Asthma in Children Risk Factors Environmental Exposures Dennis

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Asthma in Children: Risk Factors Environmental Exposures Dennis R. Ownby, MD Chief, Division of

Asthma in Children: Risk Factors Environmental Exposures 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.

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 What exposures allow wheezing in infancy to become asthma in

Concepts to Explore o What exposures allow wheezing in infancy to become asthma in childhood o How should we define “exposures” o How do exposures interact with genetic predisposition o Are environmental exposures important only in infancy or throughout life o Have we been, “looking for love in all the wrong places”

Accepted Knowledge o Most children with asthma are sensitized to allergens o Strong association

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

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

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

Previous Findings o Sporik et al, NEJM 1990 RR = 4. 8 for asthma

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

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

Cigarette Smoke Exposure and Childhood Asthma o Both chemicals and particulates from cigarette smoke

Cigarette Smoke Exposure and Childhood Asthma o Both chemicals and particulates from cigarette smoke exacerbate asthma symptoms o Maternal smoking during pregnancy increases risk of asthma in most studies o Studies are inconsistent concerning the effects of smoke exposure during childhood and the risk of asthma

Percent of Children Prevalence of Allergic Sensitivity with Exposure to Parental Smoking P =.

Percent of Children Prevalence of Allergic Sensitivity with Exposure to Parental Smoking P =. 07 P =. 18 Ownby DR, et al. Unpublished P =. 28

Cigarette Smoke Exposure and Allergic Sensitization in MAS Lau S, et al. Paediatric Resp

Cigarette Smoke Exposure and Allergic Sensitization in MAS Lau S, et al. Paediatric Resp Rev 2002; 3: 265 -272

Home VOC Exposure and Asthma in Young Children o Population based case-control study o

Home VOC Exposure and Asthma in Young Children o Population based case-control study o 88 cases (ED for asthma), 104 controls o Asthma 25 months old, controls 20 months o VOCs measured 1 week after ED visit then 6 months later o Active charcoal sampling in living room o Ten VOCs sampled Rumchev K, et al. Thorax 2004; 59: 746

Association of VOC Exposure and Asthma Rumchev K, et al. Thorax 2004; 59: 746

Association of VOC Exposure and Asthma Rumchev K, et al. Thorax 2004; 59: 746

VOC Exposure and Asthma VOC’s given off by many products Indoor VOC’s 2 -5

VOC Exposure and Asthma VOC’s given off by many products Indoor VOC’s 2 -5 times outdoor levels NHANES 1999 -2000 669 subjects Representative subgroup Wore 3 M 3520 Organic Vapor Monitors o 10 VOC’s were measured o Physician diagnosed asthma = 12. 5% o o o Arif AA, Shah SM. Int Arch Occup Environ Health 2007; 80: 711 -719

VOC Exposure and Asthma Risk Independent Variable Odds Ratio** 95% CI Factor 1* 1.

VOC Exposure and Asthma Risk Independent Variable Odds Ratio** 95% CI Factor 1* 1. 63 1. 17 – 2. 27 Benzene 1. 33 1. 13 - 1. 56 Toluene 1. 34 1. 01 – 1. 78 o-Xylene 1. 21 0. 93 – 1. 58 m, p-Xylene 1. 33 1. 08 – 1. 64 *Factor 1 = aromatic compounds, **OR adjusted for age, race, sex, BMI, atopy, Smoking, ETS, poverty level, and interactions Arif AA, Shah SM. Int Arch Occup Environ Health 2007; 80: 711 -719

Common Household Chemicals and Allergy Risks o Preschool children: 198 cases, 202 health control

Common Household Chemicals and Allergy Risks o Preschool children: 198 cases, 202 health control o Measured 8 classes of VOC’s from bedroom air samples o Only propylene glycol and glycol ethers related to being a case Choi H, et al. Plos One 2010; 18(5): e 13423

Fold-Risk with Glycol Exposure Common Household Chemicals and Allergy Risks Choi H, et al.

Fold-Risk with Glycol Exposure Common Household Chemicals and Allergy Risks Choi H, et al. Plos One 2010; 18(5): e 13423

Pets Contribute More than Allergens to Homes o 18 house dust samples from WHEALS

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 19

Bacterial Communities in House Dust from Dog verses No-Pet Households Fujimura KE, et al.

Bacterial Communities in House Dust from Dog verses No-Pet Households Fujimura KE, et al. J Allergy Clin Immunol 2010; 126: 410 -412 20

Pets Alter Home Dust Microbiome o 337 bacterial taxa significantly increased in dog-owning homes

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 21

Movement of Bacteria from House Dust to Infant Gut o Hand-to-mouth activity o Well

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 22

Soil and House Dust Ingestion by Children o Soil and dust ingestion directly related

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

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-

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

Does Pet Ownership Impact House Dust and Stool Microbiota? Lynch S, et al. unpublished 26

Feeding Bacteria or Bacterial Products Affects Response to Viral Respiratory Infection in Humans Twice

Feeding Bacteria or Bacterial Products Affects Response to Viral Respiratory Infection in Humans Twice daily treatment with L. acidophilus and B. animalis for six months reduced fever, rhinorrhea, cough, antibiotic use, and missed school days in 3 -5 y. o. children. Leyer G, Pediatrics, 2009; 124: 172 -179 Oral treatment with a mixture of lyophilized bacterial extracts (OM-85 BV) for first 10 days of 3 consecutive months reduced cumulative number of RTI’s and of wheezing episodes per child/year and reduced duration of wheezing episodes (p <0. 001) Razi, J Allergy Clin Immunol 2010; 126: 763 -0 27

Conclusions o Exposure to cigarette smoke increase asthma symptoms but not asthma or allergic

Conclusions o Exposure to cigarette smoke increase asthma symptoms but not asthma or allergic sensitization o Exposures to volatile organic compounds appears to increase asthma in children o Microbes ingested by children in infancy have strong effects on the risk of developing allergic sensitivity and disease and response to viral respiratory infections