COPD

Objectives

• How important is COPD?• What is COPD?• How to treat COPD?• What is the prognosis?

19.3% of US Adults Smoke – 2010

CDC, NHIS 2010

2010 Current Smokers% of Smokers Demographic % of Smokers Demographic

19.3% US Adults

21.5% Males Education

17.3% Females 45.2% GED diploma

Race 33.8% 9-11 yrs education

31.4% Native American/Alaska 23.8% High school diploma

27.4% Multiple race 9.9% Undergraduate degree

21.0% Caucasian 6.3% Postgraduate degree

20.6% African American Age

12.5% Hispanic 20.1% 18-24

9.2% Asian 22.0% 25-44

Poverty 21.1% 45-64

38.9% Below poverty level 9.5% 65 and older

18.3% At or above povertyCDC, NHIS 2010

Fact Sheet• 49.9 million former smokers/46.6 million current

smokers in 2009• 3rd leading cause of death in US in 2011

– 12.7 Million US adults have COPD– 24 million US adults have impaired lung function

suggesting under diagnosis• Women are more likely to have COPD and die from it

CDC, NHIS 2009, 2011

• 50% of COPD patients have limited ability to work

Prevalence (%) of COPD by State in 2011

CDC, NHIS 2011

Etiology of COPD

• 80-90% due to tobacco use• 15-20% of smokers will have clinical significant

COPD• Occupational exposures• Bacterial/viral exposures• -1 protease inhibitor deficiency

COPD RISK FACTORS

Genes

Exposure to particles

Tobacco smoke

Occupational dusts

Indoor air pollution

Outdoor air pollution

Lung Growth & Development

Oxidative stress

Gender

Age

Respiratory infections

Previous TB

Low SES

Poor Nutrition

Co-morbidities

Overall Mechanisms of Cigarette Smoke-Induced Lung Damage

Oxidative Stress

Cigarette smoke- derived

free radicals and oxidants

Antioxidantgenes

‘Susceptibility’ genes

Inactivation of antiproteases

Lipidperoxidation

Depletion of antioxidant

defenses

Neutrophilsequestration

Transcription of proinflammatory

cytokines

Epithelial permeability

Inflammation

INJURY

MacNee W. Chest. 2000;117:303S-317S.

Role of Bacterial/Viral Infections

Vicious Circle Hypothesis

Sethi S. Chest. 2000;117:286S-291S.

Initiating factors (eg, smoking, childhood respiratory disease)

Impairedmucociliary clearance

Airway epithelial injury

Progression of COPD

Altered elastaseantielastase balance

Bacterial products

Increased elastolytic activity

Inflammatory response

Bacterial colonization

Viral pathogens Associated with COPD Exacerbations

Influ

enza

Parain

fluenza

Rhinoviru

s

Coronaviru

s

Adenovirus

RSV0

10

20

30

40

% E

xace

rbati

ons

Sethi S. Infect Dis Clin Pract. 1998;7:S300-S308.

Chronic Bronchitis Prevalence 2011

CDC, NHIS 2011

Emphysema Prevalence 2011

CDC, NHIS 2011

1st Hospitalization for COPD

CDC, NHIS 2011

Pulmonary Function in COPD

• Spirometry– Decreased FEV1 more than FVC; decreased ratio

– Earliest change is a decrease in FEF25-75%

• Lung Volumes– Increased Total Lung Capacity (TLC)– Increased Residual Volume (RV)– Decreased Vital Capacity (SVC)

• DLCO– May be decreased

Spirometry in COPD

COPD Severity Classification

Severity FEV1/FVC FEV1 % predicted

Mild ≤ 0.7 > 80

Moderate ≤ 0.7 50-79

Severe ≤ 0.7 30-49

Very Severe ≤ 0.7 <30 **

** < 50%predicted plus respiratory failure or clinical signs of right heart failure

Smoking and COPD

Males Females

Former smokers

30 ml/year 22 ml/year

Current smokers

66 ml/year 54 ml/year

Anthonisen NR, et.al. Am J Respir Crit Care Med 166:675-9, 2002.

Decramer Thorax 2010;65:837-841

Disease Progression

Dynamic Hyperinflation

Obstructive Diseases

• Asthma– Reversible airflow obstruction– Inflammation prominent

• Emphysema– Permanent– Destruction of the respiratory

bronchioles

• Chronic Bronchitis– Sputum production 3

months/year for 2 years

Patients Have All Combinations

Chronic Bronchitis

Normal Lung Acinus

Centrilobular Emphysema

Panlobular Emphysema

Centrilobular emphysema in COPD with no bronchial abnormalities

Centrilobular emphysema in COPD with widespread bronchial wall thickening

Centrilobular Emphysema

• Emphysema of smokers and coal workers• Worst in upper lung fields of each lobe of the

lung• Inflammatory changes in small airways are

common

Paraseptal emphysema

• Selective expansion of alveoli adjacent to connective tissue septa and bronchovascular bundles

• Most notable sub pleural• More Common in Young (<40) smokers

Paraseptal Emphysema

Don’t mistake this for honeycombing

Panacinar = Panlobar Emphysema

• Alpha1 antitrypsin deficiency and familial cases

• Generally emphysema of non-smokers• Can co-exist with centrilobular• Most widespread and most severe• More severe at lung bases but distributed

throughout lung

Alpha 1 Antitrypsin

Alpha 1 Antitrypsin

• Lung and liver disease• Lower lung panacinar emphysema with bronchial wall

thickening• Frank bronchietasis with PiZZ phenotype• Bullous formation relative uncommon• Serum protein that inhibits lysosomal proteases during

inflammation preventing the damaging effects of elastases released by macrophages and neutrophils

PiMM Normal a1-levelsPiMZ Decreased a1-levels to 60%

PiZZ Decreased a1-levels to 10-20%

GOLD

• Collaborative project of NHLBI and WHO– Increase awareness of COPD– Decrease morbidity and mortality

Stage Criteria

Stage 0 (at risk) Chronic cough and sputum; Normal PFT

Stage I (mild) FEV1/FVC<70%; FEV1 > 80%; ± Sx

Stage IIA (moderate) FEV1/FVC<70%; FEV1 50-79%; ± Sx

Stage IIB (moderate) FEV1/FVC<70%; FEV1 > 30-49%; ± Sx

Stage III (severe) FEV1/FVC<70%; FEV1 < 30% or presence of respiratory failure or right heart failure

Modified Stepwise Approach to Treatment

MILDFEV1>80%

MODERATEFEv1 50-79%

SEVEREFEV1 30-49%

VERY SEVEREFEV1<30% or failure

Long acting bronchodilators

ICS, if freq. exac (≥ 2/yr.)

Short acting bronchodilators PRN if respiratory symptoms

Smoking cessation; Reduce risk factors; Vaccination

Pulmonary Rehab based on functional status

O2

GoldCOPD.org

Surgery

Available Drugs

LAMA

PDEI

ICSLABA

SAMA

SABA

Beta-2 agonists

Anti-muscarinics

BudesonideFluticasone

Mometasone

SalmeterolFormoterol

ArformoterolOlodaterol

Ipratropium

TiotropiumAclidinium

AlbuterolPirbuterol

Levalbuterol

RoflumilastTheophylline

???

???

Short Acting b-agonists

• All equal efficacy• Studies show HFA and CFC have equal efficacy• Tachycardia decreased with spacer use and

rinsing mouth after use

Importance of Spacer

Barnes et.al 1998 Asthma Basic Mechanisms and Clinical Management

Short Acting Anti-muscarinics

• Decreases secretions• Longer acting than albuterol• Blocks bronchoconstriction from inhaled

irritants• Spiriva

– 4x/day = once a day Spiriva– Competitive inhibitor

Cardiac Risk, Ipratroprium, Tiotropium

• Better tolerated than beta-agonists• Meta-analysis - increased CV deaths in

patients on anti-muscarinics• UPLIFT - 4 yr trial - decreased fatal

cardiovascular event risk with Tiotropium• Clinical trial safety database

Tiotropium – no increased risk

Celli. Am J Respir Crit Care Med. 2009;180(10):948Celli. Chest. 2010;137(1)20

Tiotropium Delays Next

Exacerbation/Hospitalization

Niewoehner, D. E. et. al. Ann Intern Med 2005;143:317-326

GOLD ICS Therapy

• Candidates– Symptomatic patients with spirometric response– Patient with daily sputum production– Patients with variability in symptoms– FEV1 < 50% with frequent exacerbations needing

steroids or Abx• Trial 6 weeks – 3 months

Oral Steroid Therapy

• 10-20% will have significant response to oral steroids– 2 week trial of steroids improves PFTs then

continue ICS• Effective for acute exacerbation• Antibiotics decrease relapse rate

Oral Steroid Therapy

• Conflicting results in stable COPD patients– Significant side effects

• Exacerbations (10-14 day courses)– Decreased treatment failure– Rapid improvement in PFTs and symptom scores– Decreased in hospital stay– Maximum benefit in the first 2 weeks

Thompson WH et al. Am J Respir Crit Care Med. 1996;154:407-412.Davies L et al. Lancet. 1999;354:456-460.

Niewoehner D et al. N Engl J Med. 1999;340:1941-1947.

Antibiotic Use

• Chronic Macrolides– Decreases exacerbations– Increased resistance

• Macrolides/Doxycycline at home for early exacerbation treatment

Theophilline

• Positive effects for COPD– Stimulate respiratory center– Improves muscle function– Anti-inflammatory

• Negative effects for COPD– Increases GERD– Narrow therapeutic window– Significant drug-drug interactions– Significant food interaction (fatty foods)

Roflumilast

• Unknown exact mechanism– Selectively inhibits phosphodiesterase Type 4

leading to increased intracellular cAMP• Decreases exacerbations• Use with caution in liver disease, depression

(suicide)

Is There a Drug To Cure COPD?

• No existing medications will change the inherent decline in lung function related to age/smoking

• Goal of Tx: – Decreased symptoms– Decreased complications

Other Modalities

• Nutrition• Post-nasal drip treatment• Flu vaccine reduces serious illness• Pneumovax: >65 or <65 with FEV1 <40%• Statins?!?

– Slower decline in PFTs, decrease exacerbation rate, decreased death rate

Frost. Chest 2007;131:1006-12Keddissi. Chest 2007; 132:1764-71

Aspiration and GERD - Risks

• Medical risk factors– CVA, Parkinsons, Dementia, medications

• Medication risk factors– Calcium channel blockers, bisphosphonates, iron

supplements, NSAIDS, potassium, anticholinergics, narcotics, nitrates, progesterone, benzodiazepines

Aspiration and GERD

• PPI – before meals• Lifestyle changes

– Elevation of head of bed 4-6 inches– Minimizing caffeine/mint– Avoiding eating/drinking 2-3 hours before bed

Oxygen therapy

• PaO2 < 55 or

• PaO2 = 56-59 with evidence of pulmonary hypertension, polycythemia or cor pulmonale

0 10 20 30 40 50 60 70

0

10

20

30

40

50

60

70

80

90

100

COT

MRCO2

NOT

MRCcontrols

CumulativeSurvival

(%)

Flenley DC. Chest. 1985;87:99-103

Months

Pulmonary Rehabilitation

• Benefit from exercise training programs• Improved health status

– ↑ exercise tolerance & QOL– Return to function – ↓ dyspnea & fatigue – ↓ hospitalization & LOS

• ↓ exacerbations• Improves survival

Lung Surgery

• Bullectomy• Lung Reduction Study - NETT trial

– Increased mortality in patients with DLCO<25% predicted

– Benefit in patients with asymmetric lung disease by HRCT

– 7.9% 90 day mortality vs 1.9% control– 28% had improved exercise capacity at 6

months/15% at 2 years

NETT. NEJM 2003: 348:2059-73.

Lung Transplant

• <=65• Maximal medical therapy• Body weight 80-120% of ideal• Favorable social factors• $

Lung Transplant Contraindications

• Untreatable pulmonary infection• Malignancy within last 2 years• Significant dysfunction of other organs (heart)• Significant chest wall/spine deformity• Active smoking/drug and alcohol dependency• Unresolved psychosocial problems

(noncompliance)• HIV, Hep B, Hep C• Absence of social support

Acute Exacerbation Classification

• Level 1: Treatment at home• Level 2: Hospitalization

• Level 3: ICU/Specialized Care

Clinical Factors Favoring Hospitalization

HR, RR, change in BP Hypoxia/ hypercapnea

Significant comorbidities Elderly

Poor home support Inadequate outpatient response

ER Visit in last 2 weeks

COPD Exacerbation Survival

• 6 month mortality = 24%• 12 month mortality = 33%• Survival associated with albumin, BMI, PaO2,

disease duration

Gunen H, Eur Resp J. 2005; 26:234-241.

Acute Exacerbation Treatment

• Oxygen for low saturations• Bronchodilators

– MDI vs nebulizer• Steroids 14 day max

– IV vs Oral– Improves spirometry, decreases relapse rate– No study on taper

• Education• Antibiotics

Antibiotics and Survival

• Retrospective cohort of 50K COPD pts in Netherlands

• Median time to next exacerbation delayed

• More benefit in worse exacerbations

• Fewer treatment failures with newer Abx

Roede et al. Thorax 2008: 63:968

NIPPV in Acute Exacerbations

• If pH<7.35, if tolerated• Decreases symptoms/

morbidity/ mortality• Avoid in:

– CV instability, – Uncooperative patient, – ΔMS, – Copious secretions, high

aspiration risk, – Facial abnormalities

Relapse Rate 20-40%

• If ER visit : 33% recur within 14 days, 17% eventually need hospitalization

• Risk of Relapse– Low FEV1

– Increasing medication use (BDs or steroids)– Prior exacerbations (3 within last 2 years)– Comorbid conditions

Miravitlles M. Respiration 67:495, 2000.

Heart Rate and COPD Prognosis

Jensen. Eur Respir J, 2013; 42: 341-349.

From Rabe, KF. NEJM 356:851-854.

Prognosis

• Patients hospitalized 6 mth mortality 24%; 33% 1 year; 39% 2 year; 49% 3 year

FEV1 (L) Prognosis (years)

1.4 10

1.0 4

0.5 2

Gunen H, Eur Resp J. 2005; 26:234-241.

Summary

• Prevention is key– Smoking cessation– Prevent exacerbations and infections

• Symptom management– Inhaled drugs may help symptoms

• Combination therapy is better than monotherapy

• Pneumonia risk increased with ICS• Oxygen improves longevity

The REALreason

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