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House-dust mite allergen exposure and the development of asthma in children
Guest editorial
House-dust mite allergen exposure and the development of asthma in children House-dust mites! For decades already, these little creatures are the fright of every pediatric allergist. Not only is the development of allergy ascribed to them, but they are also believed to be major risk factors for childhood asthma. Various studies have confirmed the positive association between the level of house-dust mite exposure and house-dust mitespecific atopic sensitization.1–3 Further, as mite sensitization was repeatedly observed to be strongly associated with childhood asthma,4,5 it was concluded that house-dust mite exposure must therefore also be a risk factor for asthma in children. Indeed, house-dust mite exposure is associated with an increased frequency of asthma exacerbations in mite-sensitive asthmatic patients. However, recent epidemiologic studies and intervention trials on the association of allergen exposure and the outcome of asthma in childhood, even though observing a reduced prevalence of sensitization to the respective allergen, showed neither a consistent protective effect of food allergen avoidance6 – 8 or inhalant allergen avoidance,8 nor any conclusive positive effect of increased inhalant allergen levels9,10 on the development of asthma. A recent review by Pearce et al11 concluded that there is no currently available evidence that allergen exposure in early life is a major risk factor for the development of asthma in childhood, and that population-based cohort studies are needed. In this issue of Annals of Allergy, Asthma, and Immunology, Carter et al12 present data from The Childhood Allergy Study, a birth cohort study in the Detroit area evaluating the environmental determinants of pediatric allergy and asthma in 65 children with elevated levels of cord blood immunoglobulin (Ig)E. Carter et al collected monthly dust samples from children’s bedrooms within the first 2 years of life and invited these children for clinical evaluation, including parental questionnaires on asthma, skin prick testing, and bronchial methacholine challenge at the age of 6 to 7 years. As would be expected, sensitization to house-dust mites was indeed significantly associated with physician-diagnosed asthma. However, Carter et al observed no significant differences in mite allergen levels in homes of children with and without asthma or children with and without bronchial hyperreactivity to methacholine. The authors conclude that exposure to high levels of mite allergen in early childhood is no primary cause for childhood asthma. Few studies collected data on the association of house-dust mite exposure and the development of childhood asthma in a
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prospective manner. This, however, is crucial to differentiate between cause and effect and between risk factors for the development versus risk factors for the exacerbation of disease. Two large prospective studies9,10 showed no association between allergen exposure and childhood asthma, whereas Sporik et al13 observed a nonsignificant association between early allergen exposure and asthma at the age of 11 years in a small prospective study comprising 67 children with a genetic risk for asthma. One potential reason for these discrepancies in study results are the varying ranges of levels of mite allergen in these studies, as the exposure of the German study population of the Multicenter Allergy Study10 was clearly lower than that of the British population of the study by Sporik et al.13 However, the range of mite allergen exposure in the present study is, even if not quite as high, comparable with that of the British study, thus adding further evidence to the negative results of the Multicenter Allergy Study. The prospective data evaluation is one of the major strengths of the longitudinal study by Carter et al. In addition, dust sampling was not performed only once or twice as in previous longitudinal studies, but at regular intervals over a period of 2 years, thus incorporating seasonal variations, reducing potential bias, and yielding quite accurate measures of levels of exposure to house-dust mite allergen. However, more appropriate statistical analyses than solely the unadjusted associations of mean, minimum, and maximum exposure with the outcomes would have been desirable. One point that stands out in the study by Carter et al is the rather small sample size, which limits the interpretation of the results, because large sample sizes are needed in epidemiologic studies to support negative findings. One might further wonder why only children with increased levels of cord blood IgE were followed. At the time of data evaluation (1987 to 1989), increased levels of cord blood IgE were supposed to be a major predictor for atopy and asthma. Such a comprehensive study protocol including monthly dust sampling over a period of 2 years is only feasible in a small cohort; hence, a high-risk population seemed appropriate. Unfortunately, over the last decade, repeated studies on cord blood IgE disproved the predictive value.14,15 Therefore, the study population reported in this issue of the Annals was not at risk of developing asthma, but rather comparable with a general population sample. In general population samples, the incidence of asthma and thereby the power of a study to detect
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
exposure effects is rather low. Therefore, the findings of this cohort are at most suggestive of no association between exposure and outcome. Adequately powered studies with sufficient exposure evaluation are eventually needed to confirm the null hypothesis stating that house-dust mite allergen levels are not associated with the development of childhood asthma. SABINA ILLI, MPH ERIKA VON MUTIUS, MD, MSc Department of Pulmonology and Allergology University Children’s Hospital Mu¨nchen, Germany
7.
8. 9. 10.
REFERENCES 1. Kuehr J, Frischer T, Meinert R, et al. Mite allergen exposure is a risk for the incidence of specific sensitization. J Allergy Clin Immunol 1994;94:44 –52. 2. Munir AK, Kjellman NI, Bjorksten B. Exposure to indoor allergens in early infancy and sensitization. J Allergy Clin Immunol 1997;100:177–181. 3. Wahn U, Lau S, Bergmann R, et al. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 1997;99:763–769. 4. Sears MR, Herbison GP, Holdaway MD, et al. The relative risks of sensitivity to grass pollen, house-dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 1989; 19:419 – 424. 5. Ku¨hr J, Frischer T, Meinert T, et al. Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthma signs in children. J Allergy Clin Immunol 1995;95:655– 662. 6. Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospec-
VOLUME 90, JANUARY, 2003
11. 12.
13.
14.
15.
tive randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995;95: 1179 –1190. Zeiger RS, Heller S, Mellon MH, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol 1989;84:72– 89. Hide DW, Matthews S, Tariq S, Arshad SH. Allergen avoidance in infancy and allergy at 4 years of age. Allergy 1996;51:89 –93. Burr ML, Limb ES, Maguire MJ, et al. Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child 1993;68: 724 –728. Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000; 356:1392–1397. Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55:424 – 431. Carter PM, Peterson EL, Ownby DR, et al. Relationship of house-dust mite allergen exposure in children’s bedrooms in infancy to bronchial hyperresponsiveness and asthma diagnosis by age 6 to 7. Ann Allergy Asthma Immunol 2003;90:41– 44. Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust-mite allergen (Der p 1) and the development of asthma in childhood. A prospective study. N Engl J Med 1990; 323:502–507. Tariq SM, Arshad SH, Matthews SM, Hakim EA. Elevated cord serum IgE increases the risk of aeroallergen sensitization without increasing respiratory allergic symptoms in early childhood. Clin Exp Allergy 1999;29:1042–1048. Hide DW, Arshad SH, Twiselton R, Stevens M. Cord serum IgE: an insensitive method for prediction of atopy. Clin Exp Allergy 1991;21:739 –743.
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House-dust mite allergen exposure and the development of asthma in children House-dust mites! For decades already, these little creatures are the fright of every pediatric allergist. Not only is the development of allergy ascribed to them, but they are also believed to be major risk factors for childhood asthma. Various studies have confirmed the positive association between the level of house-dust mite exposure and house-dust mitespecific atopic sensitization.1–3 Further, as mite sensitization was repeatedly observed to be strongly associated with childhood asthma,4,5 it was concluded that house-dust mite exposure must therefore also be a risk factor for asthma in children. Indeed, house-dust mite exposure is associated with an increased frequency of asthma exacerbations in mite-sensitive asthmatic patients. However, recent epidemiologic studies and intervention trials on the association of allergen exposure and the outcome of asthma in childhood, even though observing a reduced prevalence of sensitization to the respective allergen, showed neither a consistent protective effect of food allergen avoidance6 – 8 or inhalant allergen avoidance,8 nor any conclusive positive effect of increased inhalant allergen levels9,10 on the development of asthma. A recent review by Pearce et al11 concluded that there is no currently available evidence that allergen exposure in early life is a major risk factor for the development of asthma in childhood, and that population-based cohort studies are needed. In this issue of Annals of Allergy, Asthma, and Immunology, Carter et al12 present data from The Childhood Allergy Study, a birth cohort study in the Detroit area evaluating the environmental determinants of pediatric allergy and asthma in 65 children with elevated levels of cord blood immunoglobulin (Ig)E. Carter et al collected monthly dust samples from children’s bedrooms within the first 2 years of life and invited these children for clinical evaluation, including parental questionnaires on asthma, skin prick testing, and bronchial methacholine challenge at the age of 6 to 7 years. As would be expected, sensitization to house-dust mites was indeed significantly associated with physician-diagnosed asthma. However, Carter et al observed no significant differences in mite allergen levels in homes of children with and without asthma or children with and without bronchial hyperreactivity to methacholine. The authors conclude that exposure to high levels of mite allergen in early childhood is no primary cause for childhood asthma. Few studies collected data on the association of house-dust mite exposure and the development of childhood asthma in a
6
prospective manner. This, however, is crucial to differentiate between cause and effect and between risk factors for the development versus risk factors for the exacerbation of disease. Two large prospective studies9,10 showed no association between allergen exposure and childhood asthma, whereas Sporik et al13 observed a nonsignificant association between early allergen exposure and asthma at the age of 11 years in a small prospective study comprising 67 children with a genetic risk for asthma. One potential reason for these discrepancies in study results are the varying ranges of levels of mite allergen in these studies, as the exposure of the German study population of the Multicenter Allergy Study10 was clearly lower than that of the British population of the study by Sporik et al.13 However, the range of mite allergen exposure in the present study is, even if not quite as high, comparable with that of the British study, thus adding further evidence to the negative results of the Multicenter Allergy Study. The prospective data evaluation is one of the major strengths of the longitudinal study by Carter et al. In addition, dust sampling was not performed only once or twice as in previous longitudinal studies, but at regular intervals over a period of 2 years, thus incorporating seasonal variations, reducing potential bias, and yielding quite accurate measures of levels of exposure to house-dust mite allergen. However, more appropriate statistical analyses than solely the unadjusted associations of mean, minimum, and maximum exposure with the outcomes would have been desirable. One point that stands out in the study by Carter et al is the rather small sample size, which limits the interpretation of the results, because large sample sizes are needed in epidemiologic studies to support negative findings. One might further wonder why only children with increased levels of cord blood IgE were followed. At the time of data evaluation (1987 to 1989), increased levels of cord blood IgE were supposed to be a major predictor for atopy and asthma. Such a comprehensive study protocol including monthly dust sampling over a period of 2 years is only feasible in a small cohort; hence, a high-risk population seemed appropriate. Unfortunately, over the last decade, repeated studies on cord blood IgE disproved the predictive value.14,15 Therefore, the study population reported in this issue of the Annals was not at risk of developing asthma, but rather comparable with a general population sample. In general population samples, the incidence of asthma and thereby the power of a study to detect
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
exposure effects is rather low. Therefore, the findings of this cohort are at most suggestive of no association between exposure and outcome. Adequately powered studies with sufficient exposure evaluation are eventually needed to confirm the null hypothesis stating that house-dust mite allergen levels are not associated with the development of childhood asthma. SABINA ILLI, MPH ERIKA VON MUTIUS, MD, MSc Department of Pulmonology and Allergology University Children’s Hospital Mu¨nchen, Germany
7.
8. 9. 10.
REFERENCES 1. Kuehr J, Frischer T, Meinert R, et al. Mite allergen exposure is a risk for the incidence of specific sensitization. J Allergy Clin Immunol 1994;94:44 –52. 2. Munir AK, Kjellman NI, Bjorksten B. Exposure to indoor allergens in early infancy and sensitization. J Allergy Clin Immunol 1997;100:177–181. 3. Wahn U, Lau S, Bergmann R, et al. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 1997;99:763–769. 4. Sears MR, Herbison GP, Holdaway MD, et al. The relative risks of sensitivity to grass pollen, house-dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 1989; 19:419 – 424. 5. Ku¨hr J, Frischer T, Meinert T, et al. Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthma signs in children. J Allergy Clin Immunol 1995;95:655– 662. 6. Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospec-
VOLUME 90, JANUARY, 2003
11. 12.
13.
14.
15.
tive randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995;95: 1179 –1190. Zeiger RS, Heller S, Mellon MH, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol 1989;84:72– 89. Hide DW, Matthews S, Tariq S, Arshad SH. Allergen avoidance in infancy and allergy at 4 years of age. Allergy 1996;51:89 –93. Burr ML, Limb ES, Maguire MJ, et al. Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child 1993;68: 724 –728. Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000; 356:1392–1397. Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55:424 – 431. Carter PM, Peterson EL, Ownby DR, et al. Relationship of house-dust mite allergen exposure in children’s bedrooms in infancy to bronchial hyperresponsiveness and asthma diagnosis by age 6 to 7. Ann Allergy Asthma Immunol 2003;90:41– 44. Sporik R, Holgate ST, Platts-Mills TA, Cogswell JJ. Exposure to house-dust-mite allergen (Der p 1) and the development of asthma in childhood. A prospective study. N Engl J Med 1990; 323:502–507. Tariq SM, Arshad SH, Matthews SM, Hakim EA. Elevated cord serum IgE increases the risk of aeroallergen sensitization without increasing respiratory allergic symptoms in early childhood. Clin Exp Allergy 1999;29:1042–1048. Hide DW, Arshad SH, Twiselton R, Stevens M. Cord serum IgE: an insensitive method for prediction of atopy. Clin Exp Allergy 1991;21:739 –743.
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