Dennis R. Ownby, M.D. Betty B. Wray Professor of Pediatrics Georgia Health Sciences University, Augusta, Georgia, USA The Link Between Pets and Reduced Risk of Allergic Disease

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

Ideas to explore Consistency of observations about animal exposure and risk of allergic disease Other environmental exposures related to risk of allergic disease Pets and home microbiomes How much dirt and house dust do children normally eat What links these observations together

Animal Exposure and Allergy Risk Cross-sectional survey of rural areas in Austria, Germany, Switzerland (only nationals analyzed) 2618/3504 (78%) of 6-13 year old children interviewed about allergic diseases - ISAAC Measurement of allergen specific IgE antibodies (n=901) Riedler J, et al. Lancet 2001;358:

Farm Animal Exposure And Allergy Risk Drawn from Riedler J, et al. Lancet 2001;358: , table 2. Stables & Farm Milk < 1 yr Stables, No Farm Milk < 1 yr Farm Milk, No Stables < 1 yr Stables &/or Farm Milk > 1 yr Neither Stables nor Farm Milk

Detroit Childhood Allergy Study: CAS Birth cohort of 835 middle-class children living in suburbs Yearly questionnaires concerning home environments plus home visits at 2&4 years Evaluation between 6 and 8 years for asthma and allergy Ownby DR et al JAMA 2002;288:

First Year Pet Exposure And Allergic Sensitivity: CAS Ownby DR et al JAMA 2002;288: Percent of Children P =.04 P =.02 P =.003 P =.005

Lung Function And First Year Pet Exposure: CAS Percent of Children Ownby DR et al JAMA 2002;288: P =.01 P =.03 P = NS

Pet Exposure and Total IgE at 18 Years of Age: CAS All Participants All ergen Sensitized Participants 9 p =.053, p trend =.017 Total Serum IgE (95% CI) n= n= p =.029, p trend =.007 Wegienka G et al. J Allergy Clin Immunol 2010;126:

Wayne County Health Environment Allergy and Asthma Longitudinal Study = WHEALS Geographically based birth cohort – not selected for risk Detailed examination of pet effect on allergy risk especially – 1st year of life – Endotoxin – Antibiotics Diverse cohort by SES, race and urban versus suburban residence WHEALS Birth Cohort

11 Trajectory of Total Serum IgE by Prenatal Pet Exposure in WHEALS Havstad S et al. J Allergy Clin Immunol 2011;128: On average, IgE was 28% lower, over time, for children in pet homes (p<0.001), as compared to children in pet-free homes n=1187 African American = 62.5% ≥1 indoor pet = 35.4%

12 Havstad S et al. J Allergy Clin Immunol 2011;128: Trajectory of Total Serum IgE by Prenatal Pet Exposure in WHEALS n=1187 African American = 62.5% ≥1 indoor pet = 35.4%

Farm Environment and Juvenile Inflammatory Bowel Disease Case-control study, 13 children’s hospitals All 6 to 18 years of age 444 cases of Crohn disease 304 cases of ulcerative colitis 1481 controls, strabismus surgery Regular contact with pets or farm animals in first year of life Radon K, et al. Pediatrics 2007;120:

Farm Environment And Juvenile Inflammatory Bowel Disease Radon K, et al. Pediatrics 2007;120: Animal contactCrohn Disease Fully adjusted* Ulcerative colitis Fully adjusted* House pets1.0 (0.8 – 1.3)0.9 (0.6 – 1.2) Farm animals0.5 (0.3 – 0.9)0.4 (0.2 – 0.8) *adjusted for age, gender, region, parental education, birth weight, maternal smoking in pregnancy, older siblings, allergic rhinitis, parental IBD and other variables

Farm Animal Exposure? Pet Exposure? or

Meta-analysis of Farm or Pet Exposure and Allergy Risk Tse K, Horner AJ. Seminar Immunopath 2008;30:53-62

Role of Unpasteurized Milk Multi-center European study (PARSIFAL) 14,893 children 5-13 years-of-age Farm milk inversely associated with asthma, adjOR = 0.74 (95% CI ) Rhinoconjunctivitis, sensitization to pollen and food mixes also significantly inversely associated with farm milk Waser M, et al. Clinical Exp Allergy 2006;37:

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

Microbiota Hypothesis Most consistent feature of hygiene hypothesis is intensity of exposure to microbes, especially soil microbes via the gut Endotoxin – primarily surrogate marker of bacterial exposure Factors influencing the development of the microbiota of the gut – Maternal microbiota – Ingested bacteria – Diet composition – Antibiotics Evidence favors the - “Microbiota Hypothesis” Penders J, et al. Allergy 2007;62:

Common Features of Published Studies Exposure impact of animals only in 1 st year of life Farm animals and household pets have similar effects Reduced risk is not allergen specific Animal exposure alters risk of other diseases of immune dysregulation e.g. Th1 diseases – IBD

Common Features of Published Studies Impact does not correlate well with – Animal allergen concentration – Endotoxin concentration – Muramic acid concentration Effects of C-section versus vaginal delivery – Exposure to maternal microbiota

22 Do Infants Ingest Bacteria from House Dust Hand-to-mouth activity in all children Well studied by toxicologists Studies demonstrate that hand-to-mouth activity relates dust and child concentrations of toxins

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

Estimated Bacterial Ingestion from House Dust qPCR estimated bacterial load of house dust 7.2 x 10 5 cells/mg of dust Numbers of bacteria ingested by normal children – 30 mg = 2.2 x 10 7 bacteria/day – 100 mg = 7.2 x 10 7 bacteria/day Probiotic trials commonly use a dose of - 5 x 10 9 bacteria/day Pets in the home alter house dust microbiota Karkkainen PM, et al. J Environ Monit 2010;12:

25 Microbial Community Composition In Home Household Characteristics PET Prenatal Immune Status Early Immune Response & Development Persistent Immune Response Phenotype Allergic Asthma Baby/Child’s Gut Microbial Community Composition Baby’s Genotype, Season, SES, Upper Resp Infect, Antibiotics, Diet, Activity, Pets, Other Children, Pollutants, Stress Our Conceptual Model of How Pets Influence Allergic Disease

WHEALS Investigators Henry Ford Hospital Kevin Bobbitt PhD Christine Cole Johnson PhD MPH Suzanne Havstad, M.A. Al Levin PhD Edward L. Peterson PhD Ganesa Wegienka PhD, MS Kim Woodcroft PhD, MPH Edward M. Zoratti MD Georgia Health Sciences University Dennis R. Ownby MD University of California-San Francisco Homer Boushey MD Susan Lynch PhD University of Michigan Nicholas Lukacs PhD 26