Asthma: Biology, Epidemiology, and Evaluation

1. Asthma: Biology, Epidemiology, and Evaluation Gary L. Weinstein M.D., FCCP Thursday, February 2, 2006

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

3. Asthma • "A chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T lymphocytes. • In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. • These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. • The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli. NHLBI/WHO Workshop Report, US Department of Health and Human Services. National Institutes of Health, Bethesda, 1995; Pub #95-3659.

4. Asthma • Data from the Centers for Disease Control have shown that the prevalence of asthma has increased in the United States [1, 2]. • 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 to 49.4 per 1000. • 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 1000, an increase of 52 percent. • Since that time, the increase in prevalence of asthma has slowed somewhat [3] • Weiss, KB, Wagener, DK. Asthma surveillance in the United States. A review of current trends and knowledge gaps. Chest 1990; 98:179S. •  Asthma--United States, 1982-1992. MMWR Morb Mortal Wkly Rep 1995; 43:952. • Mannino, DM, Homa, DM, Akinbami, LJ, et al. Surveillance for asthma--United States, 1980-1999. MMWR Surveill Summ 2002; 51:1.

5. Asthma Prevalence* by AgeUnited States: 1980–1996 Under 18 Total 18+ Source: National Health Interview Survey * 12-month prevalence

6. Asthma Prevalence* by SexUnited States: 1982–1996 Female Total Male Source: National Health Interview Survey * 12-month prevalence

7. Asthma Prevalence* by RaceUnited States: 1982–1996 Black White Source: National Health Interview Survey * 12-month prevalence

8. Age-Adjusted* Asthma Mortality Ratesby Sex, United States: 1979–1998 Female Total Male Source: Underlying Cause of Death dataset by the National Center for Health Statistics * Age-adjusted to 2000 U.S. population

9. Costs of AsthmaUnited States, 1980–1998Projection for the Year 2000 Source: * Weiss, et al. 1992 ** Weiss, et al. 2001

10. Risk Factors for Development of Asthma • Genetic characteristics • Environmental exposures • Contributing factors

11. Risk Factors for Development of Asthma:Genetic Characteristics • Atopy • The body’s predisposition to develop immunoglobulin E (IgE) in response to exposure to environmental allergens • Can be measured in the blood

12. Biological Agents Sufficient evidence of a causal relationship House dust mite Sufficient evidence of an association None found Limited or suggestive evidence of an association Cockroach (in preschool-aged children) Respiratory syncytial virus (RSV) Clearing the AirIndoor Air Exposures and Asthma Development Chemical Agents • Sufficient evidence of a causal relationship • None found • Sufficient evidence of an association • Environmental tobacco smoke (in preschool-aged children) • Limited or suggestive evidence of an association • None found

13. Biological Agents Sufficient evidence of a causal relationship Cat Cockroach House dust mite Sufficient evidence of an association Dog Fungi/Molds Rhinovirus Limited or Suggestive Evidence of an Association Domestic birds Chlamydia and Mycoplasma pneumoniae RSV Clearing the AirIndoor Air Exposures and Asthma Exacerbation Chemical Agents • Sufficient evidence of a causal relationship • Environmental tobacco smoke (in preschool-aged children) • Sufficient evidence of an association • NO2, NOx (high levels) • Limited or suggestive evidence of an association • Environmental tobacco smoke (school-aged, older children and adults) • Formaldehyde • Fragrances

14. Asthma • Risk factors • ATOPY — Atopy is assessed in clinical and epidemiologic studies by three methods: skin test reactivity; serum IgE levels; and blood eosinophilia [1]. Serum IgE levels appear to be closely linked with both asthma and bronchial hyperresponsiveness, whether or not asthma is present. • EXPOSURE TO INDOOR ALLERGENS — Indoor allergens include house dust mites, animal allergens, cockroach allergen, and fungi. A consensus is emerging that these allergens play a significant role in the development of asthma, although not all studies agree 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. Platts-Mills, TA. How environment affects patients with allergic disease: indoor allergens and asthma. Ann Allergy 1994; 72:381.

15. Asthma • Risk factors • OUTDOOR AIR POLLUTION — There is a known correlation between levels of air pollution and lung disease, but there is no clear association between air pollution and asthma. • RESPIRATORY INFECTIONS — Viral and bacterial respiratory infections are well-known triggers that can cause exacerbations in children and adults with asthma [1,2]. Whether infections can be a cause of asthma, however, is not known. • 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. •  Nicholson, KG, Kent, J, Ireland, DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993; 307:982.

16. Asthma • Risk factors • SMOKING AND EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE — Population-based studies appear to show a relationship between smoking and airway hyperresponsiveness. However, the presence of asthma in adults has generally been unrelated to smoking history [1]. • Environmental tobacco smoke — There is a growing body of evidence that passive smoke exposure is associated with the development of asthma in early life. Maternal smoking is the most important cause of passive smoke exposure, because of the greater exposure of the child to the mother than the father [2]. 1Weiss, 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. 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.

17. Asthma • Risk factors • Prenatal exposure to maternal smoking In bivariate analyses, maternal 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), or current smoking (OR=1.70) was significantly associated with current 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 asthma/wheeze [1]. • 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 significant association was found for currently exposed children [2]. • 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. • 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.

18. Asthma • Risk factors • OBESITY — Age-adjusted prevalence rates for asthma and obesity are increasing in the United States. Experimental models, prospective cohort studies, and population-based case-control studies suggest that patients with an elevated BMI are at increased risk for developing asthma [1,2]. • A prospective cohort study of nearly 86,000 adults followed for five years showed a linear relationship between BMI and the risk of developing asthma .The relative risk of developing asthma was 2.7 for patients in the highest BMI group compared with nonobese counterparts (p for trend <0.001) [3]. • Shore, SA, Fredberg, JJ. Obesity, smooth muscle, and airway hyperresponsiveness. J Allergy Clin Immunol 2005; 115:925. •  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 Med 1999; 159:2582. •  Young, SY, Gunzenhauser, JD, Malone, KE, McTiernan, A. Body mass index and asthma in the military population of the northwestern United States. Arch Intern Med 2001; 161:1605.

19. Asthma • Risk factors • PERINATAL FACTORS (besides maternal smoking) • Maternal age – • The incidence of wheezing lower respiratory tract illnesses was inversely related to maternal age; • in contrast, the incidence of nonwheezing respiratory illnesses was independent of maternal age. • 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 compared to mothers over 30 years of age. 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; 136:1258.

20. Asthma • Risk factors • Perinatal factors • Prematurity • The prevalence of asthma was significantly increased in premature girls (odds ratio 2.6), particularly in those who required mechanical ventilation after birth (odds ratio 3.7) [1]. • Prematurity was a significant risk factor for both recurrent wheezy bronchitis and asthma in a second cross-sectional study of 1,812 primary school children [2] • von Mutius, E, Nicolai, T, Martinez, FD. Prematurity as a risk factor for asthma in preadolescent children. J Pediatr 1993; 123:223.   • Frischer, T, Kuehr, J, Meinert, R, et al. Risk factors for childhood asthma and recurrent wheezy bronchitis. Eur J Pediatr 1993; 152:771.

21. Asthma • Risk factors • Perinatal factors • Breastfeeding — A number of studies have investigated the possibility that breastfeeding protects against the subsequent development of asthma, and the results have been conflicting [1]. • Head circumference at birth – • 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 between the ages of birth and 16 years [2] • 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]. • 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. • Godfrey, KM, Barker, DJP, Osmond, C. Disproportionate fetal growth and raised IgE concentration in adult life. Clin Exp Allergy 1994; 24:641. • Fergusson, DM, Crane, J, Beasley, R, Horwood, LJ. Perinatal factors and atopic disease in childhood. Clin Exp Allergy 1997; 27:1394.

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

23. Asthma • Anti-IgE • A multicenter study of patients with severe asthma not controlled by inhaled corticosteroids and long-acting beta-agonists showed a reduction in exacerbations (by 26 percent), particularly for severe exacerbations and emergency room visits [1]. An analysis of five randomized controlled trials of over 2500 patients with severe persistent asthma showed a reduction in exacerbation rate of 38 percent and a reduction in emergency visits by almost 50 percent 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 controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309

24. Resources • Asthma and Allergy Foundation of America • http://www.aafa.org • American Lung Association • http://www.lungusa.org • American Academy of Allergy, Asthma, and Immunology • National Asthma Education and Prevention Program • http://www.nhlbi.nih.gov/about/naepp/index.htm • http://www.aaaai.org

25. Resources • Allergy and Asthma Network, Mothers of Asthmatics. Inc. • http://www.aanma.org/ • American College of Allergy, Asthma, and Immunology • http://allergy.mcg.edu • American College of Chest Physicians • http://www.chestnet.org • American Thoracic Society • http://www.thoracic.org