Updates in Diagnosis of COPD

Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university

LUNG INFLAMMATION

COPD PATHOLOGY

Oxidative

stress Proteinases

Repair

mechanisms

Anti-proteinases Anti-oxidants

Host factors

Amplifying mechanisms

Cigarette smoke Biomass particles

Particulates

Source: Peter J. Barnes, MD

Pathogenesis of COPD

*Influx of inflammatory cells into

the lung (leading to chronic

inflammation of the airways) .

Respir Res. 2006 Mar 30;7:53.

Role of apoptosis in the pathogenesis of COPD

and pulmonary emphysema.

Respir Res. 2006 Mar 30;7:53.

•Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD. There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development

of emphysema.

Role of apoptosis in the pathogenesis of COPD

and pulmonary emphysema.

Respir Res. 2006 Mar 30;7:53.

•Data from animal models suggest a role for

Vascular Endothelial Growth Factor (VEGF)

in the induction of apoptosis of structural

cells in the lung. Other mediators of

apoptosis, such as caspase-3 and ceramide,

could be interesting targets to prevent

apoptosis and the development of

emphysema.

Hypothesis: Does COPD have an autoimmune

component?

A Agustí1, W MacNee2, K Donaldson2 and M Cosio3

A new hypothesis that considers the role of

the immune system in the pathogenesis of

COPD is explored which, if true, will

generate new therapeutic opportunities in

this condition. [Thorax, 2003]

Vascular theory

10 10

Angiogenesis in COPD

Reprinted from International Journal of COPD, 2, Siafakas NM, et al., Role of angiogenesis and vascular remodeling in

chronic obstructive pulmonary disease, 453-462, Copyright 2007, with permission from Dove Medical Press Ltd.

extravasated

plasma proteins

Inflammatory cells (Mac, Neu, Epith, Lymph)

Release of angiogenic

mediators

Fibrinogen products

Inflammation Tissue

hypoxia

Airway

fibrosis

Mechanical

Injury

Increased

blood flow

Vessel growth

Angiogenesis

Vascular remodeling

Up-regulation of

Angiogenic factors

Shear stress

on the endothelium

Dr.Sarma@works 11

CLINICAL FEATURES

Dr.Sarma@works 12

CHRONIC BRONCHITIS EMPHYSEMA

1. Mild dyspnea

2. Cough before dyspnea starts

3. Copious, purulent sputum

4. More frequent infections

5. Repeated resp. insufficiency

6. PaCO2 50-60 mmHg

7. PaO2 45-60 mmHg

8. Hematocrit 50-60%

9. DLCO is not that much ↓

10. Cor pulmonale common

1. Severe dyspnea

2. Cough after dyspnea

3. Scant sputum

4. Less frequent infections

5. Terminal RF

6. PaCO2 35-40 mmHg

7. PaO2 65-75 mmHg

8. Hematocrit 35-45%

9. DLCO is decreased

10. Cor pulmonale rare.

Dr.Sarma@works 13

CHRONIC BRONCHITIS EMPHYSEMA

BLUE BLOTTER PINK PUFFER

ALPHA1 ANTITRYPSIN ↓ EMPHYSEMA

Specific circumstances of Alpha 1- AT↓include.

• Emphysema in a young individual (< 35)

• Without obvious risk factors (smoking etc)

• Necrotizing panniculitis, Systemic vasculitis

• Anti-neutrophil cytoplasmic antibody (ANCA)

• Cirrhosis of liver, Hepatocellular carcinoma

• Bronchiectasis of undetermined etiology

• Otherwise unexplained liver disease, or a

• Family history of any one of these conditions

• Especially siblings of PI*ZZ individuals.

• Only 2% of COPD is alpha 1- AT ↓

Characterization of patients with COPD: GesEPOC

Miravitlles M, et al.

Arch Bronconeumol 2012

Phenotype Infrequent

exacerbator ACOS

Exacerbator with

emphysema

Exacerbator with

chronic bronchitis

Treatment strategy* Bronchodilators Bronchodilators

+ ICS

Bronchodilators

(in some cases + ICS)

Bronchodilators

+ ICS

*Choice of treatment should be based on clinical phenotype and the

intensity determined by severity

ACOS = asthma‒COPD overlap syndrome; GesEPOC = Guía Española de la EPOC

[Spanish Guidelines for COPD]; ICS = inhaled corticosteroid

No Yes

ACOS? ACOS?

No Yes No Yes

Chronic cough?

Yes No

Diagnosis of COPD and ≥2 exacerbations per year?

Spanish COPD Phenotypes

ACOS

Non frequent exacerbator chronic bronchitis

Non frequent exacerbator emphysema

Frequent exacerbator chronic bronchitis

Frequent exacerbator emphysema

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPD

EXPOSURE TO RISK FACTORS

tobacco

occupation

indoor/outdoor pollution

SYMPTOMS

shortness of breath

chronic cough

sputum

è

SPIROMETRY: Required to establish diagnosis

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis and Assessment: Key Points

Spirometry should be performed after the administration of an adequate dose of a short- acting inhaled bronchodilator to minimize variability.

A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation.

Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly.

Acceptability

At least three (3) acceptable maneuvers:

• Good start to the test.

• No hesitation or coughing for the 1st second.

• FVC lasts at least 6 seconds with a plateau

of at least 1 second.

• No valsalva maneuver or obstruction of the

mouthpiece.

• FIVC shows apparent maximal effort.

Repeatability

Repeatability criteria act as guideline to

determine need for additional efforts.

– Largest and 2nd largest FVC must be within 150

mL.

– Largest and 2nd largest FEV 1 must be 150 mL.

– PEF values may be variable (within 15%).

If three acceptable reproducible maneuvers

are not recorded, up to 8 attempts may be

recorded.

Spirometry Value

• Spirometry is typically reported in both

absolute values and as a predicted

percentage of normal.

• Normal values vary and are dependent on:

– Gender,

– Race,

– Age,

– Weight and

– Height.

Reporting Standards

• Largest FVC obtained from all acceptable

efforts should be reported.

• Largest FEV1 obtained from all acceptable

trials should be reported.

• May or may not come from largest FVC

effort.

• All other flows, should come from the effort

with the largest sum of FEV 1 & FVC.

• PEF should be the largest value obtained

from at least 3 acceptable maneuvers.

Results Reporting Example

Pre & Post Bronchodilator Studies: Withholding

Medications

Reversibility

Reversibility of airways obstruction can be

assessed with the use of bronchodilators.

• > 12% increase in the FEV1 and 200

ml improvement in FEV1

OR

• > 12% increase in the FVC and 200

ml improvement in FVC.

Changes in Lung Volumes in

Various Disease States

Ruppel GL. Manual of Pulmonary Function Testing, 8th ed., Mosby 2003

Patterns of Abnormality

Restriction low FEV1 & FVC, high FEV1%FVC

Recorded Predicted SR %Pred

FEV 1 1.49 2.52 -2.0 59

FVC 1.97 3.32 -2.2 59

FEV 1%FVC 76 74 0.3 103

PEF 8.42 7.19 1.0 117

Obstructive low FEV1 relative to FVC, low PEF, low FEV1%FVC

Recorded Predicted SR %Pred

FEV 1 0.56 3.25 -5.3 17

FVC 1.65 4.04 -3.9 41

FEV 1%FVC 34 78 -6.1 44

PEF 2.5 8.28 -4.8 30

high PEF early ILD

low PEF late ILD

Patterns of Abnormality

Upper Airway Obstruction low PEF relative to FEV1

Recorded Predicted SR %Pred

FEV 1 2.17 2.27 -0.3 96

FVC 2.68 2.70 0.0 99

FEV 1%FVC 81 76 0.7 106

PEF 2.95 5.99 -3.4 49

FEV 1 /PEF 12.3

Discordant PEF and FEV1

High PEF versus FEV1 = early interstitial lung disease (ILD)

Low PEF versus FEV1 = upper airway obstruction

Concordant PEF and FEV1

Both low in airflow obstruction, myopathy, late ILD

Common FVL Shapes

Volume

Flo

w

Normal Young or quitter Poor effort

Hesitation Knee Coughing

Upper Airway Obstruction

0 1 2 3 4 5 6

-6

-4

-2

0

2

4

6 Age 40 yrs

FVC 3.52 L 0.84 SR

FEV1 3.0 L 0.74 SR

PEF 4.57 L/s -2.18 SR

FEV/PEF = 10.9

Inspiratory

Expiratory

Flo

w in

L/s

Volume in Litres

FEV1 in mls

PEF in L/min > 8

Diffusing Capacity

Diffusing capacity of lungs for CO

Measures ability of lungs to transport inhaled gas

from alveoli to pulmonary capillaries

Depends on:

- alveolar—capillary membrane

- hemoglobin concentration

- cardiac output

Diffusing Capacity

Decreased DLCO

(<80% predicted)

Obstructive lung disease

Parenchymal disease

Pulmonary vascular

disease

Anemia

Increased DLCO (>120-140% predicted)

Asthma (or normal)

Pulmonary hemorrhage

Polycythemia

Left to right shunt

DLCO — Indications

Differentiate asthma from emphysema

Evaluation and severity of restrictive lung disease

Early stages of pulmonary hypertension

Emphysema

histopathological definition

…..permanent abnormal enlargement of

airspaces distal to the bronchioles terminales

and

…...destruction of the walls of the involved

airspaces

And

Fibrosis is not integral part

Centrilobular Emphysema

Panlobular Emphysema

Fibrosis and Emphysema

CT findings:

• Relatively well-defined, low attenuation areas

with very thin (invisible) walls, surrounded by

normal lung parenchyma.

• As disease progresses:

– Amount of intervening normal lung decreases.

– Number and size of the pulmonary vessels

decrease.

– +/- Abnormal vessel branching angles (>90o), with

vessel bowing around the bullae.

Emphysema

•Curved arrow: area of low attenuation.

•Solid arrow: zones of vascular disruption.

•Open arrow: area of lung destruction.

Emphysematous Bullae

www.ctsnet.org/doc/6761

Where is the pathology ???????

in the areas with increased density meaning there is ground glass

in the areas with decreased density meaning there is air trapping

Pathology in black areas

Airtrapping: Airway Disease

Bronchiolitis obliterans (constrictive bronchiolitis) idiopathic, connective tissue diseases, drug reaction,

after transplantation, after infection

Hypersensitivity pneumonitis granulomatous inflammation of bronchiolar wall

Sarcoidosis granulomatous inflammation of bronchiolar wall

COPD/Asthma / Bronchiectasis / Airway diseases

Airway Disease

what you see……

In inspiration sharply demarcated areas of seemingly increased

density (normal) and decreased density

demarcation by interlobular septa

In expiration ‗black‘ areas remain in volume and density

‗white‘ areas decrease in volume and increase in density

INCREASE IN CONTRAST DIFFERENCES

AIRTRAPPING

Pathology in white Areas

Alveolitis / Pneumonitis

Ground glass desquamative intertitial pneumoinia (DIP)

nonspecific interstitial pneumonia (NSIP)

organizing pneumonia

In expiration both areas (white and black) decrease in

volume and increase in density

DECREASE IN CONTRAST

DIFFERENCES

Mosaic Perfusion

Chronic pulmonary embolism

LOOK FOR

Pulmonary hypertension

idiopathic, cardiac disease, pulmonary

disease

CTEPH =

Chronic thrombembolic

pulmonary hypertension

Quantitative CT Assessment of

Chronic Obstructive Pulmonary

Disease

1-Describe the differences between emphysema-

predominant, airway-predominant, and mixed COPD.

2-Discuss CT-based methods for quantifying the

pathologic and morphologic changes in COPD.

3-Differentiate COPD phenotypes by using a combination

of CT-based methods.

Figure 1 Axial CT image obtained in a 66- year-old man with COPD and severe airflow obstruction

Axial CT image obtained

in a 66- year-old man with

COPD and severe airflow

obstruction (percentage of

predicted FEV1, 40.8%)

shows mild emphysema

(relative low-attenuation

area with attenuation of

−950 HU or lower, 5.8%).

Low-attenuation areas

representing

emphysematous change

(―holes‖) are indicated by

arrowheads.

Figure 2 Axial CT image obtained in an asymptomatic 69-year-old smoker with normal pulmonary

Axial CT image obtained in an

asymptomatic 69-year-old smoker with

normal pulmonary function (percentage

of predicted FEV1, 87.8%) shows

moderate to severe emphysema

(arrowheads) (relative low-attenuation

area with attenuation of −950 HU or

lower, 25.8%).

Figure 4 Coronal CT image obtained in a 62-year-old man with COPD shows upper-lung–predominant

Coronal CT image obtained in a 62-

year-old man with COPD shows

upper-lung–predominant

emphysema. The relative low-

attenuation area with attenuation of

−950 HU or lower (red) is 46.8%,

and the percentage of predicted

FEV1 is 56.8%.

Figure 5 Coronal CT image obtained in a 72-year-old man shows lower-lung–predominant

Coronal CT image obtained in a 72-

year-old man shows lower-lung–

predominant emphysema. The

relative low-attenuation area with

attenuation of −950 HU or lower (red)

is 45.8%, and the percentage of

predicted FEV1 is 45.6%. The extent

of lower-lung–predominant

emphysema is more closely

correlated with the result of

pulmonary function testing than the

extent of upper-lung–predominant

emphysema. (In both figures, black

indicates areas with attenuation of

−500 to −949 HU and gray indicates

vascular and other nonparenchymal

structures.)

CT densitovolumetry

Figure 8a Volumetric CT-based measurement of airway dimensions. (a) Schema obtained

Volumetric CT-based measurement of

airway dimensions. (a) Schema obtained

with the region-growing method shows

airway segmentation and selection of a

bronchial pathway (black line) for

measurement. A curved multiplanar

reformatted image is reconstructed along

the selected pathway, and a short-axis

image is reconstructed in a plane exactly

perpendicular to the long axis of the

airway. The red dot indicates the location of

the short-axis image in b. (b) Short-axis

image with overlaid diagram shows the

radii (red and green lines) used to delimit

the inner lumen and calculate its area.

From the point of their intersection, the

centroid point, rays (blue lines) are drawn

over a 360° radius through the airway wall

to allow calculation of the airway wall

thickness by using the full width at half

maximum principle.

Vascular Alterations Pulmonary vascular alteration is a characteristic feature

of COPD. Narrowing and numeric reduction of small

pulmonary arteries can be observed in patients with

severe COPD .

Typically, passive vascular compression due to

emphysema and hypoxic vasoconstriction has been

considered the major manifestation of vascular

alteration in COPD.

However, pulmonary vascular alterations are not

exclusive to advanced-stage COPD but also have been

found in mild COPD and in smokers with normal

pulmonary function

Recent studies suggest that both

pulmonary and extrapulmonary vascular

alterations in patients with COPD are

closely related to endothelial dysfunction .

In addition, several researchers

demonstrated a close relationship between

endothelial dysfunction and emphysema .

Endothelial dysfunction results from

changes in the expression and release of

vasoactive mediators. In particular,

vascular endothelial growth factor (VEGF)

plays an important role in the pathogenesis

of both vascular alteration and emphysema

VEGF level in induced sputum from

patients with emphysema is decreased

in comparison with that from patients

with chronic bronchitis.

Vascular alterations also may be

relevant to the diagnosis and

characterization of COPD. Some

researchers have evaluated pulmonary

perfusion and its relationship to airflow

obstruction by using dynamic magnetic

resonance imaging

Quantitative CT Characteristics of

COPD according to Phenotype