The role of allergy in childhood asthma (2000)

Over the last 20–30 years, the prevalence of atopic diseases in childhood (including asthma) has increased considerably in Western industrialized countries. In population-based studies using identical methods of ascertainment at intervals of 10–15 years, an increase in doctor-diagnosed current asthma from around 4% to 7–10% has been reported ( 1–3). The steering committee of the International Study on Asthma and Allergies in Childhood (ISAAC) recently reported on the world-wide variation in the prevalence of asthma ( 4). Based on standardized simple questionnaire surveys conducted among representative samples of schoolchildren from centers in most regions of the world, marked variations in the prevalence of asthma symptoms (12-month prevalence) were reported. Up to 15-fold differences were found between countries, ranging from 4.1% to 32.1% in the younger age group and 2.1% to 32.2% in the older age group (6–7 years and 13–14 years, respectively). The prevalence of asthma was par-ticularly high in English-speaking countries and Latin America. These results suggest that the use of the term “asthma” and the translation of the word “wheezing” into other languages may produce results that cannot easily be compared, and methodological variations may, at least in part, explain the differences in the reported prevalence of asthma. A recent critical review of repeated cross-sectional surveys, published later than 1982, of the occurrence of asthma among children and young adults found that changes in the labeling of asthma and information bias (increased professional and public awareness) had probably occurred and could explain the reported trends ( 3). Other authors have concluded that there is evidence of a real increase in the prevalence of asthma in children, although there is some evidence that changes in the diagnostic approach and/or parental awareness may account for a part of the reported increase. In spite of many efforts, strict and correct classification of asthma is difficult in surveys by postal questionnaires. Certainly, not all that wheezes is asthma. Asthma is best defined as a condition of variable airflow limitation that alters over short periods of time, either spontaneously or under the influence of treatment ( 5). Thus, the diagnosis of asthma must be clinically confirmed by a doctor (doctor-diagnosed asthma). Although bronchial hyperresponsiveness (BHR) is common in asthma, BHR and diagnosed asthma are not synonymous (for review, see ref. 6). The term “atopy” was previously applied to allergic conditions that occur in families (hay fever, asthma, and atopic dermatitis). But since the discovery of IgE ( 7, 8), we consider atopy to be characterized by the production of specific IgE in response to common environmental allergens; i.e., type-I IgE-mediated allergic disease ( 9). The development and phenotypic expression of asthma (and other allergic diseases) depend on an interaction between genetic factors, environmental exposure to allergens, and nonspecific adjuvant factors (e.g., tobacco smoke, air pollution, and infections). Our understanding of the inheritance of asthma is still incomplete. At present, it is estimated that genetic factors account for about 50% of asthma and allergy. It is unlikely that a change in genetic factors can explain the increased prevalence of asthma seen during the last decades. It is evident that environmental factors play a major role in the development of asthma. The first months of life seem to be an especially vulnerable period, and there is evidence that sensitization is related to the level of allergen exposure during early life. An evaluation of the influence of genetic factors and the influence of early exposure to allergens on the develop-ment of asthma is beyond the scope of this review. These topics are covered in detail by other authors in Allergy Review Series VI “The immunology of fetuses and infants”. Up to 90% of asthmatic children have been reported to be atopic with a high frequency of positive family history of atopic disease and associated positive skin prick test to common inhalant and/or food allergens ( 10). There is some evidence that the reported increase in the prevalence of asthma is particularly due to an increase in nonatopic asthma, a finding which indicates that the causes of asthma may have changed ( 11, 12). These results emphasize the well-known fact that child-hood wheezing illnesses may have different causes and varying prognoses, particularly in young children, where different groups can be identified, such as “transient wheezers” with diminished lung function in early life (associated with maternal smoking during pregnancy), “persistent wheezers”, or “late-onset wheezers” ( 13). Table 1 shows the distribution of these different kinds of wheezers, as reported by Martinez et al. ( 13). Among children with recurrent wheezing during infancy and early childhood, 30–50% have been reported to develop persistent asthma later in childhood ( 13, 14). However, the reported prevalences of “recurrent wheezing”/asth-ma in infancy and early childhood vary widely due to differences in study design, particularly diagnostic criteria and selection of patients. Thus, in prospective studies, 21–34% of subjects have been reported to suffer from recurrent wheezing during early childhood ( 13, 15). Recently, in an ISAAC-phase II cross-sectional study in schoolchildren aged 5–7 years and 9–11 years, respectively, von Mutius et al. ( 16) found that differ-ent wheezing phenotypes exist within the “asthma syndrome”, one group of asthma children exhibiting a triggering or inducing of asthma symptoms through repeated early childhood infections (“infectious asth-ma”), and another group exhibiting “atopic asthma”. The former had a better prognosis ( 16). Similar findings have been reported by other investigators ( 17). Non-atopic asthma seems to have a better prognosis ( 16, 17). A recent study, using nonbronchoscopic lavage, has found some evidence of differences in airways inflamma-tory mechanisms between children with “atopic asthma” (increase in eosinophils and mast cells) and nonatopic asthmatics with virus-induced wheezing ( 18). Many follow-up studies of asthma have shown that 50–70% of children lose their symptoms before adulthood ( 19). The variation in reported frequencies of recovery from childhood asthma is mainly due to differ-ences in study design, such as diagnostic criteria, age at inclusion, and differences in definition of the recovery from asthma. A recent prospective study reported that only 25% of children with asthma outgrew their disorder before the age of 42 years ( 20). Many studies have identified risk factors for persistence of asthma, the most important being verified allergy, other atopic manifestations (hay fever, atopic dermatitis), exposure to tobacco smoke, BHR, impaired lung function, severity of disease, and sometimes male sex (especially in early childhood) ( 19–24). Allergic sensitization does not necessarily imply allergic airways inflammation, an almost invariable feature of asthma although not exclusive to asthma. Thus, up to about 20–40% of nonasthmatics can be shown to be atopic if this is defined as a positive skin prick test and/or positive specific serum IgE to at least one food allergen or airborne allergen in population-based studies, compared to about 90% of asthmatic children ( 25). The results of investigations of the prevalence of sensi-tization are highly influenced by methodological factors, such as the quality of extracts for skin prick test, the assay used to determine specific IgE, and the chosen cutoff level for positivity. Data from recent studies using well-described and generally accepted methods to deter-mine specific IgE by skin prick test or determination of specific serum IgE to relevant allergens in childhood asthma have improved our knowledge of the frequency of sensitization both in unselected children without asthma/atopic disease and among young children with recurrent wheezing/asthma, as well as in older children. There are few valid data on sensitization in unselected children without asthma/atopic disease. In a recent Swedish study investigating 7–8-year-old schoolchildren (n=2149), 12% of children without asthma or any atopic disease had at least one positive skin prick test out of 10 tested airborne allergens, compared to 49% of the 6% of the children with physician-diagnosed asthma ( 26). From our own series ( 27), a prospective study of a 1-year birth cohort (n=276) of unselected infants chosen at random and followed up to 10 years of age, data on sensitization to food allergens, as well as inhalant allergens (birch, grass, mugwort, dog, cat, house-dust mites, Alternaria alternata, Cladosporium herbarum, egg, and cow's milk), were determined by specific IgE (Pharmacia CAP). The frequencies of sensitization to any allergen were 7%, 23%, and 21% at the ages of 18 months, 5 years, and 10 years, respectively, among children without asthma or any atopic disease when RAST class 1 (0.35 kUA/l) was used as the cutoff level. When RAST class 2 (0.7 kUA/l) was used as the cutoff level, the frequencies of sensitization at the same ages were 3%, 10%, and 12%, respectively. The well-known pattern of sensitization was the same as in allergic children with sensitization to food allergens in infancy. In such children, the sensitization decreased with age and was replaced by sensitization to inhalant allergens later in childhood. In our 1-year birth cohort of unselected infants chosen at random and followed from birth to 10 years of age, the following frequencies of specific IgE, as measured by Pharmacia CAP to airborne allergens and food allergens, were found: 7% at 18 months, 27% at 5 years, and 25% at 10 years when RAST class 1 (0.35 kUA/l) was used as cutoff level, compared to 3%, 14%, and 16%, respectively, when RAST class 2 (0.7 kUA/l) was used as cutoff level ( 27). In a similar German study (the Multicenter Allergy Study [MAS]) of 216 children of a prospective birth cohort, a complete follow-up of specific IgE measurements to nine food and inhalant allergens was available at 1, 2, 3, 5, and 6 years of age; on the basis of these measurements, sensitization rates were estimated for the reference population of 4082 children by weighted analysis. From this study, point prevalences of allergic sensitization to at least one of the nine tested allergens (Pharmacia CAP at least 0.7 kUA/l) – hen's egg, cow's milk, soy, wheat, mixed grasses, birch pollen, house-dust mites, cat, and dog (the latter only at 3, 5, and 6 years of age) – increased from 11% at 1 year to 30% at 6 years. The point prevalence of sensitization to inhalant allergens was 1.5% at 1 year, increasing to 26% at 6 years of age, whereas sensitization to food allergens remained stable during the first 6 years of life (10%). A higher frequency of sensitization than in our study was reported at around 5–6 years of age. However, the studies are not completely comparable due to different study designs. Furthermore, in the latter study, the subsample investigated by specific IgE had an overrepresentation of predisposed children, although adjustment for this skewness via weighted analysis was reported. It is evident that a high frequency of sensitization will be found among symptomatic atopic children in such unselected series. The allergens associated with asthma depend on the age of the asthmatics; climatic, seasonal, and social factors; and housing conditions. In temperate and humid regions, allergy to house-dust mites shows the strongest association with asthma, followed by allergy to furred pets (especially cats). In arid regions of the USA, allergy to the fungus Alternaria is important; in urban com-munities, allergy to cockroach may be important, especially in the inner city. These relationships have been reviewed by Platts-Mills et al. ( 29). Character-istically, sensitization evolves in the following order of exposure: food, and indoor allergens, and outdoor allergens. These characteristics concerning sensitization to airborne allergens were clearly demonstrated in an Italian study ( 30) ( Table 2). Around 30% of children with recurrent wheezing, aged 4–60 months, were sensitized to cow's milk protein before 12 months, around 15% at 12–24 months, 10% at 24–48 months, and a very low percentage after that age. In comparison, an increasing frequency of sensitization to house-dust mites (positive skin prick test and positive RAST class 2 or greater) from 40% before 12 months to 70–80% at 4–5 years of age was reported ( 31). Similar results have been reported among asthmatic children below 3 years of age ( 32). In children with asthma and wheezing up to 6 years of age, Martinez et al. ( 13) reported at least one positive skin prick test in 33% of nonwheezing children, 38% of children with transient early wheezing during the first 3 years of life, 55% of so-called late-onset wheezers, and 51% of persistent wheezers ( Table 1). Similar results have been reported by other investigators ( 21), although a lower frequency of sensitization among nonwheezing children up to 4 years of age was reported (15.6%vs 33%). The reported differences in allergic sensitization may be due to many factors, such as different number and quality of extracts investigated, and different selection and diagnostic criteria. A comprehensive study (929 children under 18 years of age) has confirmed the strong association between indoor allergen sensitization and asthma, while finding exclusive sensitization to pollens to be associated primarily with rhinitis. Sensitization was more prevalent for indoor allergens than for outdoor allergens in all groups determined according to diagnosis or age. The prevalence and degree of sensitization were shown to peak in young adults regardless of the allergen, and to diminish with adult age ( 33). Among patients with severe asthma, a very high frequency of sensitization to indoor allergens has been reported; up to 94% to house-dust mites and up to 71% to cat ( 34). In conclusion, the majority of asthmatic children (doctor-diagnosed asthma) are atopic with IgE-mediated sensitivity to common inhalant allergens, particularly house-dust mite, cat, dog, and cockroach, depending on the local distribution and magnitude of exposure to allergens. Although true positive skin prick tests and/or positive specific IgE in serum indicate that a patient has antigen-specific IgE, these findings do not prove that exposure to the allergen in question causes significant clinical allergic symptoms. Only controlled allergen challenge can confirm the cause-effect relationship between allergen exposure and clinical symptoms. However, in daily allergy testing, there is a between a positive skin prick test at least 3 than the and/or high of specific IgE to relevant environmental allergens and clinical disease. of allergy be of the diagnostic of the applied of specific IgE to allergens – food allergens as well as inhalant allergens – are a especially in early childhood, and has clinical ( It has been the higher frequency of atopy IgE to environmental in asthmatic children is a of the atopic of these children, or the specific allergy causes the development and persistence of bronchial and severity of disease. The relationship between allergen exposure and severity of asthma in studies ( indicates that sensitization and causes the allergic to clinical symptoms. in the early manifestations of atopic disease, atopic and symptoms are by food allergy, whereas asthmatic symptoms in these infants most develop later in to sensitization to environmental inhalant allergens ( allergy has been in many prospective studies ( and early allergic as demonstrated by specific IgE to food milk protein and and house-dust mites, the later development of asthma ( It has been that the in asthma the development of sensitization to environmental allergens. does not seem to be the in the development of atopy and asthma the of the allergy in infants and the of early sensitization to food and airborne allergens to the development of allergic asthma. is there any evidence of such a in the group of so-called nonatopic asthmatics with asthma symptoms by as in recent studies ( 16, 18). in studies on asthma in childhood, be to the and of asthma, as well as the Furthermore, it is very important that studies on studies in order to information on the of the different of asthma and into (and to In nonatopic asthma, wheezing are mainly related to whereas allergy to environmental allergens does not play a major In in atopic asthma, exposure to major indoor allergens is an important risk for asthma symptoms in most of the world, and allergen exposure is related to the severity of asthma, as shown by between of asthma severity (e.g., BHR, in peak and level of allergen exposure ( There is generally accepted for of allergens inducing sensitization or allergic although there seems to be a between exposure and as well as a between exposure and severity of asthma (for review, see ref. Other studies have confirmed a with skin prick to indoor allergens as a of asthma severity ( there is evidence of a between allergy and BHR and persistence of asthma symptoms into ( challenge of allergic asthmatics with specific allergy a response ( The early asthmatic response after exposure to allergen within and is characterized by due to through of specific IgE to mast through The are mainly and which are for the and which to some of the In mast and which and of in one of the of the of allergic response is by and are in the response ( The clinical response at after allergen and this BHR for to after allergen ( and daily allergen exposure may to the development of persistent in the in and changes for asthma symptoms. Thus, in atopic asthma, allergen exposure may to development of BHR, airflow and airways inflammation, which may exposure to relevant allergens is the to allergic asthma when the allergen can be identified and is of a cause-effect be both to the allergen level and a clinical The of allergen was first by studies in which patients were from their to a and later by in the of the studies have shown that asthma and of after asthmatics allergic to house-dust to high with low of and house-dust mites ( Other studies ( demonstrated that increased in in temperate regions in decreased decreased exposure to house-dust mite, and improved asthma in asthmatics with allergy to house-dust studies on different for environmental have been (for review, see and investigating diagnostic criteria and only patients with disease and specific allergy – by bronchial allergen The patients not have other clinically important to allergens to which are during the study period, and the follow-up be to a in treatment be and to the to that may a of environmental reviewed by ( and et al. ( studies have demonstrated that some especially for allergens of house-dust mite, have to be in the level of allergens and disease of allergens of house-dust mite, of has been shown to be allergen level, BHR, and symptoms ( Other were of and at least 4 months and of and other (for review, see and the only is of the after of the it may many months before the of allergens is and it may months before the is ( Thus, environmental have been as a specific treatment of a specific allergy under the conditions – and have a cause-effect relationship between exposure to allergens and symptoms in allergic asthma. has been shown in many studies to be an treatment for patients with allergic ( in allergic asthma has previously been recent controlled of specific have in allergic asthma ( A of controlled of allergen in asthma has shown that subjects with had a significant in asthma symptoms and an in nonspecific BHR, and a significant in These were most marked for with extracts of house-dust mite, pollen, and (especially It is that these clinically were ( Recently, specific with house-dust mites in asthma patients a significant of bronchial measured by air compared to ( In allergic asthma patients with airways inflammation, BHR is a of this measured by air BHR to be a more relevant and of airways than previously used Furthermore, controlled studies have a of specific on the development of asthma in children with and allergy to (birch, ( In prospective studies, 21–34% of subjects have been reported to suffer from recurrent wheezing during early childhood. Childhood wheezing illnesses may have different causes and varying prognoses, particularly in young children where different groups can be identified, such as transient wheezers with diminished lung function in early life, persistent wheezers, or late-onset Among children with recurrent wheezing during infancy and early childhood, 30–50% have been reported to develop persistent asthma later in childhood, where at least different wheezing phenotypes have been identified within the asthma one group with asthma” and another group with “atopic asthma”. Over the last years, the prevalence of doctor-diagnosed asthma among schoolchildren seems to have increased from around 4% to The recovery from childhood asthma before adulthood has previously been reported to be recent studies indicate a prognosis with a recovery of around 25% before the age of The identified risk factors for persistence of asthma are verified allergy, other atopic exposure to tobacco smoke, BHR, impaired lung function, severity of disease, in early childhood, male The frequency of sensitization to environmental allergens on the age of the asthmatics; climatic, seasonal, and social factors; and housing conditions. sensitization evolves in the order of food, indoor allergens, outdoor allergens. In early of recurrent wheezers are sensitized to relevant environmental allergens compared to a sensitization of among in prospective In asthmatic children of age, up to are sensitized mainly to indoor inhalant allergens, as compared to a sensitization of among ( Table 3). of specific IgE to environmental allergens, food as well as are findings in early childhood and may be without clinical whereas high or specific serum IgE is of later development of asthma, as well as being significant for sensitization and clinical in although only controlled allergen challenge can confirm the cause-effect relationship between allergen exposure and clinical symptoms. There are generally accepted criteria for of allergens inducing sensitization or allergic although there is a between exposure level and as well as a between exposure and severity of asthma. challenge of allergic asthmatics with specific allergy a the early response within being characterized by due to IgE-mediated and followed by the response after which is characterized by of in the to BHR in the of daily exposure to allergen, in and changes that asthma symptoms. exposure to relevant allergens is the to allergic asthma when the allergen can be identified and is studies have that especially allergens of house-dust and have both in the level of allergens and disease Recently, specific with has been shown to be in allergic asthma in controlled with extracts of house-dust mite, pollen, and (especially A significant in asthma symptoms and and a in both nonspecific and hyperresponsiveness has been In order to treatment of childhood asthma, the clinical and of asthma be defined in all asthmatic children with persistent or recurrent symptoms and of Allergy is a for classification and specific treatment of allergic in of relevant – mainly indoor – allergens may disease and the prognosis of asthma. Furthermore, specific may be a treatment in allergic asthmatics where treatment and/or have been