Nathaniel Marchetti, DO
Temple University
Philadelphia, PA
The National Emphysema
Treatment Trial (NETT)
NETT Productivity
 >75 peer reviewed publications using NETT data
 Who should and should not have LVRS?
 What did we learn about emphysema?
 Pathobiology of emphysema
 Genetics
 Role of hyperinflation
 Hemodynamics in advanced emphysema
 Measurements of lung function in severe empysema
 Racial differences in severe emphysema
 Mortality in emphysema
 Medical therapy in severe emphysema
 Oxygen use in severe emphysema
Criner et al, AJRCCM, 2011
NETT Design
 17 clinical centers
 Randomized 1,218 patients to medical therapy or medical
therapy plus LVRS
 Screened 3,777
 Pulmonary function
 FEV1 15% to 45%
 TLC >105%
 RV > 150%
 No significant cardiac disease or pulmonary HTN
 No other pulmonary diseases present
 Bilateral emphysema amenable to LVRS
 Upper lobe predominant
 Diffuse
NETT Research Group Chest, 1999
NETT Design
 Pulmonary rehab
 16-20 sessions pre-randomization
 10 sessions post-randomization
 Long term maintenance
 Aggressive bronchodilator therapy
 Surgical therapy
 Bilateral stapled resection of 25-30% of lung
 Median sternotomy at 8 centers
 VATS at 3 centers
 6 centers randomized to MS vs VATS
NETT Research Group Chest, 1999
NETT Design
 Anesthesia
 Intra-operative care standardized
 Median sternotomy patient has epidural catheters
 Extubation within 2 hours
 Physical therapy started on 1st post-op day
NETT Research Group Chest, 1999
Outcomes
 Primary
 Survival
 10 W improvement on CPET
 Secondary
 Quality of life
 Cost effectiveness
 Pulmonary function
 CT scans and nuclear perfusion scans
 Oxygen requirement
 6 minute walk distance
 Cardiovascular measures (echo)
NETT Research Group Chest, 1999
Survival
Surgical 90-day mortality = 7.9%
Medical 90-day mortality = 1.3%
NETT Research Group NEJM, 2003
Survival
High risk group
FEV1 < 20% predicted
+
Either DLCO < 20% or
homogeneous emphysema
Surgical 30-day mortality = 16%
Medical 30-day mortality = 0%
NETT Research Group NEJM, 2003
Survival excluding high risk
Surgical 30-day mortality = 2.2%
Medical 30-day mortality = 0.2%
NETT Research Group NEJM, 2003
Survival
UL and low exercise = YES
UL and high exercise = NO
NETT Research Group NEJM, 2003
Survival
Non-UL and low exercise = NO
Non-UL and high exercise = NO
NETT Research Group NEJM, 2003
Exercise performance all patients
Months
6
12
24
10 watt improvement
LVRS
Medical Rx
28%
4%
22%
5%
15%
3%
p value
<0.001
<0.001
<0.001
NETT Research Group NEJM, 2003
Durability of LVRS
High risk patients excluded
Naunheim et al, Ann Thorac Surg 2006
Durability of LVRS
UL/Low Exercise
UL/high Exercise
Naunheim et al, Ann Thorac Surg 2006
Durability of Exercise
UL/Low
UL/High
Naunheim et al, Ann Thorac Surg 2006
Quality of Life Durability
MCID for SGRQ is -4 but a
priori was -8 for NETT
Naunheim et al, Ann Thorac Surg 2006
PaO2 Following LVRS
Snyder et al, AJRCCM 2008
O2 needs following LVRS
Snyder et al, AJRCCM 2008
LVRS Enhances CO2 Elimination
During Exercise
Sub-study CPET
with a-line (n=47)
Criner et al, Chest 2009
LVRS Improves f/VT Index
Criner et al, Chest 2009
LVRS Reduces Exacerbations
Surgical 0.27 exacerbations/patient-year
Medical 0.37 exacerbations/patient-year
30% reduction (13-48%, p=0.0005)
Washko et al, AJRCCM 2008
Most important lessons from
NETT?
 LVRS works!!
 Interventions to improve survival
 Smoking cessation
 Oxygen
 LVRS
 LVRS improves
 Oxygenation and oxygen requirements
 Favorable alters breathing patterns
 Reduces exacerbations
Who should not get surgery?
NETT Research Group NEJM, 2001
Who should not have LVRS?
Criner et al, PATS 2008
Durability of non-UL/high exercise
Naunheim et al, Ann Thorac Surg 2006
Who should not have LVRS?
Criner et al, PATS 2008
α-1 Antitrypsin Deficiency
 16 patients had severe deficiency (<80 mg/dL)
 10 randomized to surgery
 7 had upper lobe predominant emphysema
 Compared to the 6 that had medical Rx
 LVRS mortality was higher (20% vs 0%)
 Compared to normal α-1 AT levels
 Less improvement in exercise
 Less improvement in FEV1 response
Stoller et al, Ann Thorac Surg 2007
What did NETT teach us
about surgical
techniques?
LVRS and Air Leaks
 580/608 patients had surgery
 Air leak data available on 552
 90% had air leak in first 30 days
 Presence of air leak not effected by
 Surgical approach (VATS vs MS)
 Use of any buttressing agent (fibrin glue, etc)
 Stapler brand
 Intraoperative procedures


Pleurodesis
Tenting
DeCamp et al, Ann Thorac Surg 2006
Duration
Median 7 days
DeCamp et al, Ann Thorac Surg 2006
Consequence of air leak
 No difference in mortality
 Longer hospital stay (11.8+6.5 vs 7.6+4.4 d,
p=0.0005)
 Increased pneumonia (20% vs 7.4%)
 Increased ICU admission (9.3% vs 1.9%)
DeCamp et al, Ann Thorac Surg 2006
Risk Factors
 Increased risk and duration
 Lower diffusion capacity (p=0.06)
 Upper lobe disease (p=0.04)
 Presence of moderate to severe adhesions (p=0.007)
 Increased Duration
 Caucasian race (p<0.0001)
 Use of inhaled steroid (p=0.004)
 Lower FEV1 (p=0.0003)
DeCamp et al, Ann Thorac Surg 2006
Video Assisted Thorascopy (VATS)
vs Median Sternotomy (MS)
 8 centers used MS
 3 used VATS
 6 randomized to either
 Total patients: 359 MS vs 152 VATS
 Randomized patients: 77 MS vs 71 VATS
McKenna et al, J Thorac Cardiovasc Surg, 2004
VATS vs MS
 30 day mortality
 2.8% MS vs 2.0% VATS (p = 0.76)
 90 day mortality
 5.9% MS vs 4.6% (p = 0.67)
 No mortality difference for randomized patients
 Intra-operative hypoxemia more common in VATS
(0.8% vs 5.3%)
 No difference in days with air leak
 Median hospital LOS of 10 d in MS vs 9 in VATS
(p=0.01)
 Randomized patients: 15d for MS vs 9d for VATS
(p<0.001)
McKenna et al, J Thorac Cardiovasc Surg, 2004
Costs of VATS Compared to MS
 VATS = MS for outcomes and complications
 Shorter hospital stay with VATS
 Less expensive
McKenna et al, J Thorac Cardiovasc Surg, 2004
Pathologic Lessons
Small Airway Disease in Emphysema?
Thickened Epithelium
Inflammation
Subepithelial
Fibrosis
Smooth
Muscle
Hypertrophy
Nature of Small Airway
Obstruction in COPD
 159 patients across all GOLD stages
 59 GOLD III/IV patients from NETT
 100 GOLD 0–III patients
 Measure small airway (<2mm) luminal content and the
amount of inflammation in airway
 Correlated luminal occlusion and airway edema with
FEV1
Hogg et al, NEJM 2004
Luminal Occlusion
Hogg et al, NEJM 2004
FEV1 falls as lumen occludes
r = -0.505, p=0.001
Hogg et al, NEJM 2004
FEV1 falls as the airway thickens
r = -0.687, p<0.001
Hogg et al, NEJM 2004
More inflammatory cells with
increasing GOLD stage
Hogg et al, NEJM 2004
Significance of Small Airway
Disease in Emphysema
 Airway thickening is possibly tissue remodeling
 Decreased mucociliary clearance leading to
obstruction
 Increased lymphoid follicles possibly secondary to:
 Repeated infection
 Bacterial colonization
 Persistent inflammation may explain the decline in
lung function even after smoking cessation
 All NETT subject non-smokers >6 months
Hogg et al, NEJM 2004
Decreased Survival with Luminal
Occlusion
OR 3.28, 1.55-6.92; p=0.002
Hogg et al, AJRCCM 2007
Effect of ICS or Oral Steroids
 No effect on airway thickness or luminal occlusion
r = -0.505, p=0.001
 Less airway associated lymphoid follicles for those on
oral steroids
 Represents decreased adaptive immunity
 Could this explain increased pneumonia?
Hogg et al, AJRCCM 2007
Mortality and
Emphysema
Predictors of mortality in severe
emphysema
 609 patients in the medical arm of NETT
 Well characterized
 Severe disease with high mortality
 High quality long term follow up
Martinez et al, AJRCCM 2006
Mortality in Medical Arm NETT
Predictor
Age 70-83
O2 use
TLC% 140-203
RV% 262-412
Low Watts CPET
Lower lung pred
emphysema
HR
p
1.64(1.23-2.18) 0.001
1.46(1.02-2.10) 0.04
0.68(0.46-1.00) 0.05
1.57(1.03-2.39) 0.04
1.54(1.17-2.03) 0.002
1.74(1.19-2.57) 0.005
Martinez et al, AJRCCM 2006
BODE in multivariate model
Predictor
Age 70-83
Hb 9.1-13.3
RV% 262-412
Low Watts CPET
Lower lung pred
emphysema
DLCO % 6-21
HR
1. 72(1.31-2.26)
1.38(1.00-1.89)
1.48(1.04-2.37)
1.48(1.12-1.94)
1.74(1.19-2.57)
p
<0.001
0.05
0.03
0.006
0.005
1.36(1.01-1.84)
0.04
BODE 7-10
1.48(1.07-2.05)
0.02
Martinez et al, AJRCCM 2006
Not predictive
 FEV1 alone (i.e. not in BODE)
 Total % of emphysema on CT scan
 DL
was
weak
in
multivariate
CO
 PaO2 was not predictive while O2 use was
 Oxygen increases mortality or epimarker of
disease severity?
 LOTT
Martinez et al, AJRCCM 2006
mBODE Change in COPD Predicts
Mortality
 BODE change in medical and surgical arms NETT
 Divided group into BODE classes
 Decrease by 1
 No change
 Increase by 1
 Data missing
 Used to predict death
Martinez et al, AJRCCM 2008
Changes in mBODE
Martinez et al, AJRCCM 2008
mBODE Change in Surgical Cohort and
Mortality
P<0.01
Martinez et al, AJRCCM 2008
HR for Change in mBODE
P<0.01
Martinez et al, AJRCCM 2008
Genetic Epidemiology of COPD
(COPDGene) Study Design
 Multi-center (21) observational study
 Designed to identify genetic factors associated with
COPD
 Genome-wide association study (GWAS) analysis to be
done
 Will permit identification of radiographic and clinical
phenotypes to be identified
Regan et al, COPD 2011
COPDGene Study Population
 10,000 subjects enrolled with 2/3 non-Hispanic whites
and 1/3 African American
 Enrollment goals were met early
 Inclusion criteria
 Self identified as non-Hispanic white or African
American
 Age 45-80 with 10 pack-years smoking history
Regan et al, COPD 2011
COPDGene Study Population
 Exclusion criteria
 Pregnancy due to CT imaging
 Other lung disease except asthma
 Prior LVRS or lobectomy
 Active cancer
 Suspected lung cancer
 Metal in the chest
 Recent AECOPD requiring therapy
 Recent eye surgery
 1st or 2nd degree relative already in study
 History of chest radiation therapy
Regan et al, COPD 2011
Data Collected
 Blood for genetic and biomarker analysis
 Inspiratory and expiratory HRCT scans with sub-
millimeter thickness
 Pre and post bronchodilator spirometry
 ATS respiratory questionnaire
 medical history, medications
 St George’s respiratory questionnaire
 BMI, blood pressure, oxygen saturation
 Six minute walk test
Regan et al, COPD 2011
Analysis
 HRCT phenotyping
 Emphysema quantification
 Gas trapping
 Airway wall thickness
 GWAS: look for genes associated with following:
 COPD status defined by GOLD criteria
 FEV1% as a continuous variable
 HRCT parameters listed above
Regan et al, COPD 2011
Epidemiology of
COPD
GOLD Undefined Subjects
 Data from 1st 2,500 subjects
 9% of current or ex-smokers with
 Low FEV1 but preserved FEV1/FVC ratio
 GOLD-U has been described previously
 Stable pattern
 Associated with increased mortality
 Associated with significant symptoms
 COPDGene provided largest database with both
clinical and radiographic data
Wan et al, AJRCCM 2011
Comparison of GOLD U to Controls
and COPD Cases
Wan et al, AJRCCM 2011
GOLD-U Comparison
GOLD-U
Controls
COPD
Wan et al, AJRCCM 2011
GOLD-U Predictors
Wan et al, AJRCCM 2011
Significance of GOLD-U
 Represents significant # of smokers/ex-smokers
 Clinical course largely unknown
 ?progression
 Are these changes related to obesity alone?
 BMI contributes but changes in FEV1 are > than
previously reported
 No reduction in FRC compared to smoking controls
Early Onset COPD: Differences of
Race and Sex
 First 2,500 subjects only
 Early onset definition:
 Age <55
 FEV1/FVC < 0.7
 FEV1 <50% predicted
 Comparator group
 Age >64
 FEV1/FVC < 0.7
 FEV1 <50% predicted
Foreman et al, AJRCCM 2011
Demographic & Clinical Differences
Foreman et al, AJRCCM 2011
Multivariate Analysis
Foreman et al, AJRCCM 2011
Significance of Findings
 Early onset COPD is rare
 African Americans and women disproportionately
affected
 Smoked less
 Maternal history of COPD is important
 Genetic follow up studies pending
Foreman et al, AJRCCM 2011
Racial Differences in Quality of Life in
COPDGene
African Americans smoked less, were younger but had the
same lung function
Han et al, Chest 2011
St George Respiratory Questionnaire
African Americans had worse SGRQ scores (higher)
Han et al, Chest 2011
Multivariate Analysis
 After adjustment for age, sex, pack-years smoking,
education level, MMRC dyspnea, 6MWD, and current
smoking status no difference in quality of life in those
without exacerbations
 African Americans with history of prior exacerbation
(1.887 for every exacerbation, p = 0.006)
Han et al, Chest 2011
Family History as a Risk for COPD
COPD >GOLD II
Hersch et al, Chest 2011
Multivariate analysis
 Controlling for demographics, parental history of
smoking, parental history of COPD, childhood ETS
 Parental history of COPD OR 1.73 (1.36-2.2), p = <0.001
 Paternal history COPD 1.66 (1.24-2.22), p = 0.006
 Maternal history COPD 1.51 (1.10-2.09), p = 0.011
Hersch et al, Chest 2011
Clinical Phenotypes COPD
Chronic Bronchitc Phenotype
Variable
Age
Smoking, pk-yr
Current smoker %
Men %
MMRC
SGRQ total
TLC, L
FRC, L
Mean WA%
CB+ (n = 290)
62.8 + 8.4
57 + 30
48
57
3 (2-4)
49.9 + 19.7
6.30 + 1.50
4.22 + 1.19
63.2 + 2.9
CB- (n = 771)
64.6 + 8.4
52 + 25
27
50
2 (1-3)
36.6 + 20
5.88 + 1.40
3.92 + 1.28
62.6 + 3.1
P
.002
0.006
<0.001
0.027
<0.001
<0.001
.004
.002
.013
Kim et al, Chest 2011
Chronic Bronchitics and AECOPD
Kim et al, Chest 2011
Radiographic Features of
Frequent Exacerbation
Phenotype
Han et al, Thorax 2011
Frequent vs non-frequent
exacerbators
Han et al, Thorax 2011
Effect of Airway Wall Thickness and %
Emphysema on Exacerbations
Han et al, Thorax 2011
Multivariate Analysis
Han et al, Thorax 2011
Smoking Related ILD
on HRCT
 Ground glass or reticular abnormalities
 Diffuse centrilobular nodules
 Non-emphysematous cysts
 Honeycombing
 Traction bronchiectasis
Washko et al, NEJM 2011
ILA vs No ILA
Variable
No ILA
(n = 1361)
Age
60 (52-67)
BMI
27 (24-31)
Pack-yr smoking
40 (29-54)
GOLD > stage 2 (%)
41
Unclassified GOLD %
7
% emphysema
4.1 (1.3-12.4)
TLC, L
5.7 (4.8-6.78)
ILA
(n = 194)
64 (56-72)
28 (25-33)
44 (31-63)
32
14
3.3 (0.9-9.7)
5.21(4.38-6.270
P
<0.001
0.006
0.01
0.02
0.002
<0.001
.004
Washko et al, NEJM 2011
Multivariate Analysis
Adjusted for age, sex, BMI, smoking, COPD (except for COPD model)
Washko et al, NEJM 2011
ILA and lower 6MWD
Doyle et al, AJRCCM in press
Genetics
 Three genetic loci identified as being associated with
COPD susceptibility
 4q24
 6p21
 5q33
 Low BMI associated with COPD
 Pts from Eclipse, Norway-Bergen cohort, NETT and
COPDGene
 Found an association of low BMI in SNP at FTO gene

FTO gene has been associated with obesity
Castaldi et al, AJRCMB 2011
Wan et al, AJRCMB 2011
Summary
 NETT
 Most of analysis is done
 LVRS improves survival, exercise performance, QOL
 Small airway disease is important even in emphysematous
phenotype
 Use of BODE to track response to therapy
 COPDGene
 Most of analysis not yet done
 Genetics
 Definition of phenotypes which may lead to better directed Rx
 Radiographic
 Chronic bronchitis
 Smoking related diseases other than COPD exist
 GOLD U
 Interstitial changes on CT
Conclusion
 Large multi-centered studies in COPD are feasible and
lead to important findings
 NETT
 COPDGene
 ECLIPSE
 TORCH
 Continued co-operation amongst investigators will
lead to new advances in COPD