Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

0

0.5

1.0

1.5

2.0

2.5

3.0Proportion of 1965 Rate

1965 - 98

–59% –64% –35% +163% –7%

CoronaryHeart

Disease

Stroke Other CVD COPD All OtherCauses

COPD - PathogenesisTobacco Smoke

Chronic Inflammation*

EmphysemaChronic Bronchitis

*CD8+ T-lymphocytes Macrophages Neutrophils IL-8 and TNF

ProteinasesOxidative Stress

Host factors

Anti-oxidants Anti-proteinases

Repair Mechanisms

COPD Therapy

• Smoking Cessation• Oxygen• Reduce exacerbations• Pulmonary Rehabilitation• LVRS (selected patients)• Lung Transplantation

• MDI Therapy– SA beta-2 agonists– LA beta-2 agonists– SA and LA Anticholinergics

• Theophylline• Corticosteroids (inhaled or

oral)• Combination Preparations

– SABA and anticholinergic – LABA and corticosteroids

Prolong Life Symptomatic

Management of COPD Stage 0: At Risk

Characteristics Recommended Treatment

• Risk factors•Chronic symptoms

- cough- sputum

• No spirometric abnormalities

•Adjust risk factors•Immunizations

Management of COPD Stage I: Mild COPD

Characteristics Recommended Treatment

• FEV1/FVC < 70 %

• FEV1 > 80 % predicted• With or without symptoms

• Short-acting bronchodilator as needed

Management of COPD Stage II: Moderate COPD

Characteristics Recommended Treatment

•FEV1/FVC < 70%

•50% < FEV1< 80% predicted•With or without symptoms

•Treatment with one or more long-acting bronchodilators•Rehabilitation

Management of COPD Stage III: Severe COPD

Characteristics Recommended Treatment

•FEV1/FVC < 70%

•30% < FEV1 < 50% predicted•With or without symptoms

•Treatment with one or more long-acting bronchodilators•Rehabilitation•Inhaled glucocortico-steroids if repeated exacerbations (>3/year)

Management of COPD Stage IV: Very Severe COPD

Characteristics Recommended Treatment•FEV1/FVC < 70%

•FEV1 < 30% predicted or presence of respiratory failure or right heart failure

•Treatment with one or more long-acting bronchodilators•Inhaled glucocorticosteroids if repeated exacerbations (>3/year)•Treatment of complications•Rehabilitation•Long-term oxygen therapy if respiratory failure•Consider surgical options

Bronchodilator Therapy

• Inhaled therapy (with spacer) preferred• Long-acting preparations more convenient• Combined preparations improve effectiveness and

decrease risk of side effects – Ipratroprium-albuterol– Fluticasone-salmeterol– Budesonide-formoterol

• MDI almost always as effective as nebulizers (in equal doses)

Some General Principles

Effectiveness of BronchodilatorTherapy?

• FEV1 does not always correlate with symptoms– Concept of “dynamic hyperinflation” in COPD

• Quality of life issues are important– Chronic fatigue– Depression– Physical immobility– Dyspnea

COPD - Surgical Options• Giant Bullous Disease

– Consider bullectomy if see normal lung compression • Lung Volume Reduction Surgery*

– FEV1 (<20% pred) plus diffuse emphysema or Dlco<20% pred = high risk of surgical death

– Upper lobe emphysema and low exercise capacity = decreased mortality, increased exercise and QOL

• Lung Transplantation– FEV1<25% predicted, younger patient– 3-5 year mortality 55%

*NETT Research Group. N Eng J Med 348:2059, 2003

COPD Exacerbation

• Worsening dyspnea• Increased sputum purulence• Increase in sputum volume

• Severe - all 3 elements• Moderate - 2 elements• Mild - 1 element plus:

• URI in past 5 days• Fever without

apparent cause• Increased wheezing or

cough• Increase (+20%) of

respiratory rate or heart rate

Definition Elements Severity

Modified from Anthonisen et al. Ann Int Med 106:196, 1987

COPD Exacerbation

• 109 pts (mean FEV1 = 1.0 L over 4 years

• Frequent exacerbators:– faster decline in PEFR and

FEV1– more chronic symptoms

(dyspnea, wheeze)– no differences in PaO2 or

PaCO2

Donaldson et al. Thorax 57:847, 2002

Effects on Lung Function Decline

InfrequentFrequent

Conclusion:Frequent exacerbations accelerate decline in lung function

COPD Exacerbation

BacterialInfection

50%

Viral Infection

25%

AirPollution

5%

Unknown20%

Exacerbation

AcuteInflammation

Pathophysiology - Current Hypothesis

Chronic Inflammation

Therapy of COPD Exacerbation

Variable ACCP-ACPACCP-ACP GOLDGOLDDiagnostic CXR for admissions CXR, EKG, ABG,

sputum culture, lytes, cbcBronchodilators Ipratroprium, add B2

agonist. No methylxanthine

B2 agonist, add ipratroprium. Yes methylxanthine

Delivery system None preferred Not discussed

Antibiotics Yes, in selected (severe). Duration unclear

Yes, with purulence, Rx local sensitivities

Guidelines

http:/www.goldcopd.comAnn Int Med 134:595, 2001

Therapy of COPD Exacerbation

Variable ACCP-ACPACCP-ACP GOLDGOLDSteroids Yes, for up to two

weeksYes, oral or IV for 10-14 days

Oxygen Yes Yes - target PaO2 60 torr or Sat of 90% with ABG check

Chest PT No Maybe - for atelectasis or sputum control

Mucokinetics No Not discussed

Guidelines

http:/www.goldcopd.comAnn Int Med 134:595, 2001

Therapy of COPD Exacerbation

Variable ACCP-ACPACCP-ACP GOLDGOLDMechanical Ventilation

Yes - use NIPPV in severe exacerbation

Yes if ≥2 of:Severe dyspnea, access. muscle or paradox, pH <7.35 and PCO2 >45, RR>25

Other LMWH, fluids, diet

Guidelines

http:/www.goldcopd.comAnn Int Med 134:595, 2001

COPD Therapy - New Horizons• Newer anti-inflammatory agents

– Matrix metalloproteinase inhibitors– Specific phosphodiesterase (PDE4) inhibitors

• Cilomilast• Rofumilast• Piklanilast

• Anabolic steroids• Repair agents

– Retinoic acid• Long-acting anti-muscarinic agents

– tiotropium

Tiotropium

• 470 patients - stable COPD• 3 month, randomized, double

blind, once daily tiotropium vs. placebo

Conclusions:

Increased FEV1 and FVCNo tachyphylaxis Decreased rescue albuterolDecreased wheezing, SOBDry mouth in 9.3%Casaburi et al. CHEST 118:1294, 2000

Specific M1 and M3 Muscarinic Blockade

TiatropriumSpecific M1 and M3 Muscarinic Blockade

• 1207 patients, double blind, randomized trial,

• qd tiotropium vs. bid salmeterol vs. placebo

Conclusions: TiotropiumFewer exacerbationsIncreased time to first exacerbationFewer admissionsIncreased QOL

Brusasco et al. Thorax 58:399:2003

Lung Volumes in Obstructive DiseaseLung Volumes in Obstructive Disease

NormalNormal COPDCOPD

RVRV

RVRV

TLCTLC

FRCFRC

Room toRoom toBreatheBreathe

Room toRoom toBreatheBreathe

TLCTLC

FRCFRC

Volu

me

Volu

me