Asthma: Biology, Asthma: Biology, Epidemiology, and Epidemiology, and

EvaluationEvaluation

Gary L. Weinstein M.D., FCCPGary L. Weinstein M.D., FCCP

Thursday, February 2, 2006Thursday, February 2, 2006

AsthmaAsthma

Asthma ranks among the most common Asthma ranks among the most common chronic conditions in the United States, chronic conditions in the United States, affecting an estimated 14.9 million persons affecting an estimated 14.9 million persons in 1995 and causing over 1.5 million in 1995 and causing over 1.5 million emergency department visits, about emergency department visits, about 500,000 hospitalizations, and over 5,500 500,000 hospitalizations, and over 5,500 deaths.deaths.

AsthmaAsthma

"A chronic inflammatory disorder of the airways in which many cells "A chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T lymphocytes.play a role, in particular mast cells, eosinophils, and T lymphocytes.In susceptible individuals this inflammation causes recurrent In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. particularly at night and/or in the early morning. These symptoms are usually associated with widespread but These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either variable airflow limitation that is at least partly reversible either spontaneously or with treatment. spontaneously or with treatment. The inflammation also causes an associated increase in airway The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli.responsiveness to a variety of stimuli.

NHLBI/WHO Workshop Report, US Department of Health and Human Services. National Institutes of NHLBI/WHO Workshop Report, US Department of Health and Human Services. National Institutes of Health, Bethesda, 1995; Pub #95-3659. Health, Bethesda, 1995; Pub #95-3659.

AsthmaAsthmaData from the Centers for Disease Control have shown that the prevalence Data from the Centers for Disease Control have shown that the prevalence of asthma has increased in the United States [of asthma has increased in the United States [1, 21, 2]. ]. During the period from 1982 to 1992, the overall annual age-adjusted During the period from 1982 to 1992, the overall annual age-adjusted prevalence rate of self-reported asthma increased by 42 percent, from 34.7 prevalence rate of self-reported asthma increased by 42 percent, from 34.7 to 49.4 per 1000. to 49.4 per 1000. For the younger age group five to 34 years, where the diagnosis of asthma For the younger age group five to 34 years, where the diagnosis of asthma is thought to be more accurate, the rate increased from 34.6 to 52.6 per is thought to be more accurate, the rate increased from 34.6 to 52.6 per 1000, an increase of 52 percent. 1000, an increase of 52 percent. Since that time, the increase in prevalence of asthma has slowed Since that time, the increase in prevalence of asthma has slowed somewhat [3]somewhat [3]

1.1. Weiss, KB, Wagener, DK. Asthma surveillance in the United States. A review of current trends and knowledge Weiss, KB, Wagener, DK. Asthma surveillance in the United States. A review of current trends and knowledge gaps. Chest 1990; 98:179S. gaps. Chest 1990; 98:179S.

2.2.   Asthma--United States, 1982-1992. MMWR Morb Mortal Wkly Rep 1995; 43:952.Asthma--United States, 1982-1992. MMWR Morb Mortal Wkly Rep 1995; 43:952.

3.3. Mannino, DM, Homa, DM, Akinbami, LJ, et al. Surveillance for asthma--Mannino, DM, Homa, DM, Akinbami, LJ, et al. Surveillance for asthma--United States, United States, 1980-1980-1999. MMWR Surveill Summ 2002; 51:1. 1999. MMWR Surveill Summ 2002; 51:1.

Asthma Prevalence* by AgeAsthma Prevalence* by AgeUnited States: 1980United States: 1980––19961996

0

1

2

3

4

5

6

7

8

Y e a r

Pre

va

len

ce

(%

)

Source: National Health Interview Survey* 12-month prevalence

Under 18Under 18TotalTotal

18+18+

Asthma Prevalence* by SexAsthma Prevalence* by SexUnited States: 1982United States: 1982––19961996

0

1

2

3

4

5

6

7

8

Y e a r

Pre

vale

nce

(%

)

Source: National Health Interview Survey* 12-month prevalence

MaleMale

FemaleFemale

TotalTotal

Asthma Prevalence* by RaceAsthma Prevalence* by RaceUnited States: 1982United States: 1982––19961996

0

1

2

3

4

5

6

7

8

Y e a r

Pre

vale

nce

(%

)

Source: National Health Interview Survey* 12-month prevalence

BlackBlack

WhiteWhite

Age-Adjusted* Asthma Mortality RatesAge-Adjusted* Asthma Mortality Rates

by Sex, United States: 1979by Sex, United States: 1979––19981998

0

5

10

15

20

25

30

Year

Ra

te p

er

mill

ion

MaleMale

TotalTotal

FemaleFemale

Source: Underlying Cause of Death dataset by the National Center for Health Statistics

* Age-adjusted to 2000 U.S. population

Costs of AsthmaCosts of AsthmaUnited States, 1980–1998United States, 1980–1998

Projection for the Year 2000Projection for the Year 2000

0

5

10

15E stim atedcosts in b illions o f do lla rs

1 9 8 0 * 1 9 8 5 * 1 9 9 0 ** 1 9 9 4 ** 1 9 9 8 ** 2 0 0 0

Y ear

Source: * Weiss, et al. 1992** Weiss, et al. 2001

Risk Factors Risk Factors for Development of Asthmafor Development of Asthma

Genetic characteristicsGenetic characteristics

Environmental exposuresEnvironmental exposures

Contributing factorsContributing factors

Risk Factors for Development of Risk Factors for Development of Asthma:Asthma:

Genetic CharacteristicsGenetic CharacteristicsAtopy Atopy The body’s predisposition to develop The body’s predisposition to develop

immunoglobulin E (IgE) in response to immunoglobulin E (IgE) in response to exposure to environmental allergensexposure to environmental allergens

Can be measured in the bloodCan be measured in the blood

Clearing the AirClearing the AirIndoor Air Exposures and Asthma Indoor Air Exposures and Asthma

DevelopmentDevelopment Biological Agents Biological Agents • Sufficient evidence of a Sufficient evidence of a

causal relationshipcausal relationshipHouse dust miteHouse dust mite

Sufficient evidence of an Sufficient evidence of an associationassociation

None foundNone foundLimited or suggestive Limited or suggestive evidence of an associationevidence of an association

Cockroach (in Cockroach (in preschool-aged preschool-aged

children)children) Respiratory Respiratory syncytial syncytial virus (RSV)virus (RSV)

Chemical AgentsChemical AgentsSufficient evidence of a Sufficient evidence of a causal relationshipcausal relationship

None foundNone found

Sufficient evidence of an Sufficient evidence of an associationassociation

Environmental tobacco Environmental tobacco smoke (in preschool- smoke (in preschool-aged children)aged children)

Limited or suggestive Limited or suggestive evidence of an associationevidence of an association

None foundNone found

Clearing the AirClearing the AirIndoor Air Exposures and Asthma Indoor Air Exposures and Asthma

ExacerbationExacerbation Biological AgentsBiological Agents

Sufficient evidence of a causal Sufficient evidence of a causal relationshiprelationship

CatCat CockroachCockroach House dust miteHouse dust mite

Sufficient evidence of an associationSufficient evidence of an association DogDog Fungi/MoldsFungi/Molds RhinovirusRhinovirus

Limited or Suggestive Evidence of an Limited or Suggestive Evidence of an Association Association

Domestic birdsDomestic birds Chlamydia and Chlamydia and Mycoplasma Mycoplasma pneumoniaepneumoniae RSVRSV

Chemical AgentsChemical AgentsSufficient evidence of a causal Sufficient evidence of a causal relationshiprelationship

Environmental tobacco smoke Environmental tobacco smoke (in preschool-aged children)(in preschool-aged children)

Sufficient evidence of an associationSufficient evidence of an association NONO22, NO, NOxx (high levels) (high levels)

Limited or suggestive evidence of an Limited or suggestive evidence of an associationassociation

Environmental tobacco Environmental tobacco smoke (school-aged, older smoke (school-aged, older children and adults)children and adults)

FormaldehydeFormaldehyde FragrancesFragrances

AsthmaAsthma

Risk factors Risk factors ATOPYATOPY — Atopy is assessed in clinical and epidemiologic studies by three — Atopy is assessed in clinical and epidemiologic studies by three

methods: skin test reactivity; serum IgE levels; and blood eosinophilia [1]. Serum methods: skin test reactivity; serum IgE levels; and blood eosinophilia [1]. Serum IgE levels appear to be closely linked with both asthma and bronchial IgE levels appear to be closely linked with both asthma and bronchial hyperresponsiveness, whether or not asthma is present. hyperresponsiveness, whether or not asthma is present.

EXPOSURE TO INDOOR ALLERGENSEXPOSURE TO INDOOR ALLERGENS — Indoor allergens include — Indoor allergens include house dust mites, animal allergens, cockroach allergen, and fungi. A house dust mites, animal allergens, cockroach allergen, and fungi. A consensus is emerging that these allergens play a significant role in the consensus is emerging that these allergens play a significant role in the development of asthma, although not all studies agree development of asthma, although not all studies agree

Weiss, ST, Speizer, FE. Epidemiology and natural history. In: Bronchial Asthma Mechanisms Weiss, ST, Speizer, FE. Epidemiology and natural history. In: Bronchial Asthma Mechanisms and Therapeutics, 3d ed, Weiss, EB, Stein, M (Eds), Little, Brown, Boston 1993, p. 15. and Therapeutics, 3d ed, Weiss, EB, Stein, M (Eds), Little, Brown, Boston 1993, p. 15.

Platts-Mills, TA. How environment affects patients with allergic disease: indoor allergens and Platts-Mills, TA. How environment affects patients with allergic disease: indoor allergens and asthma. Ann Allergy 1994; 72:381. asthma. Ann Allergy 1994; 72:381.

AsthmaAsthma

Risk factorsRisk factors OUTDOOR AIR POLLUTIONOUTDOOR AIR POLLUTION — There is a known correlation — There is a known correlation

between levels of air pollution and lung disease, but there is no between levels of air pollution and lung disease, but there is no clear association between air pollution and asthma.clear association between air pollution and asthma.

RESPIRATORY INFECTIONSRESPIRATORY INFECTIONS — Viral and bacterial — Viral and bacterial respiratory infections are well-known triggers that can cause respiratory infections are well-known triggers that can cause exacerbations in children and adults with asthma [1,2]. exacerbations in children and adults with asthma [1,2]. Whether infections can be a cause of asthma, however, is not Whether infections can be a cause of asthma, however, is not known. known.

1.1. Johnston, SL, Pattemore, PK, Sanderson, G, et al. Community study of role of viral Johnston, SL, Pattemore, PK, Sanderson, G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 1995; 310:1225. infections in exacerbations of asthma in 9-11 year old children. BMJ 1995; 310:1225.

2.2.   Nicholson, KG, Kent, J, Ireland, DC. Respiratory viruses and exacerbations of asthma in Nicholson, KG, Kent, J, Ireland, DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993; 307:982.adults. BMJ 1993; 307:982.

AsthmaAsthma

Risk factorsRisk factors SMOKING AND EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKESMOKING AND EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE — —

Population-based studies appear to show a relationship between smoking and Population-based studies appear to show a relationship between smoking and airway hyperresponsiveness. However, the presence of asthma in adults has airway hyperresponsiveness. However, the presence of asthma in adults has generally been unrelated to smoking history [1]. generally been unrelated to smoking history [1].

Environmental tobacco smokeEnvironmental tobacco smoke — There is a growing body of — There is a growing body of evidence that passive smoke exposure is associated with the evidence that passive smoke exposure is associated with the development of asthma in early life. development of asthma in early life. Maternal smoking is the most Maternal smoking is the most important cause of passive smoke exposure, because of the important cause of passive smoke exposure, because of the greater exposure of the child to the mother than the fathergreater exposure of the child to the mother than the father [2]. [2].

11  Weiss, ST, Speizer, FE. Epidemiology and natural history. In: Bronchial Asthma Mechanisms Weiss, ST, Speizer, FE. Epidemiology and natural history. In: Bronchial Asthma Mechanisms and Therapeutics, 3d ed, Weiss, EB, Stein, M (Eds), Little, Brown, Boston 1993, p. 15. and Therapeutics, 3d ed, Weiss, EB, Stein, M (Eds), Little, Brown, Boston 1993, p. 15.

2. Weiss, KB, Gergen, PJ, Wagener, DK. Breathing better or wheezing worse? The changing 2. Weiss, KB, Gergen, PJ, Wagener, DK. Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993; 14:491. epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993; 14:491.

AsthmaAsthma

Risk factorsRisk factors Prenatal exposure to maternal smokingPrenatal exposure to maternal smoking In bivariate analyses, maternal In bivariate analyses, maternal

smoking, whether defined as ever smoking (OR=1.80), smoking during smoking, whether defined as ever smoking (OR=1.80), smoking during pregnancy (OR=1.97), smoking during the first year of the child's life (OR=1.70), pregnancy (OR=1.97), smoking during the first year of the child's life (OR=1.70), or current smoking (OR=1.70) was significantly associated with current or current smoking (OR=1.70) was significantly associated with current asthma/wheeze among the children. The number of cigarettes smoked daily by asthma/wheeze among the children. The number of cigarettes smoked daily by the mother and the number of household smokers were also related to current the mother and the number of household smokers were also related to current asthma/wheeze [1].asthma/wheeze [1].

Active asthma was significantly associated with exposure to environmental Active asthma was significantly associated with exposure to environmental tobacco smoke in pregnancy only (OR=2.70, 95% CI 1.13-6.45), and no tobacco smoke in pregnancy only (OR=2.70, 95% CI 1.13-6.45), and no significant association was found for currently exposed children [2].significant association was found for currently exposed children [2].

1.1. Ehrlich, RI, Du Toit, D, Jordaan, E, et al. Risk factors of childhood asthma and wheezing. Importance of Ehrlich, RI, Du Toit, D, Jordaan, E, et al. Risk factors of childhood asthma and wheezing. Importance of maternal and household smoking. Am J Respir Crit Care Med 1996; 154:681. maternal and household smoking. Am J Respir Crit Care Med 1996; 154:681.

2.2. Cunningham, J, O'Connor, GT, Dockery, DW, Speizer, FE. Environmental tobacco smoke, wheezing, and Cunningham, J, O'Connor, GT, Dockery, DW, Speizer, FE. Environmental tobacco smoke, wheezing, and asthma in children in 24 communities. Am J Respir Crit Care Med 1996; 153:218. asthma in children in 24 communities. Am J Respir Crit Care Med 1996; 153:218.

AsthmaAsthma

Risk factorsRisk factors OBESITYOBESITY — Age-adjusted prevalence rates for asthma and obesity are — Age-adjusted prevalence rates for asthma and obesity are

increasing in the United States. Experimental models, prospective cohort increasing in the United States. Experimental models, prospective cohort studies, and population-based case-control studies suggest that patients with studies, and population-based case-control studies suggest that patients with an elevated BMI are at increased risk for developing asthma [1,2].an elevated BMI are at increased risk for developing asthma [1,2].

A prospective cohort study of nearly 86,000 adults followed for five A prospective cohort study of nearly 86,000 adults followed for five years showed a linear relationship between BMI and the risk of years showed a linear relationship between BMI and the risk of developing asthma .The relative risk of developing asthma was 2.7 for developing asthma .The relative risk of developing asthma was 2.7 for patients in the highest BMI group compared with nonobese patients in the highest BMI group compared with nonobese counterparts (p for trend <0.001) [3].counterparts (p for trend <0.001) [3].

1.1. Shore, SA, Fredberg, JJ. Obesity, smooth muscle, and airway Shore, SA, Fredberg, JJ. Obesity, smooth muscle, and airway hyperresponsiveness. J Allergy Clin Immunol 2005; 115:925.hyperresponsiveness. J Allergy Clin Immunol 2005; 115:925.

2.2.   Camargo, CA Jr, Weiss, ST; Zhang, S, et al. Prospective study of body mass Camargo, CA Jr, Weiss, ST; Zhang, S, et al. Prospective study of body mass index, weight change, and risk of adult- onset asthma in women. Arch Intern index, weight change, and risk of adult- onset asthma in women. Arch Intern Med 1999; 159:2582. Med 1999; 159:2582.

3.3.   Young, SY, Gunzenhauser, JD, Malone, KE, McTiernan, A. Body mass index Young, SY, Gunzenhauser, JD, Malone, KE, McTiernan, A. Body mass index and asthma in the military population of the northwestern United States. Arch and asthma in the military population of the northwestern United States. Arch Intern Med 2001; 161:1605.Intern Med 2001; 161:1605.

AsthmaAsthma

Risk factorsRisk factors PERINATAL FACTORSPERINATAL FACTORS (besides maternal smoking) (besides maternal smoking)

Maternal ageMaternal age – – The incidence of wheezing lower respiratory tract illnesses was The incidence of wheezing lower respiratory tract illnesses was

inversely related to maternal age; inversely related to maternal age; in contrast, the incidence of nonwheezing respiratory illnesses was in contrast, the incidence of nonwheezing respiratory illnesses was

independent of maternal age. independent of maternal age. The odds ratio for a wheezing lower respiratory tract illness in infants The odds ratio for a wheezing lower respiratory tract illness in infants

was 2.4 for infants whose mothers were less than 21 years of age was 2.4 for infants whose mothers were less than 21 years of age compared to mothers over 30 years of age. compared to mothers over 30 years of age.

Martinez, FD, Wright, AL, Holberg, CJ, et al. Maternal age as a risk factor for Martinez, FD, Wright, AL, Holberg, CJ, et al. Maternal age as a risk factor for wheezing lower respiratory illnesses in the first year of life. Am J Epidemiol 1992; wheezing lower respiratory illnesses in the first year of life. Am J Epidemiol 1992; 136:1258. 136:1258.

AsthmaAsthma

Risk factorsRisk factors Perinatal factorsPerinatal factors

PrematurityPrematurity The prevalence of asthma was significantly increased in The prevalence of asthma was significantly increased in

premature girls (odds ratio 2.6), particularly in those who premature girls (odds ratio 2.6), particularly in those who required mechanical ventilation after birth (odds ratio 3.7) [1]. required mechanical ventilation after birth (odds ratio 3.7) [1].

Prematurity was a significant risk factor for both recurrent Prematurity was a significant risk factor for both recurrent wheezy bronchitis and asthma in a second cross-sectional wheezy bronchitis and asthma in a second cross-sectional study of 1,812 primary school children [2]study of 1,812 primary school children [2]

11 von Mutius, E, Nicolai, T, Martinez, FD. Prematurity as a risk factor for asthma von Mutius, E, Nicolai, T, Martinez, FD. Prematurity as a risk factor for asthma in preadolescent children. J Pediatr 1993; 123:223.  in preadolescent children. J Pediatr 1993; 123:223.  

22 Frischer, T, Kuehr, J, Meinert, R, et al. Risk factors for childhood asthma and Frischer, T, Kuehr, J, Meinert, R, et al. Risk factors for childhood asthma and recurrent wheezy bronchitis. Eur J Pediatr 1993; 152:771.recurrent wheezy bronchitis. Eur J Pediatr 1993; 152:771.

AsthmaAsthmaRisk factorsRisk factors

Perinatal factorsPerinatal factorsBreastfeedingBreastfeeding — A number of studies have investigated the possibility — A number of studies have investigated the possibility that breastfeeding protects against the subsequent development of that breastfeeding protects against the subsequent development of asthma, and the results have been conflicting [1]. asthma, and the results have been conflicting [1].

Head circumference at birthHead circumference at birth – – a head circumference at birth of 37 cm was associated with an odds a head circumference at birth of 37 cm was associated with an odds

ratio of 1.8 (95% CI 1.1-2.0) for any medical consultation for asthma ratio of 1.8 (95% CI 1.1-2.0) for any medical consultation for asthma between the ages of birth and 16 years [2]between the ages of birth and 16 years [2]

a head circumference of 37 cm was also associated with an odds a head circumference of 37 cm was also associated with an odds ratio of 3.0 (95% CI 1.8-5.2) for recurrent asthma [3]ratio of 3.0 (95% CI 1.8-5.2) for recurrent asthma [3]. .

1.1. Wright, AL, Holberg, CJ, Taussig, LM, Martinez, FD. Factors influencing the relation of Wright, AL, Holberg, CJ, Taussig, LM, Martinez, FD. Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood. Thorax 2001; 56:192. infant feeding to asthma and recurrent wheeze in childhood. Thorax 2001; 56:192.

2.2. Godfrey, KM, Barker, DJP, Osmond, C. Disproportionate fetal growth and raised IgE Godfrey, KM, Barker, DJP, Osmond, C. Disproportionate fetal growth and raised IgE concentration in adult life. Clin Exp Allergy 1994; 24:641.concentration in adult life. Clin Exp Allergy 1994; 24:641.

3.3. Fergusson, DM, Crane, J, Beasley, R, Horwood, LJ. Perinatal factors and atopic disease Fergusson, DM, Crane, J, Beasley, R, Horwood, LJ. Perinatal factors and atopic disease in childhood. Clin Exp Allergy 1997; 27:1394. in childhood. Clin Exp Allergy 1997; 27:1394.

AsthmaAsthma

Multiple studies have demonstrated that long-Multiple studies have demonstrated that long-acting beta agonists should not be used as acting beta agonists should not be used as monotherapy for the treatment of persistent monotherapy for the treatment of persistent asthma. asthma. However, both salmeterol and formoterol have However, both salmeterol and formoterol have the potential of improving overall asthma control the potential of improving overall asthma control when added to existing ICS in patients who are when added to existing ICS in patients who are inadequately controlled on ICS alone. inadequately controlled on ICS alone. In many cases and for many outcome measures, In many cases and for many outcome measures, the control achieved with combination therapy is the control achieved with combination therapy is superior to that seen following increasing the superior to that seen following increasing the dose of the ICS. dose of the ICS.

AsthmaAsthma

Anti-IgEAnti-IgE A multicenter study of patients with severe asthma not A multicenter study of patients with severe asthma not

controlled by inhaled corticosteroids and long-acting controlled by inhaled corticosteroids and long-acting beta-agonists showed a reduction in exacerbations beta-agonists showed a reduction in exacerbations (by 26 percent), particularly for severe exacerbations (by 26 percent), particularly for severe exacerbations and emergency room visits [1]. An analysis of five and emergency room visits [1]. An analysis of five randomized controlled trials of over 2500 patients with randomized controlled trials of over 2500 patients with severe persistent asthma showed a reduction in severe persistent asthma showed a reduction in exacerbation rate of 38 percent and a reduction in exacerbation rate of 38 percent and a reduction in emergency visits by almost 50 percent emergency visits by almost 50 percent

1. Humbert, M, Beasley, R, Ayres, J, et al. Benefits of omalizumab as add-on 1. Humbert, M, Beasley, R, Ayres, J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309INNOVATE. Allergy 2005; 60:309

ResourcesResources

Asthma and Allergy Foundation of AmericaAsthma and Allergy Foundation of America http://www.aafa.org

American Lung Association American Lung Association http://www.lungusa.org

American Academy of Allergy, Asthma, and American Academy of Allergy, Asthma, and ImmunologyImmunology

National Asthma Education and Prevention ProgramNational Asthma Education and Prevention Program http://www.nhlbi.nih.gov/about/naepp/index.htm http://www.aaaai.org

Resources Resources

Allergy and Asthma Network, Mothers of Allergy and Asthma Network, Mothers of Asthmatics. Inc.Asthmatics. Inc. http://www.aanma.org/

American College of Allergy, Asthma, and American College of Allergy, Asthma, and ImmunologyImmunology http://allergy.mcg.edu

American College of Chest Physicians http://www.chestnet.org

American Thoracic Society http://www.thoracic.org