1. The Role of Environmental Exposures and Atopy in Asthma of the Elderly Monroe James King, DO Associate Clinical Professor of Medicine College of Medicine, University of South Florida

2. Potential Conflict of Interest Consultant to Pure Air Controls, US Energy Corporation, Clearwater, FL, prior to 2007

3. What We Know About the Environment and Allergens in Asthmatics ? In The General Population Indoor Air – allergens and pollutants Outdoor Air – allergens and pollutants In Older Adults No comprehensive reviews or meta-analysis * Small studies *PubMed and Web of Science search July 24, 2008; search terms included asthma and elderly, age over 40, reviews, meta -analysis.

4. Evidence in General Population Clearing the Air: Asthma and Indoor Air Exposure 1 Institute of Medicine For EPA 2000 National Academy Press www.nap.edu

5. Indoor Air Quality Pollutants 1 Biological Animals: cats, dogs, rodents, birds Cockroaches House dust mites Endotoxins Fungi or molds Houseplants Pollen Viruses and bacteria Chemical NO x Pesticides Ozone Environmental tobacco smoke Other particulate matter SO x Volatile organics Formaldehyde Fragrances

6. Evidence Levels 1 A: Sufficient evidence of a causal relationship B: Sufficient evidence of an association C: Limited or suggestive evidence of an association D: Inadequate or insufficient evidence to determine if an association exists E: Limited or suggestive evidence of no association

7. Clearing the Air 1 DevelopmentExacerbations House Dust MitesAA Environmental Tobacco Smoke Preschool Others BDBD Preschool Others ACAC CatsDA CockroachesPreschool Other CDCD ACAC DogsDB FungiDB

8. Clearing the Air 1 Development Exacerbations FormaldehydeDB Pollen (Indoor)DD Volatile Organic Compounds DD RhinovirusEB EndotoxinsDD FragrancesDC

9. Damp Indoor Spaces and Health Institute of Medicine for CDC 2003 2 DevelopmentExacerbation (Symptoms) AsthmaCB Upper Respiratory Symptoms B CoughB WheezeB DyspneaC Meta-analysis reported 30-50% increase in respiratory and asthma related health outcomes.Fisk WJ et al in Indoor Air, 2007;Vol 17, (4) 284-296

10. Evidence Specific to Older Adults With Asthma No meta-analysis or evidence based large studies Several small studies of skin test and specific IgE prevalence studies No allergen bronchial challenge studies Few epidemiological studies of ER or hospital admissions

11. Allergy Skin Tests in Older Subjects NAgeSkin Test Positive Percent to at least 1 of 8 NHANES II 3 U.S. Population/1986 Study conducted 1980-81 250965-748 NHANES II 4 US Population/2000 Retrospective study of same NHANES II population 391060-7412.6

12. Studies of Skin Test or Specific IgE in Older Adults with Asthma Location Ref / Date N Mean Age Mean Age of Onset Skin Test Positive % Serum Spec IgE Positive % Britain 5 /1972 15 >60 27 ND Tuscon 6 /1991 46 73 52 37 ? Baltimore 7 /2001 75 74 ? 75 ND New York 8 /2002 45 69 39 ND 60 (Cockroach 47%) Clearwater,FL 9 /2004 32 >64 ? ND 56 (Dust Mite - Der P)

13. Early and Late Onset Asthma Location Ref /DateNMean Age Mean Age of Onset Skin Test Positive % Serum Spec. IgE Positive % Providence RI 10 /1991 25> 70< 43 (N=13) > 70 (N=12) 62 0 ND Rochester MN 11 /1997 63> 65< 40 (N?) > 41 (N?) > 65 (N?) 56 21 20 ND Boston MA 12 /1997 466149 ± 15.7ND24(cat) 20(Der P 1) Boston MA 12 /1997 3361 ND18 (cat) 21 (Der P 1)

14. Allergy Data from TENOR Study 13 Characteristics Younger – Age 18 - 64 N = 2912 Older – Age 65 65N=566 P value Geometric Mean IgE, IU/ml 9060<.001 Allergic Allergic Rhinitis 2134 (74 %) 341 (61 %) <.001 Atopic Dermatitis 424 (15%) 49 (9%) <.001 Never Skin Tested 202 (11%) 61 (16%) <.001 Negative Skin tests 100 (5%) 40 (10%) Positive Skin Tests 1568 (84%) 290 (74%)

15. Do Skin Tests Reflect Current Allergen Exposure ? 7 AllergenLevelsSkin Test +/n (%) Der P. Group 1> 20 µg11/42 (26) < 20 µg13/37 (35) Cockroach0.4 -17.2 U4/19 (21) Undetectable17/56 (30)

16. Do Skin Tests Reflect Current Allergen Exposure to Pets? 7 AllergenPet in homeSkin test +% Positive Cat15yes533 60no1932 Dog20yes630 55no1527

17. Do Positive Skin Tests And/Or Specific IgE Predict Clinical Allergy In Older Adults? Natural Challenge or Exposure Room - No studies in older adults Bronchial Challenge - Only small studies in general population. No studies found in older adults Nasal Challenge 14 - Few studies; older subjects less likely to have positive nasal challenge with positive skin test or specific IgE

18. Nasal Challenge to Allergens in Older Adults Location Ref /Date / Allergen NAgeSkin Test and/or Specific IgE Response Nasal Challenge Response Tampa FL 14 /2008/ Der P. 28 60 (Mean 68) 11 Pos 17 Neg 2 Pos 2020-59 (Mean 34) 10 Pos 10 Neg 10 Pos 10 Neg

19. Summary of IgE Evidence Specific to Older Asthmatics Skin tests or serum specific IgE were positive in 0 to 75%. Late onset asthmatics were less likely to have skin or serum specific IgE positive tests. Positive skin tests did not reflect current exposure to allergens. Neither skin test or serum specific IgE predicted nasal challenge response in older adults.

20. Outdoor Air Pollution Associations Survey of Los Angeles and San Diego traffic density and outdoor air pollution levels. Traffic density and ozone levels associated with poor asthma control in elderly adults. 15 Particulate air pollution and hospital admissions for cardiorespiratory diseases: are the elderly at greater risk? 16

21. What Questions Need Answering? What research is needed?

22. Questions Specific to Asthma in Older Adults Does evidence of allergy/environmental exposure in the general population apply to older adults? Is airway response to the environment in older adults different to: Allergens and other Pollutants? Temperature?

23. Questions Specific to Asthma in Older Adults Does asthma of late onset (over age 40) have a different etiology and mechanism than childhood/young adult onset? What is the role of non-IgE–mediated pathways in the development of asthma, and does this role suggest other biomarkers of effect that should be considered?

24. Questions About Methods Specific to Older Adults Is it safe to do allergen challenges? BronchialNasal SegmentalAllergen Rooms Bronchial-alveolar lavageNatural Exposure Biopsy Is it safe to do nonspecific (methacholine, histamine, or cold air) bronchial challenge after exposure to allergen?

25. Technical Capabilities and Limitations Allergen tests and assays depend on well characterized allergens. Skin tests in older subjects are sometimes limited by subjects skin aging or sun damage Need age specific cut off levels for clinical significance of specific IgE serum and skin tests Do antibodies present in skin or serum reflect antibodies in the bronchial mucosa and lungs? (Bronchial Associated Lymph Tissue)

26. Future Studies Small Mechanistic Large Natural History Observational New Methods to Determine Causation

27. Modifiers of Environmental Influence on Asthma In Elderly Female Gender Obesity Aspirin NSAIDS Aspirin NSAIDS New Ideas Genetics Infections or Insult Pollutants Genetics Infections or Insult Pollutants Co- Morbidity Dwelling Type

28. Asthma Prevalence (2001-2003) From 2007 CDC Surv. Summ on Asthma

29. Gender Patterns for Adult Asthma: 471,000 Hospitalizations in NY State Lee GB. J Allergy Clin Immunol 2008;121 (2): S1

30. References 1. Institute of Medicine. Committee on the Assessment of Asthma and Indoor Air. Division of Health Promotion and Disease Prevention. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: National Academy Press; National Academy of Sciences; 2000. Available at: http://www.epa.gov/asthma/publications.html#Clearing_the_Air. Accessed July 24, 2008. 2. Institute of Medicine. Committee on Damp Indoor Spaces and Health. Board on Health Promotion and Disease Prevention. Damp Indoor Spaces and Health. Washington, DC: National Academy Press: National Academy of Sciences; 2004. ISBN 0-309-09193-4. Available at: www.nap.edu/catalog/1011.html. Accessed July 24, 2008. 3. Gergen PJ, Turkeltaub PC. Percutaneous Immediate Hypersensitivity to Eight Allergens. United States, 1976-80. Washington, DC: National Center for Health Statistics. Vital and Health Statistics. July 1986. DHHS Pub No.(PHS) 86-1685. Series 11, No. 235. 4. Gergen JP, Turkeltaub PC, Sempos CT. Is allergen skin test reactivity a predictor of mortality? Findings from a national cohort. Clin Exp Allergy. 2000;30(12):1717-1723. 5. Lee HY, Stretton TB. Asthma in the elderly. Br Med J. October 14, 1972; 4:93-95.

31. References (continued) 6. Burrows, B, Barbee RA, Cline MG, Knudson RJ, Lebowitz. Characteristics of asthma among elderly adults in a sample of the general population. Chest. 1991;100(4):935-942. 7. Huss K, Naumann PL, Mason PJ, et al. Asthma severity, atopic status, allergen exposure, and quality of life in elderly persons. Ann Allergy Asthma Immunol. 2001;86:524-530. 8. Rogers L, Cassino C, Berger KL, et al. Asthma in the elderly: cockroach sensitivity and severity of airway obstruction in elderly nonsmokers. Chest. 2002;122(5):1580-1586. 9. King MJ, Bukantz SC, Phillips S, Mohapatra SS, Tamulis T, Lockey RF. Serum total IgE and specific IgE to Dermatophagoides pteronyssinus, but not eosinophil cationic protein, are more likely to be elevated in elderly asthmatic patients. Allergy Asthma Proc. 2004;25(5):321-325. 10. Braman SS, Kaemmerlen JT, Davis SM. Asthma in the elderly. A comparison between patients with recently acquired and long-standing disease. Am Rev Respir Dis. 1991;143(2):336-340. 11. Reed CE. The role of allergy and airway inflammation. In: Barbee RA, Bloom JW, eds. Asthma in the Elderly. New York, NY: Marcel Decker; 1997:33-52.

32. References (continued) 12. Litonjua AA, Sparrow D, Weiss ST, OConnor GT, Long AA, Ohman JL Jr. Sensitization to cat allergen is associated with asthma in older men and predicts new-onset airway hyperresponsiveness. The Normative Aging Study. Am J Respir Crit Care Med. 1997;156(1):23-27. 13. Slavin RG, Haselkorn T, Lee JH, Zheng B, Deniz Y, Wenzel SE, and the TENOR Study Group. Asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study. Ann Allergy Asthma Immunol. 2006; 96(3):406-414. 14. King MJ, Tamulus T, Lockey RF. Prick puncture skin tests and serum specific IgE as predictors of nasal challenge response to dermatophagoides pteronyssinus in older adults. Ann Allergy Asthma Immunol. 2008;101(1):12-17. 15. Meng YY, Wilhelm M, Rull RP, English P, Ritz B. Traffic and outdoor air pollution levels near residences and poorly controlled asthma in adults. Ann Allergy Asthma Immunol. 2007;98(5):455-463. 16. Anderson HR, Atkinson RW, Bremner SA, Marston L. Eur Respir J Suppl. May 2003;40:39s-46s.

33. Questions About Methods Specific to Older Adults How do we define asthma for studies? Severity Duration/ age of onset Diagnosis by questionnaire or objective measures – Is spirometry, reversibility, provocation necessary? Do we need new age specific cut off levels and norms for spirometry or other pulmonary function tests?