Environmental allergen exposure, sensitisation and asthma: from whole populations to individuals at risk
http://www.100md.com
《胸》
North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK
Correspondence to:
Professor A Custovic
North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK; a.custovic@man.ac.uk
To prevent asthma and allergies we need to design interventions appropriate for individual susceptibilities, taking account of both genes and the environment
Keywords: asthma; atopy; skin prick test; allergen; children
Sensitisation to inhalant allergens remains a major risk factor for asthma,1 but the size of the effect is hotly debated.2,3 Several cross sectional studies have suggested a simple dose-response relationship between dust mite allergen exposure and specific sensitisation, both within communities4–7 and between communities exposed to differing levels of mite allergens.8 The threshold concentration of 2 μg Group 1 mite allergen per gram of dust for developing mite sensitisation in children at high risk has been suggested, but a much higher cut off level of 80 μg/g appeared significant in low risk children.4 For other allergens the relationship between exposure and sensitisation is less well defined. Several studies in the US inner city areas reported that children are more likely to become sensitised to cockroach with increasing cockroach allergen exposure,9 and that high exposure to mouse allergen appears to be associated with an increased prevalence of sensitisation to mouse.10 Some studies in older children and adults reported a close relationship between specific allergen sensitisation and current domestic exposure for mite and cockroach, but not cat allergen.5,11 This, together with studies reporting a protective effect of high cat allergen exposure on sensitisation,12,13 raises the question of whether the dose-response relationship between exposure and sensitisation may be different for different allergens. However, there are remarkably few published data on the longitudinal relationship between allergen exposure and the development of specific sensitisation.
EVIDENCE FROM LONGITUDINAL STUDIES
Several observational birth cohort studies investigating risk factors for the development of allergen sensitisation and asthma have measured allergen levels in dust samples collected in early life to examine the association between allergen exposure and the development of specific sensitisation. The studies were based in Germany,14 Sweden,15 Holland,16 and the UK (Manchester17 and Ashford cohorts18). While this is the optimal study design for conditions which manifest early in life and progress into adulthood, these studies are difficult and expensive to run and it takes many years to obtain meaningful results.
Following several reports by the German Multicenter Allergy Study (MAS-90),19,20 in this issue of Thorax Cullinan et al become only the second birth cohort to report the exposure-outcomes relationship presenting their results for sensitisation and atopic wheeze at age 5 years in 552 children.18 This cohort from Ashford, UK is truly population based; the investigators approached every woman presenting for antenatal care to three general practices in the area. By skin prick testing the children at the age of 5 years to three common allergens (mite, cat and pollen) they identified a rate of allergic sensitisation of 17%, a figure similar to the 19.6% reported in the Isle of Wight cohort at age 4 years.21 A total of 7% of the children had atopic wheeze. Mite and cat allergen levels were measured in the living room floor at one time point (8 weeks after birth) and the levels were similar to other contemporaneous data from the UK. For the whole population there was no linear dose-response relationship between mite and cat allergen levels and the respective specific sensitisations. For mite, there was an increase in the proportion of sensitised children on moving from the 1st to the 2nd quintile of exposure, after which rates of sensitisation appeared to tail off. For cat, sensitisation increased steadily from the 2nd to the 4th quintile and then tailed off. While this pattern was not significantly altered when children with paternal atopy were considered separately, there was a significant interaction between paternal atopy and mite exposure with a considerably higher proportion of high risk children being sensitised at any given quintile of exposure (except for the lowest).
These results are markedly different from those in the MAS-90 study.19,20 The population sample in the German study was larger (939 at age 7 years) and differs from the Ashford cohort as it is enriched with high risk children. Rates of sensitisation were compared between children in the lowest and highest quartiles of mite allergen exposure. At the age of 7 those in the highest quartile were significantly more likely to be sensitised than those in the lowest quartile (14% v 4%). A similar effect was seen for cat allergen exposure and sensitisation to cat.
How do we assimilate these two apparently different sets of results? It is likely that the relationship between exposure and sensitisation differs markedly between children at high risk and those at low risk of allergic sensitisation. The MAS-90 study was weighted with high risk children and the strongest dose-response relationship was seen in this group.19 On the other hand, the study by Cullinan et al is more representative of the general population with allergen exposure likely to be of little relevance for the majority of subjects. In a population of this composition and size with a modest (by Australian standards) range of mite allergen levels, the dose-response relationship is likely to appear flat. Thus, a dose-response relationship between mite allergen exposure and sensitisation is easier to demonstrate in larger populations weighted with high risk children.
How about the relationship between allergen exposure and asthma development? The Poole cohort described by Sporik et al22 is the only longitudinal study to date to report a significant relationship between early life exposure to dust mite allergen and asthma at the age of 11 years in a small group of 69 high risk children. Most other studies were unable to reproduce these results. Burr et al23 reported no relationship between physician diagnosed asthma or wheezing at age 7 years and dust mite allergen levels in the first or seventh year of life in a prospective study of 453 children. Similarly, in the MAS-90 study, despite a strong association between sensitisation to mite and cat allergens and wheezing and the significant relationship between mite and cat allergen exposure and specific sensitisation, there was no consistent dose-response relationship between allergen exposure and doctor diagnosed asthma, wheezing within the last 12 months, or wheezing ever.20
LESSONS FROM INTERVENTION STUDIES
Intervention studies focusing on high risk children that use environmental control aimed at reducing allergen exposure from or before birth may help to explain the relationship between allergen exposure and clinical outcomes. Six ongoing studies have published results to date.
Isle of Wight Study
This study implemented an intervention designed to reduce exposure to inhalant and food allergens as part of a primary prevention programme. At the age of 1 year there was a reduction in sensitisation and in wheeze in the intervention group,24 but the differences in respiratory symptoms disappeared by age 2 and 4 years.25,26 At the age of 8 sensitisation to mite in the intervention group was reduced by more than 50%.27 Furthermore, children in the active group were significantly less likely to have current wheeze, nocturnal cough, and wheeze with bronchial hyperresponsiveness.
Canadian Asthma Primary Prevention Study (CAPPS)
A multifaceted intervention including measures to reduce exposure to inhalant and food allergens was used.28 At the age of 1 year there was a significant reduction in probable asthma and rhinitis in the active group.29 At the age of 2 years significantly fewer children had asthma in the intervention group than in the control group (16.3% v 23%) but there was no difference in sensitisation.30
Study on the Prevention of Allergy in Children in Europe (SPACE)
In this study the multifaceted intervention was directed towards both inhalant and food allergens. Results reported at the age of 1 year showed a reduction in mite sensitisation but no difference in the proportion of children who had wheezed (21% both groups).31
Childhood Asthma Prevention Study (CAPS)
The Childhood Asthma Prevention Study in Sydney, Australia reported no effect of mite allergen avoidance on sensitisation rates at the age of 18 months.32 However, by 3 years of age mite sensitisation was significantly reduced in the active mite allergen avoidance group.33 Respiratory symptoms were not affected by mite allergen avoidance but there appeared to be more eczema in this group.
Prevention and Incidence of Asthma and Mite Allergy Study (PIAMA)
The Prevention and Incidence of Asthma and Mite Allergy Study in the Netherlands achieved significantly lower mite allergen levels in the active group than in the control group 1 year after the introduction of intervention measures, but the baseline exposure was very low.34 Children in the active group appeared less likely to have had recurrent wheeze during the first year of life, but the only significant difference between groups was a reduction in night time cough without a cold in the active group at age 2 years.35 There was no difference in sensitisation between the groups.
Manchester Asthma and Allergy Study (MAAS)
This study used a much more stringent environmental control regime than other primary prevention studies.36 A significant and sustained reduction in allergen exposure was achieved in the active group.36,37 At 1 year of age there was slightly more sensitisation in the active group (17% v 14%) but this did not reach statistical significance.38 Asthma-like symptoms were consistently lower in the intervention group, and this reached significance for attacks of severe wheeze with shortness of breath, prescribed medication for wheezy attacks, and wheeze after playing or exertion. However, counter-intuitive results were reported at the follow up at 3 years of age, suggesting that stringent environmental control was associated with increased risk of sensitisation to dust mite but better lung function.39
How did the children become sensitised to mite allergens if they had low exposure at home? Even with a complex intervention there remains a residual mite allergen exposure within the home. Additional exposure in the homes of relatives or outside the home may lead to intermittent exposure, which may favour sensitisation in comparison with continuous exposure.39
CONCLUSIONS
Clinical outcomes reported from different observational and intervention studies appear inconsistent and often confusing. What are the implications of the study by Cullinan et al for the design of primary prevention strategies? These results emphasise the point that any single primary prevention strategy will not be applicable to the whole population, but only to individuals within the population with a particular susceptibility. This raises the important question of how one determines susceptibility. To date most investigators have used parental history of allergic disease and allergen sensitisation to assign risk. There is an ongoing debate about the relative role of maternal and paternal disease, with most studies (but, interestingly, not the Ashford cohort18) finding an increased influence of maternal disease. However, assigning risk based on parental history of allergy is insufficiently precise and unsatisfactory, and we have to find more specific markers. Many research groups are trying to identify genetic polymorphisms which confer an increase in risk for allergen sensitisation and for asthma with limited success. This is partly due to the difficulties in phenotype definition and the fact that genetics research has rarely taken account of the relevant environmental exposures. A particular genetic polymorphism may only be associated with an increase (or decrease) in risk in those exposed to a specific environmental factor. In order to understand risk factors for asthma and allergies, one needs to study the interaction between the inherited risk and the environment by measuring both. Future primary prevention studies aimed at prevention of asthma and allergies will be informed by studies of gene–environment interactions. We need to move away from the concept of blanket advice aimed at the whole population to tailor made individualised measures targeting individuals with specific susceptibilities who will benefit from a particular intervention.
REFERENCES
Simpson B M, Custovic A, Simpson A, et al. NAC Manchester Asthma and Allergy Study (NACMAAS): risk factors for asthma and allergic disorders in adults. Clin Exp Allergy 2001;31:391–9.
Pearce N , Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999;54:268–72.
Pearce N , Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55:424–31.
Kuehr J , Frischer T, Meinert R, et al. Mite allergen exposure is a risk for the incidence of specific sensitisation. J Allergy Clin Immunol 1994;94:44–52.
Sporik R , Squillace SP, Ingram JM, et al. Mite, cat and cockroach exposure, allergen sensitisation and asthma in children: a case-control study of three schools. Thorax 1999;54:675–80.
Lau S , Falkenhorst G, Weber A, et al. High mite-allergen exposure increases the risk of sensitization in atopic children and young adults. J Allergy Clin Immunol 1989;84:718–25.
Huss K , Adkinson NF Jr, Eggleston PA, et al. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 2001;107:48–54.
Peat JK, Tovey E, Toelle BG, et al. House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med 1996;153:141–6.
Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102:563–70.
Phipatanakul W , Eggleston PA, Wright EC, et al. Mouse allergen. II. The relationship of mouse allergen exposure to mouse sensitization and asthma morbidity in inner-city children with asthma. J Allergy Clin Immunol 2000;106:1075–80.
Custovic A , Simpson BM, Simpson A, et al. Current mite, cat and dog allergen exposure, pet ownership and sensitization to inhalant allergens in adults. J Allergy Clin Immunol 2003;111:402–7.
Custovic A , Hallam CL, Simpson BM, et al. Decreased prevalence of sensitization to cats with high exposure to cat allergen. J Allergy Clin Immunol 2001;108:537–9.
Platts-Mills T , Vaughan J, Squillace S, et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357:752–6.
Nickel R , Lau S, Niggemann B, et al. Messages from the German Multicentre Allergy Study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :7–10.
Wickman M , Kull I, Pershagen G, et al. The BAMSE Project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :11–13.
Brunekreef B , Smit J, Jongste J, et al. The prevention and incidence of asthma and mite allergy (PIAMA) birth cohort study: design and first results. Pediatr Allergy Immunol 2002;13 (Suppl 15) :55–60.
Custovic A , Simpson BM, Murray CS, et al. The National Asthma Campaign Manchester Asthma and Allergy Study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :32–7.
Cullinan P , MacNeill SJ, Harris JM, et al. Early allergen exposure, skin prick responses and atopic wheeze at age five in English children: a cohort study. Thorax 2004;59:855–61.
Wahn U , Lau S, Bergmann R, et al. Indoor allergen exposure is a risk factor for sensitisation during the first three years of life. J Allergy Clin Immunol 1997;99:763–9.
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. Lancet 2000;356:1392–7.
Arshad SH, Tariq SM, Matthews S, et al. Sensitisation to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108:e33.
Sporik R , Holgate ST, Platts-Mills TA, et al. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323:502–7.
Burr ML, Limb ES, Maguire MJ, et al. Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child 1993;68:724–8.
Arshad SH, Matthews S, Gant C, et al. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 1992;339:1493–7.
Hide DW, Matthews S, Matthews L, et al. Effect of allergen avoidance in infancy on allergic manifestations at age 2 years. J Allergy Clin Immunol 1994;93:842–6.
Hide DW, Matthews S, Tariq S, et al. Allergen avoidance in infancy and allergy at 4 years of age. Allergy 1996;51:89–93.
Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomized controlled study. Thorax 2003;58:489–93.
Chan-Yeung M , Ferguson A, Dimich-Ward H, et al. Effectiveness and compliance to intervention measures in reducing house dust and cat allergen levels. Ann Allergy Asthma Immunol 2002;88:52–8.
Chan-Yeung M , Manfreda J, Dimich-Ward H, et al. A randomized controlled study on the effectiveness of a multifaceted intervention program in the primary prevention of asthma in high-risk infants. Arch Pediatr Adolesc Med 2000;154:657–63.
Becker A , Watson W, Ferguson A, et al. The Canadian Asthma Primary Prevention Study: outcomes at 2 years of age. J Allergy Clin Immunol 2004;113:650–6.
Halmerbauer G , Gartner C, Schierl M, et al. Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization at 1 year of age in a controlled trial of allergen avoidance from birth. Pediatr Allergy Immunol 2003;14:10–17.
Mihrshahi S , Peat JK, Marks GB, et al. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2003;111:162–8.
Peat JK, Mihrshahi S, Kemp AS, et al. Three year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2004; (in press).
van Strien R , Koopman L, Kerkhof M, et al. Mattress encasings and mite allergen levels in the prevention and incidence of asthma and mite allergy study. Clin Exp Allergy 2003;33:490–5.
Koopman LP, van Strien R, Kerkhof M, et al. Placebo-controlled trial of house dust mite-impermeable mattress covers: effect on symptoms in early childhood. Am J Respir Crit Care Med 2002;166:307–13.
Custovic A , Simpson BM, Simpson A, et al. Manchester Asthma and Allergy Study: low allergen environment can be achieved and maintained during pregnancy and in early life. J Allergy Clin Immunol 2000;105:252–8.
Simpson A , Simpson B, Custovic A, et al. Stringent environmental control in pregnancy and early life: the long term effects on mite, cat and dog allergen. Clin Exp Allergy 2003;33:1183–9.
Custovic A , Simpson BM, Simpson A, et al. Environmental control in pregnancy and early life: effect on respiratory symptoms and atopy during the first year of life. Lancet 2001;31:1194–204.
Woodcock A , Lowe LA, Murray CS, et al. Early life environmental control: effect on symptoms, sensitization and lung function at age 3 years. Am J Respir Crit Care Med 2004;170:433–9.(A Custovic and A Simpson)
Correspondence to:
Professor A Custovic
North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK; a.custovic@man.ac.uk
To prevent asthma and allergies we need to design interventions appropriate for individual susceptibilities, taking account of both genes and the environment
Keywords: asthma; atopy; skin prick test; allergen; children
Sensitisation to inhalant allergens remains a major risk factor for asthma,1 but the size of the effect is hotly debated.2,3 Several cross sectional studies have suggested a simple dose-response relationship between dust mite allergen exposure and specific sensitisation, both within communities4–7 and between communities exposed to differing levels of mite allergens.8 The threshold concentration of 2 μg Group 1 mite allergen per gram of dust for developing mite sensitisation in children at high risk has been suggested, but a much higher cut off level of 80 μg/g appeared significant in low risk children.4 For other allergens the relationship between exposure and sensitisation is less well defined. Several studies in the US inner city areas reported that children are more likely to become sensitised to cockroach with increasing cockroach allergen exposure,9 and that high exposure to mouse allergen appears to be associated with an increased prevalence of sensitisation to mouse.10 Some studies in older children and adults reported a close relationship between specific allergen sensitisation and current domestic exposure for mite and cockroach, but not cat allergen.5,11 This, together with studies reporting a protective effect of high cat allergen exposure on sensitisation,12,13 raises the question of whether the dose-response relationship between exposure and sensitisation may be different for different allergens. However, there are remarkably few published data on the longitudinal relationship between allergen exposure and the development of specific sensitisation.
EVIDENCE FROM LONGITUDINAL STUDIES
Several observational birth cohort studies investigating risk factors for the development of allergen sensitisation and asthma have measured allergen levels in dust samples collected in early life to examine the association between allergen exposure and the development of specific sensitisation. The studies were based in Germany,14 Sweden,15 Holland,16 and the UK (Manchester17 and Ashford cohorts18). While this is the optimal study design for conditions which manifest early in life and progress into adulthood, these studies are difficult and expensive to run and it takes many years to obtain meaningful results.
Following several reports by the German Multicenter Allergy Study (MAS-90),19,20 in this issue of Thorax Cullinan et al become only the second birth cohort to report the exposure-outcomes relationship presenting their results for sensitisation and atopic wheeze at age 5 years in 552 children.18 This cohort from Ashford, UK is truly population based; the investigators approached every woman presenting for antenatal care to three general practices in the area. By skin prick testing the children at the age of 5 years to three common allergens (mite, cat and pollen) they identified a rate of allergic sensitisation of 17%, a figure similar to the 19.6% reported in the Isle of Wight cohort at age 4 years.21 A total of 7% of the children had atopic wheeze. Mite and cat allergen levels were measured in the living room floor at one time point (8 weeks after birth) and the levels were similar to other contemporaneous data from the UK. For the whole population there was no linear dose-response relationship between mite and cat allergen levels and the respective specific sensitisations. For mite, there was an increase in the proportion of sensitised children on moving from the 1st to the 2nd quintile of exposure, after which rates of sensitisation appeared to tail off. For cat, sensitisation increased steadily from the 2nd to the 4th quintile and then tailed off. While this pattern was not significantly altered when children with paternal atopy were considered separately, there was a significant interaction between paternal atopy and mite exposure with a considerably higher proportion of high risk children being sensitised at any given quintile of exposure (except for the lowest).
These results are markedly different from those in the MAS-90 study.19,20 The population sample in the German study was larger (939 at age 7 years) and differs from the Ashford cohort as it is enriched with high risk children. Rates of sensitisation were compared between children in the lowest and highest quartiles of mite allergen exposure. At the age of 7 those in the highest quartile were significantly more likely to be sensitised than those in the lowest quartile (14% v 4%). A similar effect was seen for cat allergen exposure and sensitisation to cat.
How do we assimilate these two apparently different sets of results? It is likely that the relationship between exposure and sensitisation differs markedly between children at high risk and those at low risk of allergic sensitisation. The MAS-90 study was weighted with high risk children and the strongest dose-response relationship was seen in this group.19 On the other hand, the study by Cullinan et al is more representative of the general population with allergen exposure likely to be of little relevance for the majority of subjects. In a population of this composition and size with a modest (by Australian standards) range of mite allergen levels, the dose-response relationship is likely to appear flat. Thus, a dose-response relationship between mite allergen exposure and sensitisation is easier to demonstrate in larger populations weighted with high risk children.
How about the relationship between allergen exposure and asthma development? The Poole cohort described by Sporik et al22 is the only longitudinal study to date to report a significant relationship between early life exposure to dust mite allergen and asthma at the age of 11 years in a small group of 69 high risk children. Most other studies were unable to reproduce these results. Burr et al23 reported no relationship between physician diagnosed asthma or wheezing at age 7 years and dust mite allergen levels in the first or seventh year of life in a prospective study of 453 children. Similarly, in the MAS-90 study, despite a strong association between sensitisation to mite and cat allergens and wheezing and the significant relationship between mite and cat allergen exposure and specific sensitisation, there was no consistent dose-response relationship between allergen exposure and doctor diagnosed asthma, wheezing within the last 12 months, or wheezing ever.20
LESSONS FROM INTERVENTION STUDIES
Intervention studies focusing on high risk children that use environmental control aimed at reducing allergen exposure from or before birth may help to explain the relationship between allergen exposure and clinical outcomes. Six ongoing studies have published results to date.
Isle of Wight Study
This study implemented an intervention designed to reduce exposure to inhalant and food allergens as part of a primary prevention programme. At the age of 1 year there was a reduction in sensitisation and in wheeze in the intervention group,24 but the differences in respiratory symptoms disappeared by age 2 and 4 years.25,26 At the age of 8 sensitisation to mite in the intervention group was reduced by more than 50%.27 Furthermore, children in the active group were significantly less likely to have current wheeze, nocturnal cough, and wheeze with bronchial hyperresponsiveness.
Canadian Asthma Primary Prevention Study (CAPPS)
A multifaceted intervention including measures to reduce exposure to inhalant and food allergens was used.28 At the age of 1 year there was a significant reduction in probable asthma and rhinitis in the active group.29 At the age of 2 years significantly fewer children had asthma in the intervention group than in the control group (16.3% v 23%) but there was no difference in sensitisation.30
Study on the Prevention of Allergy in Children in Europe (SPACE)
In this study the multifaceted intervention was directed towards both inhalant and food allergens. Results reported at the age of 1 year showed a reduction in mite sensitisation but no difference in the proportion of children who had wheezed (21% both groups).31
Childhood Asthma Prevention Study (CAPS)
The Childhood Asthma Prevention Study in Sydney, Australia reported no effect of mite allergen avoidance on sensitisation rates at the age of 18 months.32 However, by 3 years of age mite sensitisation was significantly reduced in the active mite allergen avoidance group.33 Respiratory symptoms were not affected by mite allergen avoidance but there appeared to be more eczema in this group.
Prevention and Incidence of Asthma and Mite Allergy Study (PIAMA)
The Prevention and Incidence of Asthma and Mite Allergy Study in the Netherlands achieved significantly lower mite allergen levels in the active group than in the control group 1 year after the introduction of intervention measures, but the baseline exposure was very low.34 Children in the active group appeared less likely to have had recurrent wheeze during the first year of life, but the only significant difference between groups was a reduction in night time cough without a cold in the active group at age 2 years.35 There was no difference in sensitisation between the groups.
Manchester Asthma and Allergy Study (MAAS)
This study used a much more stringent environmental control regime than other primary prevention studies.36 A significant and sustained reduction in allergen exposure was achieved in the active group.36,37 At 1 year of age there was slightly more sensitisation in the active group (17% v 14%) but this did not reach statistical significance.38 Asthma-like symptoms were consistently lower in the intervention group, and this reached significance for attacks of severe wheeze with shortness of breath, prescribed medication for wheezy attacks, and wheeze after playing or exertion. However, counter-intuitive results were reported at the follow up at 3 years of age, suggesting that stringent environmental control was associated with increased risk of sensitisation to dust mite but better lung function.39
How did the children become sensitised to mite allergens if they had low exposure at home? Even with a complex intervention there remains a residual mite allergen exposure within the home. Additional exposure in the homes of relatives or outside the home may lead to intermittent exposure, which may favour sensitisation in comparison with continuous exposure.39
CONCLUSIONS
Clinical outcomes reported from different observational and intervention studies appear inconsistent and often confusing. What are the implications of the study by Cullinan et al for the design of primary prevention strategies? These results emphasise the point that any single primary prevention strategy will not be applicable to the whole population, but only to individuals within the population with a particular susceptibility. This raises the important question of how one determines susceptibility. To date most investigators have used parental history of allergic disease and allergen sensitisation to assign risk. There is an ongoing debate about the relative role of maternal and paternal disease, with most studies (but, interestingly, not the Ashford cohort18) finding an increased influence of maternal disease. However, assigning risk based on parental history of allergy is insufficiently precise and unsatisfactory, and we have to find more specific markers. Many research groups are trying to identify genetic polymorphisms which confer an increase in risk for allergen sensitisation and for asthma with limited success. This is partly due to the difficulties in phenotype definition and the fact that genetics research has rarely taken account of the relevant environmental exposures. A particular genetic polymorphism may only be associated with an increase (or decrease) in risk in those exposed to a specific environmental factor. In order to understand risk factors for asthma and allergies, one needs to study the interaction between the inherited risk and the environment by measuring both. Future primary prevention studies aimed at prevention of asthma and allergies will be informed by studies of gene–environment interactions. We need to move away from the concept of blanket advice aimed at the whole population to tailor made individualised measures targeting individuals with specific susceptibilities who will benefit from a particular intervention.
REFERENCES
Simpson B M, Custovic A, Simpson A, et al. NAC Manchester Asthma and Allergy Study (NACMAAS): risk factors for asthma and allergic disorders in adults. Clin Exp Allergy 2001;31:391–9.
Pearce N , Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999;54:268–72.
Pearce N , Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55:424–31.
Kuehr J , Frischer T, Meinert R, et al. Mite allergen exposure is a risk for the incidence of specific sensitisation. J Allergy Clin Immunol 1994;94:44–52.
Sporik R , Squillace SP, Ingram JM, et al. Mite, cat and cockroach exposure, allergen sensitisation and asthma in children: a case-control study of three schools. Thorax 1999;54:675–80.
Lau S , Falkenhorst G, Weber A, et al. High mite-allergen exposure increases the risk of sensitization in atopic children and young adults. J Allergy Clin Immunol 1989;84:718–25.
Huss K , Adkinson NF Jr, Eggleston PA, et al. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 2001;107:48–54.
Peat JK, Tovey E, Toelle BG, et al. House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med 1996;153:141–6.
Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102:563–70.
Phipatanakul W , Eggleston PA, Wright EC, et al. Mouse allergen. II. The relationship of mouse allergen exposure to mouse sensitization and asthma morbidity in inner-city children with asthma. J Allergy Clin Immunol 2000;106:1075–80.
Custovic A , Simpson BM, Simpson A, et al. Current mite, cat and dog allergen exposure, pet ownership and sensitization to inhalant allergens in adults. J Allergy Clin Immunol 2003;111:402–7.
Custovic A , Hallam CL, Simpson BM, et al. Decreased prevalence of sensitization to cats with high exposure to cat allergen. J Allergy Clin Immunol 2001;108:537–9.
Platts-Mills T , Vaughan J, Squillace S, et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357:752–6.
Nickel R , Lau S, Niggemann B, et al. Messages from the German Multicentre Allergy Study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :7–10.
Wickman M , Kull I, Pershagen G, et al. The BAMSE Project: presentation of a prospective longitudinal birth cohort study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :11–13.
Brunekreef B , Smit J, Jongste J, et al. The prevention and incidence of asthma and mite allergy (PIAMA) birth cohort study: design and first results. Pediatr Allergy Immunol 2002;13 (Suppl 15) :55–60.
Custovic A , Simpson BM, Murray CS, et al. The National Asthma Campaign Manchester Asthma and Allergy Study. Pediatr Allergy Immunol 2002;13 (Suppl 15) :32–7.
Cullinan P , MacNeill SJ, Harris JM, et al. Early allergen exposure, skin prick responses and atopic wheeze at age five in English children: a cohort study. Thorax 2004;59:855–61.
Wahn U , Lau S, Bergmann R, et al. Indoor allergen exposure is a risk factor for sensitisation during the first three years of life. J Allergy Clin Immunol 1997;99:763–9.
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. Lancet 2000;356:1392–7.
Arshad SH, Tariq SM, Matthews S, et al. Sensitisation to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108:e33.
Sporik R , Holgate ST, Platts-Mills TA, et al. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323:502–7.
Burr ML, Limb ES, Maguire MJ, et al. Infant feeding, wheezing, and allergy: a prospective study. Arch Dis Child 1993;68:724–8.
Arshad SH, Matthews S, Gant C, et al. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 1992;339:1493–7.
Hide DW, Matthews S, Matthews L, et al. Effect of allergen avoidance in infancy on allergic manifestations at age 2 years. J Allergy Clin Immunol 1994;93:842–6.
Hide DW, Matthews S, Tariq S, et al. Allergen avoidance in infancy and allergy at 4 years of age. Allergy 1996;51:89–93.
Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomized controlled study. Thorax 2003;58:489–93.
Chan-Yeung M , Ferguson A, Dimich-Ward H, et al. Effectiveness and compliance to intervention measures in reducing house dust and cat allergen levels. Ann Allergy Asthma Immunol 2002;88:52–8.
Chan-Yeung M , Manfreda J, Dimich-Ward H, et al. A randomized controlled study on the effectiveness of a multifaceted intervention program in the primary prevention of asthma in high-risk infants. Arch Pediatr Adolesc Med 2000;154:657–63.
Becker A , Watson W, Ferguson A, et al. The Canadian Asthma Primary Prevention Study: outcomes at 2 years of age. J Allergy Clin Immunol 2004;113:650–6.
Halmerbauer G , Gartner C, Schierl M, et al. Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization at 1 year of age in a controlled trial of allergen avoidance from birth. Pediatr Allergy Immunol 2003;14:10–17.
Mihrshahi S , Peat JK, Marks GB, et al. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2003;111:162–8.
Peat JK, Mihrshahi S, Kemp AS, et al. Three year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2004; (in press).
van Strien R , Koopman L, Kerkhof M, et al. Mattress encasings and mite allergen levels in the prevention and incidence of asthma and mite allergy study. Clin Exp Allergy 2003;33:490–5.
Koopman LP, van Strien R, Kerkhof M, et al. Placebo-controlled trial of house dust mite-impermeable mattress covers: effect on symptoms in early childhood. Am J Respir Crit Care Med 2002;166:307–13.
Custovic A , Simpson BM, Simpson A, et al. Manchester Asthma and Allergy Study: low allergen environment can be achieved and maintained during pregnancy and in early life. J Allergy Clin Immunol 2000;105:252–8.
Simpson A , Simpson B, Custovic A, et al. Stringent environmental control in pregnancy and early life: the long term effects on mite, cat and dog allergen. Clin Exp Allergy 2003;33:1183–9.
Custovic A , Simpson BM, Simpson A, et al. Environmental control in pregnancy and early life: effect on respiratory symptoms and atopy during the first year of life. Lancet 2001;31:1194–204.
Woodcock A , Lowe LA, Murray CS, et al. Early life environmental control: effect on symptoms, sensitization and lung function at age 3 years. Am J Respir Crit Care Med 2004;170:433–9.(A Custovic and A Simpson)