risk factors for recurrent wheezing in children: dennis r. ownby, md chief, division of allergy,...
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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
Illi S, et al. Lancet 2006;368:763-770
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
Illi S, et al. Lancet 2006;368:763-770
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
Johnson CC, et al. J Allergy Clin Immunol 2004;114:105-10
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)
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%
Johnson CC, et al. J Allergy Clin Immunol 2004;114:105-10
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.
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 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.
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 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.
Johnson CC, et al. J Allergy Clin Immunol 2004;114:105-10
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%
Land of Low Allergen Exposure
Hassan MS et al. J Allergy Clin Immunol 2004;114:1389-94
Allergen Asthma ControlSkin test 158 303Dust 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
Land of Low Allergen Exposure
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
24Fujimura KE, et al. J Allergy Clin Immunol 2010;126:410-412
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
25Fujimura KE, et al. J Allergy Clin Immunol 2010;126:410-412
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