Family history, dust mite exposure in early childhood, and risk for pediatric atopy and asthma☆

Article Outline

• Abstract
• 1. Methods
  • 1.1. Study population and follow-up
  • 1.2. Exposure measurement
  • 1.3. Clinical measures
  • 1.4. Statistical approach
• 2. Results
• 3. Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Background

Dust mite allergen exposure is considered a major determinant of sensitization to these allergens during childhood and a risk factor for pediatric asthma.

Objective

By using a birth cohort in a setting with a substantial burden of dust mite allergen, we evaluated exposure and risk for outcomes related to allergy and asthma.

Methods

We collected dust from the bedrooms of 428 children born from 1987 to 1989 and measured Der f 1 and Der p 1 (μg/g dust, combined). Follow-up at 6 to 7 years of age included clinical examination, skin prick testing, specific serum IgE measurement, and methacholine challenge.

Results

No overall association was evident for any outcome except bronchial hyperresponsiveness (adjusted odds ratio [OR], 0.62; 95% CI, 0.38-1.00; P < .050; and OR, 0.53; CI, 0.27-1.04; P < .065 for dust mite allergen levels ≥2 μg/g and >10 μg/g, respectively). With a parental history of allergy and asthma, there was an association between a positive dust mite skin test (OR, 2.09; CI, 0.93-4.73; P < .076) and dust mite allergen level >10 μg/g. The inverse was true for children without a parental history. Dust mite exposure of >10 μg/g was associated with a decreased risk of current atopic asthma among children with a parental history (OR, 0.39; CI, 0.05-3.13; P < .376), but with increased risk if without a parental history (OR, 1.52; CI, 0.22-10.6; P < .673).

Conclusion

Parental history is an important independent variable in the relationship between early dust mite exposure and atopic outcomes. Increased exposure during infancy is associated with a higher risk for sensitization in the presence of a positive parental history, but is protective among children of parents without a history of atopic disease.

Keywords:  Allergy, asthma, atopy, bronchial hyperreactivity, children, home allergen level, IgE, skin testing

Abbreviations:  BHR, Bronchial hyperresponsiveness, OR, Adjusted odds ratio

Until recently, there has been almost universal acceptance of the premise that exposure to high levels of dust mite allergen during early childhood contributes to allergic sensitivity to dust mites and that continuing exposure to mite allergens causes airway inflammation leading to the development of asthma in childhood.¹ This doctrine is almost entirely based on data from cross-sectional studies, with 1 prospective study demonstrating this relationship.^2., ^3. This 1990 study, which estimated a statistically significant relative risk of 4.8 for asthma at age 11 years associated with household levels of Der p 1 >10 μg/g dust at 1 to 2 years, was based on a birth cohort of 59 children with parental history of asthma or hay fever, and no adjustments were made for potential confounding variables.³ A second, larger longitudinal intervention study, again among high-risk children as defined by family history, noted in their ancillary findings a lack of any association between dust mite allergen levels at 1 year of age and wheeze, atopy, or positive skin tests to mites at 7 years.⁴ One prospective study following a large birth cohort that included both low-risk and high-risk children has been reported.⁵ Lau et al,⁵ adjusting for parental history, found that relatively higher levels of household house dust mite allergen levels at age 6 months were associated with dust mite–specific IgE at age 7 years, but failed to find a relationship with asthma. This study, centered in Germany, was criticized as having unusually low levels of dust mite allergen, which could explain the failure to find the expected association.⁶

The consideration of whether mite allergen exposure is related to risk of incident asthma continues to be highly important given the worldwide increase in the prevalence of asthma over the past few decades. Resolving this question is essential because of the broad public health and clinical implications of this assumption.^7., ^8. The goal of our research was to investigate the relationship of dust mite allergen exposure during early life to allergic sensitivity and asthma at 6 to 7 years of age. This prospective study was performed by using a relatively large birth cohort of general-risk children with comprehensive longitudinal data, residing in a geographic area characterized by moderate levels of household dust mites.

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1. Methods 

1.1. Study population and follow-up 

The recruitment of the study population has been described elsewhere.⁹ As a part of the Childhood Allergy Study, all pregnant women belonging to the largest health maintenance organization in Michigan and living in a geographically defined area north of Detroit composed the eligible population. They were required to be ≥18 years old with an estimated date of confinement between April 15, 1987, and August 15, 1989. The women were interviewed by study nurses during appointments in their obstetricians' offices after their first trimester to collect information relating to the mother and the child's father. Children born at term (≥36 weeks) without complications were enrolled in the study. A cord blood sample was obtained and delivery-related data abstracted from the medical record. During the first 2 years of life, children with cord IgE levels >0.56 IU/mL were followed intensively with monthly home visits. The remaining children were followed by telephone questionnaire at their first and third birthdays and a home visit at their second and fourth birthdays. At 6 to 7 years of age, all of the children underwent a clinical evaluation by a single allergist (D. R. O.). All aspects of the study were approved by the Henry Ford Hospital Human Rights Committee, and written informed consent was obtained from all study participants.

1.2. Exposure measurement 

Dust samples were collected from the bedrooms of all children at 2 years of age (n=367; mean age, 2.1 years; SD, 0.05; range, 2.0-2.3) for measurement of Der f 1 and Der p 1, and every month from birth through 2 years for the subset of children (n=70; 19.1%) with cord IgE >0.56 IU/mL. For these children, an average of the monthly levels was used in analyses. There were 61 children missing a dust sample during this period but who had one taken from the same residence at 4 years of age. This measurement was assigned to these children to increase our sample size to 428 and to increase the precision of our estimates in the final analyses. Dust samples were obtained by vacuuming a 1-m² area of floor directly beside the child's bed for 2 minutes and were assayed for Der f 1 and Der p 1 by using monoclonal antibody based assays (Indoor Biotechnologies, Chester, United Kingdom) as described previously.¹⁰ Interassay coefficients of variation were typically <12%. The values determined to be below the detectable limit were set at 0.42 μg/g dust for Der f 1 and 0.08 μg/g for Der p 1.

1.3. Clinical measures 

The clinical evaluation included a standardized history, physical examination, methacholine challenge, blood sample, and skin prick testing using the allergens Dermatophagoides farinae, Dermatophagoides pteronyssinus, ragweed (Ambrosia artemisiifolia), cat, dog, bluegrass (Poa pratensis), and Alternaria (extracts from Bayer Biologics, Spokane, Wash). Both positive (histamine 1 mg/mL) and negative controls (glycerosaline) were used. Tests were applied by the puncture method by using a lancet (Bayer Biologics). Skin tests were considered positive if the product of perpendicular wheal diameters was ≥4 mm to any of the allergens tested when there was no reaction to glycerosaline. Atopy was defined as a positive skin test to any of the 7 allergens tested. (Alternaria was added after the study was in progress; thus, the first 44 children were not tested for this allergen. Of these 44, 34 were negative to the other 6 allergens and were assumed to be nonatopic in our final analyses. The risk estimates were virtually the same if these children were excluded.)

Blood samples were measured for concentration of allergen-specific IgE antibodies by using a commercial assay (AlaSTAT; Diagnostic Products Corp, Los Angeles, Calif) for the same allergens used in skin testing. Specific IgE levels were expressed in international units per milliliter (1 IU/mL corresponds to 2.4 μg/L), and values of >0.35 IU/mL were considered positive in accordance with the manufacturer's recommendation. Seroatopy was defined as any positive test for allergen-specific IgE. Because of information about cockroach sensitivity and asthma published after the start of this study,^11., ^12. a random sample of 100 sera was assayed for cockroach-specific IgE, but only 2 were positive, so no further testing for this allergen was performed.

Lung function was recorded with a KoKo spirometer (Pulmonary Data Service, Louisville, Colo) connected to a personal computer. Spirometry was considered acceptable if the child made a good effort and if 2 forced exhalation maneuvers showed reproducibility (±5%) for both forced vital capacity and FEV₁. Children with initial FEV₁ <70% of predicted were given a bronchodilator (albuterol sulfate by nebulization) and reassessed 15 minutes later. If the child's FEV₁ increased by ≥12%, the child was classified positive for bronchial hyperresponsiveness (BHR-positive). If the child's FEV₁ was ≥70% of predicted, the child was challenged with normal saline diluent followed by 5 sequential doses of methacholine (0.025, 0.25, 2.5, 10, and 25 mg/mL) administered with a Devilbiss 646 nebulizer (DeVilbiss Health Care, Fort Pierce, Fla) connected to a French-Rosenthal–type dosimeter integrated into the spirometer until FEV₁ fell to <80% of the best postsaline value or until the maximum concentration was reached. The nebulizer was driven by compressed air at 20 psi. The dosimeter delivered methacholine for 0.6 seconds at the initiation of inhalation during tidal breathing. Spirometry was repeated 3 minutes after each dose of methacholine. A positive methacholine challenge, which also classified a child as being BHR-positive, was defined as a decrease in FEV₁ to <80% of the postsaline value after inhalation of methacholine at concentrations up to 10 mg/mL.

A child was classified as having a history of asthma if the parent reported that the child had been diagnosed by a physician as having asthma when queried during the clinical examination. Current asthma was defined as a history of a physician diagnosis and symptoms of asthma or asthma medication use within the previous 12 months. Current atopic asthma was defined as current asthma combined with atopy or seroatopy.

1.4. Statistical approach 

The dust allergen concentrations for Der f 1 and Der p 1 were added together and log-transformed for analysis because these variables had nonnormal distributions. The concentrations were then placed into 2 categories on the basis of cutpoints in the literature: ≥2 μg/g versus <2 μg/g dust and >10 μg/g versus ≤10 μg/g dust.² The use of cutpoints addresses the possibility of threshold (nonlinear) effects. Dust mite allergen was also considered as a continuous variable. Outcome variables included a positive skin test or detectable allergen-specific IgE to either of the dust mites, atopy, seroatopy, BHR, a history of physician diagnosis of asthma, and current atopic asthma. χ² Tests and logistic regression were used to calculate risk estimates in the form of crude and adjusted odds ratios (ORs) as well as 95% CIs and P values. The ORs were adjusted for potential confounding variables including child's sex, first-born status, cord blood IgE (≥0.56 IU/mL), parental education (either parent had courses after high school), a positive parental history (either parent reporting a history of asthma, hay fever, or allergies), and early exposure to environmental tobacco smoke (smoker ever living in child's house during first 2 years of life), pets (1 or more cats and dogs in home during the first year of life), and daycare (use during first year of life). (We repeated the analyses adjusting for multiple pets [yes/no] given the importance of this variable in our previous work, but the results did not change.) Because of the importance of a positive family history, especially as a surrogate for genetic susceptibility, we repeated these analyses, stratifying by parental history.

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2. Results 

There were 835 children enrolled in the birth cohort. Just over 57% (n=480) participated in skin testing at 6 to 7 years of age; 428 of these children had at least 1 dust sample measured before 2 years of age (n=367) or taken from the same house (n=61) at 4 years of age. The 428 in the study group for these analyses did not differ statistically from the 835 enrolled in characteristics such as sex, race, birth weight, first-born status, parental history, presence of household smoker, early pet ownership or daycare use, and the average of dust mite levels measured. The parents in the study group were slightly older (fathers, 31.6 years vs 31.0 years; P < .05; mothers, 29.3 years vs 28.7 years; P < .05), and more had coursework after high school (79.9% vs 76.7%; P < .05), likely reflecting a less mobile population. Of the 428 children, 49.1% (n=210) were boys, 96.5% (n=413) were white, 44.6% were first-born children (n=191), and 56.8% (n=243) had a parental history of allergy, hay fever, or asthma.

The median concentration of bedroom dust mite allergen was 2.15 μg/g dust, with a geometric mean of 2.78 μg/g dust (Table I). Of the 428 homes, 51.9% (n=222) were classified with dust mite allergen concentrations ≥2 μg/g dust, equal to the 48th percentile, with 18.9% (n=81) having a concentration >10 μg/g dust, equal to the 81st percentile.

Table I. Characteristics of dust mite (Der f 1 and Der p 1) allergen levels in household (n=428) samples

At 6 to 7 years of age, 33.6% of the children were atopic, 37.5% were seroatopic, 24.2% were BHR-positive, 10.5% had been diagnosed with asthma, and 5.4% had current atopic asthma (Table II). Of the 379 children in the cohort with both skin tests and serum IgE measurements, 114 (31%) were both atopic and seroatopic, 216 (57%) were neither, 28 (7.4%) were seroatopic but not atopic, and 21 (5.5%) were classified as atopic but not seroatopic. Of the 23 children with current atopic asthma, 56.5% were sensitized to dust mite by either skin test or specific IgE, 20 (87%) were atopic, 21 of the 22 (95.5%) tested were seroatopic, and 13 of the 22 (59.1%) who had completed pulmonary function tests were BHR-positive.

Table II. Prevalence in study cohort (n=428) of positive skin tests to dust mites, positive dust mite–specific IgE, atopy, seroatopy, BHR, and asthma

Variable	Study cohort (n/total)
Positive skin test to either dust mite	19.2% (82/428)
With parental history	20.2% (49/243)
With maternal history	17.2% (28/163)
With paternal history	20.9% (29/136)
Detectable mite-specific IgE	14.5% (55/379)
With parental history	15.3% (32/209)
With maternal history	13.1% (18/137)
With paternal history	16.0% (20/125)
Atopy∗	33.6% (144/428)
With parental history	38.3% (93/243)
With maternal history	33.7% (55/163)
With paternal history	46.0% (64/139)
Seroatopy†	37.5% (142/379)
With parental history	41.4% (87/210)
With maternal history	38.4% (53/138)
With paternal history	46.0% (58/126)
BHR-positive	24.2% (101/418)
With parental history	21.2% (50/236)
With maternal history	17.6% (28/159)
With paternal history	23.9% (32/134)
History of physician diagnosis of asthma	10.5% (45/427)
With parental history	11.5% (28/243)
With maternal history	11.0% (18/163)
With paternal history	10.8% (15/139)
Current asthma	7.0% (30/427)
With parental history	8.6% (21/243)
With maternal history	6.7% (11/163)
With paternal history	10.8% (15/139)
Current atopic asthma	5.4% (23/427)
With parental history	7.0% (17/243)
With maternal history	4.3% (7/163)
With paternal history	9.4% (13/139)

Table III, Table IV display the risk estimates for the outcome variables considering the 2 cutpoints of ≥2 and >10 μg/g dust and stratified by parental history. Considering the total group, there was no evidence that these levels of exposure increased risk, although there was a suggestion of an inverse association with BHR (OR, 0.62; CI, 0.38-1.00; P < .050; and OR, 0.53; CI, 0.27-1.04; P < .065, respectively). However, stratifying these analyses by parental history revealed a pattern suggesting that the risks for the measured outcomes varied dependent on this variable.

Table III. Adjusted^∗ risk estimates for skin test responsiveness to dust mite allergens and detectable mite-specific IgE, atopy, seroatopy, BHR, and asthma, with dust mite [Der f 1+Der p 1] exposure at ≤2 years of age ≥2 μg per gram of house dust, by parental history

Table IV. Adjusted^∗ risk estimates for skin test responsiveness to dust mite allergens and detectable mite-specific IgE, atopy, seroatopy, BHR, and asthma, with dust mite [Der p 1+Der p 1] exposure at ≤2 years of age ≥10 μg per gram of house dust, by parental history

For children with a positive parental history, dust mite allergen levels above the cutpoints were associated with an increased risk for a positive skin test (OR, 1.45; CI, 0.74-2.82; P < .276 for ≥2 μg/g; and OR, 2.09; CI, 0.93-4.73; P < .076 for >10 μg/g) and positive specific IgE test to dust mite (OR, 1.37; CI, 0.61-3.09; P < .448 for ≥2 μg/g; and OR, 2.08; CI, 0.77-5.61; P < .150 for >10 μg/g), although these ORs were not statistically significant. The opposite trend was seen for children without a parental history, with protective estimates for positive skin tests (OR, 0.36; CI, 0.15-0.84; P < .019 for ≥2 μg/g; and OR, 0.4; CI, 0.13-1.19; P < .10 for >10 μg/g) and specific IgE tests to dust mite (OR, 0.55; CI, 0.21-1.44; P < .223 for ≥2 μg/g; and OR, 0.53; CI, 0.16-1.79; P < .308 for >10 μg/g). These patterns were reflected in the atopy and seroatopy outcomes. For the ≥2 μg/g dust cutpoint, the risk estimates were somewhat higher for children with a maternal compared with paternal history of allergy or asthma. The reverse was true for the higher cutpoint of >10 μg/g.

For asthma history and current atopic asthma, no pattern was evident for the ≥2 μg/g dust cutpoint. However, for the highest cutpoint, >10 μg/g, the trend again varied by parental history. Children with a parental history exposed to this level of dust mite allergen were at lower risk (OR, 0.39; CI, 0.05-3.13; P < .376), whereas children without a parental history were at higher risk (OR, 1.52; CI, 0.22-10.6; P < .673), although our sample sizes were too small to allow precise estimates. For BHR, the risk estimates were consistently in a protective direction regardless of parental history. However, when considering maternal versus paternal history, decreased risk was evident mainly among children with a positive maternal history. In fact, of the children with a positive maternal history and exposure at the >10 μg/g dust level, there were none with BHR or asthma.

With dust mite allergen level as a continuous variable, an increase in 1 μg/g dust of dust mite allergen was statistically significantly associated with a positive skin test to dust mites (P < .047) and was of borderline significance with a positive dust mite–specific IgE (P < .062). Although the other comparisons were not statistically significant, the pattern that an increase in dust mite concentration was associated with an increase in risk for measures related to sensitization and a decrease in risk for measures related to asthma among children with a parental history was sustained, as was the reversal of that pattern for children without a parental history and an inverse relationship with BHR in all strata.

These analyses were repeated using only one 2-year measurement for all subjects rather than the average of all measurements for the intensively followed subjects, with no differences found in the risk estimates, and the risk estimates were unchanged when excluding the 61 children for whom we used a dust mite allergen determination performed at 4 years.

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3. Discussion 

The Third International Workshop on indoor allergens and asthma in 1995 concluded that exposure to dust mites during infancy was a risk factor for the development of childhood asthma.¹ This conclusion was based on a review of the scientific literature concerning dust mite exposure and asthma and included consideration of environmental manipulation and immunologic interventions in early life for primary prevention.

Pearce et al² published a review article in 2000 challenging the assumption that dust mite or any other allergen exposure is causally related to the risk of childhood asthma. Their detailed critique of ecologic, longitudinal, and prevalence epidemiologic studies failed to support an etiologic relationship. They emphasized the absence of any longitudinal studies in large, unselected populations and the need to distinguish between primary and secondary causation.

Lau et al⁵ examined the relationship between dust mite and cat allergen exposure and allergen sensitivity, BHR, wheeze, and asthma in a birth cohort of 648 children drawn from a general population in Germany. They reported an association between being in the upper quartile of exposure to dust mite allergen at age 6 months as measured in carpet dust samples and sensitization to dust mite between 3 and 7 years of age. However, they found no relationship between dust mite or cat allergen levels and the prevalence of asthma, wheeze, or BHR at 7 years of age. The lack of association persisted after adjusting for parental smoking, atopic family history, pet ownership, and social status.¹³

The German study has been questioned because of the relatively low levels of dust mite allergen reported.⁶ Our overall nonstratified results are in agreement with the study by Lau et al,⁵ and the homes we measured had substantially higher levels of mite allergen, similar to those measured in many cross-sectional studies demonstrating an association with asthma.² Our interquartile range for total mite allergen was 0.86 to 6.97 μg/g of house dust, compared with 0.032 to 0.981 μg/g of house dust found in Germany.⁵ However, although Lau et al⁵ commented that adjusting for potential confounding variables did not affect their results, they did not report that they considered interaction terms in their statistical models or stratified by risk factors such as family history of atopy. (It is difficult, even if interaction terms are introduced, to detect a statistically significant interaction term in a logistic regression model unless sample sizes are exceptionally large.) Given our results, it is possible that their overall estimates masked the importance of family history. Unlike the German study, we did not observe an overall association of early dust mite exposure with mite sensitization determined either by skin prick testing or by measurement of specific IgE antibodies, although we did detect this association among children with a parental history of disease. Our study does not support the analyses of Sporik et al³ that demonstrated an increased risk of asthma among children with a positive family history and exposed to dust mite concentrations >10 μg/g dust.

The prospective nature of this study and the ability to assess potential confounding for a large number of pertinent variables lends credence to our findings. The prevalence of atopy was consonant with that found among children living in industrialized countries,^14., ^15., ^16., ^17. as was the prevalence of asthma diagnosis.^18., ^19., ^20. The accuracy of parental reports for many of these variables was confirmed by the in-home visits and measurements such as urine cotinine. A limitation is that the data were usually collected from the child's mother, including information regarding the father's history of allergies and asthma. Therefore, the father's history is more likely to represent current disease or to be inaccurate. We were able to analyze multiple objective outcomes in addition to the reported history of asthma diagnosis.

For many of the children, we only had a single measurement of mite allergen concentration collected from 1 site, the floor next to the child's bed. However, we have previously shown among the smaller group of intensively followed children in this cohort that a single measurement was highly correlated with the average of multiple monthly samples obtained over a period of 2 years (0.79 for Der f 1 and 0.72 for Der p 1).¹⁰ Moreover, in this study, compared with several others,^3., ^4. the measure used was always sampled from the same location. We did not collect samples from the child's mattress; however, Lau et al⁵ have suggested that a floor dust sample may be a better marker of allergen exposure than a mattress sample.⁵ Clearly all these attempts to obtain an estimate of a child's actual exposure to dust mite allergen are crude. We did not collect dust samples at 6 to 7 years, so we were unable to adjust for current allergen exposure as a confounder.

This study is limited by the loss of children from follow-up, although we could not identify important differences between subjects who remained in the study until 6 to 7 years and subjects who did not. Our study population was large enough to permit adjustment by multiple variables, but many of our risk estimates were nevertheless imprecise, particularly in our stratified analyses and in the consideration of outcomes with a lower prevalence. Our findings can only be considered applicable to comparable populations living in analogous moderate, midcontinental climates.

Because dust mites are a trigger for asthma symptoms, it would appear in cross-sectional studies of prevalent cases that these 2 factors are related, although it does not necessarily follow that dust mite exposure and sensitization lie in the causal pathway for asthma any more than do other well-known symptom triggers such as rhinovirus infection, exercise, and pets.^21., ^22., ^23. If parental history can be considered a surrogate for inherited susceptibility, our study supports the notion that potential gene-environment interactions contribute to the etiology of sensitization and atopic asthma, and that etiologic factors interrelate differently between atopy and asthma accompanied by atopy. Our results emphasize, as do those of other epidemiologic studies,^24., ^25., ^26. the methodologic importance of considering biological interaction between factors, such as family history, that contribute to these conditions.

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Acknowledgements 

We acknowledge the work of the following persons who made this study possible: Shirley Blocki and Geraldine Birg, study nurses; Judith McCullough, laboratory research coordinator; Cathy Boyer, Nonna Akkerman, and Susan McGuinness, data coordinators; Karen Wells, programmer; and the Health Alliance Plan and Henry Ford Medical Group staff.

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