AtoZZCOPDppt-2
Transcript of AtoZZCOPDppt-2
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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
Nicola Hanania, MBBS, FCCP
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
Nicola Hanania, MBBS, FCCP
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
EDUCATIONALS YMPOS I UM
CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
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MORNING
EDUCATIONALS YMPOS I UM
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
ClinicalGenderChronic bronchitisFrequent exacerbatorsLow BMIHigh BMIDyspneaICS-responsiveNon-smokers
Defining COPD Phenotypes
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 lungfunction
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Defining COPD Phenotypes
ClinicalGenderChronic bronchitisFrequent exacerbatorsLow BMIHigh BMIDyspneaICS-responsiveNon-smokers
PhysiologicAirflow limitationRapid declinerBD-responsivenessHyperresponsivenessHypercapnicPoor exercise toleranceHyperinflationLow DLCOPulmonary hypertension
RadiologicEmphysema
Airways disease
COPD is Radiographicaly Not One DiseaseFEV162% predicted FEV158% predicted
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
Defining COPD Phenotypes
ClinicalGenderChronic bronchitisFrequent exacerbatorsLow BMIHigh BMIDyspneaICS-responsiveNon-smokers
PhysiologicAirflow limitationRapid declinerBD-responsivenessHyperresponsivenessHypercapnicPoor exercise toleranceHyperinflationLow DLCOPulmonary hypertension
RadiologicEmphysema
Airways disease
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
Agusti A, et al. PLoS ONE. 2012;7(5):e37483.
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
Agusti A, et al. PLoS ONE. 2012;7(5):e37483.
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
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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
Countdown
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
MORNING
EDUCATIONALS YMPOS I UM
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
Sponsored by the American College of Chest Physicians.
This educational activity is supported by an educationalgrant from Baxter.
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Sorheim IC, et al. Chest. 2010;138:1125-1132.
2010 by American College of Chest Physicians
Emphysema: Smoking and
A1AT Phenotype Interaction
Canadian Thoracic Society Clinical Practice Guideline
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
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
Canadian Thoracic Society Clinical Practice Guideline
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
Canadian Thoracic Society Clinical Practice Guideline
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Adapted from Luisetti M.Breathe. 2007;4:39-46.
11 "M
Range of A1AT Levels with
Various Phenotypes
MMMS
MZ SS
SZ
ZZ
Canadian Thoracic Society Clinical Practice Guideline
"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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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.
Canadian Thoracic Society Clinical Practice Guideline
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
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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
Canadian Thoracic Society Clinical Practice Guideline
$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
Canadian Thoracic Society Clinical Practice Guideline
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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)
Canadian Thoracic Society Clinical Practice Guideline
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Mortality: A1AT Augmentation Therapy
A1AT Deficiency Registry Study Group.Am J Resp Crit Care Med. 1998;158:49#59.
Canadian Thoracic Society Clinical Practice Guideline
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.
Canadian Thoracic Society Clinical Practice Guideline
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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 Clinical Practice Guideline
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
For More Information:
Canadian Thoracic Societyc/o The Lung Association National Office
1750 Courtwood Crescent, Suite 300Ottawa, ON K2C 2B5
(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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Question 2: How would you prescribe
A1AT 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 derived
A1ATD. Specific treatment with inhaled
recombinant A1AT
Countdown
10
MORNING
EDUCATIONALS YMPOS I UM
Collaborative Management
of Comorbidities
The A to ZZ of COPD: A PragmaticApproach to Management of COPD
Genotypes, Phenotypes,
and Comorbidities
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Educational Support
Sponsored by the American College of Chest Physicians.
This educational activity is supported by an educationalgrant from Baxter.
Speaker
Barry J. Make, MD
National Jewish HealthUniversity of Colorado School of Medicine
Denver, Colorado
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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10
How Many Coexisting Medical Conditions
Does a Patient with COPD TypicallyHave?
!" #" $" %" &"
'( '( '('('(
A. NoneB. OneC. TwoD. ThreeE. Four or more
Countdown
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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
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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CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
MORNING
EDUCATIONALS YMPOS I UM
CaseNicola A. Hanania, MD, MS, FRCP(C), FCCP
Pulmonary and Critical Care MedicineAsthma Clinical Research CenterBaylor College of MedicineHouston, Texas
The A to ZZof COPD:
A Pragmatic Approach to Management ofCOPD Genotypes, Phenotypes, and
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
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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