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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP

MORNING

EDUCATIONALS YMPOS I UM

The A to ZZof COPD:

A Pragmatic Approach to Management ofCOPD Genotypes, Phenotypes, and

Comorbidities

Agenda5:305:35 AM Welcome and Introduction

Chair: Nicola Hanania, MBBS, FCCP

5:355:50 AM Review of Patient Case Presentation /

Collection of Benchmark Outcomes Data

Nicola Hanania, MBBS, FCCP

5:506:10 AM Management of Distinct COPD Phenotypes


6:106:30 AM Management of Alpha-1 Antitrypsin Deficiency

Gordon Ford, MD, FCCP

6:306:50 AM Collaborative Management of Comorbidities Barry Make, MD

6:507:00 AM Re-Review of Patient Case Presentation /

Collection of Post-Education Outcomes Data



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Learning Objectives

Define differences in the management of three of thedistinct phenotypes of COPD: the frequent exacerbator,the chronic bronchitic (with or without bronchiectasis),and the patient with asthma and COPD

Identify a feasible strategy to manage a patient withnewly diagnosed alpha-1 antitrypsin deficiency

Recognize and implement collaborative strategies toaddress the most common comorbidities associated withCOPD: cardiovascular disease, osteoporosis,

gastroesophageal reflux, and metabolic syndrome

MORNING



Pulmonary and Critical Care MedicineAsthma Clinical Research CenterBaylor College of MedicineHouston, Texas

The A to ZZ

of COPD:A Pragmatic Approach to Management of

COPD Genotypes, Phenotypes, and

Comorbidities


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Case Study: Mrs. K

Mrs. K is a 57-year-old Caucasian widow with no children.She is a production assistant for a television studio in alarge city

She is referred for assessment of dyspnea Breathlessness is worsened by mildly stressful physical activity,

such as walking rapidly or climbing stairs

Shortness of breath has begun to make it difficult for her to carryout her duties at work and to enjoy leisure activities (walking,gardening)

Mrs. K describes daily smokers coughespecially in themorning but no other presenting symptoms

Mrs. K has a 10 pack-year smoking history, stopped 2years ago. Since stopping smoking, she gained 30 lbswhich prompted several smoking relapses

Mrs. K also has had short bouts of respiratory illness thatshe believes to be the flu, which have occurred twice inthe past year for which she received short courses ofantibiotics

Mrs. K believes that her ability to function at work anddesire to engage in leisure activities have both declinedmarkedly in the past year and she has stopped going outwith her friends

Case Study: Mrs. K


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Mrs. Ks History

Mrs. K has a history of type 2 diabetes,hypertension, hypercholesterolemia, GERD, andmild angina

No occupational exposures to respiratory toxins Family history negative for lung, liver disease

Mrs. K: Current Treatment Mrs. K has been using inhaled short-acting

bronchodilators for her breathlessnessprescribed by her primary care physician

She is also currently takingAmlodipine (10 mg QD) and atenolol (25 mg QD)

to control her blood pressure and treat her angina

Sertraline (100 mg QD) for depression and anxietyAtorvastatin (20 mg QD) for hypercholesterolemia Metformin (850 mg TID) for diabetes Over-the-counter antacids for GERD


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Blood pressure

Heart rate

Respiratory rate

Head, eyes, ears,nose, throat

Heart

Chest

Height

Weight

151/84 mm Hg

75 bpm

17

Within normal limits

No abnormalities noted

Hyperinflated, diminished breath sounds

5'4"

190 lb

ResultParameter

Mrs. K: Physical Exam

BASELINE

FEV1 1.00 liters (30% predicted)

FVC 4.12 liters (94% predicted)FEV1/FVC 24%

DLCO 10.5 ml/min/mmHg (55%)

SaO2 97% at rest; decrease to93% after walking on levelsurface for 6 minutes

Mrs. K: Lung FunctionResultParameter

FEV1 1.21 liters (22% improvement)

POSTBRONCHODILATOR


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Appropriate assessment of Mrs. K.s condition

should focus on:

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'( '( '('('(

A. Testing for A1ATdeficiency

B. Determining the impactof her disease on herhealth status

C. Assessing her risk forfuture exacerbation

D. Looking for and treatingcomorbidities

E. All of the above

Countdown

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Mrs. Ks report of 2 short bouts of respiratory

illness in the past year that required short courses

of antibiotics suggest:

!" #" $" %" &"

'( '( '('('(

A. She is at higher risk ofsubsequent exacerbationof her COPD

B. She has immunedeficiency

C. She has bronchiectasisD. She would benefit from

chronic antibiotic therapy

E. None of the above

Countdown

10

MORNING


Management of Distinct

COPD Phenotypes

The A to ZZ of COPD: A PragmaticApproach to Management of COPD

Genotypes, Phenotypes,

and Comorbidities


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Educational Support

Sponsored by the American College of Chest Physicians.

This educational activity is supported by an educationalgrant from Baxter.

Speaker

Nicola A. Hanania, MD, MS, FRCP(C), FCCP

Pulmonary and Critical Care MedicineAsthma Clinical Research Center

Baylor College of MedicineHouston, Texas


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Faculty Disclosure

The ACCP remains strongly committed to providing the best available evidence-basedclinical information to participants of this educational activity and requires an opendisclosure of any relevant financial relationships that create a conflict of interest. It is notthe intent of the ACCP to disqualify anyone from participating in this educational activity,but to resolve any conflicts of interest that may arise from financial relationships

with commercial interests. All conflicts of interest are reviewed by the educational activitycourse director/chair, the Education Committee, and/or the Conflict of InterestSubcommittee to ensure that such situations are properly evaluated and, if necessary,resolved. The ACCP educational standards pertaining to conflict of interest are intendedto maintain the professional autonomy of the clinical experts inherent in promoting abalanced presentation of science. Through our review process, all ACCP CME activitiesare ensured of independent, objective, scientifically balanced presentations ofinformation. Disclosure of any or no relevant financial relationships will be made availableon-site during all educational activities.

Nicola A. Hanania, MD, MS, FRCP(C), FCCP

Grant monies (from sources other than industry): NIH, American Lung AssociationGrant monies (from industry related sources): Genentech, Novartis, GlaxoSmithKline,Boehringer Ingelheim, Pfizer, Forest

Consultant fee: GlaxoSmithKline, Mylan, Novartis, Pfizer, Sunovion

Learning Objective

Define differences in the management of the distinctphenotypes of COPD


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Outline

Defining a phenotype Why phenotype COPD patients? Therapeutic and clinical implications Potential phenotypes identified Future needs

Phenotype: Definition A phenotype relates to a single or combination

of attributes that describe differences betweenindividuals

For a disease these attributes relate toclinically meaningful outcomes:

Symptoms Chronic bronchitis Exacerbations Frequent Disease progression Rapid FEV

1

decliners

Response to therapy Steroid responsive Survival Poor

Han MK, et al.Am J RespirCrit Care Med. 2010;182(5):598-604.


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PT # 1

59 y

FEV1

: 28%

MRC: 2/4

PaO2: 70 mmHg

6MWD: 540 m

BMI: 30

FEV1< 35% predicted

COPD Heterogeneity

PT # 2

63 y

FEV1

: 33%

MRC: 2/4

PaO2: 57 mmHg

6MWD: 348 m

BMI: 21

PT # 3

70 y

FEV1

: 35%

MRC: 3/4

PaO2: 66 mmHg

6MWD: 230 m

BMI: 34

PT # 4

72 y

FEV1

: 34%

MRC: 4/4

PaO2: 60 mmHg

6MWD: 140 m

BMI: 24

Courtesy of C.Cote, MD

Why Phenotype COPD Patients?

COPD is a syndrome, complexpathophysiology, multiple faces

Enhances our understanding of the diseaseprocess

Allows for classification of patients into distincttherapeutic and prognostic subgroups


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Why Phenotype COPD Patients?

Ideal Phenotypic Construct

Therapeutic implications Prognostic implications

Han MK, et al.Am J RespirCrit Care Med. 2010;182(5):598-604.

Therapeutic Implications of Different

COPD PhenotypesExamples

Bronchitis and exacerbations Nutritionally depleted Exacerbations Hypoxemic Pulmonary hypertension Smokers Localized emphysema

PDE-4 Inhibitors Supplementation and training Inhaled corticosteroids LTOT Specific drugs Antismoking drugs Surgery, ? valves


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Recent Trials to Identify Phenotypes

ClinicalGenderChronic bronchitisFrequent exacerbatorsLow BMIHigh BMIDyspneaICS-responsiveNon-smokers

PhysiologicAirflow limitationRapid declinerBD-responsivenessHyperresponsivenessHypercapnicPoor exercise toleranceHyperinflationLow DLCOPulmonary hypertension

RadiologicEmphysema

Airways disease

Systemic

Inflammation

Comorbidities

Defining COPD Phenotypes


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The Chronic BronchitisPhenotype is Characterized by all except:

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'( '( '('('(

A. Increased risk ofexacerbation

B. Increased cough andsputum production

C. Thick airway wall on CTscan

D. Increased lung markingson chest X-ray

E. Rapid decline in lungfunction

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Chronic bronchitis subjects:

Younger Smoked more More current smokers More wheezing and

nocturnal awakenings

Thicker airways airwaywall %

More exacerbations; moresevere AECOPD

Chronic Bronchitis as a Phenotype

Kim V, et al; COPDGene Investigators. Chest. 2011;140(3):626-633.

0

0.2

0.4

0.6

0.8

1

1.2

1.4

CB+ CB-

AECOPD Frequency Is Increased in

Chronic Bronchitis

1.21

0.63

AE

COPDperyear

P< 0.0001

Kim V, et al; COPD Gene Investigators. Chest. 2011;140(3):626-633.


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Risk of Future Exacerbations

Is Predicted By:

!" #" $" %" &"

'( '( '('('(

A. Severity of airflowlimitation

B. History of previousexacerbations

C. History of daily coughand sputum

D. History of GERDE. All of the above

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The Frequent Exacerbator Phenotype

Frequency/Severity of Exacerbations by GOLD Stage

Both P< 0.01

Hurst JR, et al. N Engl J Med. 2010;363:1128-1138.

Hospitalized for exacerbation in yr 1 Frequent exacerbations (2 or more)

ECLIPSE 1 year data


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71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3

74% of patients having no exacerbations in Years 1 and Year 2 had no exacerbations in Year 3

Hurst JR, et al. N Engl J Med. 2010;363:1128-1138. ECLIPSE 3 year data

The Frequent Exacerbator PhenotypeStability of the Exacerbator Phenotype

Hurst JR, et al. New Engl J Med.2010;363:1128-1138.

ExacerbationDuring

Previous Year

FEV1(per 100 mL

decrease)

White Cell Count(per increase

of 1000/mL)

P < 0.001

P < 0.001 P = 0.002

Odd

sRatiofor!2vs0Exacerbations

SGRQ score(per 4-point

increase)

Positive historyof reflux or

heartburn

P < 0.001

P < 0.001

The Frequent Exacerbator Phenotype

Parameters Associated with Exacerbation inYear 1 (multivariate analysis)

Analysis by GOLD Stage showed similar results:

The best predictor of future exacerbation is a

history of previous exacerbations.


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RadiologicEmphysema

Airways disease

COPD is Radiographicaly Not One DiseaseFEV162% predicted FEV158% predicted


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Radiographic Characterization of COPD

VisualEmphysema

Pattern Extent Distribution

Airways abnormality Airway wall thickening Bronchial dilation

Small airways Centrilobular nodules Expiratory air trapping

Interstitium Interstitial lung

abnormality

QuantitativeEmphysema

Extent Distribution

Airways Diameter Bronchial wall thickening

Expiratory airtrapping

COPD CT-Definable Subphenotypes

Pattern Centrilobular Panlobular Paraseptal Bulla Mixed

Region Upper Lower diffuse

Severity

Small airways Ground glass opacities Centrilobular nodules Expiratory gas trapping

Bronchial wall thickening Other abnormalities

Bronchiectasis Bronchial outpouching Saber tooth trachea Tracheobronchomalacia

Emphysema Airway


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CT Phenotypes and Exacerbations:

COPDGene Study

1002COPDGenesubjects

Assessed by CT Emphysema Airway wall

thickness

Self-reportedexacerbations

Exacerbations

peryear

Han M, et al. Radiology. 2011;261:274-282.

Martnez-Garca MA, et al. Chest. 2011;140(5):1130-1137.

Bronchiectasis in COPD

92 patients with moderateor severe COPDunderwent HRCT

57.6% (n = 53) hadbronchiectasis

90.6% (n = 48) cylindrical 18.9% (n = 10) cystic


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Bronchiectasis in COPD

Clinical Implications More frequent exacerbations, hospitalizations, and

worse lung function

Infection (vicious circle) driven disease Possible clinical implications

Aggressive evaluation (Sputum cultures) and antibiotictreatment (broad spectrum antibiotics, longer courses) of acute

exacerbations

? Chronic inhaled (aminoglycosides, fluoroquinolones) or oral(macrolide or intermittent fluoroquinolones) antibiotics

? Secretion clearance

Pulmonary Arterial Enlargement and

Acute Exacerbations of COPD

3,464 subjects with COPDStage 24

2,985 with longitudinalAECOPD follow-up

Validation cohort: 2,005ECLIPSE subjects

Pulmonary artery diameter /aortic diameter on chest CTscan > 1 associated with

AECOPD

Wells MJ, et al. N Engl J Med. 2012;367(10):913-921.


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Summary: Quantitative CT

Phenotypes in COPD

CT findings correlate with clinical symptoms,exacerbations, osteoporosis, etc

Research tool Selection of candidates for lung volume

reduction surgery

Future clinical application Determining treatment selection

SystemicInflammation

Comorbidities




RadiologicEmphysema

Airways disease


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Systemic Inflamed Phenotype of

COPD ECLIPSE Study 1755 COPD patients

297 smokers 202 non-smoker controls

WBC count, CRP, IL-6,IL-8, fibrinogen andTNF!measured atbaseline and 1 yr

3 years follow-up

Agusti A, et al. PLoS ONE. 2012;7(5):e37483.

Systemic Inflamed Phenotype: Determinants( by logistic regression analysis)

Odds Ratio (95% CI) P-value

Current smoker, % 2.228 (1.471, 3.375)


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Relationship with Outcomes

Number Elevated

at Both Visits

0 2+ P-value

All-cause mortality 2% 13% < 0.001

Annual exacerbation rate 0.9 (1.1) 1.5 (1.5) < 0.001


Systemic Inflamed Phenotype

Clinical Implications

Persistently inflamed vs non-inflamed patients:

Higher mortality (13 vs 2%) More exacerbations (1.5 vs 0.9/yr)

No difference in Rate of FEV1decline Weight loss CVS events

Strengths Large size Adequate controls Longitudinal follow-up

Limitations Very large scatter in values No predictive cut-offs and

values provided

Systemic inflammation likelydoes not reflect lunginflammation



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Conclusions

Phenotyping COPD is the path to personalizedmedicine

Can be achieved by several methods withconsiderable progress and much more to come

A phenotype without clear implications in terms ofprognosis and treatment will be of little clinical use

Clinical, physiological, and radiological tools havebeen used to identify phenotypes of COPD

Frequent exacerbators, patients with emphysema,patients with chronic bronchitis are somephenotypes that have been identified

Conclusions

Quantitative chest CT scan is helpful in identifyingradiologic phenotypes which may have clinical andtherapeutic implications

Future research needs to: Validate potential phenotypes in longitudinal studies Identify mechanisms and course of the different

phenotypes including gender differences

Examine therapeutic response of different phenotypesto existing and future interventions


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The Chronic BronchitisPhenotype is Characterized by all except:

!" #" $" %" &"

'( '( '('('(

A. Increased risk ofexacerbation

B. Increased cough andsputum production

C. Thick airway wall on CTscan

D. Increased lung markingson chest X-ray

E. Rapid decline in lungfunctionCountdown

10

Risk of Future Exacerbations

Is Predicted By:

!" #" $" %" &"

'( '( '('('(

A. Severity of airflowlimitation

B. History of previousexacerbations

C. History of daily coughand sputum

D. History of GERDE. All of the above

Countdown

10


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MORNING


Management of Alpha-1

Antitrypsin (A1AT)

Deficiency

The A to ZZ of COPD: A Pragmatic

Approach to Management of COPDGenotypes, Phenotypes,

and Comorbidities

Educational Support




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Speaker

Gordon T. Ford MD, FCCP

University of CalgaryCalgary, Alberta, Canada

Faculty DisclosureThe ACCP remains strongly committed to providing the best available evidence-basedclinical information to participants of this educational activity and requires an opendisclosure of any relevant financial relationships that create a conflict of interest. It is notthe intent of the ACCP to disqualify anyone from participating in this educational activity,but to resolve any conflicts of interest that may arise from financial relationshipswith commercial interests. All conflicts of interest are reviewed by the educational activitycourse director/chair, the Education Committee, and/or the Conflict of InterestSubcommittee to ensure that such situations are properly evaluated and, if necessary,resolved. The ACCP educational standards pertaining to conflict of interest are intendedto maintain the professional autonomy of the clinical experts inherent in promoting abalanced presentation of science. Through our review process, all ACCP CME activities

are ensured of independent, objective, scientifically balanced presentations ofinformation. Disclosure of any or no relevant financial relationships will be made availableon-site during all educational activities.

The following faculty member of this educational activity has disclosed to the ACCP thatno potential conflict of interest exists with any respective company/organization, and thisshould be communicated to the participants of this educational activity:Gordon T. Ford MD, FCCP


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Learning Objective

Identify a feasible strategy to manage apatient with newly diagnosed alpha-1antitrypsin deficiency

Canadian Thoracic Society Clinical Practice GuidelineCan Respir J.2012;19:109-116.


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Strength of Evidence and

Grading of Recommendations

Quality of Evidence

Grade A Well designed randomized controlled trials with consistent and directlyapplicable results

Grade B Randomized trials with limitations including inconsistent results or majormethodological weaknesses

Grade C Observational studies, and from generalization from randomized trials inone group of patients to a different group of patients

Strength of Recommendations

Grade 1 Strong recommendation, with desirable effects clearly outweighingundesirable effects (or vice versa)

Grade 2 Weak recommendation, with desirable effects closely balanced withundesirable effects

Marciniuk DD, et al. Can Respir J. 2012;19:109-116. Canadian Thoracic Society Clinical Practice Guideline

A1AT Deficiency Background

Laurell and Eriksson (1963) first noted association between absentalpha-1 band and emphysema; Sharp (1969) first noted associationbetween A1AT deficiency and cirrhosis

A 394 amino acid glycoprotein; Molecular weight 52k Dalton Gene (SERPINA1) located on long arm of chromosome 14 Autosomal co-dominant genetic disorder; > 120 alleles Produced predominantly in liver and reaches lungs by diffusion from

bloodstream

A1AT traps and inactivates proteases (eg, neutrophil elastase)providing defence against unchecked proteolysis Affected individuals with severe A1AT deficiency have two abnormal

alleles; heterozygotes (eg, carriers) have mildly reduced A1AT levels

Lomas DA, Parfrey H. Thorax. 2004;59:529-535.

Stoller JK, Aboussouan LS.AJRCCM.2012;185:246-59.Canadian Thoracic Society Clinical Practice Guideline


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Imbalance of proteases-antiproteases:

A1AT deficiency results in an imbalance of neutrophilelastase (increased due to smoking) and other proteasesand anti-proteases leading to emphysema

Enhanced neutrophil chemotaxis to the lungs:

Augment lung inflammation and injury Increased release of cytokines (eg, LTB4, IL8)Abnormal Z A1AT polymers

A1AT protective threshold for lung disease is 11 "M (NHLBIstandard) or 0.5 g/L by nephelometry corresponding to0.8 g/L by radial immunodiffusion

Mechanisms of Lung Disease

Stoller JK, Aboussouan LS.Am J Resp Crit Care Med.2012;185:246-59.Canadian Thoracic Society Clinical Practice Guideline

Banauch GI, et al. Chest. 2010;138:1116-1124.

2010 by American College of Chest Physicians

Lung Function Decline 4-Years Post Sept 2011

in FDNY Rescue Workers

Canadian Thoracic Society Clinical Practice Guideline


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Sorheim IC, et al. Chest. 2010;138:1125-1132.

2010 by American College of Chest Physicians

Emphysema: Smoking and

A1AT Phenotype Interaction


Question 1: Which population(s) are most appropriate

for targeted A1AT level testing to improve case-findingof patients with A1AT?

!" #" $" %"

&' &'&'&'

A. Patients diagnosed withCOPD prior to age 65, with asmoking history of < 20 packyears

B. Patients with asthma;bronchiectasis; or commonvariable immunodeficiency

C.Patients with hepatitis;panniculitis; or antiPR-3antibody vasculitis

D.All of the above

Canadian Thoracic Society Clinical Practice GuidelineMarciniuk DD, et al. Can Respir J.2012;19:109-116. Countdown

10


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Screening searching for a disease or abnormality inthe general population, usually to make an earlydiagnosis or at pre-symptomatic stage

A1AT screening was performed in Scandinaviancountries and certain US states (eg, Oregon)

Targeted Testing case-finding for a disease orabnormality in an at-risk or symptomatic population

Which test is most appropriate?

A1AT level initial test in case-finding versus phenotyping orgenotyping for genetic counseling

Targeted Testing


A1AT serum levels initial screening blood test done byimmunochemical methods using differing protein standards. Anacute phase reactant (eg, check CRP)

Phenotype Pi (serine protease inhibitor) refers to A1ATprotein expression us. determined by speed of migration on gelelectrophoresis (eg, isoelectric focusing)

Normal phenotype is homozygous PiMM; commonest deficient allelevariants are S (4-11%) and Z (2-3%)

Genotype refers to specific allelic combination, determined byallele specific amplification (M, S or Z) or full gene sequencing(rarer variants)

A1AT Testing



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Adapted from Luisetti M.Breathe. 2007;4:39-46.

11 "M

Range of A1AT Levels with

Various Phenotypes

MMMS

MZ SS

SZ

ZZ


"M

Pi Type

Targeted Testing:

Asthma and Bronchiectasis

4 studies in patients with asthma and 3 studies in patients withbronchiectasis did not find an increased frequency of severe

A1AT deficiency or abnormal alleles at the Pi locus comparedwith rates reported in control populations

One small case-control study reported possible increasedfrequency of the Z allele in patients with bronchiectasis andcommon variable immunodeficiency

Radiographic evidence of bronchiectasis is often seen inpatients with PiZZ phenotype

Assumes that the diagnosis of asthma is correct; consider otherdiagnoses if PFTs remain abnormal despite asthma treatment

Marciniuk DD, et al. Can Respir J.2012;19:109-116..Canadian Thoracic Society Clinical Practice Guideline


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Recommendation #1a: Testing for A1AT deficiency beconsidered in individuals with COPD diagnosed before age 65

years, with a smoking history of < 20 pack years.

[Grade of recommendation: 2C]

Recommendation #1b: Targeted testing for A1AT deficiencyshould not be undertaken in individuals with bronchiectasis or

asthma. [Grade of recommendation: 2C]

Question 1: Which population(s) are most

appropriate for targeted A1AT level testing toimprove case-finding of patients with A1AT

deficiency?

Marciniuk DD, et al. Can Respir J. 2012;19:109-116.


Question 2: How would you prescribeA1AT augmentation therapy?

!" #" $" %"

&' &'&'&'

A. Specific treatment with weekly,intravenous infusion of purified,pooled human plasma derivedA1AT

B. Specific treatment with daily,intravenous infusion of purified,pooled human plasma derivedA1AT

C. Specific treatment with monthly,intravenous infusion of purified,pooled human plasma derivedA1AT

D. Specific treatment with inhaledrecombinant A1AT

Countdown

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Provide in addition to usual, optimal therapy for COPD Specific treatment with weekly, intravenous infusion of purified,

pooled human plasma derived A1AT

Biochemical efficacy - raise functional, serum A1AT level aboveprotective threshold (eg, 11 M)

Generally well tolerated infrequent SE include fever, chills,nausea, vomiting, urticaria

No transmission of HIV, Hepatitis, prion reported

Expensive therapy (~ $100,000/year/patient) costeffectiveness was not addressed in this CPG

Augmentation Therapy

Marciniuk DD, et al. Can Respir J. 2012;19:109-116.. Canadian Thoracic Society Clinical Practice Guideline

Effectiveness of A1ATAugmentation Therapy

Limited high quality evidence available 2 small RCTs Danish-Dutch (56 subjects; FEV1 primary outcome) and

EXACTLE (96 subjects; CT scan density primary outcome) publishedseparately and also in pooled analyses (Stockley et al; Gotzsche et al)

2 non-randomized, observational cohort studies (NHLBI registry of 1129patients; German-Danish study of 295 patients)

On the basis of the 2 underpowered RCTs of augmentation therapy, nosignificant differences in lung function decline (FEV1, DLCO), exacerbationfrequency, or health status (SGRQ)

Marciniuk DD, et al. Can Respir J. 2012;19:109-116..Canadian Thoracic Society Clinical Practice Guideline


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F

EV

1Decline(mL/yr)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

< 35% 35#49% 50#79% !80%

No Augmentation Augmentation

Baseline FEV1% Predicted

"*P = 0.03

A1AT Deficiency Registry Study Group.Am J Resp Crit Care Med.1998;158:49-59.

Lung Function Decline:

A1AT Augmentation Therapy


$30% 31#65%

N = 112

> 65%

Initial FEV1% Predicted

D

eclineinFEV

1(ml/yr)

"

*P = 0.04

N = 75N = 27

N = 58

N = 11

N = 12

Seersholm N, et al. ERJ.1997;10:2260#2263.

Lung Function Decline:

A1AT Augmentation Therapy



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CT scan Evidence of Progression of Emphysema:

A1AT-Treated Versus Placebo (modified ITT)

Stockley RA, et al. Respir Res. 2010;11:136-143.

Gotzsche PC, Johansen HK. Coch Data Syst Rev. 2010.

Pooled results of 119 subjects from 2RCTs (Stockley)

PiZZ FEV125/30-80%A1AT iv replacement monthly

(Danish-Dutch), weekly (EXACTLE)

Mean F/U 2.3 years Cochrane Review reached similar

conclusion (Gotzsche)


CT Scan Assessment of

Emphysema in A1AT

CT scan lung density score - Pros:

Surrogate marker correlates with pathology scores ofemphysema, FEV1, DLCO, health status, and mortality

Change is associated with frequency of acute exacerbationsCT scan lung density score Cons:

Requires specialized equipment and expertise Variable methodology (eg, correction for lung volume) Low intra and inter-operator agreement Unclear what magnitude of change has clinical relevance

Marciniuk DD, et al. Can Respir J.2012;19:109-116.Canadian Thoracic Society Clinical Practice Guideline


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Mortality: A1AT Augmentation Therapy

A1AT Deficiency Registry Study Group.Am J Resp Crit Care Med. 1998;158:49#59.


Question 2: Is A1AT augmentation therapy effective

in patients with documented A1AT deficiency?

Recommendation #2: A1AT augmentation therapy may beconsidered in non-smoking or ex-smoking patients withCOPD (FEV125-80% predicted) attributable to emphysemaand documented A1AT deficiency (level $11 "mol), who arereceiving optimal pharmacologic and non-pharmacologic

therapies (including comprehensive case management and

pulmonary rehabilitation)because of benefits in CT scanlung density [Grade of recommendation: 2B] and mortality

[Grade of recommendation: 2C]

Marciniuk DD, et al. Can Respir J.2012;19:109-116.



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Discussion Points

Systematically reviewed the evidence and utilized theexperience of an interprofessional panel of experts

Numerous gaps in our understanding and practices to bestmanage A1AT deficiency remain, including:

Understanding prevalence and pathophysiological mechanisms ofspecific lung diseases

Assessing implications of surrogate markers, eg, CT densitometry, FEV1decline, HRQL

Conducting adequately powered RCTs with longer follow-up periodsassessing meaningful patient-related outcomes and cost

Assessing future treatment prospectsMarciniuk DD, et al. Can Respir J.2012;19:109-116.


Canadian Thoracic Society

Recommendations

Recommendation #1a: Testing for A1AT deficiency be considered inindividuals with COPD diagnosed before age 65 years, with a smokinghistory of < 20 pack-years. [Grade of recommendation: 2C].

Recommendation #1b: Targeted testing for A1AT deficiency should not beundertaken in individuals with bronchiectasis or asthma. [Grade ofrecommendation: 2C]

Recommendation #2:A1AT augmentation therapy may be considered innon-smoking or ex-smoking patients with COPD (FEV125-80% predicted)

attributable to emphysema and documented A1AT deficiency (level $11"mol), who are receiving optimal pharmacologic and non-pharmacologictherapies (including comprehensive case management and pulmonary

rehabilitation)because of benefits in CT scan lung density [Grade ofrecommendation: 2B] and mortality [Grade of recommendation: 2C]


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For More Information:

Canadian Thoracic Societyc/o The Lung Association National Office

1750 Courtwood Crescent, Suite 300Ottawa, ON K2C 2B5

[email protected]

(613) 569-6411, ext. 270

www.lung.ca/ctswww.respiratoryguidelines.ca

Question 1: Which population(s) are most

appropriate for targeted A1AT level testing toimprove case-finding of patients with A1AT?

!" #" $" %"

&' &'&'&'

A. Patients diagnosed withCOPD prior to age 65, with asmoking history of < 20 packyears

B. Patients with asthma;bronchiectasis; or commonvariable immunodeficiency

C.Patients with hepatitis;panniculitis; or antiPR-3antibody vasculitis

D.All of the aboveCanadian Thoracic Society Clinical Practice GuidelineMarciniuk DD, et al. Can Respir J.2012;19:109-116. Countdown

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Question 2: How would you prescribe

A1AT augmentation therapy?

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&' &'&'&'

A. Specific treatment with weekly,intravenous infusion of purified,pooled human plasma derivedA1AT

B. Specific treatment with daily,intravenous infusion of purified,pooled human plasma derivedA1AT

C. Specific treatment with monthly,intravenous infusion of purified,pooled human plasma derived

A1ATD. Specific treatment with inhaled

recombinant A1AT

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MORNING


Collaborative Management

of Comorbidities

The A to ZZ of COPD: A PragmaticApproach to Management of COPD

Genotypes, Phenotypes,

and Comorbidities


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Educational Support



Speaker

Barry J. Make, MD

National Jewish HealthUniversity of Colorado School of Medicine

Denver, Colorado


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Faculty Disclosure

The ACCP remains strongly committed to providing the best available evidence-based clinicalinformation to participants of this educational activity and requires an open disclosure of any relevantfinancial relationships that create a conflict of interest. It is not the intent of the ACCP to disqualifyanyone from participating in this educational activity, but to resolve any conflicts of interest that mayarise from financial relationships with commercial interests. All conflicts of interest are reviewed by theeducational activity course director/chair, the Education Committee, and/or the Conflict of InterestSubcommittee to ensure that such situations are properly evaluated and, if necessary, resolved. The

ACCP educational standards pertaining to conflict of interest are intended to maintain the professionalautonomy of the clinical experts inherent in promoting a balanced presentation of science. Throughour review process, all ACCP CME activities are ensured of independent, objective, scientificallybalanced presentations of information. Disclosure of any or no relevant financial relationships will be

made available on-site during all educational activities.

Barry J. Make, MDUniveristy Grant Monies: GlaxoSmithKline, Boehringer Ingelheim, Forest, Spiration, AstraZeneca, Novartis, Aeris,

Aerocrine, Sunovian and possibly others I am unaware of have or may provide funds to National Jewish Health forresearch studies.

Grant monies (from sources other than industry: National Heart, Lung, Blood InstituteGrant monies (from industry related sources):AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sunovian,

Forest for clinical trials provided to and controlled by National Jewish HealthSpeaker Bureau: GlaxoSmithKlineAdvisory Committee: GlaxoSmithKline, Boehringer Ingelheim, Forest, Sunovian, AstraZeneca, AerocrineEducationl speaking, etc.: Cedars Sinai LA, National Jewish Health, Consensus Medical, Forest, WebMD,

Convergent Health, Up-to-DateProduct/procedure/technique that is considered research and is NOT yet approved for any purpose. Potential

topics: Bronchoscopic lung volume reduction surgery, inhaled steroids effect on patient-reported outcome, macrolidesto prevent COPD exacerbations, inhaled bronchodilators to prevent exacerbations of COPD

Learning Objective

Recognize and implement collaborativestrategies to address the most commoncomorbidities associated with COPD:cardiovascular disease, osteoporosis,gastroesophageal reflux, and metabolicsyndrome


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Which of These Medical Conditions are

Commonly Encountered in Patients with

COPD?

!" #" $" %" &"

'( '( '('('(

A. HypertensionB. DepressionC. OsteoporosisD. Hypertension and

depression

E. All of the above

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How Many Coexisting Medical Conditions

Does a Patient with COPD TypicallyHave?

!" #" $" %" &"

'( '( '('('(

A. NoneB. OneC. TwoD. ThreeE. Four or more

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COPD Increases Risk for Medical Events

Angina

Cataracts

Respiratory Infection

Myocardial Infarction

Fractures

Osteoporosis

Glaucoma

Skin Bruises

Soriano JB, et al. Chest.2005;128:2099-2107.

RR in COPD versus non-COPD

Rateper10000

Comorbidome :

Comorbidities and Associated Mortality

Divo M, et al. AJRCCM. 2012;186:155-161.


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Gastroesophageal Reflux Is

Common in COPD

Patel ARC, Hurst JR. Eur Resp Monogr. 2013;29:105-116.Mokhlesi B, et al. Chest. 2001;119:1043-1048.

2,138 COPD patients observed for 3 years

Inclusion criteria: age 40-75 years; %10 pack-years smoking history; post-bronchodilator FEV1 < 80% of predicted, FEV1/FVC ratio < 0.7

Hurst JR, et al. N Engl J Med. 2010;363(12):1128-1138.


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5.72

1.11 1.07

2.07

1.08

0

1

2

3

4

5

6

7

ExacerbationDuring Previous

Year

FEV (per 100 mLdecrease)

SGRQ Score (per4 point increase)

Positive History forReflux/Heartburn

White Cell Count(per increase of

1000/mL)

Factors Associated With

Frequent Exacerbations (!2)

1

Odds Ratio for !2 versus 0 Exacerbations*

*

N = 2138

*P< 0.001**P= 0.002

Adapted from Hurst JR, et al. N Engl J Med. 2010;363:1128-1138.

***

**

Gastroesophageal Reflux in COPD

GERD is not increased acid; transient loweresophageal relaxations are more important

Kahrilas PJ, et al. Gastroenterology. 1988;94:73-80.

Also consider:reduced esophagealperistalsis anddelayed gastricemptying


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GERD Diagnosis

Questionnaires More than once a week is significant

Impedance pH monitoring pH monitoring alone will miss non-acid reflux Assess acid and non-acid reflux and clearance Results:

! Upright event frequency and duration! Recumbent event frequency and duration

Aanen MC. Scand J Gastroenterol. 2008;43:1442-1447.

GERD Diagnosis Clinical diagnosis based on symptoms

Confirm with therapeutic trial Barium swallow

Not recommended Endoscopy

Not routinely recommended Bleeding

Katz PO, et al.Am J Gastroenterol. 2013;108:308-328.


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GERD Treatment

Lifestyle modifications require patient acceptance1: Weight loss reduces occurrence, severity, and

response to therapy for GERD2

Elevate the head of the bed Avoid food and liquids prior to recumbency Avoid large meals and dietary triggers: fat, caffeine,

chocolate, spicy food, carbonated beverages

Promote salivation with lozenges/gum Avoid tobacco and alcohol Avoid tight clothes

1. Katz PO, et al.Am J Gastroenterol. 2013;108:308-328.2. Dent J.Am J Gastroenterol. 2013;108:383-385.

GERD Medication

Proton-Pump Inhibitor orHistamine-2 Receptor Antagonist?

PPI are more potent acid suppressants, initiallyonce daily

Administer 30-60 minutesprior to breakfast May use twice daily or increase dose

H2RA have been suggested prior to retiring Baclofen: increases gastric emptying, reduces

transient LES relaxations (not FDA approved forGERD)

Katz PO, et al.Am J Gastroenterol. 2013;108:308-328.


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Sin DD, et al.Am J Med. 2003;114:10-14 .

Osteoporosis in COPD

Risk Factors for Osteoporosis

Smoking Increased alcohol intake Low vitamin D levels Genetic factors Reduced skeletal muscle mass and strength Low BMI and changes in body composition Reduced levels of insulin-like growth factors Chronic systemic inflammation Treatment with corticosteroids

Ionescu AA, et al. Eur Respir J. 2003;22 (Suppl 46):64s-75s.


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Severe COPD Use of ICS

Adjusted Odds Ratio

for Osteoporotic

Fracture

No No 1.06

No Yes 1.08

Yes No 1.47*

Yes Yes 1.48*

*P < 0.05

De Vries F, et al. Eur Respir J. 2005;25:879-884.

COPD, ICS, and Osteoporotic Fracture

Risk of Osteoporosis

Bon J, et al.Am J Respir Crit Care Med. 2011; 183:885-890.

190 subjects with cigarette smoking history COPD Stage 2-4: 43% Osteopenia: 58% Osteoporosis: 9% Moderate/Severe emphysema: 19%


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Risk of Osteoporosis

Bon J, et al.Am J Respir Crit Care Med. 2011;183:885-890.

Evaluation of Osteoporosis

Presence of risk factors To exclude other causes of osteoporosis: Vitamin D level CBC, calcium, phosphorus, parathyroid hormone,

magnesium

TSH, creatinine LFTs Testosterone Consider: protein electrophoresis, TTG, iron

National Osteoporosis Foundation. Clinicians Guide to Prevention and Treatment of Osteoporosis 2013.www.nof.org.


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Management of Osteoporosis

Weight-bearing exercise Pulmonary rehabilitation

Medications Vitamin D: 800 1000 IU/day

If deficient: 6000 IU/day; 50,000 IU/week Calcium

Men 50-70: 1000 mg Women > 50 and Men >70: 1200 mg

Bisphosphonates Oral Intravenous

National Osteoporosis Foundation. Clinicians Guide to Prevention and Treatment of Osteoporosis 2013.www.nof.org.

Off-Label Use

Pulmonary rehabilitation is not FDA-approved Pulmonary rehabilitation is evidence-based

(Statements by ATS / ERS, ACCP / AACVPR)


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Collaborative Management of

Comorbidities in COPD Total patient care collaborators

Pulmonary specialist Primary care physician Other specialists cardiology, gastroenterology,

endocrinology, rheumatology, mental health, sleepmedicine

The patient

Key Messages Consider the total management of patients with

COPD with assistance from the patient, primarycare, other specialists

COPD Comorbidities

Consider evaluation for osteoporosis in all yourpatients with COPD

Consider evaluation for gastroesophageal refluxin all patients with AECOPD


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Which of These Medical Conditions are

Commonly Encountered in Patients withCOPD?

!" #" $" %" &"

'( '( '('('(

A. HypertensionB. DepressionC. OsteoporosisD. Hypertension and

depression

E. All of the above

Countdown

10

How Many Coexisting Medical ConditionsDoes a Patient with COPD Typically

Have?

!" #" $" %" &"

'( '( '('('(

A. NoneB. OneC. TwoD. ThreeE. Four or more

Countdown

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MORNING



Pulmonary and Critical Care MedicineAsthma Clinical Research CenterBaylor College of MedicineHouston, Texas

The A to ZZof COPD:


Comorbidities

Mrs. K: Summary 57-year-old Caucasian, 10 pack-year smoking history,

stopped 2 years ago.

Referred for assessment of dyspnea. Daily smokers cough. Two short bouts of respiratory illness in past year treated with

antibiotics

Decreased functional ability Multiple comorbidities: DM, hypertension, GERD, angina FEV1:1.00 liters (30% predicted), FEV1/FVC:24%, low DLCO Hyperinflation (emphysema) on chest X-ray


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Appropriate assessment of Mrs. K.s

condition should focus on:

!" #" $" %" &"

'( '( '('('(

A. Testing for A1ATdeficiency

B. Determining the impactof her disease on herhealth status

C. Assessing her risk forfuture exacerbation

D. Looking for and treatingcomorbiditiesE. All of the above

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Mrs. Ks report of 2 short bouts of respiratory

illness in the past year that required short courses

of antibiotics suggest:

!" #" $" %" &"

'( '( '('('(

A. She is at higher risk ofsubsequent exacerbationof her COPD

B. She has immunedeficiency

C. She has bronchiectasisD. She would benefit fromchronic antibiotic therapyE. None of the above

Countdown

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The A to ZZof COPD:


Comorbidities

atozzcopdppt-2

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