RADIOGRAPHIC RADIOGRAPHIC PHENOTYPING OF COPDPHENOTYPING OF COPD

ARZU BALKAN, MDARZU BALKAN, MD

GATA, DEPARTMENT OF PULMONARY GATA, DEPARTMENT OF PULMONARY MEDICINEMEDICINE

CONFLICT OF INTEREST CONFLICT OF INTEREST DISCLOUSUREDISCLOUSURE

There is no any conflict of There is no any conflict of interest in my presentationinterest in my presentation..

OUTLINEOUTLINE

• Basics of COPD radiologyBasics of COPD radiology• Measurement of emphysemaMeasurement of emphysema• Airway morphometryAirway morphometry• Studies about radiographic phenotypingStudies about radiographic phenotyping• Therapotic contribution of radiographic Therapotic contribution of radiographic

phenotypingphenotyping

COPD

Small Airways Disease•Airway inflammation•Airway fibrosis, luminal plugs•Increased airway resistance

Parenchymal Destruction•Loss of alveolar attachments•Decrease of elastic recoil

AIRFLOW LIMITATION

Disrupted alveolar attachments

Inflammatory exudate in lumen

Peribronchial fibrosisLymphoid follicle

Thickened wall with inflammatory cells- macrophages, CD8+ cells, fibroblasts

Changes in Small Airways in COPD Patients

Source: COLD 2007

Alveolar wall destruction

Loss of elasticity

Destruction of pulmonarycapillary bed

↑ Inflammatory cells macrophages, CD8+ lymphocytes

Source: GOLD 2007

Changes in Lung Parenchyma in COPD

COPD PhenotypingCOPD Phenotyping

• Emphysema sub-typeEmphysema sub-type

• Emphysema distributionEmphysema distribution

• Airways diseaseAirways disease

• Relative importance of componentsRelative importance of components

Chronic Chronic bronchitisbronchitis EmphysemaEmphysema

AsthmaAsthma

Airflow Airflow obstructionobstruction

Centrilobular emphsema

Borders of holes have no perceptible wall

Panlobular emphsema

Panlobüler amfizem Sentrilobuler amfizem

Normal COPD

IMAGING TECHNICSIMAGING TECHNICS

• CHEST RADIOGRAPHYCHEST RADIOGRAPHY• THORAX CTTHORAX CT• HIGH RESONANCE CTHIGH RESONANCE CT• MDCTMDCT• INSPIRATUAR-EKSPİRATUAR CTINSPIRATUAR-EKSPİRATUAR CT• SPİROMETRY (GATED) BTSPİROMETRY (GATED) BT• MRGMRG• 3 He MR3 He MR

Measurement of Emphysema Measurement of Emphysema

1.1. Qualitative assesmentQualitative assesment

2.2. Quantitative assesmentQuantitative assesment

Visual ScoringVisual ScoringSEVERITY (%)SEVERITY (%)

• 0 0 Yok Yok• 1 1 < 5 mm < 5 mm• 2 2 > 5 mm > 5 mm • 3 3 Difüz Difüz

EXTENTIONEXTENTION(% )(% )• 11 % 1-25 % 1-25• 22 % 26-50 % 26-50• 33 % 51-75 % 51-75• 44 % 76-100 % 76-100

•In general, visual inspection has yielded good correlations between CT and pathological measures of the extent and severity in all but the mildest cases

•Visual assessment may lead to an overestimation of the extent of disease.•As an alternate to routine visual inspection: Minimum-intensity projection (MinIP) is more sensitive (%62- %81) Spouge D, Mayo JR, Cardoso W, et al.J Comput Assist Tomogr 1993;17:710–713 Gevenois PA, Yernault JC. Eur Respir J 1995;8:843–848 emy-Jardin M, Remy J, Gosselin B, et al. Radiology 1996;200:665–671

Quantitative Assesment

•Lung mask density.

•Wall thickness.

•Percentage of wall area.

•Geometric measures: curvature of airway lumen.

Quantitative AssesmentQuantitative Assesment

İntra / inter-observer variability is high

Error ratio is high because of the oblique airways

Quantitative analysisQuantitative analysis

11--Definition of a lung mask is the first Definition of a lung mask is the first step of the processing pipeline.step of the processing pipeline.

22-Havayolları segmentlere ayrılır-Havayolları segmentlere ayrılır

33- Hava yollarının duvar - Hava yollarının duvar kalınlıkları, havayolu duvar kalınlıkları, havayolu duvar kkalınlığının lümen genişliğine alınlığının lümen genişliğine oranı oranı

Airway Analysis•Lumen segmentation•Wall segmentation

Lung Mass

LUNG MASK DENSİTY

Lung mask extraction for a HRCT

Mask extraction allows lung mask density analysis.

PixelPixel

VoxelVoxel

512 512 PixelsPixels

-550

-950

Principles of CT DensitometryPrinciples of CT Densitometry

PixelPixel

VoxelVoxel

512 512 PixelsPixels

-550

-950

Principles of CT DensitometryPrinciples of CT Densitometry

The softwares are devoloped automatic analysis of bronchial lumen and wall area on CT

Airway measurement

Focusing on the airway wall by traveling along the airway.

New CT view in planes orthogonal to the airway.

Principles of Airway MorphometryPrinciples of Airway Morphometry

Full Width Half MaximumFull Width Half Maximum

Lumen diameter/areaWall diameter/area

HipereiflationMosaic perfusion

EkspiriumInspirium

CT acquisition technique and quantitative CT acquisition technique and quantitative analysis of the lung parenchyma: variability analysis of the lung parenchyma: variability

and correctionsand corrections

•   • Bin ZhengBin Zheng*a*a, J. Ken Leader, J. Ken Leaderaa, Harvey O. , Harvey O.

CoxsonCoxsonbb, Frank C. Scuirba, Frank C. Scuirbacc, Carl R. , Carl R. FuhrmanFuhrmanaa, , Arzu BalkanArzu Balkandd, Joel L. , Joel L. WeissfeldWeissfeldee, Glenn S Maitz, Glenn S Maitzaa, David Gur, David Guraa

•   • Proc of SPIE, 2006, 6143:2S-1 to 2S-8. Proc of SPIE, 2006, 6143:2S-1 to 2S-8. 

The Prevalence of Radiographic The Prevalence of Radiographic Emphysema in a Lung Cancer Emphysema in a Lung Cancer

Screening CohortScreening Cohort

A.A. Balkan Balkan 1,21,2, F.C. Sciurba, MD, F.C. Sciurba, MD22, C.R. , C.R. FuhrmanFuhrman22, S.N. Fisher, S.N. Fisher22, D.O. Wilson, D.O. Wilson22, J.G. , J.G.

SchraginSchragin22 ,J.L. Weissfeld ,J.L. Weissfeld22

1 1 GGATAATA, Ankara, Turk, Ankara, Turkiiyyee 22 University of Pittsburgh, Pittsburgh, PA, US University of Pittsburgh, Pittsburgh, PA, USAA

Yayınlanmamış veriATS 2005 , San Diego

Aim of the studyAim of the study

The purpose of the study The purpose of the study is to explore the is to explore the correlation between the degree of airflow correlation between the degree of airflow obstruction as staged by GOLD criteria and obstruction as staged by GOLD criteria and the presence and severity of emphysema the presence and severity of emphysema detected by low-dose helical CT scans in a detected by low-dose helical CT scans in a large population of current and former large population of current and former smokers undergoing CT lung cancer smokers undergoing CT lung cancer screening.screening.

MetodMetod

3301 3301 participantsparticipantsLow dose CTLow dose CTPresence and absense of emphysemaPresence and absense of emphysemaTraceTrace, , mildmild, , moderatemoderate, , severesevere emphysema emphysema

kategorilerine ayrıldıkategorilerine ayrıldıby using by using NETT multisentrik NETT multisentrik studies’sstudies’s

standart referanstandart referancece imagesimagesThe investigators developed a The investigators developed a

semiquantitative scoring systemsemiquantitative scoring system

ResultsResults

In this studyIn this studyThere was no statistically difference There was no statistically difference

according to genders, race and ethnicity.according to genders, race and ethnicity.(p>0.05)(p>0.05)

Results between the groups of age, smoking Results between the groups of age, smoking status, duration of cigarette use, dose and status, duration of cigarette use, dose and duration of smoking intensity, history, and duration of smoking intensity, history, and GOLD were statistically different. (p<0.001GOLD were statistically different. (p<0.001 p<0.001,<0.001,<0.001) p<0.001,<0.001,<0.001)

Emphysema score, by GOLD stage (p<0.0001)

0

10

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80

GOLD 0 GOLD I GOLD II GOLD III GOLD IV

Perc

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none trace mild moderate severe

CT evidence of moderate emphysema was detected in 29 subjects with GOLD 0 spirometry..

AbAbsence of CT evidence of emphysema was sence of CT evidence of emphysema was detected in 57 subjects with GOLD 3 or 4 detected in 57 subjects with GOLD 3 or 4

spirometryspirometryEmphysema score, by GOLD stage (p<0.0001)

0

10

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30

40

50

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70

80

GOLD 0 GOLD I GOLD II GOLD III GOLD IV

Per

cen

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none trace mild moderate severe

ResultsResults

Zone Symptoms CT emphysem

a

PFT obstruction

   

1 No No No 501 15.740%

2 Yes Yes Yes 660 20.735%

3 No Yes Yes 206 6.472%

4 Yes No Yes 370 11.624%

5 No No Yes 160 5.027%

6 Yes Yes No 312 9.802%

7 No Yes No 162 5.090%

8 Yes No No 812 25.511%3183 100.00%

SFT’ye dayalı KOAH

CT’ye dayalı KOAH

Semptoma dayalı KOAH

1%15.7

ConclusionConclusion

More studies are needed to standardize and More studies are needed to standardize and validate CT that it did for spirometry in validate CT that it did for spirometry in GOLD.GOLD.

ConclusionConclusion

The ratio of CT detected emphysema is The ratio of CT detected emphysema is extremely high in smoker who has not extremely high in smoker who has not been diagnosed with normal or airway been diagnosed with normal or airway obstructionnobstructionn

ConclusionConclusion

Fizyolojik obstruksiyona karşı, herbir Fizyolojik obstruksiyona karşı, herbir GOLD sınıflamasında sigaraya bağlı GOLD sınıflamasında sigaraya bağlı parankimal destrüksiyonun fenotipik parankimal destrüksiyonun fenotipik görüntüsü arasında önemli farklılıklar görüntüsü arasında önemli farklılıklar mevcuttur.mevcuttur.

Phenotyping of COPD patients Phenotyping of COPD patients according to CT emphysema score according to CT emphysema score

Boschetto P et al, Thorax 2006;61:1037

Phenotyping of COPD patients according to CT Phenotyping of COPD patients according to CT emphysema score emphysema score

Boschetto P et al, Thorax 2006;61:1037

Health related quality of life (SGRQ) Health related quality of life (SGRQ) varies by the extent of CT varies by the extent of CT

emphysema in severe COPDemphysema in severe COPDFeature Parameter

estimate95% CI P value

BODE 4.16 3.77, 4.34 <0.0001

Age (yrs) -0.39 -0.49, -0.28 <0.0001

Whole lung emphysema (-910 HU)

-11.8 -17.2, -6.42 <0.0001

Pack yrs 0.02 -0.005, 0.04 0.12

Female gender -2.42 -3.83, -1.01 0.0008

Martinez et al. AJRCCM 2007; 176: 243-52

CT phenotype and clinical CT phenotype and clinical correlatescorrelates

em

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0

20

40

60

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100

MMRC

0 1 2 3 4

Walk distance (meters)

0 100 200 300 400 500 600 700

Em

ph

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ma

pe

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20

30

40

50

60

70

BMI

10 20 30 40 50 60

Em

ph

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perc

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0

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70

FEV1 %predicted

0 20 40 60 80 100 120 140

Em

ph

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70

Han et al. COPD 2009; 6: 459-67

FactorFactor EstimateEstimate p valuep value

AgeAge 0.010.01 0.120.12

GenderGender 0.220.22 0.050.05

CigsCigs -0.14-0.14 0.450.45

Pack yrsPack yrs 0.0060.006 <0.001<0.001

Emp%Emp% 0.040.04 <0.0001<0.0001

RUL AS RUL AS WA%WA%

00040004 0.560.56

CT emphysema is associated CT emphysema is associated with significant comorbiditywith significant comorbidity

• Lung cancerLung cancer1,2,31,2,3

• Cardiovascular diseaseCardiovascular disease4,5,64,5,6

• OsteoporosisOsteoporosis7,97,9

• Fat free mass lossFat free mass loss99

1Wilson DO et al. AJRCCM. 2008; 178: 738-44; 2de Torres JP et al. Chest. 2007; 132: 1932-8; 3Li et al. Cancer Prev Res (Phila) 2011; 4: 43-50; 4Barr RG et al. AJRCCM. 2007; 176: 1200-7; 5Barr et al. NEJM 2010; 362: 217-27; 6Dransfield et al. COPD 2010; 7: 404-10; 7Ohara et al, Chest 2008; 134: 1244-9; 8Bon et al. AJRCCM 2010 [epub ahead of pring Oct 8]; 9Kurosaki et al, Inter Med 2009; 48: 41-8

Association of Radiographic Emphysema and Airflow

Obstruction with Lung Cancer Risk

David Wilson, Joel Weissfeld, Arzu Balkan

Jeffrey Schragin, Carl Fuhrman, Stephen Fisher,

Jonathan Wilson, Jill Siegfried, Steven Shapiro,

and Frank Sciurba

University of Pittsburgh, ABDGATA, Ankara, Türkiye

Am J Respir Crit Care Med Vol 178. pp 738–744, 2008

ObjectiveObjective

• To study lung cancer related to To study lung cancer related to radiographic emphysema and radiographic emphysema and spirometric airflow obstruction in spirometric airflow obstruction in tobacco-exposed persons who were tobacco-exposed persons who were screened for lung cancer using screened for lung cancer using chest computedchest computed

Method-CTMethod-CT

• CT scans CT scans are visually scored are visually scored for for emphysema presence and severity.emphysema presence and severity.

• Scoring procedures used a five level Scoring procedures used a five level semi-quantitative scale, based on semi-quantitative scale, based on National Emphysema Treatment Trial National Emphysema Treatment Trial (NETT) criteria, to represent no, trace, (NETT) criteria, to represent no, trace, mild, moderate, and severe emphysemild, moderate, and severe emphysema.ma.

ResultsResults• The study group included 3,638 persons. The study group included 3,638 persons. 57.5 %, no57.5 %, no18.8 %, trace18.8 %, trace14.6 %, mild14.6 %, mild9.1 % moderate-severe emphysema9.1 % moderate-severe emphysema

• The study group included 3,638 personsThe study group included 3,638 persons, ,

%57.3, no%57.3, no%13.6, mild (GOLD I)%13.6, mild (GOLD I)%22.8, moderate (GOLD II), %22.8, moderate (GOLD II), %6.4 ,severe(GOLD III-IV) airflow obstruction%6.4 ,severe(GOLD III-IV) airflow obstruction

ResultsResults

• Ninety-nine lung cancers (Ninety-nine lung cancers (2.7 % of 3638)2.7 % of 3638) were diagnosed were diagnosed on average 20.9 (0.4-on average 20.9 (0.4-61.8) months after 61.8) months after initial screening. initial screening.

ResultsResults• The expected lung cancer risk related to the The expected lung cancer risk related to the

presence of airflow obstructionpresence of airflow obstruction

GOLD I-IV, OR 2.09, (95% CI 1.33 - 3.27)GOLD I-IV, OR 2.09, (95% CI 1.33 - 3.27)

• Lung cancer risk related to emphysema Lung cancer risk related to emphysema • OR 3.56 (95% CI 2.21 - 5.73)OR 3.56 (95% CI 2.21 - 5.73)

• After additional adjustments for GOLD class, After additional adjustments for GOLD class, emphysema remained a strong and statistically emphysema remained a strong and statistically significant risk factor (OR 3.14, 95% CI 1.91 - 5.15, p significant risk factor (OR 3.14, 95% CI 1.91 - 5.15, p < 0.0001) < 0.0001)

BulgularBulgular• PPersons with both emphysema and ersons with both emphysema and

severe airflow obstruction (GOLD III-severe airflow obstruction (GOLD III-IV) had the greatest lung cancer IV) had the greatest lung cancer risk (adjusted OR 6.29, 95% CI 2.91-risk (adjusted OR 6.29, 95% CI 2.91-13.5713.57))

0.1 1.0 10.0 100.0

Odds ratio

Reference

GOLD Yes No

III-IV Yes 15 154

III-IV No 0 63

II Yes 32 472

II No 4 320

I Yes 11 287

I No 5 190

0 Yes 17 558

0 No 15 1,495

Lung cancerEmphy-sema

ConclusionConclusion

• WWe have shown that both COPD as e have shown that both COPD as measured by GOLD I - IV and emphysema measured by GOLD I - IV and emphysema assessed semi-quantitatively on CT scan, assessed semi-quantitatively on CT scan, are independently related to the risk of are independently related to the risk of developing lung cancer in a high risk developing lung cancer in a high risk population, and that the highest risk is in population, and that the highest risk is in patients with both COPD and patients with both COPD and emphysema.emphysema.

RADIOGRAPHIC PHENOTYPING-RADIOGRAPHIC PHENOTYPING-THERAPYTHERAPY

• Preoperative and postoperative evaluation of emphysema

• Bullectomy

• Lung Volume Reduction Surgery

• Lung Transplantation

Weder et al. Ann Thorac Surg 1997

Morphology of Emphysemamarkedly

heterogeneousintermediatelyheterogeneous

homogeneous

• Patient with Patient with large upper lobe lesions large upper lobe lesions respond better to LVRS than patients with respond better to LVRS than patients with small uniformly distributed disease small uniformly distributed disease

• LLVRSVRS is more successful in cases dominant is more successful in cases dominant findings peripherally with respect to cases findings peripherally with respect to cases showing remarkable findings centrallyshowing remarkable findings centrally

Coxson HOCoxson HO. . Thorax 2003;58:510–514.Thorax 2003;58:510–514.

Nakano YNakano Y. . Am J Respir Crit Care Med Am J Respir Crit Care Med 2001;164:2195–21992001;164:2195–2199

LVRS

Patients at high risk of death after Patients at high risk of death after lung volume reduction surgerylung volume reduction surgery

National Emphysema Treatment Trial Research GroupNational Emphysema Treatment Trial Research Group FEV1 < 20 % pred. and homogeneous distribution of emphysema or DLCO < 20 % pred.

N Engl J Med, Vol. 345, No. 15 – Okt. 11, 2001

Survival LVRS vs Medical Therapy Survival LVRS vs Medical Therapy from the NETTfrom the NETT

All patientsupper lobe+ low ex

upper lobe+ high ex

Ann Thorac Surg 2006;82:431-43

Non upper lobe+ high ex

Non upper lobe+ low ex

* = p < 0.05

* * * *

* * *

Weder Ann Thorac Surg. 2009* = p < 0.05

TransplantationTransplantation free sfree survival urvival according to emphysema according to emphysema

morphologymorphology

Hazard Ratio: 0.80, 95% CI 0.66 - 0.98, p = 0.03

0 20 40 60 80 100 120 140 160

Months

0.0

0.1

0.2

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0.6

0.7

0.8

0.9

1.0

Cu

mu

lati

ve P

ro

po

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on

Su

rviv

ing

non- heterogeneous

heterogeneous

Weder Ann Thorac Surg. 2009

CONCLUSIONCONCLUSION• COPD is a heterogeneous disorder with different COPD is a heterogeneous disorder with different

phenotypes and subphenotypesphenotypes and subphenotypes

• CT is a non-invasive CT is a non-invasive in vivoin vivo measure of emphysema and measure of emphysema and airway morphologyairway morphology

• Valid method for COPD phenotypingValid method for COPD phenotyping

• Valid outcome measure for therapeutic trials of disease Valid outcome measure for therapeutic trials of disease modifying therapy in emphysemamodifying therapy in emphysema

• Technical advances are likely to improve the methodologyTechnical advances are likely to improve the methodology