Update Of Common Pulmonary Conditions

Moises R Cossio DO. FCCP., FACP.

Carilion Clinic - Pulmonary Critical Care Division

September 24 , 2011

Objectives• Review the definition of COPD, asthma, Idiopathic pulmonary fibrosis (IPF), and

pulmonary arterial hypertension (PAH).

• Explore the impact of COPD, Asthma, IPF, PAH, including rates of morbidity and mortality

• Review the risk factors for COPD, asthma, IPF, PAH

• Explore the natural history of COPD, Asthma, IPF, PAH from its earlier asymptomatic stages to the late stages associated with morbidity and mortality

• Explore the current understanding of the pathophysiology of these diseases : the pathologic consequences of airway inflammation and parenchymal lung destruction.

• Explore the systemic consequences of the disease and the comorbidities associated with these diseases

• Review the current state of pharmacologic and no pharmacologic therapy for these diseases, including preventive measures

Cumulative Exposure to Noxious Particles isthe Key Risk Factor for COPD

1. Maninno. MMWR 2002;51(SS-6):1-16.2. published analysis of NHANES (National Health and Nutrition Examination) III data Survey GSK, June 2001.3. Confronting COPD in America Survey. Available at URL: www.copdinamerica.com. Accessed January 21, 2004.4. NIH/NHLBI. Morbidity and Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood Diseases. May 2004:17.

Impact of COPD in the U.S.• Affected an estimated 23.6 million (13.9% of

the adult population) Americans in 20011,2

– 10.5 million diagnosed1,

– 48% increase in the number of patients with COPD between 1980 and 20001

– 39% not currently treated with prescription medicine3

• Estimated annual cost in 2004: $37.2 billion4

– $20.9 billion in direct healthcare costs– $16.3 billion in indirect healthcare costs

Prevalence of COPD in the US

*Age-adjusted to 2000 US population.†Represents a statistically significant difference from rate among males.

Mannino et al. MMWR. 2002;51(SS-6):1-16.

Rat

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000

Po

pu

lati

on

*

0

20

30

40

50

60

70

80

90

1980 1982 1984 1986

Year

MaleFemaleTotal10

1988 1990 1992 1994 1996 1998 2000

• Since 1987, the prevalence of COPD among women has been significantly higher than that among men

† †† †

†

†

††

††

††

†

†

†

NIH/NHLBI. Morbidity and Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood Diseases. May 2004:58-59.

Impact of COPD in the U.S.

COPD was responsible for an estimated:

• 13.8 million physician office visits*

• 673,000 hospitalizations†

• 118,000 deaths*

*2001 data

†2002 data

NIH/NHLBI. Morbidity and Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood Diseases. May 2004:10.

Leading Causes of Deaths: U.S. 2002

· Heart Disease 695,794· Cancer 558,847· Cerebrovascular disease (stroke) 163,010· COPD and allied conditions* 125,550· Accidents 102,303· Diabetes 73,119· Influenza and pneumonia 65,984· Alzheimer’s disease 58,785· Nephritis 41,018· Septicemia 33,881· All other causes of death 529,661

*Chronic lower respiratory diseases

Cause of Death Number

Increase in COPD Mortality: 1990-2000

-50

-40

-30

-20

-10

0

10

20

30

40

50

Pe

rce

nt

Ch

an

ge

HIV

CAD

Stroke Cancer

COPD

Percent Change in Age-Adjusted Death Rates in the US Over 10 Years (1990-2000)

–48.0%

–19.9%

–6.9%

25.5%

–6.9%

Mannino et al. MMWR. 2002;51(SS-6):1-16.Pastor et al. Chartbook on Trends in the Health of Americans. Health, United States, 2002. Hyattsville, Md: National Center for Health Statistics. 2002. DHHS publication 1232-1.

Facts About COPD Worldwide• In 2000, there were an estimated 2.5

million deaths worldwide from COPD1

• In 1990, COPD was ranked 12th as a burden of disease; by 2020 it is projected to rank 5th2

• It is estimated that by 2020 COPD will be the third leading cause of death in the world3

1. WHO, Number of Registered Deaths, WHO Mortality Database, 25 Feb 2003.2. NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease (“GOLD”). April 2001. NIH Publication Number 2701. Updated 2004, available at URL: www.goldcopd.com.3. Murray, et al. Lancet 1997;349:1498-1504.

Asthma Incidence In The US 2001-2009MMWR

Asthma - Age-Adjusted Death Rates Based on the 1940 and 2000 Standard populations, 1979-2007

Emphysema

• Abnormal permanent enlargement of the air spaces distal to the terminal bronchioles accompanied by destruction of their walls and without obvious fibrosis*

Walls of individual sacs torn (repair not possible)

Inelastic collapsible bronchioles

Enlarged air sacs due to destruction of alveolar

walls (bullae)

Destruction of the alveolar wall damages pulmonary capillaries by tearing, fibrosis,

or thrombosis

*American Thoracic Society. Am J Respir Crit Care Med 1995;152:S77-S121.

Structural Changes* in COPD

• Epithelial changes– Ciliary dysfunction– Increase in mucus-secreting

cells• Fibrosis of the small airways• Destruction of alveolar walls

– Reduction in area for gas exchange

– Loss of elastic recoil (emphysema)

• Vascular changes may lead to pulmonary hypertension

Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: NHLBI; NIH;

March 2001. NIH publication 2701A.

* No medication has been shown to reverse the structural changes associated with COPD.

AbnormalNormal

Gross Appearance of Human Lung

Normal Asthma Emphysema

Question 1. Which of the following tests bestdistinguish asthma from COPD?

• a) Bronchial inhalation challenge with methacholine

• b) An FEV1 response to a short acting beta agonist of > 12% improvement (and > 200 cc increase)

• c) Measurements of lung volumes (TLC, FRC, RV)

• d) Sputum eosinophil count

Choose the best answer

Correlation of CD8+ T-Lymphocyte Infiltration and Airflow Limitation in Smokers

CD

8+ (

cells

/mm

2 )

FEV1 (% predicted)

1000

00 11050 70 90

400

200

800

600

60 80 100

P = 0.01r = -0.63

Saetta et al. Am J Respir Crit Care Med. 1998;157:822-826.

Peripheral airways were evaluated from surgical specimens from smokers with normal lung function and from patients with COPD.

Differentiating COPD and Asthma

• Approximately 40% of patients diagnosed with COPD also had an asthma diagnosis, based on an analysis of ICD-9 electronic claims data over a 2-year period1

• Some patients with chronic asthma cannot be distinguished from those with COPD with current diagnostic tests2

• Management of these patients should be similar to that of patients with asthma2

1. Surveillance Data, Inc. (SDI). COPD/Asthma Diagnoses Overview; 2001-2003. March 2004. 2. Celli et al. Eur Respir J. 2004;23:932-946.

Distinguishing Asthma and COPD

• Both may lead to fixed airflow obstruction but most show reversibility to short-acting bronchodilators

• Differences in lung function tests (diffusing capacity, residual volume, PaO2) statistically significant but there is

large overlap

• COPD has higher emphysema score on HRCT

• Exhaled NO higher in asthmatics but there is overlap

• Asthmatics have significantly more eosinophils in the peripheral blood, sputum and BAL

Nearly 2/3 of patients with severe COPD (mean FEV1 39.3% pred)respond to bronchodilators* (15% or 12% & 200 ml increase in FEV1)

* Ipratropium and albuterolTashkin DP, et al. Eur Respir J.2008;31:742-750.

COPD and ASTHMA: Different Diseases

Airway Remodeling Fixed Airway Obstruction In Asthma

Impact Of Smoking

Fletcher C and Peto R. BMJ. 1977;1:1645-1648.

severe

Facts About Tobacco Use and COPD• Cigarette smoking is the primary cause

of COPD1

• In the U.S. in 2000, 46.5 million adults (23.3%) were current smokers -- 25.7% of men and 21.0% of women2

• At least one-third of the global adult population, or 1.1 billion people, use tobacco3

1. NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease (“GOLD”). April 2001. NIH Publication Number 2701. Updated 2004, available at URL: www.goldcopd.com.2. MMWR 2002;51(29):642.3. WHO Fact Sheet No. 222, April 1999.

Alpha1 –Antitrypsin Deficiency• Patients with emphysema: 1%-2%

• Common variants: S and Z - Point mutations in alpha1-antitrypsin gene

• S-variant (264GluVal) in 28% of Southern Europeans – Alpha1-antitrypsin levels = 60%

• no pulmonary effects

• Z-variant (342Glu Lys) is associated with severe deficiency – Levels ≈ 10% of normal – Accumulation of alpha1-antitrypsin in the rough endoplasmic

reticulum of the liver – Predisposed to juvenile hepatitis, cirrhosis, and hepatocellular

carcinoma

Mahadeva R and Lomas DA. Thorax. 1998;53:501-505.

Clinical Features Of COPD

• Typical smokers—mean 20 cigarettes/day for 20 years

• Usually present in fifth decade of life with productive cough or acute chest illness

• Dyspnea with exertion• History of wheezing and dyspnea may lead

to an erroneous diagnosis of asthma

American Thoracic Society. Am J Respir Crit Care Med 1995;152:S77-S121.

Celli BR, et al. Eur Respir J 2004;23:932-946.

American Thoracic Society Statement: 2004

“Some patients with asthma cannot be

distinguished from COPD with the current

diagnostic tests. The management of these

patients should be similar to that of asthma.”

Sleep-disordered breathing and COPD:The overlap syndrome

The overlap syndrome

Atopic Asthma (extrinsic)

Genetic susceptibility for developing Immunoglobulin IgE directed to epitopes expressed on common environmental allergens such as dust mites, animal proteins, pollens and fungi.

Ag enters mucosa, exposes to Langerhan’s cells, APC’s, then presented to ThO cells (naïve CD4), differentiated into TH2 cells, different from TH1-associated with delayed hypersensitivity reaction

IL4 enhances synthesis of IgE Ig from plasma cells, IgE then becomes fixed to mast cells, basophils, and dendritic cells , this sets the stage for acute allergic response with the inhalation of more antigen. The reaction is manifested as acute bronchospasm and delayed inflammatory response.

Nonatopic Asthma

Older patients

Generally have negative hypersensitivity reaction to skin prick-tests

More intense inflamatory cell infiltrate with CD3, CD4, leukocytes and macrophages

Natural History of Asthma

Peak prevalence is in childhood and is about 10% of the population

Declines to 5-6% in adolescence, and remissions are quiet high in early adulthood.

The prevalence rises again during late adulthood to 7-9%.

Recent statistics show that early childhood asthma remits by early adulthood in only 30-50%.

Chest X-rays Of A Patient With Advanced Emphysema

Flattened diaphragm

Enlarged retrosternal air space

Posteroanterior Lateral

Flattened diaphragm

Centrilobular Emphysema

Emphysema CT-Scan

Stage Characteristics0: At risk Normal spirometry

Chronic symptoms (cough, sputum) 

I: Mild FEV1/FVC < 70%; FEV1 > 80% predicted With or without chronic symptoms (cough, sputum)

II: Moderate FEV1/FVC < 70%; 50% < FEV1 < 80% predicted With or without chronic symptoms (cough, sputum,

dyspnea)

III: Severe FEV1/FVC < 70%; 30% < FEV1 < 50% predicted With or without chronic symptoms (cough, sputum,

dyspnea)

IV: Very Severe FEV1/FVC < 70%

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Classification by Severity

NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease (“GOLD”). Updated 2004, available at URL: www.goldcopd.com

COPD Exacerbations: Impact Survival

Soler-Cataluña JJ et al. Thorax. 2005;64:925-31

Q3. Which of the following therapeutic measures has no improvement in

exacerbation rate?

• a) Inhaled corticosteroid• b) Oral corticosteroid• c) Long term antibiotic prophylaxis• d) Pneumococcal vaccine

TORCH: Lower Exacerbation Rate WithLABA Plus ICS

Calverley PM, et al. N Engl J Med. 2007;356:775-789.

UPLIFT Study – Effects onExacerbations

0.85/yr

Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554.

Macrolide Therapy Prevents Exacerbations

Pneumococcal and Influenza VaccinationsReduce COPD Exacerbations

Nichol et al. Arch Intern Med. 1999;159:2437-2442

Question 3A 65 year old patient with GOLD Stag III COPD hasjust been entered into a pulmonary rehabilitation

program. Which of the following is an unlikely outcomeof this program?

• a. Reduced hospitalization rate for respiratory

illnesses• b. Reduced all cause hospitalization rate• c. Improvement in FVC and FEV1• d. Improvement in walking time

Pulmonary Rehab: Effect on COPD

Addition of Omalizumab reduced percentage of patients experiencing exacerbations*

* Defined as a course of systemic corticosteroids with an associated asthma worsening adverse event.†P<0.001

Ayres JG, et al. Allergy. 2004;59:701-708.

Idiopathic Pulmonary Fibrosis

Introduction

• In fibrosing diseases, form in inappropriate locations such as the heart, lungs, and liver. There are at least 62 different fibrosing diseases, and collectively these are associated with 45% of deaths in ∼the United States.

• The lung manifests multiple forms of fibrosis. Many of these diseases are associated with a secondary diagnosis such as underlying

autoimmune disease or gastrointestinal reflux. Occupational exposures, such as asbestos and heavy metals, are another important cause of lung fibrosis.

• ‘Idiopathic pulmonary fibrosis’ (IPF) is defined as fibrosis in the

setting of a high-resolution CT scan pattern and/or lung biopsy consistent with usual interstitial pneumonia (UIP) and lack of a known risk factor for interstitial lung disease. IPF affects 130,000 patients in ∼the United States and has a 5-year mortality rate of 80%.

Classification Of Diffuse Parenchymal Lung Diseases

Proc Am Thorac Soc Vol 3. pp 81–95, 2006

Epidemiology of ILD

New York: Marcel Dekker; 2004. p. 772.

Idiopathic Interstitial Pneumonitis

goss

Gross Changes In IPF

IPF- Histology

Survival in patients with IIP

Am J Respir Crit Care Med 1998;157:199–203.

Combined Corticosteroid and Cyclophosphamide Therapy Does Not Alter Survival in Idiopathic Pulmonary Fibrosis

(CHEST 2004; 125:2169–2174)

Acetylceistine Trial - Vital Capacity and Single-Breath Carbon Monoxide Diffusing Capacity (Dlco) at 6 and 12 Months, as Compared

with Baseline

N Engl J Med 2005;353:2229-

Pirfenidone in idiopathic pulmonary fibrosis

• Not available in the US. Europe and Asia routinely used for IPF. The FDA has issues….

• Ongoing phase 3 trial,

Clinical Pearls for UIP

• If a surgical lung biopsy is required, biopsy specimens should be obtained from more than one lobe of the lung.

• If areas of NSIP and UIP are present on the lung biopsy specimen, then UIP determines the prognosis.

• Oxygen desaturation of 88% on a 6-min walk test is a predictor of decreased survival in UIP patients.

• Serology is useful for excluding collagen vascular diseases that may mimic IPF and for excluding other causes of diffuse parenchymal lung disease. However, serologic tests do not confirm a diagnosis of IPF.

• Desaturation to 88% on a 6-minute walk test is a predictor of decreased survival in patients with idiopathic interstitial pneumonias.

• Recent data demonstrate that pathologists who routinely evaluate interstitial lung diseases often disagree about the histologic diagnosis, even when the diagnosis is based on multiple biopsy specimens,

• Patients should consider registering on the transplant list early, even before a significant decline in lung function is experienced.

• The lung may be precede joint involvement in patients with autoimmune diseases.

Pulmonary Hypertension

Definition

• Pulmonary arterial hypertension (PAH) - Hemodynamic state defined by

Sustained elevation of pulmonary arterial pressure to

> 25 mm Hg at rest or 30 mm Hg with exercise

- PCWP < 15 mm Hg

• Which is shared by many conditions

Updated Clinical Classification of Pulmonary Hypertension (Dana Point, 2008)

J Am Coll Cardiol 2009;54:S43–54)

Survival-PAH

A. Survival with various origins of PAH. B. Survival of sclerodermapatients with and without PAH

with PAH

without PAH

x

PAH- Clinical Presentation

Functional Classification (WHO,NYFC)

Risk Assessment (death)

Treatment Algorithm

Results-Mortality