Risk factors for recurrent wheezing in children
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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. In the past year I have been: A consultant to CarboNix, LLC

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Risk factors for recurrent wheezing in children

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

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

Disclosures


Concepts to explore

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

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

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


Risk factors for recurrent wheezing in children

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


Risk factors for recurrent wheezing in children

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


Risk factors for recurrent wheezing in children

Dust mite allergen exposure:

the first allergen though to

“cause” the development of

asthma.


Mite allergen exposure and disease

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

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

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

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


Clinical evaluation at 6 7 years

Clinical Evaluation at 6 – 7 Years

  • 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

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


Cas exposure variables

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

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


Examined children n 480

Examined Children (n=480)

  • Age, years 6.72 range 6.1- 7.7

  • Girls:boys242:232 1.04:1

  • Atopic165/470 34.4%

  • Seroatopic147/407 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%

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


Outcomes by dust mite allergen 10 g gm all children

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

VariableOR95% CIP-value

+DM SPT 1.090.58-2.06 0.78

+DM IgE 1.190.57-2.50 0.64

Atopy 1.130.66-1.94 0.66

Seroatopy1.020.58-1.81 0.93

+BHR 0.530.27-1.04 0.07

Asthma 0.680.27-1.70 0.41

Current 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.

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


Outcomes by dust mite allergen 10 g gm for children with no family history

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

VariableOR95% CIP-value

+DM SPT 0.40 0.13-1.19 0.100

+DM IgE 0.53 0.16-1.79 0.308

Atopy 0.69 0.29-1.62 0.392

Seroatopy 0.62 0.26-1.49 0.286

+BHR 0.62 0.26-1.49 0.285

Asthma 2.80 0.66-11.9 0.163

Current Atopic

Asthma 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.

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


Outcomes by dust mite allergen 10 g gm for children with a positive family history

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

VariableOR95% CIP-value

+DM SPT 2.090.93-4.730.076

+DM IgE 2.08 0.77-5.61 0.150

Atopy 1.72 0.83-3.59 0.147

Seroatopy 1.73 0.77-3.87 0.182

+BHR 0.46 0.15-1.41 0.175

Asthma 0.27 0.03-2.12 0.212

Current Atopic

Asthma 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.

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


Multivariable models predicting allergic sensitization at 6 7 years

Multivariable Models Predicting Allergic Sensitization at 6-7 Years

Specific IgE +Skin Prick Test


Land of low allergen exposure

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


Land of low allergen exposure1

Land of Low Allergen Exposure

  • 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%

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


Land of low allergen exposure2

Land of Low Allergen Exposure

Allergen Asthma Control

Skin test 158 303

Dust mites 31 (20%) 13 (4%)

Cat 73 (46%) 46 (15%)

Dog 55 (35%) 31 (10%)

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


Pets contribute more than allergens to homes

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

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


Bacterial communities in house dust from dog verses no pet households

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

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


Pets alter home dust microbiome

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

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


Movement of bacteria from house dust to infant gut

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


Soil and house dust ingestion by children

Soil and House Dust Ingestion by Children

U.S. EPA. Child Specific Exposure Factors Handbook 2008

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


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

Role of Unpasteurized 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

Drinking Water Microbes and Atopy

Von Hertzen L, et al. Allergy 2007;62:288-292


Risk factors for recurrent wheezing in children

Does Pet Ownership Impact House Dust and Stool Microbiota?

Lynch S, et al. unpublished


Conclusions

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


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