copdwhat has happened to the airway system - dr amira 031211 respina

COPDWHAT HAS HAPENNED

TO AIRWAY SYSTEM

Amira Permatasari Tarigan

RESPINA 2011RESPINA-2011

CHRONIC OBSTRUCTIVE PULMONARY DISEASE(GOLD, PDPI)

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( )

a preventable and treatable disease state characterised by airflow limitation that is not fully

reversiblereversible.

The airflow limitation is usually progressive and i d i h b l i flassociated with an abnormal inflammatory

response of the lungs to noxious particles or gases, primarily caused by cigarette smokingprimarily caused by cigarette smoking

R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Fi Di i f h i b i l di (COPD) Di i d dFigure . Diagnosis of chronic obstructive pulmonary disease (COPD). Diagnosis depends on clinical suspicion driven by the presence of risk factors and symptoms, followed by

objective testing with spirometry. The most important risk factor for COPD in the developed world is cigarette smoking , though in the developing world exposure to biomass

fuels is also important Other factors including occupational exposures malnutritionfuels is also important . Other factors including occupational exposures , malnutrition , genetics , infections in early life , and airway hyperreactivity and asthma also contribute.

Currently, a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio below the fixed value of 0.70 is used to define the presence of airflow obstruction. R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Cigarette smokeCigarette smokePathogenesis of COPD0 5 / 1 2 / 2 0 1 1

Host factorsAmplif in m h ni m

ggBiomass particlesBiomass particles

ParticulatesParticulates

LUNG INFLAMMATIONLUNG INFLAMMATION

Amplifying mechanisms

LUNG INFLAMMATIONLUNG INFLAMMATIONAntiAnti--proteinasesproteinasesAntiAnti--oxidantsoxidants

OxidativeOxidativestressstress ProteinasesProteinases

Repair Repair mechanismsmechanisms

COPD PATHOLOGYCOPD PATHOLOGYSource: Peter J. Barnes, MDR E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Cigarette smoke Cigarette smoke (and other irritants)(and other irritants)

Inflammatory Cells Involved in COPD0 5 / 1 2 / 2 0 1 1

(and other irritants)(and other irritants)

Alveolar macrophageAlveolar macrophageEpithelialEpithelialllll

p gp gcellscells

Chemotactic factorsChemotactic factors

CD8CD8+ +

lymphocytelymphocyteFibroblastFibroblast

PROTEASES PROTEASES Neutrophil elastaseNeutrophil elastaseCathepsinsCathepsins

MonocyteMonocyteNeutrophilNeutrophil

CathepsinsCathepsinsMMPsMMPs

Alveolar wall destructionAlveolar wall destruction Mucus hypersecretionMucus hypersecretionFibrosisFibrosis(Emphysema)(Emphysema)(Obstructive(Obstructive

bronchiolitis)bronchiolitis)Source: Peter J. Barnes, MDR E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Figure. Connective tissue destruction and fibrosis coexist in chronic obstructive pulmonary disease (COPD). Matrix metalloproteinase-9 (MMP-9) is the major elastolytic enzyme released by alveolar macrophages and is generated from an inactive precursor pro-MMP-9. MMP-9 causes elastolysis directly but also releases chemotactic peptides that attract neutrophils whichcauses elastolysis directly, but also releases chemotactic peptides that attract neutrophils, which release neutrophil elastase. The elastolytic effect of neutrophil elastase is enhanced as MMP-9 inactivates its specific antiproteinase α1‐antitrypsin (α1‐AT), resulting in emphysema. MMP-9 also activates transforming growth factor-β (TGF-β) from a latent precursor, which leads to the fibrosis of small airways. TGF-β also plays a role in activating MMP-9, so the interplay between these mediators leads to tissue destruction and fibrosis simultaneously, as observed in COPD lungs. R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Inflammatory process located in :0 5 / 1 2 / 2 0 1 1

Inflammatory process located in :

• Mucosa Gl d d• Gland ducts

• Glands of intermediate ( 2-4 mm )( )• Parenchyma


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THE SITE OF AIRWAYS 0 5 / 1 2 / 2 0 1 1

OBSTRUCTION

The peripheral airways were the major it f b tr ti n in COPDsite of obstruction in COPD

Smaller conducting airways(B hi d B hi l f l h(Bronchi and Bronchioles of less than

2 mm diameter))


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AIFLOW LIMITATION of COPD due to :0 5 / 1 2 / 2 0 1 1

Peribronchial FibrosisPeribronchial Fibrosisairway obstruction airflow limitation

Alveoli Destructionloss of lung elastic recoilincrease intraalveoli pressure when exhalationdecrease intraluminal and loss of alveoli attachment in Emphysemadecrease intraluminal and loss of alveoli attachment in Emphysemacollaps of small airways expiration airflow limitation

Mucus HypersecretionMucus HypersecretionSmooth Muscle ContrictionR E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Overview of small airways in COPD: schematic viewschematic view

Figure : Small airways in chronic obstructive pulmonary disease patients. The airway wall is thickened and infiltrated with inflammatory cells, predominantly macrophages and CD8+lymphocytes, with increased numbers of fibroblasts. In severe COPD there also are lymphoid follicles, which consist of a central core of B lymphocytes surrounded by T lymphocytes and are thought to indicate chronic exposure to antigens (bacterial viral or autoantigens)are thought to indicate chronic exposure to antigens (bacterial, viral, or autoantigens). Similar changes are also reported in larger airways. The lumen is often filled with an inflammatory exudate and mucus and there is peribronchial fibrosis, resulting in progressive and irreversible narrowing of the airway.05/12/2011 Respina,Jakarta 3 Desember 2011 10

Figure.Mechanisms of airflow limitation in chronic obstructive pulmonary disease (COPD). The airway in normal subjects is distended by alveolar attachments, which contain elastin fibers y j y ,during expiration, allowing alveolar emptying and lung deflation. In COPD these attachments are disrupted due to emphysema, thus contributing to airway closure during expiration, trapping gas in the alveoli and resulting in hyperinflation. 05/12/2011 Respina,Jakarta 3 Desember 2011 11

AIR TRAPPING AND HYPERINFLATION IN COPD

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Normal Mild - ModerateCOPD

Severe – Very Severe COPD

InspirationCOPD

small airway

Expiration

alveolar attachments loss of elasticity loss of alveolar attachments

closure

Courtesy of Barnes P R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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AIR TRAPPING AND HYPERINFLATION IN COPD

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Normal Mild - ModerateCOPD

Severe – Very Severe COPD

InspirationCOPD

small airway

Air trapping and HyperinflationAir trapping and Hyperinflation

Expiration

alveolar attachments loss of elasticity loss of alveolar attachments•• ↑↑ TLCTLC

•• ↑↑ Residual volume (RV)Residual volume (RV)

•• ↑↑ FRCFRC

↑ ExertionalExertionaldyspnoeadyspnoea

↓↓ ExerciseExercise

closure

•• ↑↑ FRCFRC

•• ↓↓ Inspiratory capacity (IC)Inspiratory capacity (IC)

•• ↓↓ Inspiratory reserve volume (IRV)Inspiratory reserve volume (IRV)

↓↓ ExerciseExercisetolerancetolerance

↓↓ Inspiratory reserve volume (IRV)Inspiratory reserve volume (IRV)

Courtesy of Barnes P R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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DYNAMIC HYPERINFLATION IN COPD0 5 / 1 2 / 2 0 1 1

TLC Exercise↓ HealthyIRV

IC

EELV

VC

RV

TLCIC

Exercise↓

VCCOPD

EELV

RVDecreases in inspiratory capacity (IC) & inspiratory reserve volume (IRV) duringRV inspiratory reserve volume (IRV) during

exercise is dynamic hyperinflation

O’Donnell DE Eur Respir Rev 2006; 15:37-41 R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Figure. Left, Scanning electron micrograph of a patient with emphysema showing the enlargement of alveoli and destruction of the alveolar walls. Right, Changes in lung parenchyma in chronic obstructive pulmonary disease. There is loss of elasticity and alveolar wall p y ydestruction, as well as accumulation of inflammatory cells, predominantly macrophages and CD8+ lymphocytes. The destructive changes reduce the pulmonary capillary bed.


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Figure. Mucus hypersecretion in chronic obstructive pulmonary disease. Mucus gland secretion may be stimulated via neural mechanisms and the release of acetylcholine (ACh) from cholinergic nerves and of substance P (SP) from sensory nerves. It is likely that the most important stimulants of mucus secretion are neutrophil elastase (NE) from activated neutrophils and epithelial growthof mucus secretion are neutrophil elastase (NE) from activated neutrophils and epithelial growth factor receptor ligands such as transforming growth factor-α (TGF-α). Several stimulants of mucus hypersecretion, such as cigarette smoke and reactive oxygen species (ROS), also appear to activate epidermal growth factor receptors .R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Figure. Changes in large airways of chronic obstructive pulmonary disease patients. The epithelium often shows squamous metaplasia and there is goblet cell and submucosal gland hyperplasia, resulting in mucus hypersecretion. The airway wall is infiltrated with macrophages and CD4+ and g yp y p gCD8+ lymphocytes, whereas neutrophils predominate in the airway lumen and around submucosalglands. Airway smooth muscle and basement membrane are minimally increased compared to the findings in asthma. R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Figure. Epidermal growth factor receptor (EGFR) in chronic obstructive pulmonary disease. EGFR l k l i h l i f h i i h i d i fEGFRs play a key role in the regulation of mucus hypersecretion, with increased expression of mucin genes (MUC5AC, MUC5B) and differentiation of goblet cells and hyperplasia of mucus-secreting cells. These effects are mediated via the activation of mitogen-activated protein (MAP) kinases. EGFR are activated by transforming growth factor-α (TGF-α), which is in turn activated by y g g ( ), ythe tumor necrosis factor-α converting enzyme (TACE), which is activated via release of oxidants from cigarette smoke and neutrophils. EGFR may also be activated by epidermal growth factor (EGF). R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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PATHOPHYSIOLOGY OF COPD:VAGAL NERVE SYSTEM

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Central nervous system

VAGAL NERVE SYSTEM

system

Vagus nerveAirway smooth muscle

Parasympatheticganglion

ACh

ACh

ACh SubmucosalCh li i

Airway smooth muscleconstriction

Airway epithelium

AChInflammatorycell mediators

glandCholinergic receptors

Airway epithelium

Adapted from: Hansel T/Barnes P. An Atlas of COPD. 2004

Irritants(e.g. cigarette smoke, bacteria, viruses)

MucusHypersecretion


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ANTICHOLINERGICS BLOCK VAGAL “TONE” IN THE AIRWAYS

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Normal COPD

VAGAL TONE IN THE AIRWAYS

Vagal

“tone”Resistance

~ 1/radius4

Ch li i

Post-ganglionic nerve

Cholinergic blocker

Adapted from: Hansel T/Barnes P. An Atlas of COPD. 2004

Acetylcholineg g


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Figure. Transforming growth factor-β (TGF-β) in chronic obstructive pulmonary disease. TGF-β is released in a latent form that is activated by matrix metalloproteinase-9 (MMP-9). It may then cause fibrosis directly through the effects on fibroblasts or indirectly via the release of connective tissue growth factor (CTGF). TGF-β may also downregulate β2-adrenoceptors on cells such as airway smooth muscle to diminish the bronchodilator response to β-agonistscells such as airway smooth muscle to diminish the bronchodilator response to β agonists.


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Figure. Vascular changes in chronic obstructive pulmonary disease. Chronic hypoxia results in hypoxic pulmonary vasoconstriction and, over time, leads to structural changes in pulmonary vessels that result in secondary pulmonary hypertension. An inflammatory response similar to that found in airways is also seen in the vessel wall. Over time, this may lead to right-sided heart failure (cor pulmonale), which has a poor prognosis, with most patients surviving only 6 to 12 months. R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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Fig. - Pulmonary muscular artery from a patient with chronic obstructive pulmonary disease,h i i t i ti l thi k i d l i l i ) I t i i ithshowing prominent intimal thickening and luminal narrowing. a) Immunostaining with

monoclonal antibody against a-smooth muscle actin, showing abundant proliferation ofsmooth muscle cells in the intima. b) Orcein stain showing abundant deposition of elasticfibres in the intimallayer. Internal scale bar=42.2 mm.R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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CONCEPTS OF DISEASE PROGRESSION

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Clinical Manifestations(Patient-Centered Outcomes)

Physiological (Functional) Abnormalities

Seve

rity

Radiographic Abnormalities

Pathological (Structural) Evidence

Biochemical and Cellular EventsL

DiseaseOnset

AdvancedDisease

Biochemical and Cellular EventsInduction Latency

ExposureGenetic

Predisposition

Time (age)


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FEV1 MODEL OF DISEASE PROGRESSION IN COPD

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PROGRESSION IN COPD

100% COPDStages

75%

at a

ge 2

5)

ModerateDiagnosis

50%

of v

alu

e a Moderate

S

Treatment

25%

FE

V1

(% Severe

Very

0%25 50 75

Very Severe

25 50 75Age (years)

Adapted from Fletcher C and Peto R, BMJ 1977; 1:1645-1648. Imagery courtesy O’Donnell DR E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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UNDERDIAGNOSIS AND MISDIAGNOSIS: PATIENT PERCEPTIONS

•Patients may‘I don’t need meds for my breathing because it’s not a Patients may

misunderstand or minimize symptoms,

‘I’ve been coughing when I wake up each morning, but

it’s just smoker’s cough. This is normal and not harmful to

serious problem’

y psuch as fatigue, dyspnoeaand cough

‘Carrying these

my health’

•As a result, they may not mention these

h i

Carrying these groceries is harder than it used to be. I must be old and

out of shape’

symptoms to their physicians

Mannino DM and Braman S. Proc Am Thoracic Soc 2007;4:502–6

THE BENEFITS OF EARLIER DIAGNOSIS AND INTERVENTION

The area under the curve is an opportunity to:• Improve symptoms• Improve exercise capacity• Reduce rate of decline in lung function

The area under the curve is an opportunity to : -Improve symptoms-Improve exercise capacity-Reduce rate of decline in lung function

• Reduce frequency of exacerbations• Prevent complications• Reduce mortality

-Reduce frequency of exacerbations-Prevent complications-Reduce mortality

Graph represents an typical profile of a patient with COPD (smoker from age of 16)

Adapted from: Fletcher C, Peto R. BMJ 1977; 1: 1645–8.R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1 29

THE BENEFITS OF SMOKING CESSATION

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Adapted from: Fletcher C, Peto R. BMJ 1977; 1: 1645—8.R E S P I N A , J A K A R T A 3 D E S E M B E R 2 0 1 1

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KEY INDICATORS FOR CONSIDERING A DIAGNOSIS OF COPD

Dyspnea that is… • Progressive (worsen over time)y p g ( )

• Usually worse with exercise

• Persistent (present every day)

• Described by patients as: ‘increased effort to breath’, ‘heaviness’, ‘air hunger’ or gasping’

Chronic cough… • May be intermittent and may be g y yunproductive

Chronic sputum production… • Any pattern of chronic sputum production may indicate COPD

History of exposure to risk factors, especially…

• Tobacco smoke

• Occupational dusts and chemicals

k f h k d h• Smoke from home cooking and heating fuels

Rabe KF et al. GOLD 2007. Am J Respir Crit Care Med 2007;176:532-555

KEY INDICATORS FOR CONSIDERING A DIAGNOSIS OF COPD

Dyspnea that is… • Progressive (worsen over time)y p g ( )

• Usually worse with exercise

• Persistent (present every day)

• Described by patients as: ‘increased effort to breath’, ‘heaviness’, ‘air hunger’ or gasping’

Chronic cough… • May be intermittent and may be ‘Spirometry is needed to establish a diagnosis of

COPD’g y y

unproductive

Chronic sputum production… • Any pattern of chronic sputum production may indicate COPD

COPD.’

History of exposure to risk factors, especially…

• Tobacco smoke

• Occupational dusts and chemicals

k f h k d h• Smoke from home cooking and heating fuels

Rabe KF et al. GOLD 2007. Am J Respir Crit Care Med 2007;176:532-555

COPD POPULATION SCREENER™ (COPD-PS)

• Simple, validated questionnaire

• Can help identify people age ≥35 years in the general population who are at risk of COPD

• Identifies COPD symptoms and risks and considers age as a

fscreening factor

• This tool may:Increase awareness of COPD– Increase awareness of COPD

– Help with earlier symptom recognition

– Facilitate case identification– Lead to the use of spirometry for

diagnosisMartinez FJ et al. J COPD 2008;5:85–95.

COPD: IMPACT ON QUALITY OF LIFE

Airflow Decreased ExacerbationsAirflow Limitation

DecreasedExercise Capacity

Quality of Life Burden of M di l C

Insomnia,F i Quality of Life Medical CareFatigue

Dyspnea,Cough

Loss of Independence

Social Isolation,Depression,

CoughIndependenceAnxiety

What can we do ???

CONCLUSION0 5 / 1 2 / 2 0 1 1

1. Cholinergic tone is one of the basic of COPDgpatophysiology

2 Airflow limitation in COPD due to : perinbronchial2. Airflow limitation in COPD due to : perinbronchialfibrosis, alveoli destruction, mucus hypersecretionand smooth muscle airway constriction.

3. Simple, easy-to-use and inexpensive questionnairesand handheld devices are useful for screening (PDPIV i )Version)

4. Diagnose earlier - treat earlierg


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copdwhat has happened to the airway system - dr amira 031211 respina

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