Indoor Allergens and Allergen Avoidance. Dennis R. Ownby, MD Georgia Regents University Augusta, GA

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1 Indoor Allergens and Allergen Avoidance Dennis R. Ownby, MD Georgia Regents University Augusta, GA

2 Disclosure Employment Georgia Regents University Financial Interests Nothing to disclose Research Interests NIAID, NHLBI Organizational Interests - Fellow: AAAAI Gifts - Nothing to disclose Other Interests - Member: FDA Asthma and Pulmonary Drugs Advisory Committee

3 Learning Objectives Upon completion of this session, participants should be able to: List all major indoor allergens and the variables that most closely control the content of these allergens in homes and public buildings Discuss current knowledge and its limitations concerning the reduction of indoor allergens in homes

4 Topics House dust Indoor allergens Exposure-disease relationships Control measures Other indoor biologics

5 House Dust Complex mixture of everything found in homes House dust extracts have been widely used clinically but are impossible to standardize Variable quantities of allergens mites, cat, dog, mice, rat, insects, foods, molds, & outdoor allergens Potential immune modifiers: chitin, endotoxin, flagellin, DNA

6 Monoclonal Antibodies Specific for Allergens Major advance for indoor allergens Sensitive and specific assays for measuring allergens Measurement of allergens in dust, air and other samples estimates of exposure value of abatement efforts standardized extracts

7 Environmental Sampling Most literature based on settled dust Floors - risk of dilution by large particles, e.g.soil Beds covers, pillows, mattresses Air highly dependent on sampling method (filter type, air volume, time), activity in area, season Dust and air concentrations typically poorly correlated Exposure estimate concentration or amount per unit area

8 Dust Mites in Homes Studied by counting mites measuring allergen to group 1 allergens Pyroglyphid mites dominate (D. pteronyssinus, D. farinae, Euroglyphus maynei) Tropical areas: Blomia tropicalis Occasionally storage mites: Lepidoglyphus destructor, Tyrophagus putrescentior

9 Dust Mite Allergens Mites growth dependent on water and temperature relative humidity >50% absolute humidity 6 g/kg temperature of 65 to 80 F Fecal particles are μm in size particles contain digestive enzymes surrounded by a chitinous peritrophic membrane Settle out of air quickly so airborne levels depend upon disturbance in room

10 Seasonal Change in Dust Mite Allergen Concentrations Peterson EL, et al. J Allergy Clin Immunol 1999;104:348-55

11 Dust Mite Group 1 & 2 Allergens Group 1 allergens Der f 1, Der p 1 24-kD glycoprotein enzymatically active cysteine proteinases Group 2 allergens Der f 2, Der p 2 >90% sequence homology Cannot currently be separated by monoclonal antibodies

12 Commercial Mite Allergen Extracts In US extracts are all from isolated mite bodies; similar concentrations of group 1 and group 2 allergens 40 µg/ml Der p 1, 30 µg/ml Der p 2 European extracts both whole culture and isolated bodies, more group 1 than group 2 (approximately 10-fold)

13 Clinically Important Facts on Mites Limited cross-reactivity between pyroglyphid mites and tropical mite, Blomia tropicalis (Florida) Der f/p 10 (tropomyosins) crossreact with shrimp (food), cockroach, limpet and possibly other invertebrate tropomyosins May be cause of oral allergy syndrome in some persons

14 Effectiveness of Mite Avoidance 2007 Expert Panel Report 3 Most important step in controlling allergeninduced asthma reduce exposure 2009 Global Initiative for Asthma and British Thoracic Society Guidelines no consistent evidence for allergen avoidance in preventing asthma only tenuous evidence that reducing allergen exposure can reduce asthma morbidity Tovey ER, Marks GB. J Allergy Clin Immunol 2011;128:723-7

15 Effectiveness of Mite Avoidance for Asthma Symptoms Cochrane Analysis: 10/05/ randomized trials, 3121 people with asthma No overall reduction in measures of asthma control Chemical control in 10 trials Physical methods in 37 trials Combined methods in 8 trials Questions concerning effectiveness of control measures

16 Primary Prevention of Asthma by Dust Mite Avoidance 7 prospective studies of allergen avoidance to prevent asthma 2 studies showed reduction of asthma 5 studies showed no effect on asthma Sensitization to dust mites was significantly reduced in only 1 study Sensitization to cats was not reduced in any study Simpson A, Custovic A. Curr Allergy Asthma Report 2009;9:363-9

17 Cat and Dog Allergen in US Homes National sample of 831 homes 54.9% of homes had no dog or cat 10.4% both dog and cat 21.4% with dog(s) 13.4% with cat(s) Percent of Homes with Allergen Can f 1 Fel d 1 Bed Sofa LR Floor Arbes SJ, et al. J Allergy Clin Immunol 2004;114:

18 Cat Allergens Easily recognized by patients remains airborne in undisturbed home small (<10 μm) particles Major allergen: Fel d 1 Homologous with uteroglobulin Primarily synthesized in the skin Biological function is unknown Composed of 2 heterodimers Minor allergens: Fel d 2 (albumin), Fel d 3 (cystatin), Fel d 4 (lipocalin)

19 Clinically Important Facts - Fel d 1 Diagnostic and therapeutic cat extracts in US are assigned potency based on Fel d 1 content Biologic Allergy Units (BAU) 10,000 BAU targeted to contain 15.0 FDA units/ml (1 u = 4 μg)

20 Dog Allergens Major allergen is Can f 1, mw = 25 kd Lipocalin cysteine protease inhibitor Found in hair, dander, pelt & saliva not in urine or feces Concentrations vary by breed recent studies do not show breed specific allergens

21 Dog Allergens Can f 2 lipocalin MW 19 kd in dander and saliva Can f 3 dog serum albumin 69 kd protein found in dander, epithelia, saliva and serum Can f 4 in dog dander

22 Rodents Rats, mice, rabbits, gerbils, hamsters, guinea pigs Mouse allergen, mouse urinary protein (MUP) is on small particles similar to cat allergen Mouse appears to be important allergens in inner-city homes and schools (?rat) Important occupational allergen

23 Insects Cockroaches major source of indoor allergens especially in inner cities Moths, crickets, locusts, may flies, beetles, nimitti flies and house flies Known occupational allergens Different allergens from those causing reactions following insect bites or stings

Cockroaches Most common species indoors: Blattella germanica, German Periplaneta americana, American World wide distribution, common in inner cities

24 Cockroaches Most common species indoors: Blattella germanica, German Periplaneta americana, American World wide distribution, common in inner cities Allergens from feces, saliva or debris (frass) Allergens not easily detected in undisturbed air, large particles (like dust mites) Highest levels usually in kitchens

25 Common Indoor Cockroaches in USA German Cockroach Oriental Cockroach American Cockroach

26 Major Cockroach Allergens Bla g 1 complex allergen, repeating gene, 2 sequences with novel folding of 6 helices create a large hydrophobic cavity Bla g 2 homodimer Binds to mannose receptor (CD206) on human fibroblasts Stimulates inflammatory cytokines (TNF, IL6), activates NF-k

27 Allergen Avoidance for Prevention Primary prevention can allergen sensitization be prevented by reducing allergen exposure Secondary prevention will reducing exposure prevent progression from sensitization to allergic disease Tertiary prevention can symptoms of allergic disease be reduced or prevented by reducing allergen exposure

28 Mite Allergen Exposure & Disease Dust mites: sensitization at 2-10 μg/g of dust in most studies For nonallergic children higher threshold of 20 μg/g Mite allergen consistently related to asthma in many countries Mite allergen related to rhinitis atopic dermatitis anaphylaxis from ingestion Actual daily dose of allergen unknown

29 Cat Allergen Cat room with Fed d 1 level of ~500 μg/g produced symptoms in all sensitive persons within 2 hours Levels of >10 μg/g are a risk factor for acute asthma attacks in sensitive persons Levels of > 2 μg/g increase risk of sensitization Van Metre TE, et al. J Allergy Clin Immunol 1986;78:62-75

30 Indoor Allergen Avoidance Strict avoidance: hospital room or mountain sanatoria associated with reduced symptoms and BHR Elimination of animals leads to a fall in allergen levels over months, 4 months are required to reach basal level Trials of dust mite avoidance rarely reduce allergen levels to levels of hospital rooms

31 Dust Mite Avoidance - Bedroom Impermeable mattress and pillow covers Wash bedding weekly at 130 F Remove carpets, stuffed animals, & clutter from bedroom Vacuum weekly with high-efficiency bag or HEPA filter vacuum Is this really the most important location

32 Dust Mite Control in Homes Home furnishings hard floors vinyl or leather furniture Control humidity kept below 50% (6 g/kg absolute water content) humidity inside materials is important Chemical treatments benzyl benzoate powder 3% tannic acid Especially avoid carpets on concrete slabs or other unventilated floors

33 Cat Allergen Avoidance Removal of cat only clearly effective avoidance Cat washing only temporarily reduces allergen shedding from cats Aggressive cleaning of homes can reduce allergen levels more rapidly Steam cleaning of carpets did not seem more effective than regular vacuuming

34 Fel d 1 after Cat Removal from Home Wood RA, et al. J Allergy Clin Immunol 1989;83:

35 Fel d 1 after Cat Removal from Home Wood RA, et al. J Allergy Clin Immunol 1989;83:

36 Air Cleaners or Filters Two common types Electrostatic precipitators HEPA, high efficiency particulate air Most electrostatic filters produce ozone Studies are inconclusive on health benefits of air filters

37 Ionisers for Asthma Cochrane Review: 09/12/2012 The few studies conducted in the homes of people with asthma, demonstrate no significant benefit

38 Indoor Molds and Fungi Consistent associations between excess indoor dampness and cough, wheezing, and asthma in both children and adults Relationship between dampness in homes and the level of exposure to molds is not well defined No widely adopted methods of assessing indoor mold beyond questionnaires Douwes J, Pearce N. Am J Epidemiology 2003;158:

39 Humidity Control for Chronic Asthma Cochran Review: 06/13/2013 Only two studies Little clinical benefit for persons with asthma from the use of dehumidification using mechanical devices

40 Reducing Mold Exposure in Buildings to Improve Asthma Cochran Review: 09/07/2011 Eight studies with 6,538 participants 3 randomized trials 5 non-randomized reports Extensive remediation compared to information only Moderate-quality evidence asthma symptom days did not decrease but, ED visits and hospitalizations decreased

41 Endotoxin Gram-negative cell wall product Potent immune stimulant Complex receptor-tlr4, MD-2, CD14 Measured with Limulus assay High levels on farms and maybe with furred pets in homes Higher endotoxin levels are associated with less allergic sensitization in children

42 Chitin 2nd most abundant polysaccharide in the world - insects, crustaceans, parasites, fungi Size dependent lung inflammation effects Medium sized induce inflammation Small sized reduce inflammation Human chitinase SNP s strongly associated with asthma risk

43 Conclusions We live indoors Sensitivity to indoor allergens is strongly associated with allergic disease, particularly asthma Dominant indoor allergens: dust mites, cat, dog, cockroach, mouse, rat, fungi

Assessing Allergic Sensitivities and Allergen Exposures

Assessing Allergic Sensitivities and Allergen Exposures James A. MacLean, M.D. Partners Asthma Center North Shore Asthma and Allergy Affiliates Massachusetts General Hospital Harvard Medical School Objectives