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Endotoxin and Allergen Exposure in Early Life and Asthma and Allergies in Childhood Juan C. Celedón, M.D., Dr.P.H.

Channing Laboratory and Respiratory Disorders Program Division of Pulmonary and Critical Care Medicine Department of Medicine Brigham and Women’s Hospital Harvard Medical School BRIGHAM AND WOMEN’S HOSPITAL

HARVARD MEDICAL SCHOOL


Outline • Background • Early Endotoxin and Allergen Exposure in the Epidemiology of Home Allergens and Asthma Study – Methods – Results

• Conclusions and future directions


1.

Background


1a.

Early Exposure to Dust Mite Allergen and Asthma


House Dust Mite Allergen • House dust mite allergen levels are: – higher in single-family homes, carpeted floors,

and humid areas (Chew G, 1998) – inversely associated with low household income, African-American ethnicity, and Hispanic ethnicity (Kitch B, 2000; Leaderer B, 2002)


House Dust Mite Allergen and Sensitization to Dust Mite • Exposure to high levels of house dust mite allergen has been associated with sensitization to house dust mite in cross-sectional (Huss K, 2001) and longitudinal studies (Lau S, 2000; Sporik R, 1990)


Dust Mite Allergen Exposure in Early Life and Asthma • Sporik et al. reported an association between early exposure to house dust mite allergen (>10 g/g) and asthma at age 11 years – Limitations: • Small sample size (93 infants) • 28% of participants lost to follow-up at age 11 years


Dust Mite Allergen Exposure in Early Life and Asthma • Lau and colleagues found no association between early exposure to house dust mite allergen and asthma at age 7 years – Limitations: • Low levels of allergen exposure in the vast majority of children


Dust Mite Allergen Exposure in Early Life and Asthma • In a clinical trial, strict allergen avoidance (in combination with other interventions) resulted in a reduced risk of sensitization to house dust mite and asthma symptoms at age 8 years – Arshad SH, et al. Thorax 2003;58:489-93.


1b.

Early Exposure to Dogs and Asthma


Dog exposure in infancy and childhood wheeze (Remes et al. JACl 2001;108:509-15) 1

≼ 1 dogs

.9

.8

0 dogs

P=0.004 .7 0

3

6 Age, years

9

12


Study Findings • Dog exposure was inversely associated with frequent wheeze ONLY among children without parental history of asthma • No relation between dog exposure and allergen sensitization, but only half of the children had allergy skin testing data at age 11 years

Remes et al. JACl 2001;108:509-15


Pet exposure in the First Year of Life and Atopy at Age 7 Yrs One dog or cat

At least two dogs or cats

Variable

OR P-value

OR

Atopy

1.03 0.890

0.36 0.003

Adj* Atopy 1.01 0.973

0.31 0.007

Sero-atopy 1.11 0.645

0.35 0.003

Adj-Sero

0.43 0.039

1.20 0.502

Ownby D et al. JAMA 2002;288:963-72.

P-value


60

Dog Ownership, Atopy & Wheeze (Custovic et al.) p=0.003

Dog owner No dogs

50

40

% 30

p=0.01 p=0.01

17 .7 2

20

10

0 Atopy

SPT+ dog

SPT+ mite

SPT+ egg

Wheeze ever

Recent wheeze M

e ste r c h a n

Ast h ma

a n d

Alle rg y

dy St u


Airborne Endotoxin Levels by Home Characteristics 1.4 1.2 1 0.8 No Yes

0.6 0.4 0.2 0

Dog

Dehumidifier Concrete Floor

Water Damage

Park J et al. Environ Health Perspect 2001;109:859-864)


Endotoxin and dog allergen levels in homes with a dog (Custis N et al.)

Airborne Endotoxin (EU/24hrs)

10,000

r2=0.510

1,000

100

10 0.01

0.1

1

Airborne Can f 1 (Âľg/24hrs)

10

100


1.c.

Early Exposure to Endotoxin and Asthma


Endotoxin and Allergen-induced IL-13 Production Stimuli Cockroach Allergen

Cytokine

Spearman r

p-value

IL-13

-0.31

0.01

Dust Mite Allergen

IL-13

-0.27

0.02

Cat Allergen

IL-13

-0.21

0.08

PHA Mitogen

IL-13

0.12

0.34


Multivariate Predictors of Eczema in the First Year of Life among High-Risk Children Covariate

Model 1

Model 2

Model 3

0.4(0.2-0.9)

0.5(0.3-1.1)

0.7(0.6-0.9)

0.8(0.6-0.9)

Paternal history of eczema Maternal IgE

1.6(0.8-3.3)

2.0(1.1-3.7)

1.9(1.1-3.5)

2.0(1.2-3.4)

1.6(1.0-2.5)

1.6(1.1-2.6)

Fall birth

1.9(1.1-3.3)

1.5(0.9-2.5)

1.6(0.9-2.6)

Dog Endotoxin

Phipatanakul W, Celedón JC, et al. Pediatrics 2004;114:13-18.


Dog Exposure and Wheeze Over a Four Year Period (Siblings) 3 2.5 2 1.5

1.52

1.74

1 0.5 0 <81.3 >81.3

<0.05 >0.05 Endotoxin (Eu/mg) Bla g (u/g)

0.38

0.62

No Yes <1 >1 Dog Cat (Fel d 1) (碌g/m)

Litonjua A, Milton D, Celed贸n JC, et al., J Allergy Clin Immunol 2002; 110:736-42


Early Endotoxin Exposure and Asthma and Atopy • Early endotoxin exposure has been associated with increased risk of wheeze up to age 2 years – Gehring U, et al. J Allergy Clin Immunol 2001;108(5):847-54. – Bolte G, et al. Clin Exp Allergy 2003; 33(6):770-6. – Perzanowski MS, et al. J Allergy Clin Immunol 2006;117(5):1082-9.


Early Endotoxin Exposure and Asthma and Atopy â&#x20AC;˘ In a cross-sectional study of schoolchildren, endotoxin exposure was inversely associated with allergen sensitization. There was no association between endotoxin exposure and either asthma or allergic rhinitis. â&#x20AC;&#x201C; Gehring U, et al. AJRCCM 2002;166:939-44.


Environmental Exposure and Prevalence of Health Outcomes According to Farming Status NEJM 2002;347(12):869-77


Smooth Plots of the Prevalence of Atopic Wheeze and Non-Atopic Wheeze: Atopic Wheeze

Adjusted Prevalence of Atopic Wheeze (%)

Adjusted Prevalence of Atopic Wheeze (%)

In Relation to Log-Transformed Endotoxin-Load Values

Non-Atopic Wheeze

Endotoxin Load in Mattress (units/m2) NEJM 2002;347(12):869-77


Association of the Prevalence of Symptoms and Disease with Current Endotoxin Load and Early Exposure to Farming NEJM 2002;347(12):869-77


Endotoxin Exposure and Asthma and Atopy â&#x20AC;˘ In a cross-sectional study of schoolchildren, endotoxin exposure was inversely associated with allergen sensitization. There was no association between endotoxin exposure and either asthma or allergic rhinitis. â&#x20AC;&#x201C; Gehring U, et al. AJRCCM 2002;166:939-44.


Endotoxin Exposure and Asthma and Atopy • In a cross-sectional study of 831 adults in the U.S., endotoxin exposure was associated with increased risks of – Asthma and asthma symptoms – Medication use for asthma

• Similar findings in atopic and non-atopic T subjects

h o Thorne PS, et al. Am J Respir Crit Care Med 2005;172(11):1371-7. r n


1.d.

Early Exposure to Endotoxin and Allergens and Asthma: Summary


Early Allergen Exposure and Asthma • Data on dust mite exposure and childhood asthma – Limited – Conflicting results


Early Allergen Exposure and Asthma • Relation between early dog exposure and childhood asthma – Most studies suggest a protective effect of dog exposure against atopy – Conflicting data with regard to wheezing and asthma


Early Endotoxin Exposure and Asthma • Most studies have been cross-sectional • The relation between endotoxin exposure and asthma may be complex and dependent on exposure dose and host factors – Potential protective effect against atopy – May protect against atopic asthma but be associated with non-atopic asthma/wheeze


2.

Early Exposure to Endotoxin and Allergens and Asthma in the Home Allergens and Asthma Study


Methods • 505 infants with parental history of asthma or allergies; 7 excluded because of missing data in the first year of life • Telephone questionnaires: – Every two months from 2 to 24 months of age – Every six months from 2 to 7 years of age


Methods • Dust samples collected at age 2 to 3 months for measurement of – Endotoxin – Der p and Der f – Can f 1


Outcomes • At age 7 years: – Asthma – Persistent wheezing – Allergic rhinitis

• At age 6 to 9 years: – Sensitization to at least one allergen

• Parental report of wheezing between ages 1 and 7 years


Statistical Analysis • Logistic regression to study relation between early endotoxin/allergen exposure and – Asthma, persistent wheeze, and rhinitis at Age 7 years – Allergen sensitization at age 6 to 9 years

• Proportional hazards models to study relation between endotoxin/allergen exposure and wheeze from ages 1 to 7 years


Results â&#x20AC;˘ Of 498 children, 440 (88.4%) followed up to the age of 7 years â&#x20AC;˘ No significant difference in early exposure to endotoxin, dust mite allergen, or dog allergen between children with and without 7-year followup


Dust Mite Allergen Exposure in Early Life and Asthma at Age 7 Years Der p or Der f 1, childâ&#x20AC;&#x2122;s bed (Âľg/g)

Asthma Yes No

< 0.05

14

184

0.05 - < 2

16

119

1.8 (0.8 - 3.8) 1.3 (0.6 - 2.9)

> 2 - < 10

5

59

1.1 (0.4 - 3.2) 1.4 (0.5 - 4.1)

> 10

8

34

3.1 (1.2 - 7.9) 3.0 (1.1 - 7.9)

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

1.0

1.0

Adjusted for sex, household income, and maternal history of asthma.


Dust Mite Allergen Exposure in Early Life and Allergic Rhinitis at Age 7 Years Der p or Der f 1, childâ&#x20AC;&#x2122;s bed (Âľg/g)

Rhinitis Yes No

<2

42

290

>2

22

84

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

1.0

1.0

1.8 (1.0 - 3.2) 2.3 (1.2 - 4.3)

Adjusted for endotoxin levels, maternal history of hay fever, living in a single detached home, low birth weight, and number of older siblings.


Endotoxin Exposure in Early Life and Allergic Rhinitis at Age 7 Years Endotoxin, living room (EU/mg)

Rhinitis Yes No

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

1.0

1.0

2.14 - 52.48

13

70

52.49 - 79.99

12

78

0.8 (0.4 - 1.9) 0.8 (0.3 - 1.9)

80.48 - 125.59

17

74

1.2 (0.6 - 2.7) 1.0 (0.4 - 2.4)

125.6 - 713.20

8

80

0.5 (0.2 - 1.4) 0.3 (0.1 - 0.9)

Adjusted for dust mite allergen levels, maternal history of hay fever, living in a single family home, low birth weight, and number of older siblings.


Endotoxin Exposure in Early Life and Allergen Sensitization at School Age Endotoxin, living room (EU/mg)

Allergen sensitization Unadjusted Adjusted OR OR (95% CI) (95% CI) Yes No

First quartile

34

16

Upper three quartiles

90

81

1.0

1.0

0.5 (0.3 - 1.0) 0.5 (0.2 - 0.9)

Adjusted for sex, household income, and living in a single-family home.


Endotoxin Exposure in Early Life and Wheezing between Ages 1 and 7 Years Endotoxin, living room (EU/mg)

Unadjusted OR (95% CI)

Adjusted OR (95% CI)

2.14 - 52.48

1.0

1.0

52.49 - 79.99

1.0 (0.6 - 1.6)

1.0 (0.6 - 1.7)

80.48 - 125.59 1.4 (0.9 - 2.0)

1.5 (1.0 - 2.3)

125.6 - 713.20 1.6 (1.0 - 2.4)

1.7 (1.1 - 2.7)

Adjusted for sex, household income, dog exposure, day care or having at least 2 siblings, and gestational age.


Longitudinal Analysis â&#x20AC;˘ Exposure to endotoxin levels at age 2-3 months was associated with an increased risk of wheezing between ages 1 and 7 years (HR for each quartile increment in endotoxin levels=1.23, 95% CI=1.07-1.43) â&#x20AC;˘ Similar results for the association between early endotoxin exposure and persistent wheeze (OR for each quartile increment in endotoxin levels=1.53, 95% CI=1.1-2.1)


Results • In children at risk for atopy, early exposure to high levels of house dust mite allergen is associated with increased risks of – Asthma at age 7 yrs – Allergic rhinitis at age 7 yrs


Results • In children at risk for atopy, early exposure to endotoxin is associated with increased risk of whee – Asthma at age 7 yrs – Allergic rhinitis at age 7 yrs


Results â&#x20AC;˘ In children at risk for atopy, early exposure to high levels of dog allergen or endotoxin allergen is associated with an increased risk of wheeze between ages 1 and 7 yrs â&#x20AC;&#x201C; Similar findings in atopic and non-atopic children


Study Limitations â&#x20AC;˘ Limited statistical power to detect weak to moderate associations between endotoxin exposure and some of the outcomes of interest (e.g., asthma) â&#x20AC;˘ Limited statistical power to examine potential modification of the effect of endotoxin on asthma by atopy


3.

Conclusions and Future Directions


Conclusions and Future Directions â&#x20AC;˘ Early exposure to high levels of dust mite is associated with an increased risk of childhood asthma in high-risk children â&#x20AC;&#x201C; Can allergen avoidance prevent the development of asthma and allergen sensitization in a subset of high-risk children?


Conclusions and Future Directions • Early exposure to endotoxin is associated with a decreased risk of allergic rhinitis and atopy at school age – What is the combined effect of early and current endotoxin exposure on atopy? – Is endotoxin a marker of another exposure?


Conclusions and Future Directions • Exposure to endotoxin is associated with an increased risk of wheezing between ages 1 and 7 years in high-risk children – Are there independent effects of dog allergen and endotoxin exposure? – Is there effect modification by exposure to other allergens?


Acknowledgments Diane Gold, M.D., M.P.H. Clare D. Ramsey, M.D., M.P.H. Don Milton, M.D., Dr.P.H. Augusto A. Litonjua, M.D., M.P.H. Diane Sredl, M.P.H. Louise Ryan, Ph.D. Scott T. Weiss, M.D., M.S.


Exposición a endotoxinas y alergenos en la in  

Exposición a endotoxinas y alergenos en la in

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