD. DA Lipson et al. IMPACT trial. NEJM 2018; 378: ,355 patients: COPD plus CAT score > 10 FEV1 < 50% w/ 1 moderate to severe AECOPD FEV w/ severe AECOPD Methods: ICS/LABA/LAMA (4151) vs ICS/LABA (4134) vs LAMA/LABA (2070) Primary outcome = Annual rate of moderate-to-severe AECOPD Results ICS/LABA/LAMA (0.91) vs ICS/LABA (1.07) vs LAMA/LABA (1.21) RR 0.75 (95% CI; 0.70 to 0.81, p<.001) Higher eosinophil counts revealed greater benefit with Triple therapy Triple therapy also has higher trough FEV1 compared to LAMA/LABA (54mL) GOLD 2019 report Reproduced with permission from the Global Initiative for Chronic Obstructive Lung Disease Non-pharmacologic Management of COPD Pulmonary Rehabilitation: The Evidence ATS/ERJ Statement. AJRCCM Smoking cessation (Disease Modifying #1) O 2 improves survival in resting chronic hypoxemia Disease modifying #2 Influenza vaccine & pneumococcal vaccine reduces incidence of LRI Pulmonary rehabilitation improves symptoms, quality of life, and participation in everyday activities Lung cancer screening (Disease Modifying #3?) Advanced refractory emphysema, surgical or bronchoscopic intervention may be beneficial Highly selected patients (Disease Modifying #4) Increased exercise capacity (Grade 1A) Higher intensity = greater benefits (1B) Reduce Dyspnea (Grade 1A) Improve HRQL (Grade 1A) Benefits of 6-12 weeks program last for months (Grade 1A) No improvement in lung function Mortality benefit inconclusive

9 Lung cancer Screening: Disease Modifying!?! NLST. NEJM ARM NLST ( ) 53,000 patients assigned to three Low-dose CT scans or chest x-ray Total lung cancers diagnosed per 100,000 personyears Lung cancer deaths per 100,000 patientyears Relative Reduction in lung cancer mortality (%) False Positive rate (%) LDCT % CXR % Inhaler Technique: Key Points Choice of inhaler device should be individually tailored to patient Clinicians must demonstrate proper inhaler technique when prescribing device Clinicians must re-check inhaler technique at each visit Inhaler technique (and adherence) must be assessed before therapy modification Inhaler Devices MDI Portable/compact Multidose Cannot contaminate contents Available for most inhaled Dose indicator Improved with Spacer Not breath actuated Many patients use incorrectly Requires coordination DPI Portable/compact Breath actuated (no coordination needed) Dose indicator Requires minimum inspiratory flow (60 L/min) Many patients use incorrectly Many types moisture sensitive SMI Portable/compact Low dependence on inspiratory flow High lung deposition Dose indicator Not breath actuated Nebulizer May be used by any age No specific inhalation technique May dispense drugs not available in other forms Not portable Takes longer Need to clean Need outside energy source Risk of contamination Dekhuijzen et al. Patient Prefer Adherence. 2016; 10: Common Errors 90% of patients use inhalers incorrectly Determinants of poor technique Old age Use of multiple devices Lack of previous education Most common inhalation errors Inhalation rate /Inhalation duration Coordination Exhalation Prior to maneuver Sanchis J et al. Chest. 2016; 150(2):

10 Overview Diagnosing COPD Focus on spirometry GOLD directed assessment GOLD directed therapeutics Pharmacology (mostly inhalers) Non-pharmacology COPD phenotypes in Primary Care Case #4 67 year-old female (50 pack years) quit in exacerbations /year Recent hospitalization for AECOPD Does well on steroids; flares when weaned Current Treatments Triple inhaler therapy Chronic azithromycin 10mg prednisone Exam: diffuse wheezing with rales Objective Studies PFTs Severe obstructive defect Vital Capacity suggests restriction or co-existing air trapping? Bronchodilator reversibility Diffusion Capacity Substantially Reduced Date 4/ /2017 9/ /2018 Absolute Eosinophil count IgE = 760 Zone 2 IgE: negative aeroallergen panel

11 COPD phenotypes Observable traits Interaction of genes and environments Links to clinically meaningful outcomes? Modifiable with specific therapies Validated Phenotypes in COPD Mirza and Benzo: Mayo Clin Proc Alpha-1-antitripsin deficiency Upper lobe predominant emphysema w/ poor exercise capacity Frequent exacerbators > 2 exacerbations / year Early use of Triple inhaler therapy Additional oral pharmacotherapy Hunt for obvious triggers Daily Roflumilast to Prevent AECOPD FJ Martinez. REACT trial. Lancet 2015; 385; eligible patients 973 to Roflumilast 500 ug daily vs 972 to placebo Inclusion criteria = COPD plus 2 exacerbations past year Primary endpoint Rate of moderate-to-severe exacerbation per patient per year Results 0.85 vs (RR p =.053) Add statistics vs (RR= 0.858; p =.0424) Common Side effects: Weight loss / Diarrhea Azithromycin For Prevention of Exacerbations of COPD RK Albert et al. NEJM. 2011; 365: patients screening 1142 randomized 570 (Azithromycin 250mg daily) vs 572 (placebo) Inclusion: COPD plus any of the following in past year Exacerbation requiring ER or hospitalization (50%) Oral steroids for outpatient exacerbation (84%) Long-term oxygen use alone (13%) Primary endpoint: Time to first exacerbation 266 days vs 174 days (p<.0001) 741 (rate =1.48) vs 900 exacerbations Number needed to treat to prevent 1 exacerbation = 2.86

12 Asthma COPD overlap vs Eosinophilic COPD Mirza and Benzo: Mayo Clin Proc Major criteria or 1 Major and 2 minor criteria Major Criteria FEV1 improvement > 15% and 400mL Personally history of Asthma and Sputum Eosinophils Minor Criteria Elevated total IgE History of Atopy FEV1 > 12% and 200mL Unclear role of FENO; blood eosinophils; age on onset of symptoms Potential Escalating Treatments Triple Inhaler therapy with high dose ICS? Montelukast (Singulair)? What about biologics? Mepolizumab for Eosinophilic COPD NEJM Modest at best improvement in primary endpoint with Mepolizumab Higher baseline blood eosinophil count, the greater the benefit of mepolizumab Not approved by FDA Benralizumab for COPD (GALATHEA) AZ released statement it did not achieve primary endpoint TERRANOVA study ongoing Clinical Pearls in Primary Care Spirometry is underutilized REQUIRED for COPD diagnosis GOLD assessment leads to therapeutic options ABCD group determine inhalers Inhaler technique is often terrible Like throwing a pill over your shoulder! Smoking cessation/vaccines Rehab/Lung Cancer Screening!! ASK QUESTIONS USING OUR NEW SOCIAL Q&A FEATURE! Navigate to Click a Session Ask a Question Up-Vote a Question