1. Alpha-1: Demystifying the Mystery 1 Miranda D. Withers, MSN, APRN

2. 2 Affiliation to disclose: Speaker for Grifols

3. 3 Includes chronic bronchitis and emphysema 1 More than 3 million people died of COPD in 2012, which is equal to 6% of all deaths globally that year 2 Third leading cause of death in the US 3 What is COPD? 1. American Thoracic Society website; http://www.thoracic.org/clinical/copd-guidelines/resources/copddoc.pdf Accessed February 21, 2015http://www.thoracic.org/clinical/copd-guidelines/resources/copddoc.pdf 2. WHO website http://www.who.int/mediacentre/factsheets/fs315/en/. Accessed February 21, 2015http://www.who.int/mediacentre/factsheets/fs315/en/ 3. Miniño AM, et al. Natl Vital Stat Rep. 2010;59(2):1-52. 4. Mannino DM. Chest. 2002;121(5 suppl):121S-126S.

4. COPD Risk Factors  Smoking 1 − At least 25% of long-term smokers develop COPD 2  Other inhaled agents 1  Genetic factors 1  Lung growth and development 1  Asthma/bronchial hyperreactivity 1  Age 1  Respiratory infections 1  Socioeconomic status 1 4 COPD, chronic obstructive pulmonary disease. 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease—Updated 2014. Available at: www.goldcopd.org. Accessed February 21, 2015. 2. Løkke A, et al. Thorax. 2006;61(11):935-939.

5. Facts About Alpha-1 5  Up to 25 million Americans have an abnormal allele (S or Z) 2  An estimated 100,000 Americans have alpha-1 3  90% remain undiagnosed 4,5  Early diagnosis and treatment is associated with health benefits 6  Most common inherited risk factor for COPD (1 in 10 COPD patients) 6 COPD, chronic obstructive pulmonary disease. 1. de Serres FJ. Environ Health Perspect. 2003;111(16):1851-1854. 2. de Serres FJ, et al. Clin Genet. 2003;64(5):382-397. 3. Campos MA, et al. Chest. 2005;128(3):1179-1186. 4. Silverman EK, Sandhaus RA. N Engl J Med. 2009;360(26):2749-2757. 5. About AAT deficiency. http://www.alpha1health.com/healthcare- professionals/about-aat-deficiency/. Accessed February 21, 2015. 6. Brantly M. Clin Chem. 2006;52(12):2180-2181.

6. What is Alpha-1 Antitrypsin and What does it do? 6 Protein produced in the liver Purpose is to protect the lungs from neutrophil elastase, which is an enzyme that digests damaged or aging cells and bacteria Neutrophil elastase can also affect good, healthy tissue if left unchecked Alpha-1 Foundation Website www.alpha1.org

7. 7 Sharp, R, Serres, F, Newman, L, Sandhaus, R, Walsh, J, Hood, E and Harry, G 2003, ‘Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency,’ Environmental Health Perspectives, vol. 111, no. 14, November, pp. 1749-1752.

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9. Alleles of Alpha-1 9 AAT Deficiency is a genetic mutation of SERPINA1 Most common allele is M and is considered normal Most common variations are S and Z Z produces the least alpha-1 and can cause the most problems Individuals who have two copies of the deficient alleles are considered to have Alpha-1 NIH Website; http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency; Accessed February 21, 2015http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency

10. 10 All COPD (especially emphysema) is caused by smoking Alpha-1 is rare, so I don’t need to test my patients Alpha-1 results exclusively in emphysema I don’t need to test for alpha-1 since there are no treatments If I test, I only have to consider homozygous patients (Pi ZZ) There is no need to test a smoker for alpha-1 I do not need to test older patients for alpha-1 A complete diagnosis of alpha-1 can be made on serum levels alone I know an alpha-1 patient when I see one Myths surrounding COPD

11. 11 What does an “Alpha” look like?

12. 12

13. 13 Photo taken from Boston University Website; http://www.bumc.bu.edu/supportingbusm/research/alpha-1/. Accessed February 21, 2015http://www.bumc.bu.edu/supportingbusm/research/alpha-1/

14. Have you seen this patient? 14  Dyspnea  Decreased exercise tolerance  Wheezing, Cough  Excess sputum production  Frequent lower respiratory tract infections  History of suspected allergies and/or asthma

15. 15 Test all adults with symptomatic COPD, regardless of smoking history Test all adults with symptomatic asthma whose airflow obstruction is incompletely reversible after bronchodilator therapy Test asymptomatic patients with persistent obstruction on pulmonary function tests with identifiable risk factors (eg, smoking, occupational exposure) Test siblings of individuals with alpha-1 ATS Testing Guidelines Am J Respir Crit Care Med Vol 168. pp 818–900, 2003 DOI: 10.1164/rccm.168.7.818 Internet address: www.atsjournals.org

16. Pay special attention to these: 16 Family history of lung or liver disease Early onset emphysema or emphysema in the absence of a known risk factor Frequent, severe respiratory infections Significant decline in lung function following severe respiratory infection Lung function decline that seems greater than a patient’s smoking history would predict American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med. 2003;168(7):818-900

17. 17 Lab testing including Alpha-1 phenotype and level and possibly LFT Levels alone cannot diagnose Alpha-1 (acute phase reactant) Free Testing is available from companies that provide Augmentation therapy Making the Diagnosis

18. Diagnosis is important 18  Promotes smoking prevention and cessation and other healthy lifestyle modifications  Increases potential for family testing and genetic counseling  Raises awareness to avoid hazards of occupational respiratory pollutants

19. 19 Importance of Finding Carriers

20. Management of Alpha-1  Family testing and counseling  Lifestyle changes – Smoking cessation – Exercise – Avoidance of environmental pollutants – Limit alcohol consumption  Vaccinations – Influenza/pneumococcal – Hepatitis A/B  Drug therapy for lung disorders – Bronchodilators – Inhaled steroids – Antibiotics – Oxygen  Pulmonary rehabilitation  Surgical procedures – Lung transplantation in end- stage lung disease – Lung volume reduction surgery  Augmentation therapy 20 SaO 2, oxygen saturation in arterial blood; VO 2 max, maximal oxygen uptake. 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease—Updated 2014. Available at: www.goldcopd.org. Accessed July 7, 2014. 2. British Thoracic Society. Thorax. 2001;56(11):827-834. 3. Ortega F, et al. Am J Respir Crit Care Med. 2002;166(5):669-674. 4. Ries AL, et al. Am J Respir Crit Care Med. 2003;167(6):880-888.

21. Benefits of Pulmonary Rehab 21 Reduces dyspnea 1-3 Improves endurance 2 Reduces number of hospitalizations 2,3 Improves exercise capacity 1,3 Improves HRQOL 3 Improves survival 3 Reduces anxiety and depression associated with COPD 3 COPD, chronic obstructive pulmonary disease; HRQOL, health-related quality of life. 1. British Thoracic Society. Thorax. 2001;56(11):827-834. 2. American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2003;168(7):818- 900. 3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease—Updated 2014. Available at: www.goldcopd.org. Accessed February 21, 2015..

22. 22 How can I make time for Alpha-1 testing in my busy practice?

23. Testing Strategies 23 Establish a formal practice protocol for ruling out alpha-1 in COPD patients ATS guidelines recommend testing all COPD patients Seek out protocols/guidance from the Alpha-1 Foundation’s Clinical Resource Centers (alpha- 1foundation.org/clinical-resource-centers) or from published literature and choose what’s right for your practice Identify 1 to 2 in-office “champions” Include alpha-1 testing in your practice EMR for current and newly diagnosed COPD patients Place test kits near COPD medication samples

24. Resources for Providers & Patients  AlphaNet 1-800-577-2638 www.alphanet.org  Alpha-1 Foundation 1-877-228-7321 www.alpha- 1foundation.org  Alpha-1 Association Genetic Counseling Center 1-800-785-3177 www.alpha1.org/support/ genetic-counseling-program  Clinical Resource Centers alpha-1foundation.org/ clinical-resource-centers 24

25. 25 Case Studies

26. Would you test? 26 Ethnicity, age, and sex: 76-year-old white female Profession: Retired administrative assistant Personal history: 40 pack-year smoker Medical history: Diagnosed with advanced COPD 20 years ago; stable lung function Current COPD medications LAMA SABA ICS/LABA Family medical history: 2 brothers diagnosed with COPD Pulmonary function testing results: FEV 1 45% of predicted

27. 27 Diagnosis: COPD confirmed Heterozygote for alpha-1 with MZ genotype (“carrier”) Actions taken: Maintain current COPD medications Maximize bronchodilators Treat lung infections aggressively Avoid all tobacco and environmental hazards

28. 28  Actions taken for her family:  Family testing/genetic counseling offered  Family testing results: 1 MZ (patient) yielded 3 ZZ  Son (50 years old): ZZ with normal lung function  Granddaughter (26 years old): ZZ; new diagnosis of COPD  Great-granddaughter (14 years old): ZZ with normal lung function  Daughter (53 years old): MZ; Daughter’s husband: MZ  All counseled to avoid tobacco and environmental hazards  Routine follow-up for all to monitor PFTs

29. 29  Ethnicity, age, and sex:  62-year-old white male  Profession:  Plumbing contractor  Personal history:  30 pack-year smoker; quit 5 years ago  Routinely consumes up to 4 beers/day  Medical history:  Diagnosed with COPD 5 years ago  Current COPD medications  LAMA  SABA  Lab results from recent yearly physical showed elevated LFTs (negative hepatitis virus panel) Would you test?

30. 30  Family medical history:  Father died of emphysema  Sister diagnosed with COPD and heterozygous alpha-1 MZ genotype  7 brothers in the family  Pulmonary function testing results:  FEV 1 70% of predicted  FEV 1 /FVC ratio 62% of predicted

31. 31  Intervention/Testing:  Tested for alpha-1 based on COPD diagnosis and elevated LFTs  AAT serum levels confirmed at 5 µM  (normal level for ZZ 3-7)  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  COPD confirmed  Alpha-1

32. 32  Actions taken:  Genetic counseling and family testing recommended  Lifestyle changes  Limit alcohol intake  Continue liver function monitoring  Influenza, hepatitis A, hepatitis B, pneumococcal vaccinations  Treat lung infections aggressively  Maximize bronchodilators  Follow up with pulmonologist in 6 months to review PFTs and determine need for augmentation therapy

33.  Ethnicity, age, and sex:  55-year-old white male  Profession:  Welder/forklift driver in a gate shop  Personal history:  81 pack-year smoker (3 ppd x 27 years); quit 4 years ago  Lives with smoker of 1 ppd  Medical history:  HTN; mild  Diagnosed with COPD 4 years ago; moderate obstruction  Current COPD medications  LAMA  SABA  ICS/LABA COPD, chronic obstructive pulmonary disease; HTN, hypertension; ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; LAMA, long-acting muscarinic antagonist; ppd, pack per day; SABA, short-acting beta 2 -agonist. Would you test?

34.  Family medical history:  Father died from MI at age 62  Mother had moderate asthma  Pulmonary function testing results:  FEV 1 43% of predicted  FEV 1 /FVC ratio 62% of predicted FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; MI, myocardial infarction.

35.  Intervention/Testing:  Symptoms were more severe than expected based on PFT results; sent for cardiac work-up (negative)  Tested for alpha-1 by practitioner after attending medical conference  AAT serum levels confirmed at 5 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha-1 AAT, alpha 1 -antitrypsin; COPD, chronic obstructive pulmonary disease; PFT, pulmonary function test.

36. Would you test a heavy smoker?  Ethnicity, age, and sex:  60-year-old white male  Profession:  Owner of family retail hardware store  Personal history:  30 pack-year smoker  Works in a retail hardware store and is exposed to dust and some pollutants  Medical history:  Diagnosed with asthma 30 years ago  Current asthma medications  SABA  ICS/LABA  Diagnosed with sleep apnea 4 years ago ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; SABA, short-acting beta 2 -agonist.

37. Would You Test a Heavy Smoker? (cont.)  Family medical history:  Father had COPD and died of emphysema  Brother has been diagnosed with COPD and liver disease  Pulmonary function testing results:  FEV 1 45% of predicted prebronchodilator; 70% of predicted postbronchodilator  FVC 70% of predicted prebronchodilator; 100% postbronchodilator  RV 200% of predicted  D LCO 67% of predicted COPD, chronic obstructive pulmonary disease; D LCO, diffusing capacity; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume.

38. Would You Test a Heavy Smoker? (cont.)  Intervention/Testing:  Symptoms continued to worsen; referred to pulmonary specialist, who performed alpha-1 testing  AAT serum levels confirmed at 15 µM  (normal MZ 15-42)  MZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Asthma with reversibility  Heterozygote for alpha-1 with MZ genotype (“carrier”) AAT, alpha 1 -antitrypsin.

39. Would You Test If No COPD Family History?  Ethnicity, age, and sex:  45-year-old white male  Profession:  Marketing consultant  Personal history:  20 pack-year smoker; still smokes half a pack per day  Works in an office setting  Medical history:  Daily sputum production over past 6 years with blood tingeing  Diagnosed with chronic bronchitis 3 years ago with episodes 3-4 times per year and multiple regimens of oral antibiotics  Symptoms improve then return

40. Would You Test If No COPD Family History?  Family medical history:  No known history of lung disease  Father had cirrhosis of the liver  Pulmonary function testing:  FEV 1 45% of predicted prebronchodilator; no significant change postbronchodilator  FVC 85% of predicted prebronchodilator; no significant change postbronchodilator  RV 300% of predicted  D LCO 65% of predicted D LCO, diffusing capacity; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume.

41. Would You Test If No COPD Family History? (cont.)  Intervention/Testing:  CT scan revealed bronchiectasis and evidence of mild emphysema  Alpha-1 testing performed  AAT serum levels confirmed at 6 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha-1 AAT, alpha 1 -antitrypsin; CT, computed tomography.

42. CT, computed tomography. Courtesy of Kyle Hogarth, MD, University of Chicago Medical Center. Bronchiectasis: Confirmed by CT Scan

43. Would You Test an 82-Year-Old? 43  Ethnicity, age, and sex:  82-year-old white female  Profession:  Retired  Personal history:  20 pack-year smoker; quit in her late 40s before COPD diagnosis at age 52  Widowed 10 years ago with 3 daughters (aged 47, 53, and 55), 8 grandchildren, and 2 grandnieces  Medical history:  Diagnosed with COPD at age 52; on COPD medications for more than 30 years  LAMA  ICS/LABA  Symptoms worsening despite COPD treatment and occasional use of oxygen ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; LAMA, long-acting muscarinic antagonist.

44. 82 Year-old  Family medical history:  Both father and mother were smokers  Mother died of lung disease  Father died of cardiovascular and liver disease  Pulmonary function testing results:  FEV 1 35% of predicted prebronchodilator; no significant change postbronchodilator  FVC 80% of predicted prebronchodilator; no significant change postbronchodilator  RV 350% of predicted  D LCO 45% of predicted D LCO, diffusing capacity; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume.

45.  Intervention/Testing:  Changed to new primary care physician who routinely tests all COPD patients based on newly implemented alpha-1 in-office testing protocol  Alpha-1 testing performed  AAT serum levels confirmed at 7 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha-1 AAT, alpha 1 -antitrypsin; COPD, chronic obstructive pulmonary disease. 82 Year-old

46. Would You Test a Nonsmoker?  Ethnicity, age, and sex:  62-year-old Hispanic female  Profession:  Mathematics professor  Personal history:  Nonsmoker  Medical history:  Diagnosed with COPD 5 years ago at age 57  Frequent bouts of bronchitis—2-3 times per year  Dyspnea and cough present over the past 5-6 years, worsening at last visit  Significant drop in lung function over last 5 years despite COPD medications  LAMA, SABA, ICS/LABA COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta 2 -agonist.

47.  Family medical history:  No other lung diseases in first-degree relatives  Recalls that her father had frequent bouts of bronchitis but was not a smoker  Intervention/Testing:  Tested for alpha-1 based on emphysema diagnosis  AAT serum levels confirmed at 6 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha-1 AAT, alpha 1 -antitrypsin. Nonsmoker

48. Would You Test in Presence of Worsening COPD?  Ethnicity, age, and sex:  60-year-old white male  Profession:  Delicatessen owner/operator  Personal history:  20 pack-year smoking history  Quit smoking at age 40  Occasional exposure to environmental pollutants  Medical history:  COPD diagnosed 4 years ago  Dyspnea and cough present for 10 years, worsening at last visit  Significant drop in lung function over last 3 years  Patient frustrated due to minimal response to COPD medications  LAMA, SABA, ICS/LABA COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta 2 -agonist.

49.  Family medical history:  Mother died of COPD complications at age 69  No other lung diseases in first-degree relatives  Intervention/Testing:  Performed alpha-1 testing  AAT serum levels confirmed at 4.7 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha-1 COPD, chronic obstructive pulmonary disease. Worsening COPD

50. Would You Test Based on Exposure to Pollutants?  Ethnicity, age, and sex:  53-year-old white male  Profession:  Construction contractor  Personal history:  Nonsmoker  Exposure to environmental pollutants, primarily carbon monoxide fumes and particulates from construction demolitions  Medical history:  COPD diagnosed 5 years ago  Current medications  LAMA  SABA  ICS/LABA  Frequent bronchitis attacks (2-3 per year) COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting beta 2 -agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta 2 -agonist.

51.  Family medical history:  Unknown  Intervention/Testing:  Performed alpha-1 testing  AAT serum levels confirmed at 6.7 µM  ZZ allele combination identified through genotype testing  Confirmed through Pi testing (phenotyping)  Diagnosis:  Emphysema  Severe alpha- 1 AAT, alpha 1 -antitrypsin. Exposure to Pollutants

52. 52 When in doubt, refer to the Guidelines…

53. 53 Test all adults with symptomatic COPD, regardless of smoking history Test all adults with symptomatic asthma whose airflow obstruction is incompletely reversible after bronchodilator therapy Test asymptomatic patients with persistent obstruction on pulmonary function tests with identifiable risk factors (eg, smoking, occupational exposure) Test siblings of individuals with alpha-1 ATS Testing Guidelines Am J Respir Crit Care Med Vol 168. pp 818–900, 2003 DOI: 10.1164/rccm.168.7.818 Internet address: www.atsjournals.org

54. 54 Questions?