ASTHMA PATHOPHYSIOLOGYASTHMA OVERVIEW

Presented by:Michelle Harkins, MD

University of New Mexico

This session will cover

• Review asthma statistics• Define asthma• Outline key pathophysiologic features• Review signs and symptoms of asthma• Reference to NAEPP – EPR-3: asthma severity

classification system-including impairment and risk domains

• Diagnosing asthma

Prevalence vs Incidence

• Prevalence - the proportion or percentage of a population that has disease at a specific point or period of time

• Incidence – the number of new cases of disease that develop in a population of individuals at risk during a specific point or period of time

• 1980-1996 prevalence of asthma in US increased

• Since 1999, mortality and hospitalization due to asthma have decreased

Under 5 5-17 <18 18-44 45-64 65+0

20

40

60

80

100

120

68.5

105.594.9

79.986.7

79.4

Asthma – Current Prevalence by Age, 2011CU

RREN

T PR

EVAL

ENCE

RAT

E PE

R 1,

000

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Total Under 18 18 and Over0

20

40

60

80

100

120

71.9

101.7

61.8

97.387.8

100.1

Asthma – Current Prevalence by Sex and Age, 2011

Male Female

Curr

ent P

reva

lenc

e pe

r 1,0

00

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Total Under 18 18 and Over0

50

100

150

200

250

300

350

80.4

147.3

238

118

314.2287.9

Asthma – Current Prevalence by Race, 2011

Whites Blacks

Curr

ent P

reva

lenc

e pe

r 1,0

00

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

New Mexico BRFSS Results for 2010: Current Prevalence: Percent of New Mexico Children who Currently Have Asthma by Various Demographic Characteristics

Race/Ethnicity:White, Non-Hispanic 8.1%Hispanic 7.4%Native American 13.1%SOURCE: Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2009

Total <5 5-17 18-44 45-64 65+0

10

20

30

40

50

60

70

80

90

100

Asthma – Attack Prevalence by Age and Race, 2011

White Black

ATTA

CK P

REVA

LEN

CE p

er 1

,000

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

0

5

10

15

20

25

30

14.3

9

28.5

11.6

Asthma – First-Listed Hospital Discharges by Race, 2010Total White Black All Other

DISC

HARG

ES P

ER 1

0,00

0

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Asthma age-adjusted hospitalization rates per 10,000 standard population by county, New Mexico, 2007-2011 average

LegendRate per 10,000 populationState Rate: 8.8

2.5 - 5.9

5.9 - 7.2

7.2- 10.0

10.0 - 12.2

12.2- 21.6

Asthma hospitalization rates per 10,000 standard population among youth (0-14 years) by county, New Mexico, 2007-2011 average

Rate per 10,000 populationState Rate: 16.9

0.0- 6.9

6.9 - 11.4

11.4 - 15.1

15.1- 18.1

18.1 - 57.1

Series10

2

4

6

8

10

12

Asthma – Crude Death Rate by Age Group, 2009

1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+

CRU

DE D

EATH

RAT

E PE

R 10

0,00

0

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Total White Black Hispanic0

0.5

1

1.5

2

2.5

3

Asthma – Age-Adjusted Death Rates by Sex and Race, 2009

Male Female

AGE-

ADJU

STED

DEA

TH R

ATE

PER

100,

000

Trends in Asthma Morbidity and Mortality. American Lung Association, Epidemiology and Statistics Unit, Research and Program Services Division. September, 2012.

Asthma Age-Adjusted Death Rates Based on the 1940 and 2000 Standard populations, 1979-2005

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 20051940 0.9 1.0 1.0 1.0 1.2 1.1 1.2 1.2 1.3 1.4 1.4 1.4 1.5 1.4 1.4 1.5 1.5 1.5 1.4 1.4 1.2 1.1 1.0 1.0 1.0 0.9 0.92000 1.3 1.4 1.5 1.5 1.7 1.6 1.8 1.8 1.9 2.0 2.1 2.1 2.2 2.0 2.1 2.2 2.2 2.2 2.1 2.0 1.7 1.6 1.5 1.5 1.4 1.3 1.3

Asthma Impact – Economic Burden

• Childhood asthma accounts for 14.4 million days missed from school annually – The number-one chronic

condition causing children to be absent from school and the third highest ranked cause of pediatric hospitalizations in the United States

– On average, a child with asthma will miss one full week of school each year due to the disease

Asthma Impact – Economic Burden

• Adult asthma accounts for 14.2 million missed workdays annually

• 4th leading cause of missed work days

National Burden of Asthma

$19.7 billion annually

• $14.7 billion in direct costs (prescription medications, hospital care, and physician services)

• $5 billion in indirect costs (lost productivity due to missed work or school and premature mortality)

DEFINE ASTHMA

Develop a collaborative working definition of asthma

Evolution of the Definition of Asthma

• Episodic disease characterized by:– Reversible airway

constriction– Increased airway

responsiveness

• Chronic disease characterized by:– Chronic airway

inflammation– At least partially

reversible airway obstruction

– Increased airway responsiveness

1962 2007American Thoracic Society, 1962. NAEPP, EPR3, 2007.

3M Resource Cards Doctors Designers

11-96

3M Resource Cards Doctors Designers

11/96

3M Resource Cards Doctors Designers

11-96

Pathophysiology of Asthma

Epithelial Damage in Asthma

AsthmaticNormal

Asthma: Pathophysiology

• Inflammatory cell infiltrate consists of mainly of eosinophils and lymphocytes

• “Sudden death” asthma associated with an infiltrate of neutrophils

• Denudation of airway epithelium• Mucus gland hyperplasia and hypersecretion• Smooth muscle cell hyperplasia• Submucosal edema and vascular dilatation• Fibrin deposition/airway remodeling

• Mast Cells• Macrophages• Eosinophils• T-Lymphocytes• Epithelial Cells• Platelets• Neutrophils• Myofibroblasts• Basophils

Multiple Mechanisms Contribute to Asthma: Inflammatory Mediators

HistamineLipid Mediators*

Peptides†

Cytokines‡

Growth Factors

MediatorSoup

Bronchoconstriction

Microvascular Leakage

Mucus Hypersecretion

AirwayHyperresponsiveness

*For example, prostaglandins and leukotrienes.†For example, bradykinin and tachykinin.‡For example, tumor necrosis factor (TNF).Adapted with permission from Barnes PJ. In: Barnes PJ et al, eds. Asthma: Basic Mechanisms and Clinical Management. 3rd ed. Academic Press; 1998:487-506.

NAEPP, EPR-3, pg. 15.

FACTORS LIMITING AIRFLOW IN ACUTE AND PERSISTENT ASTHMA

Inflammation in Asthma

IgE = immunoglobulin E.National Asthma Education and Prevention Program Guidelines, 1997.Busse WW et al. N Engl J Med. 2001;344:350-362.Bousquet J et al. Am J Resp Crit Care Med. 2000;161:1720-1745.

Airway Inflammation

Allergen/Trigger

T-cell

B-cell

IgEEosinophil

Mast cell

CytokinesHistamine

Macrophage

Aftermath of Inflammation

• Reversibility– Occurs in most

asthma episodes– Airway returns to

normal caliber– Flow of air through

airways returns to normal “speed”

• Remodeling– Airway lining builds up

persistent fibrotic changes

– Airway caliber remains abnormal

– Air flow is decreased– Permanent changes

appear to begin in childhood, but become recognizable in adults

Asthma is a Chronic Inflammatory Disease: Pathophysiologic Changes

Hematoxylin and eosin stain.Photographs courtesy of Nizar N. Jarjour, MD, University of Wisconsin.

Bronchial Mucosa From a Subject Without Asthma

Bronchial Mucosa From a Subject With Mild Asthma

Normal Architecture Disrupted Architecture

Lumen

Epithelium

Subepithelial Collagen Deposition

Consequences of Persistent Asthma:Subepithelial Collagen Deposition

Reprinted with permission from Holloway L et al. In: Busse WW, Holgate ST, eds. Asthma and Rhinitis. Blackwell Scientific Publications; 1995:109-118.

FEV 1

% P

redi

cted

Duration of Asthma (years)

80

40

120

10 20 5040300

r = -0.47n = 89

P<.001

60

20

100

Consequences of Persistent Asthma: Progressive Decline in FEV1

FEV1 = forced expiratory volume in 1 second.Adapted with permission from Brown PJ et al. Thorax. 1984;39:131-136.

1. Chronic inflammatory disorder of the airways– Mast cells, eosinophils and lymphocytes infiltrate into

airway lining– Airway hyperresponsiveness develops

2. Excessive reaction to “minor” irritants results in a host of deleterious airway changes– Bronchial wall edema– Smooth muscle contraction– Excess mucus production

3. Patchy, mostly reversible regions of airway narrowing cause asthma symptoms

Asthma is. . .

Acute Reaction to Triggers

1. Irritated airways become more inflamed after exposure to stimuli

2. Muscle layers around airway constrict

3. Airway lining swells4. Excess mucus builds up

in lumen5. Result: symptoms of

cough, wheeze, shortness of breath, chest tightness

• Genetic predisposition• Atopy• Airway hyperresponsiveness• Gender• Race/Ethnicity

Risk Factors for Developing Asthma

What Parameters Affect Disease ?

• Intrinsic factors– Genetics– Duration of asthma– Severity of childhood

asthma– Gender – Response to therapy

• Extrinsic factors– Viral infections– Allergen exposure– Airway irritants– Exercise– Compliance– Season– Time of day– Occupational—10-

15% of adult asthma– Western Lifestyle--

obesity

Environmental Risk Factors for Development of Asthma

• Indoor allergens• Outdoor allergens• Occupational sensitizers• Tobacco smoke• Air Pollution• Respiratory Infections

• Parasitic infections• Socioeconomic

factors• Family size• Diet and drugs• Obesity• Hygiene hypothesis

INFLAMMATION

Risk Factors(for development of asthma)

BronchialHyperresponsiveness

Airflow Obstruction

Risk Factors(for exacerbations)

Symptoms

Genetic Environmental

Asthma & Airway Inflammation

Multiple Triggers Can StimulateAcute Reaction

• Upper Respiratory Infections (URI’s)– Viral Respiratory infections are the #1 trigger behind asthma hospitalizations– Influenza vaccines are recommended for people with asthma

• Allergens• Irritants• Sudden or extreme changes of weather• Exercise• Intense emotions

Exercise Induced Bronchospasm

• Bronchospasm caused by activity– Some activity more likely than others to trigger it

• Cold environment: skiing, ice hockey• Heavy exertion: Soccer, long distance running• Exercising when you have a viral cold

Exercise Induced Bronchospasm• Symptoms include

– Coughing– Wheezing– Chest tightness

• Symptoms may begin during activity and peak in severity 10-20 minutes after stopping

• Can spontaneously resolve 20-30 minutes after its onset

Epidemiology

• Prevalence 7-20% of the general population• 80% of patients with asthma have some degree

of EIB• Exercise is not a risk factor for asthma, rather a

trigger• ?Exercise may help prevent onset of asthma in

children– Decrease in physical activity may play a role in

increased in asthma prevalence• JACI 2005 Lucas SR, Platts-Mills TA

Prevention of EIB

• Use bronchodilator 10-15 minutes before onset of activity

• Do warm-up/cool down exercises

• Check ozone/allergy warnings

• Never encourage anyone to “tough it out”

Management

• Increasing fitness: decreases minute ventilation needs with exercise

• Less severe if inspired air is warmer, more humid (Evidence Class C)

– Scarf or mask if cold weather– Warm-up period before exercise

• Good asthma control: EIB more frequent in patients with poorly controlled disease (Class A)

– Check for asthma control– Treating appropriately will reduce frequency and severity of EIB

Impairment and Risk Domains

• Impairment-frequency and intensity of symptoms and functional limitations the patient is experiencing or has experienced

• Risk-the likelihood of either asthma exacerbations, progressive decline in lung function or risk of adverse effects from medication

NIH. NAEPP Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, October 2007.

• History of severe exacerbations• Prior intubation for asthma• Prior admission to Intensive Care Unit• 2 or more hospital admissions in the past year• 3 or more emergency room visits in the past

year• Hospital or emergency room visit past month• Use of >2 canisters per month of inhaled short-

acting beta2 –agonist

Risk Factors for Death from Asthma

• Chronic use of systemic corticosteroids• Poor perception of airflow obstruction or its severity• Co-morbid conditions (other diseases)• Serious psychiatric disease or psychosocial

problems• Low socioeconomic status and urban residence• Illicit drug use• Sensitivity to alternaria-mold• Lack of written asthma action plan

Risk Factors for Death from Asthma

• Recurrent episodes of coughing or wheeze• Asthma may be present without a wheeze -

cough may be the sole symptom• Shortness of breath or difficulty breathing• Chest Tightness• Wheezing does not always mean asthma• Absence of symptoms and physical findings at

the time of the examination does not exclude asthma

Diagnosing Asthma

Asthma

• Diagnosis by history of wheeze, shortness of breath, cough, chest tightness

• Spirometry can help define the severity of the disease, however may be normal if asthma is under control

• Lack of bronchodilator response does not rule out asthma

• Following Peak Flows may be useful

• Spirometry should be performed:– at initial assessment– after treatment is initiated and symptoms and PEFs

have stabilized– at least every 1-2 years to assess maintenance of

airway function if well controlled– More often if poor asthma control

Measures of Assessment & Monitoring

• Peak Flows may be performed:– In all moderate and severe persistent asthmatics

• establish a personal best• useful in exacerbations and maintenance/ changes of

therapy, • Can be helpful with ‘poor perceivers’

Measures of Assessment & Monitoring

< 2 Years Old: When Is It Asthma?

•Family history of asthma•Atopy, eczema•Perinatal exposure to aeroallergens and irritants (e.g., passive smoke)•Wheezing triggered by factors other than upper respiratory infections

Risk Factors

for Develo

ping Asthma

< 2 Years Old: When Is It Asthma?

TWO GROUPS OF INFANTS WHEEZE

ASTHMA NOT ASTHMA

Asthma Predictive Index

• MAJOR CRITERIA– Atopic dermatitis– Parental Asthma

• MINOR CRITERIA– Wheezing apart

from colds– Allergic rhinitis– Blood eosinophilia

1 of 2 major criteria or 2 minor criteria

> ¾ of children with a positive index had some active asthma symptoms between 6 and 13 years of age

In an infant or young child with > 3 episodes of wheezing in the past year

Asthma: Children vs. Adults

Children

•Present with symptoms of cough ± noisy or rapid breathing, usually before 5 years of age

Adults

•Present with symptoms of cough, shortness of breath, chest pain, wheezing, often intermittent or nocturnal

Asthma Misdiagnosis

Commonly Misdiagnosed in

Children as:CHRONIC/WHEEZY

BRONCHITIS

RECURRENT CROUP

RECURRENT UPPER RESPIRATORY INFECTION

RECURRENT PNEUMONIA

Commonly Misdiagnosed in Adults as:

RECURRENTBRONCHITIS

Asthma Severity Assessments

•< 6 year old often cannot perform reliable Pulmonary Function Test’s (PFT’s) or peak flow measurements•Older children with even severe symptoms often have fairly normal PFT’s between episodes•Severity assessment often focuses on symptoms more than lung function measurements

CHILDREN

•PFTs play more important role in assessment•PFT’s performed at diagnosis and routinely at least every 1-2 years

ADULTS

Long-Term Management of Asthma in Children: Initiation of Control Therapy

• Symptoms > 2 x week• Severe exacerbations < 6 weeks apart• 2 or more burst of prednisone in 6 months for

ages 0-4• 2 or more burst of prednisone in 1 year for ages

5-11• Positive Asthma Predictive Index

Questions?