Risk Factors for Recurrent Wheezing in Children Allergens

Risk Factors for Recurrent Wheezing in Children: Allergens Dennis R. Ownby, MD Chief, Division of Allergy, Immunology, Rheumatology Georgia Health Sciences University Augusta, GA, USA

Disclosures o In the past year I have been: n A consultant to Carbo. Nix, LLC n Advisory board, Merck Childhood Asthma Network o No discussion of off label drug use o Research Support: National Institutes of Health o Legal Fees: None o Gifts: None

Concepts to Explore o Does allergen exposure promote or allow allergic disease o Is exposure to some allergens typically associated with exposure to some other immunomodulatory influence

Accepted Knowledge o Most children with asthma are sensitized to allergens o Strong association between allergic sensitization and persistence of asthma o Stronger association between sensitization to perennial allergens and asthma than seasonal allergens

Early Allergen Sensitization and Chronic Asthma in Children o German MAS Study o 1314 children: birth to 13 years of age o Allergen exposure at 6 & 18 months and at 3, 4, 5 years o Lung function at 7, 10 , 13 years o Ig. E’s at 1, 2, 3, 5, 6, 7 and 10 years Illi S, et al. Lancet 2006; 368: 763 -770

Prevalence of Current Wheezing: Birth to 13 Years Non-atopic, n=94 Atopic, n=59 at school age Illi S, et al. Lancet 2006; 368: 763 -770

Effect of Sensitization at ≤ 3 Years and Lung Function at 13 Years of Age NS = not sensitized S/LE = sensitized to dust mite ± cat, low exposure at 3 and 5 years S/HE = sensitized to dust mite ± cat, high exposure at 3 and 5 years Illi S, et al. Lancet 2006; 368: 763 -770

Dust mite allergen exposure: the first allergen though to “cause” the development of asthma.

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

Previous Findings o Sporik et al, NEJM 1990 RR = 4. 8 for asthma at age 11 associated with Der p 1>10 μg/g dust at 1 -2 yrs o Burr et al, Arch Dis Child 1993 No association between dust mite levels at 1 yr and wheeze or atopy or +ST to mites at 7 yrs o Lau et al, Lancet 2000 No association between dust mite levels in infancy and asthma at 7 yrs o Johnson et al, J Allergy Clin Immunol 2004 No association between dust mite levels in infancy and seroatopy, atopy or asthma at 6 -7 yrs

Dust Mite Exposure and Wheezing in MAS = 1 st quartile of dust mite at 6 months of age = 4 th quartile of dust mite at 6 months of age Lau S, et al. Paediatric Resp Rev 2002; 3: 265 -272

Childhood Allergy Study (CAS) o 835 middle-class children living in suburbs of Detroit, MI, recruited at birth o Selected by geographic area of residence, not selected for allergic risk factors o Yearly questionnaires concerning home environment and home visits at 2 & 4 years o Evaluation between 6 & 7 years for asthma and allergy Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Clinical Evaluation at 6 – 7 Years o Medical history and physical examination o Skin puncture tests: mites (D. farinae, D. pteronyssinus), Phleum pratense, Ambrosia artemisiifolia, cat, and dog o Specific Ig. E to same allergens plus Alternaria alternata (DPC Ala. STAT) o Total Ig. E (DPC Ala. STAT) o Spirometry and methacholine challenge o 474 children completed study Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

CAS Exposure Variables o Clinical diagnoses of infection from medical records n Upper respiratory infections, URI (otitis media, cough, croup, rhinitis, viral syndrome, etc) n Lower respiratory infections, LRI (bronchitis, pneumonia, wheezing, etc) o Day care exposure o Number of older siblings Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Examined Children (n=480) o o o o Age, years Girls: boys Atopic Seroatopic +BHR Ever Asthma Current Atopic Asthma 6. 72 range 6. 1 - 7. 7 242: 232 1. 04: 1 165/470 34. 4% 147/407 36. 1% 105/462 22. 7% 45/427 10. 5% 33/473 7. 0% 25/473 5. 2% Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Outcomes by Dust Mite Allergen > 10μg/gm* All Children Variable +DM SPT +DM Ig. E Atopy Seroatopy +BHR Asthma Current Atopic Asthma OR 1. 09 1. 13 1. 02 0. 53 0. 68 95% CI 0. 58 -2. 06 0. 57 -2. 50 0. 66 -1. 94 0. 58 -1. 81 0. 27 -1. 04 0. 27 -1. 70 0. 74 0. 21 -2. 62 P-value 0. 78 0. 64 0. 66 0. 93 0. 07 0. 41 0. 64 *adjusted for gender, firstborn status, cord blood Ig. E, parental education and history of allergies and asthma, and early exposure to household cats or dogs, tobacco smoke or daycare. Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Outcomes by Dust Mite Allergen > 10 μg/gm for Children with No Family History* Variable +DM SPT +DM Ig. E Atopy Seroatopy +BHR Asthma Current Atopic Asthma OR 0. 40 0. 53 0. 69 0. 62 2. 80 95% CI 0. 13 -1. 19 0. 16 -1. 79 0. 29 -1. 62 0. 26 -1. 49 0. 66 -11. 9 P-value 0. 100 0. 308 0. 392 0. 286 0. 285 0. 163 1. 52 0. 22 -10. 67 *adjusted for gender, firstborn status, cord blood Ig. E, parental education, early exposure to household cats or dogs, tobacco smoke or daycare. Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Outcomes by Dust Mite Allergen > 10 μg/gm for Children with a Positive Family History* Variable +DM SPT +DM Ig. E Atopy Seroatopy +BHR Asthma Current Atopic Asthma OR 2. 09 2. 08 1. 72 1. 73 0. 46 0. 27 0. 39 95% CI 0. 93 -4. 73 0. 77 -5. 61 0. 83 -3. 59 0. 77 -3. 87 0. 15 -1. 41 0. 03 -2. 12 0. 05 -3. 13 P-value 0. 076 0. 150 0. 147 0. 182 0. 175 0. 212 0. 376 *adjusted for gender, firstborn status, cord blood Ig. E, parental education, early exposure to household cats or dogs, tobacco smoke or daycare. Johnson CC, et al. J Allergy Clin Immunol 2004; 114: 105 -10

Multivariable Models Predicting Allergic Sensitization at 6 -7 Years Specific Ig. E Variable 1 yr +Skin Prick Test OR P-value OR P-Value Respiratory Infection 1. 22 0. 38 1. 15 0. 50 Daycare 0. 90 0. 19 1. 09 0. 19 Number older sibs 1 dog/cat 0. 46 0. 01 0. 80 0. 42 1. 19 0. 54 1. 02 0. 94 > 2 dogs/cats 0. 27 0. 003 0. 24 0. 002

Land of Low Allergen Exposure o 161 Kuwaity children, 9 -16 years with asthma and 303 healthy controls o Few pets in homes for religious reasons o Dry climate n relative humid low, 15%-30% n low levels of dust mites Hassan MS et al. J Allergy Clin Immunol 2004; 114: 1389 -94

Land of Low Allergen Exposure o Allergen levels in 383 mattresses n Der p 1, 99. 7% below detection n Der f 1, 98. 1% below detection n Fel d 1, 15. 2% below detection, median 0. 14 n Can f 1, 83. 4% below detection n Bla g 1, 51. 9% below detection, median 0. 05 n Cat ownership: 4. 1% n Dog ownership: 1. 5% Hassan MS et al. J Allergy Clin Immunol 2004; 114: 1389 -94

Land of Low Allergen Exposure Allergen Skin test Dust mites Cat Dog Asthma 158 31 (20%) 73 (46%) 55 (35%) Control 303 13 (4%) 46 (15%) 31 (10%) Hassan MS et al. J Allergy Clin Immunol 2004; 114: 1389 -94

Pets Contribute More than Allergens to Homes o 18 house dust samples from WHEALS o 6 ≥ 1 dogs, 6 ≥ 1 cat, 6 without pets o Phylo. Chip analysis of microbial taxa present n Insufficient DNA in 2 dust samples o Homes with dogs n More types of bacteria present, richer, p <. 04 n More diverse, p <. 04 Fujimura KE, et al. J Allergy Clin Immunol 2010; 126: 410 -412 23

Bacterial Communities in House Dust from Dog verses No-Pet Households Fujimura KE, et al. J Allergy Clin Immunol 2010; 126: 410 -412 24

Pets Alter Home Dust Microbiome o 337 bacterial taxa significantly increased in dog-owning homes • • Proteobacteria (112 taxa) Actinobacteria (63 taxa) Firmicutes (47 taxa) Bacteroidetes (41 taxa) Spirochaetes (22 taxa) Verrucomicrobia (7 taxa) These are phyla common in the human gastrointestinal tract Fujimura KE, et al. J Allergy Clin Immunol 2010; 126: 410 -412 25

Movement of Bacteria from House Dust to Infant Gut o Hand-to-mouth activity o Well studied by toxicologists o Studies demonstrate that hand-tomouth activity relates dust and infant concentrations of toxins 26

Soil and House Dust Ingestion by Children o Soil and dust ingestion directly related to hand to mouth and object to mouth activity in children o Hand to mouth activity is highly variable in children and varies indoors and outdoors o Average dust ingestion is 30– 100 mg/day for children 6 months – 11 years of age o Pica (ingestion of large quantities of soil ~5 gm/day) is relatively common in children U. S. EPA. Child Specific Exposure Factors Handbook 2008

Role of Unpasteurized Milk o Multi-center European study (PARSIFAL) o 14, 893 children 5 -13 years-of-age o Farm milk inversely associated with asthma, adj. OR = 0. 74 (95% CI 0. 61 -0. 88) o Rhinoconjunctivitis, sensitization to pollen and food mixes also significantly inversely associated with farm milk Waser M, et al. Clinical Exp Allergy 2006; 37: 661 -670

Drinking Water Microbes and Atopy o 563 children, 7 -16 years, living in Finnish- and Russian-Karelia o Skin prick tested with 14 common allergens and foods o Finnish children significantly more sensitization – 48% vs 16% o Multivariable analysis – sex, cat < 1 yr, density of microbes in water Von Hertzen L, et al. Allergy 2007; 62: 288 -292

Does Pet Ownership Impact House Dust and Stool Microbiota? Lynch S, et al. unpublished 30

Conclusions o Exposure to allergens allows predisposed persons to become sensitized by exposure dose not change the person’s predisposition o Exposures to allergens are often associated with exposures to other agents which alter immune responses o Microbes ingested by children in infancy have strong effects on the risk of developing allergic sensitivity and disease