OBSTRUCTIVE DISEASES

radius

Res

ista

nce

Causes of airway narrowing• Loss of tethering• Airway smooth muscle constriction• Airway plugging (mucous, foreign body)• Airway edema

Normal

Emphysema

radius

Res

ista

nce

Causes of airway narrowing• Loss of tethering• Airway smooth muscle constriction• Airway plugging (mucous, foreign body)• Airway edema

Air

Smooth Muscle Cell

Epithelial Cell

radius

Res

ista

nce

Causes of airway narrowing• Loss of tethering• Airway smooth muscle constriction• Airway plugging (mucous, foreign body)• Airway edema

Mucus filling the airway lumen in asthma

radius

Res

ista

nce

Causes of airway narrowing• Loss of tethering• Airway smooth muscle constriction• Airway plugging (mucous, foreign body)• Airway edema

Normal

Airway Edema

Measuring airway obstruction

time (sec)

0 1 2 3

Vol

ume

(L)

normal

airway obstruction

start expiring

FEV1.0

FVC

AIRWAY OBSTRUCTION: FEV1/FVC < 80%

Vo l

ume

(L)

0

time (seconds)

FRC TLC

RV

VC

VT

Normal values for lung volume depend on:

• Age • Sex • Height• Race• Weight (for some subdivisions of lung volume)

DEFINITION OF ASTHMA

1. Reversible Airway Narrowing

2. Increased Airway Responsiveness

3. Airway Inflammation

(History of Allergy)

Air

Smooth Muscle Cell

Epithelial Cell

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

MUCOUS HYPERSECRETION IN ASTHMA

DEFINITION OF ASTHMA

1. Reversible Airway Narrowing

2. Increased Airway Responsiveness

3. Airway Inflammation

(History of Allergy)

Histamine (mg/ml)

.01 .03 .1 .3 1 3 10

FEV 1.

0 (%

bas

elin

e)

100

90

80

70

Normal

Asthma

AIRWAY HYPERRESPONSIVENESS

DEFINITION OF ASTHMA

1. Reversible Airway Narrowing

2. Increased Airway Responsiveness

3. Airway Inflammation

(History of Allergy)

Th2-lymphocytes• promotes IgE formation (IL-4, IL-13)• promotes eosinophil migration (IL-5)

• promotes contraction of smooth muscle• promotes recruitment of more eosinophils

Eosinophil

van den Toorn et al, Am. J. Respir. Crit. Care Med. 2001 164: 2107-2113

Normal

Asthma

Major Basic ProteinStaining (eosinophils)

Symptoms of Asthma:

• cough

• shortness of breath

• chest tightness

• wheezing

HISTOLOGICAL FEATURES OF ASTHMA

• Subepithelial fibrosis• Mucous cell hyperplasia• Smooth muscle hypertrophy• Increased vascularity

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

BASEMENT MEMBRANE THICKENING IN ASTHMA

Ordonez et al, Am. J. Respir. Crit. Care Med. 2001 163: 517-523

INCREASED MUCOUS PRODUCING CELLS(blue purple stain)

Normal Asthma

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

MUCOUS HYPERSECRETION IN ASTHMA

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

AIRWAY SMOOTH MUSCLE HYPERTROPHY IN ASTHMA

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

INCREASED AIRWAY VASCULARITY IN ASTHMA

Pulmonary Function

• Total lung capacity is usually normal, but the FRC is elevated and RV is increased

• Decreased FEV1/FVC ratio

• Lung stiffness is usually normal or low

• Airway obstruction is due to smooth muscle constriction and mucus hypersecretion

time (sec)

0 1 2 3

Vol

ume

(L)

normal

airway obstruction

start expiring

FEV1.0

FVC

AIRWAY OBSTRUCTION: FEV1/FVC < 80%

Vo l

ume

(L)

0

time (seconds)

FRC TLC

RV

VC

VT

asthma

Blood gases

• PaO2 - low because of mismatch of ventilation and perfusion

• PaCO2 • often low (hyperventilation due to anxiety)• if PaCO2 increases it’s usually a sign that

respiratory failure is approaching (patient needs to be ventilated)

Epidemiology of Asthma• currently affects 5-10% of US population

• incidence and severity are increasing • mortality has plateaued

• Still relatively rare

• highest in industrialized countries• Higher in urban than rural areas

Asthma PrevalenceUnited States, 1980-2004

0

2

4

6

8

10

12

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004 Year

Prev

alen

ce (%

)

Source: National Health Interview Survey; National Center for Health Statistics

12-Month

Lifetime

Attack

Current

IgE

Allergen

Chemicals released:

Mast cell

• histamine• leukotrienes• proteases• cytokines (IL-4, IL-5)

Smooth Muscle CellMast Cell(releases chemicals)

(contracts)

Time (hours)Allergen 1 2 3 4 5 6 7 8

100

90

80

70

60

FEV

1.0 (

% b

asel

ine)

EarlyResponse

LateResponse

Mast Cell

White blood cells

Mast Cell

Smooth Muscle Cell

Time (hours)Allergen 1 2 3 4 5 6 7 8

100

90

80

70

60

FEV

1.0 (

% b

asel

ine)

EarlyResponse

LateResponse

Allergen avoidance

Allergy skin testing

team.zobel.dlsu.edu.ph/sites/students/G6/List...

MOST IMPORTANT ALLERGENS IN THE US

• Cat• House dust• Cockroach• Mold

Cat washing itself aerosolizes allergen

www.tiedye.com/cats.htm

Cat being washed – helps reduce allergen exposure(recommended 2X/week)

www.dkimages.com/.../Cat-Care/Cat-Care-054.html

100 mm

House Dust Mite - Dermatophagoides sp.

The average pillow is home to 10,000 of these!

Avoiding exposure to dust mite allergens

• Encase pillows and mattresses

• Use HOT (>130oC) water to wash bedding and clothes

• Reduce carpeting (in particular wall to wall carpeting, which cannot be adequately cleaned)

• Reduce humidity (mites are dependent on water in the air for their water supply)

• Avoid fabric coverings on furniture and windows

Platts-Mills et al, J Allergy Clin Immunol. 2000 Nov;106(5):787-804

The American cockroach

• A particular problem in low income housing• Insects move from one apartment to another

Mold

TRIGGERS FOR ASTHMA

• allergen exposure• exercise• breathing cold dry air• viral infections• irritants (ex: ozone)• occupational exposure to dust or fumes

PREVENTION AND TREATMENT OF ASTHMA

• Medications

• Education

• Allergen Avoidance

ASTHMA THERAPY

1. b-agonists2. Corticosteroids3. Leukotriene antagonists and inhibitors4. Anti-IgE

b-agonists

• Mimic adrenalin• Relax smooth muscle• Effects are immediate but not sustained• Provide symptom relief, but do not remove the underlying causes

before after before after

High resolution CT scans of airways before and after a b-agonist

New England Journal of Medicine 352:15, 2005

FEV1 Before: 1.27 L After: 1.76 L

Corticosteroids:

• Reduce inflammation• Improve lung function and symptoms • Decrease airway hyperresponsiveness• Reduce exacerbations• Must be taken regularly regardless of

symptoms• Not immediately effective

cme.med.harvard.edu/syl/fanta.html

Actions of Leukotrienes• Very potent constrictors of airway smooth muscle • Mucus hypersecretion • Edema formation • Eosinophil chemoattraction

Leukotriene synthesis inhibitors and receptor antagonists

• Prevent synthesis or effects of leukotrienes

cme.med.harvard.edu/syl/fanta.html

• Reduces corticosteroid requirements• Reduces symptom scores• Reduces rescue medication use• Improves lung function• Reduces exacerbations

Efficacy of anti-IgE Therapy in Humans

Fahy et al. AJRCCM 1997 155:1828

Anti-IgE therapy also:Fahy et al. AJRCCM 1997 155:1828

Genes

Environment

Asthma

WHAT CAUSES ASTHMA?

-exposure to allergens -pollution-cigarette smoke-viruses

Genes

Environment

Asthma

- cytokines- genes that regulate IgE levels- others

From: Camargo et al, Arch Intern Med 159:2582-2588, 1999

Evidence for the hygiene hypothesis

• Less asthma in individuals who grow up on farms

• Less asthma in individuals with older siblings

• Less asthma in children in daycare

New Engl J Med 343:538-543

Gold and Wright, Ann Rev Public Health, 26:89-113, 2005

Asthma is more common in the developed than the developing world

COPD – chronic obstructive pulmonary disease

• 4th leading cause of death in the US• 2nd leading cause of disability• Smokers disease• Consists of 2 diseases (many have both)

- emphysema- chronic bronchitis

Other consequences of smoking

•Heart disease•Stroke •Cancer*

*In 2000, cancer due to cigarette smoking accounted for 20% of allcancer deaths worldwide in 200

Consequences of passive smoking in children

• Lower birth weight in children of mothers who smoke

• Lower lung size in children of parents who smoke

• Increased incidence of asthma, bronchitis, and pneumoniain children of parents who smoke

From the US Department of Health and Human Services, 2003

Smoking is the leading cause of preventable death in the US

Year45 50 55 60 65 70 75

age

adju

sted

mor

talit

y ra

tes

(per

100

,000

)

1

10

Men Women

Thun et al, Carcinogenesis 31:100, 2010

Global burden of smoking

1.3 billion people smoke

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

EMPHYSEMA

Jeffrey et al, Am. J. Respir. Crit. Care Med. 2001 164: 28S-38S

Emphysema Normal male lung

Mucous gland hypertrophy in chronic bronchitis

Pressure

Volume

Healthy

Lung Pressure Volume Curves

Emphysema

ETIOLOGY

Cigarette smoke (particles and chemicals)

Inflammation

Influx of activation of neutrophils and macrophages• release of proteases• release of oxygen radicals• release of inflammatory mediators

Destruction of lung tissue

Production of mucous

Airway remodeling

Signs and Symptoms

Emphysema• Dyspnea at rest• Thin• Barrel chest• Wheeze on expiration

Chronic Bronchitis• Cough • Sputum• No dyspnea at rest but does occur with exertion• Cyanosis• Frequent respiratory infections• Pops and rales

FEV1

(% o

f val

ue a

t age

25)

Age (years)

Never smoked orNot susceptible

Smoked regularlyAnd susceptible

Stopped at 45

Stopped at 65disability

death

25 50 75

Evidence for genetic susceptibility for COPD

• Familial association of low FEV1.0

• Linkage analysis studies• Genes associated with COPD susceptibility

1. a1-antitrypsin (anti-protease)2. microsomal epoxide hydrolase (degradation of chemicals in smoke) 3. glutathione-S-transferases (degradation of chemicals in smoke) 4. Hemeoxygenase 1 (antioxidant)5. TNFa (inflammation)

Blood gases

Emphysema• PaO2 is low but not very low

cause: V/Q mismatch• “pink puffers” - increase ventilation to keep bloodgases normal• PaCO2 is normal

Chronic Bronchitis• PaO2 usually very low

cause: V/Q mismatch and hypoventilation• “blue bloaters” – do not increase ventilation tokeep blood gases normal• PaCO2 is high

Chronicbronchitis

Normal

Consequences of low PaO2

1) Polycythemia – increased numbers of red blood cells (RBC’s)

Low PaO2

Increased erythropoetin release from kidney

Acts of bone marrow to increased production of RBC’s

2) Right heart hypertrophy (cor pulmonale)

• Due to pulmonary hypertension (hypoxic vasocontrictionand loss of capillary bed)

• Can lead to right heart failure and death

Cyanosis

• Occurs when deoxygenated hemoglobinexceeds 5 g/100 ml

typical total hemoglobin is 15 g/100 ml

• Low PaO2 and increased numbers of redblood cells both contribute to cyanosis in chronic bronchitis

Treatment

• Smoking cessation – prevents further loss of lung function

• Bronchodilators, particularly anticholinergics

• Increasing use of corticosteroids – data are not yet inregarding efficacy

• Lung reduction surgery – not usually recommended

Indoor air pollution – biomass fuels

Fullerton D et al Occup Env Med 66:777, 2009

Smith KR et al Thorax 55:518, 2000

Smith KR et al Thorax 55:518, 2000

US EPA 24 hour standard not to be exceeded more than once/year: 260 ug/m3

Indoor air pollution

• Responsible for 1.6 million deaths/year

• Disease burden worldwide exceeds outdoor air pollution 5-fold

• Most lethal killer worldwide after malnutrition, unsafe sex,lack of safe drinking water and sanitation

• Increases risk of COPD in women about 3-fold

• Responsible for 0.7 of the 2.7 million COPD deaths worldwide/year

• Burden is mostly on women and children

Source: World Health Organization

Hours per day near stove

Smith KR et al Thorax 55:518, 2000

Acute respiratory tract infection and exposure to biomass fuels

Smith KR et al Thorax 55:518, 2000