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

Risk Factors for Recurrent Wheezing in Children:

Dennis R. Ownby, MDChief, Division of Allergy, Immunology, RheumatologyGeorgia Health Sciences UniversityAugusta, GA, USA

Allergens

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

Concepts to Explore

Does allergen exposure promote or allow allergic disease

Is exposure to some allergens typically associated with exposure to some other immunomodulatory influence

Accepted Knowledge

Most children with asthma are sensitized to allergens

Strong association between allergic sensitization and persistence of asthma

Stronger association between sensitization to perennial allergens and asthma than seasonal allergens

Early Allergen Sensitization and Chronic Asthma in Children

German MAS Study 1314 children: birth to 13 years of

age Allergen exposure at 6 & 18 months

and at 3, 4, 5 years Lung function at 7, 10 ,13 years IgE’s at 1, 2, 3, 5, 6, 7 and 10 years

Illi S, et al. Lancet 2006;368:763-770

Prevalence of Current Wheezing: Prevalence of Current Wheezing: Birth to 13 YearsBirth to 13 Years


at school ageNon-atopic, n=94Atopic, n=59

Effect of Sensitization at Effect of Sensitization at ≤ ≤ 3 Years and Lung 3 Years and Lung Function at 13 Years of AgeFunction at 13 Years of Age


NS = not sensitizedS/LE = sensitized to dust mite ± cat, low exposure at 3 and 5 yearsS/HE = sensitized to dust mite ± cat, high exposure at 3 and 5 years

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

Mite Allergen Exposure and 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 and atopic dermatitis, anaphylaxis from ingestion

Actual daily “dose” of allergen unknown

Previous Findings

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

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

Lau et al, Lancet 2000 No association between dust mite levels in infancy and asthma at 7 yrs

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

= 1st quartile of dust mite at 6 months of age = 4th quartile of dust mite at 6 months of age

Lau S, et al. Paediatric Resp Rev 2002;3:265-272

Childhood Allergy Study (CAS)

835 middle-class children living in suburbs of Detroit, MI, recruited at birth

Selected by geographic area of residence, not selected for allergic risk factors

Yearly questionnaires concerning home environment and home visits at 2 & 4 years

Evaluation between 6 & 7 years for asthma and allergy

Johnson CC, et al. J Allergy Clin Immunol 2004;114:105-10

Medical history and physical examination Skin puncture tests: mites (D. farinae, D.

pteronyssinus), Phleum pratense, Ambrosia artemisiifolia, cat, and dog

Specific IgE to same allergens plus Alternaria alternata (DPC AlaSTAT)

Total IgE (DPC AlaSTAT) Spirometry and methacholine challenge 474 children completed study

Clinical Evaluation at 6 – 7 Years


CAS Exposure Variables Clinical diagnoses of infection from

medical records Upper respiratory infections, URI (otitis

media, cough, croup, rhinitis, viral syndrome, etc)

Lower respiratory infections, LRI (bronchitis, pneumonia, wheezing, etc)

Day care exposure Number of older siblings


Examined Children (n=480)

Age, years 6.72 range 6.1- 7.7 Girls:boys 242:232 1.04:1 Atopic 165/470 34.4% Seroatopic 147/407 36.1% +BHR 105/462 22.7% Ever Asthma 45/427 10.5% Current Asthma 33/473 7.0% Current Atopic Asthma 25/473 5.2%


Outcomes by Dust Mite Allergen > 10μg/gm* All Children

Variable OR 95% CI P-value+DM SPT 1.09 0.58-2.06 0.78 +DM IgE 1.19 0.57-2.50 0.64Atopy 1.13 0.66-1.94 0.66Seroatopy 1.02 0.58-1.81 0.93+BHR 0.53 0.27-1.04 0.07Asthma 0.68 0.27-1.70 0.41Current Atopic Asthma 0.74 0.21-2.62 0.64

*adjusted for gender, firstborn status, cord blood IgE, parental education and history of allergies and asthma, and early exposure to household cats or dogs, tobacco smoke or daycare.


Outcomes by Dust Mite Allergen > 10 μg/gm for Children with No Family History*

Variable OR 95% CI P-value+DM SPT 0.40 0.13-1.19 0.100+DM IgE 0.53 0.16-1.79 0.308Atopy 0.69 0.29-1.62 0.392Seroatopy 0.62 0.26-1.49 0.286+BHR 0.62 0.26-1.49 0.285Asthma 2.80 0.66-11.9 0.163Current AtopicAsthma 1.52 0.22-10.6 0.67

*adjusted for gender, firstborn status, cord blood IgE, parental education, early exposure to household cats or dogs, tobacco smoke or daycare.


Outcomes by Dust Mite Allergen > 10 μg/gm for Children with a Positive Family History*

Variable OR 95% CI P-value+DM SPT 2.09 0.93-4.73 0.076+DM IgE 2.08 0.77-5.61 0.150Atopy 1.72 0.83-3.59 0.147Seroatopy 1.73 0.77-3.87 0.182+BHR 0.46 0.15-1.41 0.175Asthma 0.27 0.03-2.12 0.212Current AtopicAsthma 0.39 0.05-3.13 0.376

*adjusted for gender, firstborn status, cord blood IgE, parental education, early exposure to household cats or dogs, tobacco smoke or daycare.


Multivariable Models Predicting Allergic Sensitization at 6-7 Years

Variable 1 yr

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

0.46 0.01 0.80 0.42

1 dog/cat 1.19 0.54 1.02 0.94

> 2 dogs/cats 0.27 0.003 0.24 0.002

Specific IgE +Skin Prick Test

Land of Low Allergen Exposure

161 Kuwaity children, 9-16 years with asthma and 303 healthy controls

Few pets in homes for religious reasons

Dry climate relative humid low, 15%-30% low levels of dust mites

Hassan MS et al. J Allergy Clin Immunol 2004;114:1389-94

Allergen levels in 383 mattresses Der p 1, 99.7% below detection Der f 1, 98.1% below detection Fel d 1, 15.2% below detection, median 0.14 Can f 1, 83.4% below detection Bla g 1, 51.9% below detection, median

0.05 Cat ownership: 4.1% Dog ownership: 1.5%



Allergen Asthma ControlSkin test 158 303Dust mites 31 (20%) 13 (4%)Cat 73 (46%) 46 (15%)Dog 55 (35%) 31 (10%)



Pets Contribute More than Allergens to Homes

18 house dust samples from WHEALS 6 ≥ 1 dogs, 6 ≥ 1 cat, 6 without pets PhyloChip analysis of microbial taxa

present Insufficient DNA in 2 dust samples

Homes with dogs More types of bacteria present, richer, p

< .04 More diverse, p < .04

23Fujimura KE, et al. J Allergy Clin Immunol 2010;126:410-412

Bacterial Communities in House Dust from Dog verses No-Pet Households


Pets Alter Home Dust Microbiome

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


Movement of Bacteria from House Dust to Infant Gut

Hand-to-mouth activity Well studied by toxicologists Studies demonstrate that hand-to-

mouth activity relates dust and infant concentrations of toxins

26

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

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 0.61-0.88) 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

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;62:288-292

Does Pet Ownership Impact House Dust and Stool Microbiota?

30Lynch S, et al. unpublished

Conclusions

Exposure to allergens allows predisposed persons to become sensitized by exposure dose not change the person’s predisposition

Exposures to allergens are often associated with exposures to other agents which alter immune responses

Microbes ingested by children in infancy have strong effects on the risk of developing allergic sensitivity and disease

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

Documents

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