Jann Mortensen

Final Phil meeting, 29 april 2004

Overview ofObstructive Diseases of the

Lung, Lung Physiology andImaging Modalities

Disposition

Obstructivedisease

• Definition• Epidemiologi• Mechanisms• Natural history• Treatment• Diagnosis

Physiology• Dynamic

spirometry• Lung volumes• Transfer

factor• Reversibility

Imaging•Chest X-ray

•CT

•Nuclear medicine

•V/Q

•MCC

•PET

Change in mortalityUSA 1965 - 1998

3.0

0

2.5

2.0

1.0

1.5

-59% -64% -35% +163% -7%

1965- 1998

www.copdgold.com

Compared to 1965

0.5

1965- 1998 1965- 1998 1965- 1998 1965- 1998

Other reasonsCOPDOther cardio-vascular dis.

StrokeIschemic heart disease

Chronic obstructive disease

AsthmaObstructionFEV1 / FVC < 70 %

Chronicbronchitis

Emphysema

Obstruction is measuredwith Spirometry

FEV1 = Forced expiratory volume in the 1 secondFVC = Forced vital capacity

Obstruction: FEV1 / FVC < 70 %

COPD and asthma definitions

Asthma

Chronicbronchitis

Emphysema

ProductiveCoughMost days>3 months>2 yrsie. Based onsymptoms

Reversible airways-obstructionie. based on objective measures

Destruction ofalveolar walls,resulting inpermanentenlargementof airspacesand loss of lungelasticityie. Based on patoanatomy

COPD and asthmaDestruction ofalveolar walls,resulting inpermanentenlargementof airspaces(and loss of lungElasticity)ie. Based on patoanatomy

Emphysema Normal

Asthma & COPD

Asthma COPD

Ca. 10% have both

NeutrophilsEosinophils*No airwayhyperresponsiveness

Airwayhyperresponsiveness

Bronchodilatorresponse

*No bronchodilatorresponse

*No steroid responseSteroid response

Symptoms episodicNight/early morning

Symptoms progressive

*No < 15%

Onset:Early/Childhood

Onset:mid-lifeSmokinghistory

Pathological airway changes

Normal airwayConstricted airway

in asthma and COPD

Epithelium

Basement membrane

Smooth muscle

Mucus plug

Mucus glandshypertrophy

Inflammation

Airway generations andregional localisation?

Asthma

Chronicbronchitis

Emphysema

Definition of asthma

Global Initiative for Asthma (GINA). WHO/NHLBI, 1995

• A chronic inflammatory disorder of the airway

• Infiltration of mast cells, eosinophils and lymphocytes

• Recurrent episodes of wheezing, coughing and shortness of breath

• Widespread, variable and often reversible airflow limitation

• Airway hyperresponsiveness

(GOLD) Definition of COPD

‘Chronic obstructive pulmonary disease (COPD) is a

disease state characterized by airflow limitation, that is not fully reversible.

The airflow limitation is generally both progressive and associated with an abnormal inflammatory response of the

lungs to noxious particles or gasses.’

http://www.goldcopd.com

This definition does not use the tems chronic bronchitis and emphysema, and excludes asthma (reversible airflow limitation)

What causes COPD

Including passive smokingOther causes: Occupational dust and chemicalsIndoor air pollution to cooking and heatingOutdoor air pollutionRespiratory infections in early childhood increase risk in adulthood

Natural history: Effect of smoking on annual decline in lung function

Adapted from Fletcher & Peto. Br Med J 1977

100

75

50

25

025 50 75

Age (years)

Smoked regularlyand susceptibleto its effects

Disability

Death

Never smoked or notsusceptible to smoke

Stoppedat 45

Stoppedat 65

FE

V1

(% o

f va

lue

at

ag

e 2

5)

† †

20%

Smoking cessation improves decline in FEV1

The Lung Health Study

• 5.887 with mild to moderate COPD

• Multicenter RCT

• Initial improvement & slower decline in FEV1

• Anthonisen et al, JAMA 1994

Screen 2 1 2 3 4 5

Pos

t-br

onch

odil

ator

FE

V1

(L)

2.4

2.5

2.6

2.7

2.8

2.9

"Continuing Smokers"

"Sustained Quitters"

years

Natural history of COPD

Age20 30 40 50 60 70 80

FE

V1

in %

pre

d.

20

40

60

80

100

Dyspnea

Bothering exacerbationsDisability

Hospital admission

Pulmonary hypertensionHypoxemia

Deconditioning

Systemic disease

Death

290 patienter, parallel design, 3 yr, 800-1200 ug budesonide or placebo

Copenhagen City Lung Study:

No effect of budesonide on ÄFEV1in early COPD

Can steroids modify development of COPD?

EUROSCOPE :

•No effect of budesonide onÄFEV1 in mild COPD

•Initial improvement of FEV1

1.277 patienter, parallel design,

3 yr, 800 ug budesonide eller placebo

ISOLDE

• No effect of fluticasone on ÄFEV1in moderate/severe COPD

• 25 % reduction in no. of exacerbations by fluticasone

• Improved “health status” (SGRQ)

Can steroids modify development of COPD?

751 patients, parallel design,3 yr, 1000 ug fluticasone or placebo

Conclusion on inhaled steroids:

1. Do not change the decline of FEV1 but

2. improve the rate of exacerbations in severe COPD

Guidelines for management of COPD

• Smoking cessation

• Influenza vaccination

• Exercise where possible

• Bronchodilator treatment

• Inhaled steroids

• Pulmonary rehabilitation

• Long-term oxygen therapy

• Lung volume reduction Surgery •Transplantation

SYMPTOMSCoughCoughSputumSputumDyspneaDyspnea

RISK FACTORS

TobaccoTobaccoOccupational exposureOccupational exposure

Air pollutionAir pollution

SPIROMETRISPIROMETRI

Diagnosis: Consider COPDDiagnosis: Consider COPD

èè

Spirometry

Reference values:Age, sex, height, etnic group

Flow rate = driving elastic Pressure / Airway resistance

AsthmaCOPD

Emphysema

Increase inAirway resistance

Low elasticrecoil

Reversibility:spirometric (FEV1) tracings

1 2 3 4 5

Time (seconds)

FEV1

Volume

Normal subject

Asthmatic (after bronchodilator)

Asthmatic (before bronchodilator)

Each FEV1 curve represents the highest of three repeat measurements Global Initiative for Asthma (GINA). WHO/NHLBI, 1995

Establish the diagnosis of COPD

• History• Physical examination

• Lung function tests• Spirometry• Lung volumes• Carbon monoxide diffusing capacity• Arterial blood gases

• Imaging

(slow) Spirometry:Static lung volumes

Body plethysmography = Bodybox

ÄV

ÄP

P P

P x V = (P + ÄP) x (V - ÄV)

BodyboxBodybox

∆P ´0.75

0.50

0.25

0

0.25

0.75

0.50

1.0

1.0

∆ P box

P mouth

Exp

iratio

n

I

nspi

ratio

n

V FRC = x (PFRC – PH20)∆V box

∆ Pmouth

∆Pbox ~∆V

∆P box ~∆V from calibra-Tion with pumped air

BodyboxBodybox

∆P ´0.75

0.50

0.25

0

0.25

0.75

0.50

1.0

1.0

∆ P box

P mouth

Exp

iratio

n

I

nspi

ratio

n

V FRC = x (PFRC – PH20)∆V box

∆ Pmouth

∆Pbox ~∆V

∆P box ~∆V from calibra-Tion with pumped air

Typical Static volumes

Patophysiology• Progressive airways

obstruction->– hyperinflation,

increased work ofbreathing, dyspnea

• Impaired gas exhange– loss of alveoli/airways

obstruction-> disturbedperfusion/ventilation

– hypoxemia and hypercapnia, and eventually acidosis

Carbon monoxide diffusing capacity(mmol/min/Kpa)

= Transfer faktor

Diffusion of gas is proportional with:

The membrane’s AreaThickness

and the difference in concentration over the membrane

Single breath

1) simple2) rapid 3) reproducible 5% (10%)

Inspiration of 0,3% CO og 10% He:

• = CO conc. falls due to dilution + diffusion

• = He conc. falls due todilution only

Alveolus Blood vesselHb

In:

Ex:

Conc.:

Diffusion capacity for CO is low if:

• Small area– Emphysema

– Pulmonary fibrosis

• Thick membrane–Pulmonary fibrosis

• Ventilation / Perfusion disturbancy

V/P V PV/P

• Low Hemoglobin in capillaries (anemia, destruction of vascular tree)

Interpretation:Ventilation and Diffusion Capacity

Irreversible obstructive lung functionlow FEV1/FVC, FVC, FEV1, and

high RV, FRC, TLC

&

Low diffusion ~ COPD with emphysema

Normal diffusion ~ COPD without emphysema

Establishing the diagnosis of COPD

• Imaging

• Chest X-ray

• CT of chest

• Nuclear medicine

• V/Q

• MCC

• PET

1 choice: Chest x-rayMild COPD:•Normal

Advanced COPD:•Hyperinflation •Flat diagfragm•Vaskular markings•Thin heart shadow

•Complications•Infiltrates if pneumonia•Cor pulmonale

•Alternative diagnosis: nodules, pleural disease, interstitial disease

Computerised tomographySuperior to demonstrate (type, distribution and severity of) emphysema:

Findings:•Low attenuation areas•Bullae•Attenuation and abnormal vascular tree

Monitoring:•the progress through lung density measurements

•Centriacinar•Involves primarily the respiratory bronchiole •The distal acinus or alveoli are unchanged.•Occurs more commonly in the upper lobes. •Most common type.•Seen in cigarette smokers

•Panacinar•Involves entire respiratory acinus, •commonly in the lower lobes. •1/20 as rare as centricular emphysema.• in alpha 1 - antitrypsin deficiency

•Paraseptal•The distal respiratory acinus, includingalveolar duct and alveoli, is expanded.•primarily adjacent to the pleura and connective tissue septa,• especially in the upper lobes.

Emphysema types demonstrated on CT:

Monitoring the progress throughlung density measurements

A

B

The gray area represent the relativ area (RA) of emphysematic lung, (threshold value of –910 HU)

A) RA 10%, 15th percentile –894 HU

B) RA 31%, 15th percentile –946 HU.

Computerised tomography

If complications aresuspected:

•Lung cancer

•Pulmonary embolism

•Confirm alternative diagnosis

Positron emission Tomography (PET)

65 yrs female COPD, CT: 13 mm nodule in Right apex

18 F-flouro-deoxy-glucose (FDG)

Single pulmonary nodule: Lung Cancer ?

Diagnostics in single pulmonary nodules

57 yr male COPD, 9 mm nodule

9 mm nodule

(Nucl Med Comm 2004)

Major indications for PETin lung cancer

• ”Diagnostical use”(Tumor)– indeterminate SPN on CT

• Staging in NSCLC

Relatively good evidence: class B

55 studies 1500 patients

Good evidence: class A

Lancet Oncol 2001;2:659-66

CT+PETCT PET

Integrated PET-CT improves the diagnostic accuracy of the staging of NSCLC. N Engl J Med 2003; 348: 2500-7

Gamma camera

Perfusion Ventilation

Perfusion / Ventilation scintigraphy: Pulmonary embolism ?

Emphysema: is LVRS possible ?

After

lg/jm

Before

Anterior/posterior projections

LVRS in severe COPD

Special Genetic types of COPD:a1-antitrypsin deficiency emphysema

a1-antitrypsin deficiency causes proteolytic damage of the lungs and emphysema

TLC

FRC

RV

Homozygotic PiZZ, blod a1-antitrypsin test, 1 % of COPD cases, Early onset: 30-40 yrs

Panlobular:

Special Genetic types of COPD:Primary ciliary dyskinesia

Ultrastructural defects in cilia impairs mucus transport in the airways and results in infections and

chronic sinusitis/otitis, bronchiectasis and (mild) COPD

Homozygotic, Mucociliary function test; Rare:1 in 15.000 subjects; Very early onset: from 0 yrs

Impaired mucociliary clearance inPrimary Ciliary Dyskinesia

start

2 h

1 h

24 h

Markers

Stomach

Unresolved questions ?Unresolved questions ?

• Why do only 15-20 % of smokers develop COPD?

• Why do some develop bronchitis and others emphysema?

• Are asthma and COPD different entities or interconnected ?

• The patogenesis of COPD (genes and molecular biology)?

• How do we improve treatment?

• How do we identify pre-clinical (early) COPD?– PHIL ?