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Allergen exposure and the development of specific IgE
REVUE FRANCAISE D'ALLERGOLOGIE ETD'IMMUNOLOGIECLINIQUE
Allergen exposure and the development of specific IgE L.M. WHEATLEY,
T.A.E.
PLATTS-MILLS
StYMMAnY
m~SUME
The increasing prevalence of asthma is associated with a concurrent rise in the prevalence of other atopic diseases. Common to these problems is the acquisition of specific IgE to allergens. The reason for the increase of sensitization to proteins in the environment is not entirely clear. Exposure has certainly increased due to changes in lifestyle which have facilitated allergen concentrations in indoor environments as well as increased the time spent indoors. This c o m b i n a t i o n has increased allergen exposure which in turn has probably recruited individuals with lower degrees of genetic susceptibility into the pool of allergic individuals. However, specific sensitization does not always parallel allergen exposure even in large populations who are genetically similar. This suggests that other factors are involved in the development of atopy. Many candidates have been proposed which are either pro-allergic (pollution, passive smoke), anti-allergic (large family size) or both depending on the situation (viruses). Until there is definitive proof and therefore specific remedy, there is still some evidence that avoidance of exposure in young children may prevent the acquistion of specific IgE and the consequences of allergic disease.
Exposition aux allergtnes et dtveloppement des IgE sptcifiques.- La prtvalence croissante de l'asthme est associte fi une 616vation concomitante de la prtvalence des autres maladies atopiques. Ces notions ont en commun l'acquisidon d'IgE sptcifiques de l'allerg~ne. Les raisons de cette augmentation des sensibilisations aux prottines de l'environnement ne sont pas parfaitement claires, L'exposition s'est certainement accrue du fair de changements du style de vie qui ont facilit6 les concentrations d'allergtnes dans l'environnement domestique et aussi augment6 la durte du temps pass6 ~t domicile. Ces difftrents facteurs ont accru l'exposition a l'allergtne qui, son tour, a probablement recrut6 dans le groupe des individus allergiques, des sujets qui n'avaient q u ' u n faible degr6 de susceptibilit6 gtnttique. Cependant la sensibilisation sptcifique n'est pas toujours paralltle fi l'exposition /t l'allerg~ne, m t m e darts de grandes populations qui sont gtndtiquement semblables. Ceci suggtre que d'autres facteurs j o u e n t u n r61e dans le ddveloppement de l'atopie. Beaucoup ont 6t6 avancts qui sont les uns pro-allergiques (pollution, tabagisme passif), d'autres anti-allergiques (families nombreuses) ou encore tantgt Fun t a n t t t l'autre selon la situation (virus). En attendant une solution et par constquent u n remtde sptcifique, il reste bien certain que le fait d'tviter l'exposition des jeunes enfants aux allergtnes peut prtvenir l'acquisition d'IgE sptcifiques, et par constquent, de la maladie allergique.
KEY-WORDS : IgE - Sensitization - Exposure - Pollution Avoidance.
MOTS-CLI~S: IgE - Sensibilisation Pollution - Evitement.
Department of Internal Medicine, Asthma and Mlergic Diseases Center University of Virginia, (USA). Correspondence: L.M. Wheatley, MD Asthma & Mlergic Diseases Center Box 225 University of Virginia, Health Sciences Center, CHARLOTTESVILLE,VA 22908, (USA). Interasma Marrakech' 98.
Exposition -
WHEATLEY L.M., PLA-FrS-MILLS T.A.E.- Allergen exposure and the development of specific IgE. Rev. fr. Allergol., 1998, 38 (7S), $60-S64.
© Expansion Scientifique Publications. 1998
/ ALLERGEN EXPOSURE AND THE DEVELOPMENT OF SPECIFIC IGE •
The increase in the prevalence of asthma is concurrent with an increase in the prevalence of allergic rhinitis and atopic dermatitis [1]. Clearly the common denominator of these diseases is allergic sensitization. There is evidence that allergic sensitization is higher in populations where asthma is a growing problem, and some evidence that allergic sensitization is itself increasingly common. This phenomenon has been documented in a study of serum samples collected for other reasons from girls 13-14 years of age over a 14 year period in Japan. The prevalence of sera positive to one or more of 16 allergens increased from 21.4% in 1978 to 39.4% in 1991 [2]. Although the development of IgE to a specific e n v i r o n m e n t a l p r o t e i n is to some e x t e n t a phenotypic expression of a genetic susceptibility, the increase in atopic disease has clearly been too rapid to be the result of a genetic shift in the worlds communities. Instead, it seems likely that individuals with a less pronounced tendency to make IgE are being recruited into the pool of atopic individuals. While no one has a complete understanding of the mechanisms by which this expansion of the allergic pool is occurring, clearly exposure is a key step in the process, for without exposure, sensitization is impossible. Sensitization to allergens was first studied in a retrospective fashion, starting with a group of affected individuals. Individuals were then tested for specific IgE and e n v i r o n m e n t a l levels measured. From such studies it was determined that sensitization and exposure to predominantly indoor allergens was strongly associated with the development of asthma [3]. Although allergic responses to dust mites are the most widely reported, clearly the specific allergen is not crucial and animal dander, mite or cockroach have all been reported to dominate in various locations based on local conditions [4,6]. M o r e recently, p r o s p e c t i v e studies were undertaken to evaluate what level of exposure is associated with sensitization. This is a more complex question as the dose required to cause sensitization is likely to vary with the genetic susceptibility of the child. This c o n c e p t was exemplified in a study by Kuehr et al where the acquisition o f sensitization to Der p 1 in elementary school children was followed. In the total population, a level of 10 p g / g m mattress dust was statistically significantly associated with sensitization, whereas in atopy prone children (those with pre-existent non-mite positive skin tests) sensitization became significant at a level of Rev. Jh. Allergol., 1998, 38, 7S
$61
2 lag/gm, a n d for c h i l d r e n w i t h o u t o t h e r sensitizations, sensitization to dust mite only became significant at levels >80 lag/gm mattress dust [7]. This variation in predisposition has also been seen in other studies where a child with a high risk of sensitization (an atopic history in both parents) developed IgE to dust mites with exposure o f < 0.11ag/gm [8]. Nor is it a surprise to anyone that some people can live in conditions with extraordinarily high levels of allergen and never d e v e l o p sensitivity. Again, this is a demonstration of the old principle that defined t h r e s h o l d values have g r e a t e r relevance to populations than to individuals. H o w have e x p o s u r e s changed? Clearly in Western Societies, life has essentially been moved indoors, such that people live, work, play and travel in enclosed spaces. The indoor space has been modified so that it has relatively little in c o m m o n with the o u t d o o r environment with controlled temperature, stable and sometimes high ambient humidity and slow air exchange. In a study in Australia, an increase in the level of dust mite allergen in residential reservoirs was d o c u m e n t e d over a ten year period [9]. This is not a universal finding, however [10]. In addition, things which were formerly outdoors, such as pets and plants, have moved inside. Since people spend as many as 23 out of 24 hours inside an enclosed space, any increase in the concentration of allergen would need to be adjusted for the duration of exposure to get an accurate idea of the ~dose,,. An increase in exposure fails to explain all of the p h e n o m e n o n associated with the rise in prevalence of allergic sensitization that has been observed. For example, skin test positivity to inhalant allergens was higher in the former West Germany than in the former East Germany where allergen levels were higher [11]. In addition, it has been d o c u m e n t e d that allergen sensitization is higher in urban Antwerp than suburban areas when there was no significant difference in the percent of mattress dust samples over the 2lag Der p 1/gin threshold [12]. It is hard to imagine that housing or lifestyle are significantly different between the two areas. This suggests that other factors are augmenting the tendency to an IgE r e s p o n s e . Some factors which have b e e n suggested are decreasing family size, b e t t e r hygiene, decreased numbers of viral infections, childhood vaccinations, diet, obesity, maternal smoking and pollution. Many of these factors have scarcely been investigated and others are
$62 potentially inter-related (family size with viral infection, vaccination and viral infection, diet and obesity). Multiple points for interaction add further difficulty to analysis. For instance viral infections may have different effects at different times. A study of Italian military recruits found a lower p r e v a l e n c e of positive skin tests in individuals with serologic evidence of previous hepatitis A. The conclusion was that early or frequent infections in a small child might prevent allergic sensitization [13]. No one has clearly defined which infections might be protective, and a small study by Frick first detected specific IgE in the same s p e c i m e n s as c o m p l e m e n t fixing antibodies to several common pathogens [14]. Additionally, c o m m o n viral respiratory infections in children who already have specific IgE to aeroallergens have been shown to be a risk factor for acute wheezing episodes [15]. The data for pollution is also confused, in part because it is unclear which chemicals are most likely to be the offending agents, and in part because some of the major indicators of pollution have improved over the same time frame that allergy has increased. Further, exposure estimates are for large areas rather than personal exposure. In addition, many investigators have focused on the role played in disease manifestation (i.e. asthma or atopic dermatitis) rather than primary sensitization. However, there is evidence for the role of pollutants from traffic in the epidemic of atopy [16]. The most striking clinical evidence comes from the studies of cedar pollinosis in Japan [17]. There, sensitivity to cedar is most c o m m o n not in areas with the highest pollen counts but in areas where there is some pollen but also heavy traffic. However, this study is based on symptoms, not on specific IgE. Another study looking at the incidence of skin test positivity to aeroallergens in school children showed an increased risk of atopy for residence near an aluminum smelter during early childhood [18]. Several studies have demonstrated an increased risk of atopy associated with urban rather than rural residence which may relate to air quality but p r o o f is lacking [19, 20]. In vitro studies have also d e m o n s t r a t e d an increased tendency to IgE p r o d u c t i o n (albeit f r o m already c o m m i t t e d precursors) with exposure to diesel particulates [21]. Finally, a specific f o r m of i n d o o r air pollution, environmental tobacco smoke has been associated with elevations of IgE and development of a t o p y in infants, as well as increasing sensitization in occupational allergic disease in adults [16, 22, 23].
• L.M. WHEATLEY, T.A.E. PLATTS-MILLS /
An interesting study in England used diet as a measure of assimilation into the Western lifestyle [24]. In that study, an increasingly English diet was associated with an increasing incidence of atopy among Asian children, as well as increasing b r o n c h i a l hyperreactivity. T h e only specific dietary factor examined, vegetarianism, showed no influence on the outcome so it is not possible to say whether diet was itself important or merely a reflection of some other factor changing in concert with diet. Given that e x p o s u r e is necessary for the development of sensitization, to what degree does allergen avoidance prevent the acquisition of sensitization? Studies have focused primarily on infants for the obvious reason that it is likely to be easier to prevent sensitization than to reverse it, and also because there is data which suggests that acquisition of sensitivity is early. For example, persons born in Finland a few months prior to birch season are more at risk of birch pollen allergy than those born in other months, and this month of birth effect can still be distinguished in some populations in the third decade of life [25, 26]. Studies concentrating on controlling the introduction of food allergens have tended to show short term reduction of sensitization and disease but a tendency to converge with the controls or general population by or before the age of four [27, 28]. The study of Hide et a l o n the Isle of Wight is a broader study that emphasized both food and house dust mite control measures in children at high risk for allergy. At 4 years of age, specific sensitization to house dust mite and molds was significantly less in the avoidance group than among control group. Additionally, prevalence of skin test positivity and definite allergy was less in the prophylactic group than both the controls and a birth cohort from the previous year [29]. Unfortunately, there was less passive smoke exposure in the prophylactic group and, as discussed above, this may have had the effect of improving the outcome. However, this might simply be incorporated into an allergen avoidance regimen. Clearly, the major factors in the <~Western lifestyle,, that are causing the increase in allergic sensitization remain to be definitively identified. However, even while work continues there is some evidence that aggressive avoidance can decrease exposure. If exposure is decreased, at least some individuals will no longer reach the allergic threshold, however low outside and undefined factors push it. If sensitization is prevented, we Rev. fr. Allergol.,
1998,38, 7S
/ ALLERGEN EXPOSURE AND THE DEVELOPMENT OF SPEC1FIC IGE •
$63
I Pollution Viral infection Sensitization+Passive Smoke A- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Allergen Exposure
| % Familysize | viral infection |
/
-
Genetic Susceptibility
Fig. 1 - Schematic of the reciprocal relationship b e t w e e n allergen e x p o s u r e a n d genetic susceptibility as well as the influence of o t h e r factors o n the d e v e l o p m e n t of allergen sensitization. ~
can potentially prevent allergic disease (Fig. 1). However, the increase in symptomatic atopic disease, particularly asthma, is clearly more rapid than the increase in the allergic pool. Therefore, since it is unlikely with the present approaches based on avoidance we can eliminate a large proportion of the allergen sensitized pool, it may be more important to understand what factors are
associated with conversion of specific IgE to the manifestations of allergic disease. For it is clear, many people have specific IgE to environmental allergens but do not have asthma. Many of the same agents suspected of increasing sensitization are being investigated as precipitating disease, but again, the only obvious conclusion is that some aspect of the ,~Western lifestyle,, is responsible.
REFERENCES
1. Schafer T., Ring J. - Epidemiology of allergic diseases. Allergy, 1997, 52, 14-22. 2. Nakagomi T., Itaya H., Tominga T., Yamaki M., Hisamatsu S-i., Nakagomi O. - Is atopy increasing? Lancet, 1994, 343, 121-122. 3. Platts-Mills T.A., Vervloet D., Thomas W.R., A R C . , Chapman M.D. - I n d o o r allergens and asthma: Report of the Third International Workshop.J. Allergy Clin. ImmunoL, 1997, 100, s2-s24. 4. SquiUace S.P., Sporik R.B., Rakes G., et al. - Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: multiple regression of a populationbased study. A m . ) Respir Crit. Care Med., 1997, 156, 1760-1764. 5. Rosenstreich D., Eggleston E, Kattan M., et al. - The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N. Engl.J. Med., 1997, 336, 1356-1363. 6. Platts-MIlls T.A., Sporik R., IngramJ., Honsinger R. - Dog and cat allergens and asthma among school children in Los Alamos, New Mexico, USA: altitude 7,200 feet. Intern. Arch. Allergy Immunol., 1995, 107, 301-303. 7. 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. 8. Munir A.K.M., Max K. Bjorksten B. - Exposure to indoor allergens in early infancy and sensitization. J. Allergy Clin. ImmunoL, 1997, 100, 177-181. 9. Peak J.K., van den Berg R.H., Green W.F., Mellis C.M., Leeder S.R., Woolcock A.J. - Changing prevalence of asthma and atopy in Australian children. Br. Med. J., 1994, 308, 1591-1596.
Rev. fr. Allergol., 1998, 38, 7S
10. Sporik R., Holgate S., Platts-Mills T.A., CogswellJ.J. - Exposure to house-dust mite allergen (Der p 1) and the development of asthma in childhood. N. Engl.J. Med., 1990, 323, 502-507. 11. von Mutius E., Martinez E, Fritsch C., Nicolai T., Roell G., Theimann H.H. - Prevalence of asthma and atopy in two areas of West and East Germany. Am. J. Respir. Crit. Care Med., 1994, 149, 358-364. 12. Wieringa M., Weyler J., Van Bastelaer E, Nelen V., Van Sprundel M., Vermeire E - Higher asthma occurrence in an urban than a suburban area: role of house dust mite skin allergy. Eur Respir.J., 1997, 10, 1460-1466. 13. Matricardi EM., Rosmini E, Ferrigno L., et al. - Cross sectional retrospective study of prevalence of atopy a m o n g Italian military students with antibodies against hepatitis A virus. Br. Med.f, 1997, 314, 999-1003. 14. Frick O., German D., Mills J. - Development of allergy in children. I. Association with virus infections. J. Allergy Clin. ImmunoL, 1979, 63, 228-241. 15. Rakes G., Arruda E., Ingrain J., et al. - H u m a n rhinovirus in wheezing children: relationship to s e r u m IgE and nasal eosinophil cationic protein.J. Allergy Clin. ImmunoL, 1995, 95, 95. 16. Wardlaw A., Burge S. - Sensitization and enhanced allergen responsiveness. Clin. Exp. Allergy, 1995, 25, 56-59. 17. Ishizaki T., Koizumi K., Ikemore R., Ishiyama Y., Kushibiki E. Studies of prevelance of Japanese cedar pollinosis among residents in a densely cultivated area. Ann. Allergy, 1987, 58, 265-270. 18. Soyseth V., Kongerud J., Boe J. - Allergen sensitization and exposure to irritants in infancy. Allergy, 1996, 51, 719-723.
$64
* L.M. WHEATLEY, T.A.E. PLATTS-MILLS /
19. Popp W., Zwick H., Steyrer K., Rauscher H., Wanke T. Sensitization to aeroallergens depends on environmental factors. Allergy, 1989, 44, 572-575. 20. Brabeck L., Kalvesten I. - Urban living as a risk factor for atopic sensitization in Swedish schoolchildren. Pediatr Allergy ImmunoL, 1991, 2, 14-19. 21. Peterson B., Saxon A. - Global increases in allergic respiratory disease: the possible role of diesel exhaust particles. Ann. Allergy Asthma [mmunol., 1996, 77, 263-270. 22. Kjellman N. - Effect of parental smoking on IgE levels in children. Lancet, 1981, i, 993-994. 23. Magnussen C. - Maternal smoking influences cord serum IgE and IgD levels and increases the risk for subsequent infant allergy. J. Allergy Clin. ImmunoL, 1986, 78, 898-904. 24. Carey o.J., Cookson J.B., Britton J., Tattersfield A.E. - The effect of lifetstyle on wheeze, atopy, and bronchial hyperreactivity in Asian and White children. Am. J. Respir. Crit. Care Med., 1996, 154, 537-540.
25. Bjorksten E, Suoniemi I., Kiski V. - Neonatal birch-pollen contact and subsequent allergy to birch pollen. Clin. Allergy, 1980, 10, 585-591. 26. Bjorksten E, Suoniemi I. - Time and intensity of first pollen contacts and risk of subsequent pollen allergies. Acta Med. Scand., 1981, 209, 299-303. 27. Hattevig G., Host A., Hansen L., Osterballe O. - Preventive effect of feeding high-risk infants a casein hydrolysate or an unfiltered whey hydrolysate f o r m u l a . Aprospective, r a n d o m i z e d , comparative clinical study. Pediatr. Allergy Immunol., 1993, 4, 173181. 28. Zieger R., Heller S. - The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance, j~ Allergy Clin. Immunol., 1995, 95, 1179-90. 29. Hide D., Matthews S., Tariq S., Arshad S. - Allergen avoidance in infancy and allergy at 4 years of age. Allet~y, 1996, 51, 89-93.
mmm
Rev. f r AllergoL, 1998, 38, 7S
Allergen exposure and the development of specific IgE L.M. WHEATLEY,
T.A.E.
PLATTS-MILLS
StYMMAnY
m~SUME
The increasing prevalence of asthma is associated with a concurrent rise in the prevalence of other atopic diseases. Common to these problems is the acquisition of specific IgE to allergens. The reason for the increase of sensitization to proteins in the environment is not entirely clear. Exposure has certainly increased due to changes in lifestyle which have facilitated allergen concentrations in indoor environments as well as increased the time spent indoors. This c o m b i n a t i o n has increased allergen exposure which in turn has probably recruited individuals with lower degrees of genetic susceptibility into the pool of allergic individuals. However, specific sensitization does not always parallel allergen exposure even in large populations who are genetically similar. This suggests that other factors are involved in the development of atopy. Many candidates have been proposed which are either pro-allergic (pollution, passive smoke), anti-allergic (large family size) or both depending on the situation (viruses). Until there is definitive proof and therefore specific remedy, there is still some evidence that avoidance of exposure in young children may prevent the acquistion of specific IgE and the consequences of allergic disease.
Exposition aux allergtnes et dtveloppement des IgE sptcifiques.- La prtvalence croissante de l'asthme est associte fi une 616vation concomitante de la prtvalence des autres maladies atopiques. Ces notions ont en commun l'acquisidon d'IgE sptcifiques de l'allerg~ne. Les raisons de cette augmentation des sensibilisations aux prottines de l'environnement ne sont pas parfaitement claires, L'exposition s'est certainement accrue du fair de changements du style de vie qui ont facilit6 les concentrations d'allergtnes dans l'environnement domestique et aussi augment6 la durte du temps pass6 ~t domicile. Ces difftrents facteurs ont accru l'exposition a l'allergtne qui, son tour, a probablement recrut6 dans le groupe des individus allergiques, des sujets qui n'avaient q u ' u n faible degr6 de susceptibilit6 gtnttique. Cependant la sensibilisation sptcifique n'est pas toujours paralltle fi l'exposition /t l'allerg~ne, m t m e darts de grandes populations qui sont gtndtiquement semblables. Ceci suggtre que d'autres facteurs j o u e n t u n r61e dans le ddveloppement de l'atopie. Beaucoup ont 6t6 avancts qui sont les uns pro-allergiques (pollution, tabagisme passif), d'autres anti-allergiques (families nombreuses) ou encore tantgt Fun t a n t t t l'autre selon la situation (virus). En attendant une solution et par constquent u n remtde sptcifique, il reste bien certain que le fait d'tviter l'exposition des jeunes enfants aux allergtnes peut prtvenir l'acquisition d'IgE sptcifiques, et par constquent, de la maladie allergique.
KEY-WORDS : IgE - Sensitization - Exposure - Pollution Avoidance.
MOTS-CLI~S: IgE - Sensibilisation Pollution - Evitement.
Department of Internal Medicine, Asthma and Mlergic Diseases Center University of Virginia, (USA). Correspondence: L.M. Wheatley, MD Asthma & Mlergic Diseases Center Box 225 University of Virginia, Health Sciences Center, CHARLOTTESVILLE,VA 22908, (USA). Interasma Marrakech' 98.
Exposition -
WHEATLEY L.M., PLA-FrS-MILLS T.A.E.- Allergen exposure and the development of specific IgE. Rev. fr. Allergol., 1998, 38 (7S), $60-S64.
© Expansion Scientifique Publications. 1998
/ ALLERGEN EXPOSURE AND THE DEVELOPMENT OF SPECIFIC IGE •
The increase in the prevalence of asthma is concurrent with an increase in the prevalence of allergic rhinitis and atopic dermatitis [1]. Clearly the common denominator of these diseases is allergic sensitization. There is evidence that allergic sensitization is higher in populations where asthma is a growing problem, and some evidence that allergic sensitization is itself increasingly common. This phenomenon has been documented in a study of serum samples collected for other reasons from girls 13-14 years of age over a 14 year period in Japan. The prevalence of sera positive to one or more of 16 allergens increased from 21.4% in 1978 to 39.4% in 1991 [2]. Although the development of IgE to a specific e n v i r o n m e n t a l p r o t e i n is to some e x t e n t a phenotypic expression of a genetic susceptibility, the increase in atopic disease has clearly been too rapid to be the result of a genetic shift in the worlds communities. Instead, it seems likely that individuals with a less pronounced tendency to make IgE are being recruited into the pool of atopic individuals. While no one has a complete understanding of the mechanisms by which this expansion of the allergic pool is occurring, clearly exposure is a key step in the process, for without exposure, sensitization is impossible. Sensitization to allergens was first studied in a retrospective fashion, starting with a group of affected individuals. Individuals were then tested for specific IgE and e n v i r o n m e n t a l levels measured. From such studies it was determined that sensitization and exposure to predominantly indoor allergens was strongly associated with the development of asthma [3]. Although allergic responses to dust mites are the most widely reported, clearly the specific allergen is not crucial and animal dander, mite or cockroach have all been reported to dominate in various locations based on local conditions [4,6]. M o r e recently, p r o s p e c t i v e studies were undertaken to evaluate what level of exposure is associated with sensitization. This is a more complex question as the dose required to cause sensitization is likely to vary with the genetic susceptibility of the child. This c o n c e p t was exemplified in a study by Kuehr et al where the acquisition o f sensitization to Der p 1 in elementary school children was followed. In the total population, a level of 10 p g / g m mattress dust was statistically significantly associated with sensitization, whereas in atopy prone children (those with pre-existent non-mite positive skin tests) sensitization became significant at a level of Rev. Jh. Allergol., 1998, 38, 7S
$61
2 lag/gm, a n d for c h i l d r e n w i t h o u t o t h e r sensitizations, sensitization to dust mite only became significant at levels >80 lag/gm mattress dust [7]. This variation in predisposition has also been seen in other studies where a child with a high risk of sensitization (an atopic history in both parents) developed IgE to dust mites with exposure o f < 0.11ag/gm [8]. Nor is it a surprise to anyone that some people can live in conditions with extraordinarily high levels of allergen and never d e v e l o p sensitivity. Again, this is a demonstration of the old principle that defined t h r e s h o l d values have g r e a t e r relevance to populations than to individuals. H o w have e x p o s u r e s changed? Clearly in Western Societies, life has essentially been moved indoors, such that people live, work, play and travel in enclosed spaces. The indoor space has been modified so that it has relatively little in c o m m o n with the o u t d o o r environment with controlled temperature, stable and sometimes high ambient humidity and slow air exchange. In a study in Australia, an increase in the level of dust mite allergen in residential reservoirs was d o c u m e n t e d over a ten year period [9]. This is not a universal finding, however [10]. In addition, things which were formerly outdoors, such as pets and plants, have moved inside. Since people spend as many as 23 out of 24 hours inside an enclosed space, any increase in the concentration of allergen would need to be adjusted for the duration of exposure to get an accurate idea of the ~dose,,. An increase in exposure fails to explain all of the p h e n o m e n o n associated with the rise in prevalence of allergic sensitization that has been observed. For example, skin test positivity to inhalant allergens was higher in the former West Germany than in the former East Germany where allergen levels were higher [11]. In addition, it has been d o c u m e n t e d that allergen sensitization is higher in urban Antwerp than suburban areas when there was no significant difference in the percent of mattress dust samples over the 2lag Der p 1/gin threshold [12]. It is hard to imagine that housing or lifestyle are significantly different between the two areas. This suggests that other factors are augmenting the tendency to an IgE r e s p o n s e . Some factors which have b e e n suggested are decreasing family size, b e t t e r hygiene, decreased numbers of viral infections, childhood vaccinations, diet, obesity, maternal smoking and pollution. Many of these factors have scarcely been investigated and others are
$62 potentially inter-related (family size with viral infection, vaccination and viral infection, diet and obesity). Multiple points for interaction add further difficulty to analysis. For instance viral infections may have different effects at different times. A study of Italian military recruits found a lower p r e v a l e n c e of positive skin tests in individuals with serologic evidence of previous hepatitis A. The conclusion was that early or frequent infections in a small child might prevent allergic sensitization [13]. No one has clearly defined which infections might be protective, and a small study by Frick first detected specific IgE in the same s p e c i m e n s as c o m p l e m e n t fixing antibodies to several common pathogens [14]. Additionally, c o m m o n viral respiratory infections in children who already have specific IgE to aeroallergens have been shown to be a risk factor for acute wheezing episodes [15]. The data for pollution is also confused, in part because it is unclear which chemicals are most likely to be the offending agents, and in part because some of the major indicators of pollution have improved over the same time frame that allergy has increased. Further, exposure estimates are for large areas rather than personal exposure. In addition, many investigators have focused on the role played in disease manifestation (i.e. asthma or atopic dermatitis) rather than primary sensitization. However, there is evidence for the role of pollutants from traffic in the epidemic of atopy [16]. The most striking clinical evidence comes from the studies of cedar pollinosis in Japan [17]. There, sensitivity to cedar is most c o m m o n not in areas with the highest pollen counts but in areas where there is some pollen but also heavy traffic. However, this study is based on symptoms, not on specific IgE. Another study looking at the incidence of skin test positivity to aeroallergens in school children showed an increased risk of atopy for residence near an aluminum smelter during early childhood [18]. Several studies have demonstrated an increased risk of atopy associated with urban rather than rural residence which may relate to air quality but p r o o f is lacking [19, 20]. In vitro studies have also d e m o n s t r a t e d an increased tendency to IgE p r o d u c t i o n (albeit f r o m already c o m m i t t e d precursors) with exposure to diesel particulates [21]. Finally, a specific f o r m of i n d o o r air pollution, environmental tobacco smoke has been associated with elevations of IgE and development of a t o p y in infants, as well as increasing sensitization in occupational allergic disease in adults [16, 22, 23].
• L.M. WHEATLEY, T.A.E. PLATTS-MILLS /
An interesting study in England used diet as a measure of assimilation into the Western lifestyle [24]. In that study, an increasingly English diet was associated with an increasing incidence of atopy among Asian children, as well as increasing b r o n c h i a l hyperreactivity. T h e only specific dietary factor examined, vegetarianism, showed no influence on the outcome so it is not possible to say whether diet was itself important or merely a reflection of some other factor changing in concert with diet. Given that e x p o s u r e is necessary for the development of sensitization, to what degree does allergen avoidance prevent the acquisition of sensitization? Studies have focused primarily on infants for the obvious reason that it is likely to be easier to prevent sensitization than to reverse it, and also because there is data which suggests that acquisition of sensitivity is early. For example, persons born in Finland a few months prior to birch season are more at risk of birch pollen allergy than those born in other months, and this month of birth effect can still be distinguished in some populations in the third decade of life [25, 26]. Studies concentrating on controlling the introduction of food allergens have tended to show short term reduction of sensitization and disease but a tendency to converge with the controls or general population by or before the age of four [27, 28]. The study of Hide et a l o n the Isle of Wight is a broader study that emphasized both food and house dust mite control measures in children at high risk for allergy. At 4 years of age, specific sensitization to house dust mite and molds was significantly less in the avoidance group than among control group. Additionally, prevalence of skin test positivity and definite allergy was less in the prophylactic group than both the controls and a birth cohort from the previous year [29]. Unfortunately, there was less passive smoke exposure in the prophylactic group and, as discussed above, this may have had the effect of improving the outcome. However, this might simply be incorporated into an allergen avoidance regimen. Clearly, the major factors in the <~Western lifestyle,, that are causing the increase in allergic sensitization remain to be definitively identified. However, even while work continues there is some evidence that aggressive avoidance can decrease exposure. If exposure is decreased, at least some individuals will no longer reach the allergic threshold, however low outside and undefined factors push it. If sensitization is prevented, we Rev. fr. Allergol.,
1998,38, 7S
/ ALLERGEN EXPOSURE AND THE DEVELOPMENT OF SPEC1FIC IGE •
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I Pollution Viral infection Sensitization+Passive Smoke A- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Allergen Exposure
| % Familysize | viral infection |
/
-
Genetic Susceptibility
Fig. 1 - Schematic of the reciprocal relationship b e t w e e n allergen e x p o s u r e a n d genetic susceptibility as well as the influence of o t h e r factors o n the d e v e l o p m e n t of allergen sensitization. ~
can potentially prevent allergic disease (Fig. 1). However, the increase in symptomatic atopic disease, particularly asthma, is clearly more rapid than the increase in the allergic pool. Therefore, since it is unlikely with the present approaches based on avoidance we can eliminate a large proportion of the allergen sensitized pool, it may be more important to understand what factors are
associated with conversion of specific IgE to the manifestations of allergic disease. For it is clear, many people have specific IgE to environmental allergens but do not have asthma. Many of the same agents suspected of increasing sensitization are being investigated as precipitating disease, but again, the only obvious conclusion is that some aspect of the ,~Western lifestyle,, is responsible.
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mmm
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