Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם

Chronic Obstructive Pulmonary Disease

(COPD)

פרופ' רפאל ברויארמכון הריאה

ביה"ח האוניברסיטאי הדסה עין-כרם

Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD)

Asthma Bronchiectasis Cystic fibrosis Bronchiolitis obliterans Alpha-1-antitrypsin deficiency




Relative Mortality, Leading Causes of Death in the US, 1980-2010

Proportion of 1980 Rate

U.S. Centers for Disease Control (CDC)

1 Heart disease 595,4442 Cancer 573,855

3 Chronic lower respiratory disease (COPD) 137,7894 Cerebrovascular disease (stroke) 129,1805 Accidents 118,0436 Alzheimer’s Disease 83,3087 Diabetes 68,9058 Nephritis, nephrotic syndrome, nephrosis 50,4729 Influenza & pneumonia 50,00310 Suicide 37,79311 Septicemia 34,84312 Chronic liver disease & cirrhosis 31,80213 Essential hypertension & hypertensive renal disease 26,57714 Parkinson’s disease 21,963

Pneumonitis due to solids & liquids 17,001

Leading Causes of Death in the US, 2010

U.S. CDC, 2012

COPD Clinical presentation Pathophysiology Management strategy Treatment

COPD אבחנה של

Airflow obstruction that is irreversible

FEV1 / FVC < 70%

Chronic Obstructive Pulmonary Disease (COPD)

:גורמי סיכון

- אקטיבי ופסיבי עישון–

זיהום אוויר –חשיפות תעסוקתיות לאבק/עשן–).alpha-1-antitrypsin(חסר ב גורמים גנטיים –

COPDועישון

– עישון הוא הגורם העיקרי

אם אין עישון – יש לחשוב על אבחנה אחרת!

בכלל האוכלוסיה – ככל שאדם עישן יותר יורד.FEV1"שנות קופסא" –

.(שנות קופסה) ”גם הסיכון למחלה תלוי ב”מינון

COPDרמזים מרכזיים לאבחנה של

:מאפיינים מרכזיים50גיל > –קוצר נשימה (דיספניאה) – –

פרוגרסיבי / קבוע.שיעול פרודוקטיבי כרוני.–חשיפה לגורמי סיכון – בעיקר עישון–

COPD: Traditional Classification

Emphysema Phenotype The Pink Puffer

Chronic Bronchitis Phenotype The Blue Bloater

Irreversible airflow obstruction

COPD—Emphysema PhenotypeThe Pink Puffer

COPD – Emphysema Phenotype

“An anatomical alteration of the lung characterized by an abnormal enlargement of the air spaces distal to the nonrespiratory bronchioles, accompanied by destructive changes of the alveolar walls."

Emphysema PathologyBullous Emphysema Centriacinar Emphysema

Emphysema Pathology

Normal lung Emphysematous lung

COPD – Emphysema PhenotypeClinical Features

:סמפטומים–Dyspnea.קוצר נשימה פרוגרסיבישיעול לא בולט.–מיעוט (יחסי) בזיהומים ריאתיים.–

:בדיקה גופנית).astheniaרזים, חולשת שרירים (–חזה חביתי, טכיפניאה.–ללא כיחלון בולט ("ורודים").–ירידה דיפוזית בקולות הנשימה, אקספיריום מוארך.–סרעפות נמוכות.–קולות לב מרוחקים.–

:ציר ימני, קומפלקסים קטנים.אק"ג

:תמונה חסימתית אקספירטורית–FEV1 ,מופחת FEV1 / FVC .מופחת

למרבית החולים אין שיפור משמעותי עם מרחיבי –סימפונות.

:היפראינפלציה ולכידת אוויר–TLC, RV-ו TLC / RV.מוגברים

:ירידה ביכולת הדיפוזיה של חמצן– DLCO.מופחת

תקין.Pco2היפוקסמיה קלה עם –

COPD – Emphysema Phenotypeתפקודי ריאה

Effect of Emphysema on Diffusion Capacity

Emphysema- CXR היפראינפלציה, חדירות יתר

סרעפות שטוחות מרווח רטרוסטרנלי גדול

Emphysema- HRCT

Normal Emphysema

COPD—Chronic Bronchitis PhenotypeThe Blue Bloater

COPD – Chronic Bronchitis Phenotype

" A clinical disorder characterized by excessive mucus secretion... chronic or recurrent productive cough... on most days for a minimum of three months in the year for not less than two successive years."

סמפטומים:שיעול יצרני כרוני, שפע ליחה "מוגלתית"–זיהומים ריאתיים והתלקחויות תכופות.–קוצר נשימה (מתגבר בהתלקחויות).–

:בדיקה גופניתעודף משקל.–נטיה לכיחלון.–אקספיריום מוארך עם צפצופים.–סימנים של אי-ספיקת לב ימנית –

)Cor Pulmonale.(

COPD - Chronic Bronchitis PhenotypeClinical Features

:תמונה חסימתית אקספירטורית–FEV1 ,מופחת FEV1 / FVC מופחת

ללא שיפור משמעותי עם מרחיבי סימפונות–) נפחי הריאה ויכולת דיפוזיהDLCO – (תקינים

COPD - Chronic Bronchitis Phenotype תפקודי ריאה

Chronic Bronchitis with Cor Pulmonale—CXR

משמעותיים בריאות ללא ממצאיםעצמן

לב מוגדל

כלי דם ריאתיים מודגשים

Cor Pulmonale Phenotype in COPD

COPD - Cor Pulmonale Phenotype

:שכיחות יותר שלהיפוקסמיה קשה

היפרקפניאה חמצת נשימתית כרונית.

Normal

Chronic Bronchitis

Emphysema

COPD

Clinical presentation Pathophysiology Management strategy Treatment

Airway Obstruction Pathophysiology

Destruction of peribronchial supporting tissue

Plugging, inflammation & narrowing of airways

Findings in Human BAL Studies

Smokers’ BAL contain 4-5 times more neutrophils than non-smokers

Neutrophils in BAL fluid are the main source of elastase

Cigarette smoke and neutrophils suppress anti-elastase activity

Conclusion: Quantity and activity of elastase is increased in smokers

alpha-1-antitrypsinElastase

Anti-Elastase

COPD - PathophysiologyHYPOTHESIS

COPD - Pathophysiology

Barnes, Nat Rev 2008


Relieve symptoms Improve exercise tolerance Improve health status

AND Prevent disease progression Prevent & treat exacerbations Reduce mortality

REDUCE SYMPTOMS

REDUCE RISK

COPD Management Philosophy

COPD Management

To determine disease severity & guide therapy, assess: – Symptoms – Severity of airflow limitation – Risk of exacerbation– Presence of comorbidities

Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

COPD Management

To determine disease severity & guide therapy, assess: – Symptoms: clinical assessment, mMRC or CAT– Severity of airflow limitation– Risk of exacerbation– Presence of comorbidities


COPD Assessment Tool—CATScore > 10 considered symptomatic

Symptom Assessment

COPD Management

To determine disease severity & guide therapy, assess: – Symptoms (clinical assessment, mMRC or CAT)– Severity of airflow limitation (GOLD I-IV)– Risk of exacerbation– Presence of comorbidities


Grading COPD Severity

STAGE CHARACTERISTICS(Post Bronchodilator FEV1)

FEV1 / FVC < 70%

I Mild FEV1 ≥ 80% predicted

II Moderate 50% ≤ FEV1 ≤ 80% predicted

III Severe 30% ≤ FEV1 ≤ 50% predicted

IV Very Severe FEV1 ≤ 30% predicted

COPD Management

To determine disease severity & guide therapy, assess: – Symptoms (clinical assessment, mMRC or CAT)– Severity of airflow limitation (GOLD I-IV)– Risk of exacerbation (frequency/year)– Presence of comorbidities


Definition of COPD Exacerbation

Symptoms worsening beyond daily variations

– Cough / sputum / dyspnea

Leads to change in medications

Cause:– Viral infection– Bacterial infection– Pollutants

Diagnosis based on clinical presentation

Exacerbations—Critical Events in the Natural History of COPD

Poor quality of life

Accelerated loss of lung function

Exacerbations increased risk future exacerbations

Increased risk of hospitalization

All-cause 3-year mortality after hospitalization up to

49% (GOLD 2011)

Prospective study, cohort 304 males, exacerbations requiring hospitalization, 5-year follow-up

Soler-Cataluῆa, Thorax 2005

Frequency of COPD Exacerbation & SurvivalP

roba

bili

ty o

f sur

viva

l

Time (months)

Hurst et al, ECLIPSE, NEJM 2010

Frequent Exacerbator Phenotype

Hurst et al, ECLIPSE, NEJM 2010

Pats with no exacerbation

Pats with ≥2 exacerbations

Year 1 Year 2 Year 3

Treatment of COPD Exacerbations

Treat early aggressively to minimize duration, prevent recurrence

Short-acting inhaled bronchodilators (Ventalin, +/- Aerovent, as needed)

Systemic corticosteroids Antibiotics

Noninvasive ventilation

7 days

COPD: Antibiotic treatment Pathogens:

– Streptococcus pneumonia– Haemophilus influenza– Moraxella catarrhalis

Antibiotics:– Cefuroxime, beta-lactam, macrolides,

doxycycline

Impact of COPD Exacerbations

Acceleratedlung function

decline

Impact on symptoms&

quality of life

Increased mortality

Exacerbations

Increased economic

costs

Treat early aggressively to minimize duration, prevent recurrence

COPD Management

To determine disease severity & guide therapy,

assess: – Symptoms (clinical assessment, mMRC or CAT)– Severity of airflow limitation (GOLD I-IV)– Risk of exacerbation (frequency / year)– Presence of comorbidities


Systemic Manifestations & Comorbidities

Cardiovascular disease – Pulmonary hypertension– Ischemic heart disease – Congestive heart failure– Stroke

Lung cancer Diabetes, metabolic syn Osteoporosis Skeletal muscle

dysfunction Depression

COPD—Independent Risk Factor for Cardiovascular Morbidity

Pe

rce

nt w

ith C

on

diti

on

16.5

15

10.211

9.8

7

3 2.6

12.6

10.29.5

2.93.6

1.6 0.4 10

2

4

6

8

10

12

14

16

18

Hypertension IHD Diabetes Pneumonia CHF RF PVD TM

Pe

rce

nt o

f Su

bje

cts

COPD

No COPD

Higher Rates of Hospitalization Due To Comorbidities

Reproduced with permission of Chest, from “Comorbidity and Mortality in COPD Related Hospitalizations in the United States, 1979 to 2001,” Holguin F et al, Vol 128, pp 2005-2011, Copyright © 2005.

Higher Mortality Rates Due to Cormorbidities

37

25

22.5

19

1312

11

5

22

14

1012

8.56.5

10

3

0

5

10

15

20

25

30

35

40

RF Pneumonia Heart Failure IHD Hypertension TM Diabetes PVD

In H

osp

ital M

ort

alit

y (a

s %

of d

isch

arg

es)

COPD

No COPD

IHD = ischemic heart diseaseCHF = congestive heart failureRF = respiratory failurePVD = pulmonary vascular diseaseTM = thoracic malignancy

Holguin et al Chest 2005

Comorbidity in COPD

Traditional View Airflow obstruction & emphysema affect

gas exchange systemic implications

Current Debate Is airways compromise the central

disease process? OR

Is it one manifestation of a “systemic” inflammatory state with multiple organ compromise?


Risk

of E

xace

rbati

on≥2

1

0

Frequency of Exacerbations

COPD Risk Assessment

C D

A B

Increasing Symptoms (mMRC or CAT score)

mMRC 0-1CAT < 10

mMRC > 2CAT > 10

GOLD IV

GOLD III

GOLD II

GOLD I

Severity of Obstruction


COPD Treatment

Smoking Cessation

Short-Term↓ cough, sputum↑ lung function

Long-Term↑ survival↑ QOL↓ lung function↓cormorbidities

COPD Risk and Smoking Cessation

Fletcher CM, Peto R. BMJ. 1977;1:1645-1648

FE

V1

(% o

f va

lue

at a

ge

25)

Smoked regularly and

susceptible to effects of smoke

Never smoked or not susceptible to smoke

Stopped smoking at 45 (mild COPD)

Stopped smoking at 65 (severe COPD)

Disability

Death

25

50

75

100

0

Age (years)25 50 75

COPD Treatment

Influenza, Pneumococcal Immunization

Short-Term Long-Term↓ exacerbation

frequency

Short-Term Long-TermBronchodilators: Long-acting Beta2 Agonist or Anti Cholinergic

↓ airflow obstruction↓ hyperinflation↑ exercise endurance↑ tremors, dry mouth

↑ Quality of life↓ exacerbations

Combination: Inhaled Corticosteroid & Long-acting Beta2 Agonist

↓ airflow obstruction↓ hyperinflation↓ dyspnea↑ exercise tolerance

↑ Quality of life↑ possibly survival↓ exacerbations↑ risk of pneumonia

COPD Treatment

Symptom- and Risk-Based Treatment Paradigm

FEW SYMPTOMS, HIGH RISK OF EXACERBATIONS

1: Combination inhaled corticosteroid/long-acting beta2 agonist or long-acting anticholinergic

2: Combination 2 long-acting bronchodilators or combination inhaled corticosteroid / long-acting anticholinergic

MANY SYMPTOMS, HIGH RISK OF EXACERBATIONS

1: Combination inhaled corticosteroid/long-acting beta2 agonist or long-acting anticholinergic

2: Combination inhaled corticosteroid/long-acting beta2 agonist, long-acting anticholinergic

3: May add phosphodiesterase-4 inhibitor or short-acting bronchodilator and theophylline or carbocysteine

FEW SYMPTOMS, LOW RISK OF EXACERBATIONS

1: Short-acting bronchodilator

2: Combination of short-acting bronchodilators / introduce long-acting bronchodilator

MORE SYMPTOMS, LOW RISK OF EXACERBATIONS

1: Long-acting bronchodilators recommended

2: Combination of long-acting bronchodilators in patients with severe breathlessness

A B

C D

INCR

EASI

NG

AIR

WAY

S O

BSTR

UCT

ION

INCR

EASI

NG

EXA

CERB

ATIO

NS

INCREASING SYMPTOMS Global Initiative for COPD (GOLD) 2011

COPD Treatment

Short-Term Long-TermOxygen Therapy ↑ exercise endurance ↑ survival

Oxygen Therapy Improves Survival

"The more hours, the better!"

Lancet 2003 362:1053-1061

Indications for Oxygen Therapy

PaO2 <55 mm Hg or SaO2 ≤88%

Milder hypoxemia - – In the presence of cor pulmonale or hematocrit >55%

Normoxemic at rest but desaturation during exercise or sleep

Oxygen Therapy

Aim: PaO2 60-70mm Hg or SatO2 >88% Nasal masks 1-2L/min Venturi masks 24%, 28%, 35% Monitor SatO2, PaCO2 and pH If hypoxemia persists or CO2 retention worsens:

optimize bronchodilators, consider using assisted noninvasive ventilation

Noninvasive Ventilation If hypoxemia persists or CO2 retention

worsens: – Optimize bronchodilators and consider using assisted

noninvasive ventilation

COPD Treatment

Short-Term Long-TermPulmonary Rehabilitation

↓ dynamic hyperinflation↓ functional dyspnea↑ exercise endurance

↑ QOL↑ possibly survival

Pulmonary Rehabilitation

Goals: Reduce symptoms, improve quality of life, and increase participation in daily activities

Program includes:– Exercise training (tolerance and muscle strength)– Nutrition counseling– Education

Pulmonary Rehabilitation

Components:– Exercise training

(bicycle ergometry/treadmill & upper limb exercises)– Education– Nutrition counseling– Smoking cessation

8-12 week duration Beneficial in a wide range of disability

Improves exercise capacity Improves recovery from exacerbation Improves QOL Reduces perceived intensity of breathlessness Reduces hospitalizations, days in hospital Reduces anxiety & depression Benefits beyond immediate training period May improve survival

Benefits of Pulmonary Rehabilitation in COPD

Acute reversibility of airways obstruction in response to bronchodilator is a poor predictor of benefit to FEV1 after 1 year

SF BUILD THIS SLIDE UP

Exercise Tolerance & Survival in COPD 365 patients, 2 centers, 1994-

2005 Smoking history >10 years FEV1/FVC < 0.70 171 deaths (47%, 43±24 mo),

respiratory failure (majority), cardiovascular disease (9%), lung cancer (18%), other causes (23%)

Nonsurvivors older, more severe airflow limitation, lower mean exercise capacity

6MWD best predictor of all-cause mortality

Cote & Celli et al, Chest 2007

Exercise tolerance predicts survival in COPD

Cote & Celli et al, Chest 2007

Exercise Capacity & Survival in COPD

F/U (months)

Surv

ival

pro

babi

lity

1.00.80.60.40.20

0 12 24 36 48 60 72 84 96

>350 m

<350 m

COPD Phenotypes Emphysema-hyperinflation Dyspnea, exercise intolerance,

hyperinflation Chronic bronchitis Cough & sputum 3 mos/yr, 2 yr Frequent exacerbator ≥ 2 exacerbations / year Cor pulmonale

COPD w bronchiectasis HRCT diagnosis, airways colonization? Mixed asthma-COPD Increased reversibility of obstruction COPD-eosinophilia Comorbidities & systemic inflammation ↑ biomarkers

(C-reactive protein, serum alymoid A, IL-6, IL-8, tumor necrosis factor α, leukocytes)

α1 antitrypson

Phenotype-Specific COPD TreatmentTreatment Phenotype BenefitRoflumilast Frequent exacerbator

(≥ 2 / yr)↓ exacerbations↑ quality of life↑ lung function

Azithromycin Frequent exacerbator (≥ 2 / yr)

↓ exacerbations↑ QOL

Chronic antibiotic COPD with bronchiectasis

↓ exacerbations↓ eradicate colonizing

microorganisms↓ chronic inflammation

Inhaled corticosteroids

COPD-eosinophilia and Mixed asthma-COPD

↑ lung function

COPD Treatment

Treatment Phenotype BenefitLung Volume Reduction Surgery / Bronchoscopy

Predominantly upper lobe emphysema

↑ exercise capacity

Lung Transplantation

With failure of medical treatment, select patients

↓ exacerbations↑ quality of life↑ lung function

COPD – Conclusions COPD: underdiagnosed; high & rising mortality

Dyspnea, chronic cough, +/- sputum, risk factors consider COPD

Diagnosis by spirometry: FEV1 / FVC < 70%

Treatment of stable COPD: consider symptoms, severity of obstruction, frequency of exacerbations

Manage exacerbations: bronchodilators, corticosteroids, +/- antibiotics

High rates of comorbidities

Rehabilitation: a standard of care to break the cycle of dyspnea, fear, anxiety, increasing inactivity

A heterogeneous disease: the future is phenotype-specific treatment

COPD – Conclusions




Emphysema

AsthmaBronchitis

Other

Airways Obstruction

Differential Diagnosis: COPD and Asthma

COPD Onset in mid-life

Symptoms slowly progressive

Long smoking history

Dyspnea during exercise

Largely irreversible airflow limitation

ASTHMA Onset early in life (often

childhood)

Symptoms vary from day to day

Symptoms at night/early morning

Allergy, rhinitis, and/or eczema also present

Family history of asthma

Largely reversible airflow limitation

COPD – Differential DiagnosisHistory

Asthma EmphysemaChronic Bronchitis

+/- + + Smoking

Common (usually

nocturnal)

May be absent

Main complaint

Productive Cough

EpisodicMain

complaintMay be absent

Dyspnea

++ - ++ Exacerbations

Common - - Allergy

COPD - Differential DiagnosisPhysical Examination

Asthma EmphysemaChronic

Bronchitis

Rare + +/- Barrel Chest

+ + +Prolonged Expiration

In severe exacerbation Typical In severe

exacerbation

Decreased BreathingSounds

-/+/++ Rare +/- Wheezing

In severe exacerbation +/- ++ Cyanosis

- In advanced disease - Weight Loss

COPD - Differential DiagnosisPFT

Asthma Emphysema

Chronic Bronchitis

Pulmonary Function Component

Normal/ FEV1

/No change

/No changeFEV1 after

Bronchodilator

Normal/ Normal/ Residual Volume (RV)

Normal Normal Total Lung Capacity (TLC)

Normal NormalDiffusion Capacity

(DLCO)

COPD - Differential DiagnosisComplications

Asthma EmphysemaChronic

Bronchitis

During exacerbation

Common Common Hypoxemia

RareIn advanced

diseaseCommon Erythrocytosis

In severe exacerbation

End-stage disease

Common Hypercarbia

RareIn advanced

diseaseCommon Cor-pulmonale




Bronchiectasis - Definition

מצב בו דלקות וזיהומים גורמים נזק לדרכיהאוויר, כך שאלו הופכים למעוותים

ריר מצטבר בדרכי האוויר וקיים קושילסלקו בשל פגיעה במנגנוני סילוק

ההפרשות של דרכי האווירהתוצאה – זיהומים חוזרים וקשים

Bronchiectasis - Pathology

Bronchiectasis - Etiology

Recurrent bronchial infections – Airway obstruction (localized) caused by foreign

body, benign tumor – Post-infectious (measles, pertussis, S. aureus, TB)

Immune deficiency- hypoglobulinemia, leukocyte dysfunction

Cystic fibrosis Ciliary dyskinesia (Kartagener's syndrome) Allergic bronchopulmonary aspergillosis

Bronchiectasis - Clinical Features

Chronic productive cough Coarse crackles, clubbing Hemoptysis Obstructive lung disease Respiratory failure

Bronchiectasis - Diagnosis

Chest x-ray Bronchography High-resolution CT

BronchiectasisChest x-ray

Bronchiectasis

Bronchography

Bronchiectasis

High-resolution CT

Bronchiectasis - Treatment

Antibiotics (p. aeruginosa, s. aureus) Vaccinations Physiotherapy Bronchodilators Surgery for localized disease







Bronchiolitis Obliterans - Definition

תהליך הצטלקות כרוני של דרכי האווירהקטנות של הריאה.

בעקבות כך - הרס פרוגרסיבי של דרכי אוויראלו המביאה להתפתחות מחלת ריאות

חסימתית. .מדובר בהתהליך בלתי הפיך בעיקרו

Bronchiolitis Obliterans - Etiology

Inhalation of toxic fumes (smoke) Connective tissue disease (RA) Post BMT, lung & heart-lung transplant Drugs (eg., gold, penicillamine) Consequent to respiratory infections

(adenovirus, mycoplasma) Cryptogenic

Cryptogenic Bronchiolitis ObliteransClinical Features

Onset: months to years Dyspnea and cough with minimal

sputum production Normal breathing sounds, occasionally

rhonchi CXR= normal or hyperinflation, CT= mosaic attenuation, ground-glass

pattern

Bronchiolitis ObliteransInspiratory & Expiratory HRCT

מוזאיקה (אוויר כלוא) זכוכית חול



Asthma Bronchiectasis Cystic fibrosis Bronchiolitis obliterans Alpha-1-antitrypsin

deficiency

Alpha-1-Antitrypsin Deficiency

5% מחולי אמפיזמה-35%רמות האנזים בחולים קטנות מ הגנוטיפ התקין מכונהPiMM והפגום

PiZZ :הביטויים הקליניים

אמפיזמה–שחמת והפטומה.–

) טיפול – תחליף האנזיםZymera (

Documents

Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם