The Majority of Children Sensitized Before School-Age Develop Allergic Disease Before Adulthood: A Longitudinal Population-Based Study

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INTRODUCTION
Asthma and rhinitis are global public health concerns, and in high-income countries they are the most common diseases in childhood and young adulthood. 1,2They frequently occur together, but although most people affected by asthma also have rhinitis, a large proportion of individuals with rhinitis do not have asthma. 3,46][7][8] Preschool sensitization is also a risk factor for asthma persistence during adolescence. 9In addition, allergic sensitization has been strongly associated with early onset of asthma among adults with asthma. 108][19][20][21] The high prevalence of sensitization in young adulthood is a result of high incidence and low remission during childhood and adolescence. 17,18,203][24][25] Even though this is a well-researched area, there is still a lack of longitudinal studies investigating the significance of age at onset of aeroallergen sensitization in relation to development of airway symptoms up to young adulthood.
The primary aim of this study was to examine the impact of age at onset of sensitization to airborne allergens on the development of asthma and rhinitis during childhood and adolescence.A secondary aim was to examine to what extent individuals sensitized to airborne allergens remain free from symptoms of asthma and rhinitis in a longitudinal perspective up to age 19 years.

Study population
In 1996, within the research program Obstructive Lung Disease in Northern Sweden (OLIN) studies, a population-based cohort of schoolchildren was invited to a questionnaire survey about allergic diseases. 22All children in first and second grade, aged 7 to 8 years (median, 8 years), in 3 municipalities of Northern Sweden were invited to participate in the study.From first grade, school is mandatory in Sweden.All children in 2 of the municipalities were also invited to skin prick test (SPT) for common airborne allergens. 22,23The cohort was reexamined at 11 to 12 years (median, 12 years) and 19 years. 11,20,26,27At recruitment, participation in the questionnaire was 97%, and 88% (n ¼ 2148) participated in SPT.This article is based on the 1510 individuals (70% of the participants at age 8 years) who participated in SPT at all 3 examinations.At age 19 years, at the same occasion as the SPT, a random sample of the cohort had their blood drawn for serum studies (n ¼ 770). 10The studies were approved by the Regional Ethical Review Board in Umeå, Sweden.The parents and/or the participants gave informed consent.

Questionnaire
The questionnaire was based on the International Study of Asthma and Allergy in Childhood (ISAAC) questionnaire, 28 but included additional questions about physician diagnoses, use of medication, and symptoms and risk factors for allergic sensitization, asthma, and allergic rhinitis. 22,29The questions regarding symptoms and diseases were identical in the 3 surveys.The first 2 questionnaires were distributed by the schools and completed by the caregivers, predominantly mothers, whereas the survey at age 19 years was completed by the participants themselves.The question about physician-diagnosed asthma has been validated and showed high specificity, 23 and the agreement between the answers given by the parents and the children for questions regarding asthma and rhinitis was excellent. 30

Allergic sensitization
The SPTs were performed at the schools and by a limited number of specifically trained staff during February to April at all examinations, and in line with the European Academy of Allergy and Clinical Immunology recommendations. 31The test panel included 10 common airborne allergens: birch, timothy, mugwort, dog, cat, horse, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Cladosporium herbarum, and Alternaria alternata (Soluprick, ALK, Hørsholm, Denmark).Histamine (10 mg/mL) and glycerol were used as positive and negative controls, respectively.The tests were performed on the volar part of the forearm using 1mm tip lancets.A positive reaction was defined as a wheal diameter 3 mm or more after 15 minutes.The SPTs have been validated against specific IgE in serum with good agreement. 7,14,26,27For the current study, serum was available for 770 randomly selected individuals at age 19 years, and analyses of specific IgE to cat, dog, horse, birch, and timothy were performed by commercially available ImmunoCAP provided by ThermoFisher Scientific, Uppsala, Sweden. 11The detection level for serum IgE was 0.35 International Unit/mL, and levels below that were set to 0.18 International Unit/mL.

Definitions
The main definitions are presented below, and a complete list of definitions is presented in Table E1 in this article's Online Repository at www.jaci-inpractice.org.
The definition of age at onset of sensitization was based on the 3 time points of SPT of the cohort and corresponds to sensitization to any allergen, any animal, any pollen, and a specific allergen.The main outcomes were current wheeze, current asthma, current symptoms of rhinitis, and current rhinitis.

Statistical analysis
Analyses were performed using IBM SPSS Statistics, Version 26.0.(IBM Corp, Armonk, New York, NY).Differences in proportions between 2 groups were analyzed by c 2 test, and by Mantel-Haentzel tests for more than 2 groups.The differences in geometric mean levels of specific IgE, and the sum of the IgE titers to the major specific IgE (cat, dog, horse, birch, and timothy) at age 19 years by age at onset of a positive SPT result, were analyzed by Kruskal-Wallis nonparametric test.Significance was defined as a P value of less than .05.The associations between asthma and rhinitis at age 19 years and age at onset of allergic sensitization were calculated using Poisson regression analyses and expressed as risk ratios (RRs) with 95% confidence intervals (CI).Dependent variables were current wheeze, current asthma, current symptoms of rhinitis, and current rhinitis.Covariates included in the models were sex, family history of asthma or rhinitis, urban versus rural living at age 8 years, having a smoking mother at age 8 years, ever having pets at home at age 8 years, and age at onset of allergic sensitization with never sensitized as reference.The cumulative incidence was defined as report of the condition at a specific age or in any of the previous surveys.For analyses of the combined effect of age at onset of allergic sensitization and family history of asthma and rhinitis, respectively, on the cumulative incidence of asthma and rhinitis at age 19 years, 8 mutually exclusive categories based on age at onset of allergic sensitization and on family history of asthma (rhinitis) were created, using those never sensitized with no family history of asthma (rhinitis) as reference category, and included in a Poisson model as presented above.

Prevalence of asthma, rhinitis, and allergic sensitization by age
The prevalence of all outcomes increased by age and was highest at age 19 years; current wheeze 15.4%, current asthma 10.9%, current symptoms of rhinitis 28.3%, and current rhinitis 13.4%.For most outcomes, the prevalence was higher among boys than among girls at early ages, but at age 19 years, an opposite pattern or no difference by sex was found (Figure 1; see  1; Table E2).The same pattern was found for sensitization to any animal and any pollen (Figure 1).A low prevalence of positive SPT result to mite and mold was found at all ages, 1.1% to 1.5% at age 8 years, and 2.4% to 3.8% at age 19 years (data not in figure).Of the 1510 individuals participating in the study, 323 (21%) had developed sensitization at age 8 years or earlier, 160 (11%) between age 8 and 12 years, and 184 (12%) between age 12 and 19 years, whereas 843 (56%) were never sensitized.

Asthma and rhinitis in relation to age at onset of allergic sensitization
At age 19 years, the prevalence of all outcomes was highest among those sensitized at age 8 years or earlier, declined by increasing age at onset of sensitization, and was lowest among those never sensitized.The relationships between outcomes and age at onset of sensitization were similar for sensitization to any allergen, any animal, and any pollen, and the patterns were similar for boys and girls (Table I; see Table E3 in this article's Online Repository at www.jaci-inpractice.org).
The association between age at onset of sensitization and asthma and rhinitis, respectively, at age 19 years remained after adjustment for covariates.In general, allergic sensitization had a stronger association with outcomes of rhinitis than with outcomes of asthma.The RR for current rhinitis at age 19 years was 22.3 (95% CI, 13.3-37.6)for those sensitized at age 8 years or earlier versus those never sensitized to any allergen.The corresponding RR for current asthma was 4.68 (95% CI, 3.15-6.97)(Table II).The pattern was similar among girls and boys (see Tables E4 and E5 in this article's Online Repository at www.jaciinpractice.org).
Sensitization at age 8 years or earlier to any pollen and any animal were both strongly associated with rhinitis, with higher RRs for pollen.The RR for current rhinitis at age 19 years was 20.5 (95% CI, 13.3-31.6)for those sensitized at age 8 years or earlier versus those never sensitized to any pollen, and was 12.1 (95% CI, 8.15-18.0)for those sensitized at age 8 years or earlier versus those never sensitized to any animal.For the asthma variables, the associations with sensitization to any pollen and any animal were of similar strength (RR, 3-4 for those sensitized at age 8 years or earlier vs those never sensitized to any pollen and any animal, respectively; Table II).The pattern was similar among girls and boys (Tables E4 and E5).
During the study period, 42.1% reported current wheeze at any survey up to age 19 years (cumulative incidence) among those sensitized at age 8 years or earlier compared with 16.4% among those never sensitized.For current asthma, the corresponding percentages were 30.7% and 6.3%, respectively (Figure 2).The cumulative incidence of current symptoms of rhinitis at age 19 years was 76.2% among those sensitized at age 8 years or earlier versus 23.5% among those never sensitized.The corresponding figures for current rhinitis were 56.7% among those sensitized at age 8 years or earlier versus 3.3% among those never sensitized (Figure 3).At age 19 years, 84.2% of those sensitized at age 8 years or earlier had reported symptoms or diagnosis of asthma or rhinitis in any of the surveys; thus, 15.8% remained free from symptoms of asthma and rhintis.

The combined effect of age at onset of sensitization and family history of allergic disease
The cumulative incidence of asthma and rhinitis up to age 19 years was highest among those with both a family history and onset of allergic sensitization to any allergen before the age of 8 years.The effect of allergic sensitization was generally stronger than that of a family history of the disease.Sensitized at age 8 years or earlier with a family history of rhinitis, compared with never sensitized without family history, yielded very high RR for current rhinitis, 36.3 (95% CI, 18.9-69.7).The corresponding RR for current asthma was 10.6 (95% CI, 6.71-16.7)(Tables III and IV).The level of sensitization judged by number of positive SPT results and by the titers of specific IgE At age 19 years, 66% of individuals who developed their sensitization at age 8 years or earlier had 4 or more positive SPT reactions, compared with 9.2% among those sensitized between age 12 and 19 years (P < .001)(Figure 4, A).Also, at first time of reading a positive SPT result, multisensitization was more common among those sensitized at age 8 years or earlier than among those who had developed sensitization later (Figure 4, B).At age 19 years, the cumulative titer of IgE antibodies to the 5 allergens analyzed (cat, dog, horse, birch, and timothy) was significantly higher among those sensitized early (geometric mean, 30.0) compared with those sensitized between age 12 and 19 years (3.21).The same pattern was found for each of the individual allergens (Table V).

DISCUSSION
In this population-based study following a cohort of children from age 8 to 19 years, age at onset of allergic sensitization to aeroallergens was important for the risk of development of asthma and rhinitis.The risk was consistently highest for those who were sensitized before the age of 8 years, independent of sex and family history of allergic disease.In addition, children with early sensitization had higher levels of specific IgE to aeroallergens at age 19 years and were more often sensitized to multiple allergens compared with children first found to be sensitized at the preteenage or teenage stage.Finally, most children sensitized before age 8 years had experienced symptoms of asthma or rhinitis by age 19 years.
There are a number of possible contributing factors to why individuals with early sensitization were at such high risk of developing clinical symptoms until young adulthood.A long duration of sensitization increases the risk of developing high levels of specific IgE, molecular spreading, and multisensitization, all of them associated with both asthma and rhinitis. 11,17,19,20,26Also, longer the time at risk when being sensitized, the higher the risk of developing clinical symptoms. 11,19Concordantly, at age 19 years (study end point), those who were sensitized early had higher specific IgE levels and were  more often multisensitized than those who developed sensitization later.Notably, as presented in Figure 4, B, sensitization to multiple allergens also at first time of reading a positive SPT result was more common among those with early sensitization compared with individuals first found to be sensitized at the preteen or teenage stage.This suggests a more rapid progress of sensitization among early sensitized.Our results are in line with a British birth cohort with follow-ups up to the age of 8 years, which found the "early multiple sensitization cluster" most strongly associated with asthma. 32Also, a Danish longitudinal study investigating IgE sensitization to 22 food and aeroallergens in a cohort between age 6 months and 13 years found that multisensitization, increasing specific IgE levels, and persistent sensitization during childhood were associated with increased risk of asthma at age 13 years. 33Similarly, a German multicenter study showed an association between early sensitization and asthma at age 7 years. 34his is in accordance with the thesis that the conditions   required for an "atopic march" from sensitization to persistent allergy symptoms are often set very early in life. 35Thus, it seems that those highly genetically predisposed for allergy are sensitized early in life, contributing to the high incidence of clinical symptoms in this group also until young adulthood.Even though we know that genetic predisposition for allergic diseases, sex, early-onset eczema, and environmental factors such as allergen exposure, number of siblings, and the microbial setting surrounding the child compose important factors for health and disease, 1,2,7,22,27,[36][37][38] we are still far from understanding the complex enigma of allergy and tolerance development.Future studies including genetics and stratification by age of onset of allergic sensitization may identify an allergy-prone genotype that could better clarify the process of developing allergic diseases.
Cross-sectional analyses based on the cohort showed a strong association between sensitization to airborne allergens and asthma already at the age of 8 years, 14,22 results in line with well-known findings. 16,39In the longitudinal setting, the cumulative incidence of asthma and rhinitis continued to increase by age, and at age 19 years the prevalence of these conditions was by far the highest among those sensitized early.The development of allergic disease among those not sensitized at age 8 years was highly dependent on the development of sensitization in the subsequent years.For those who developed sensitization between age 8 and 12 years, the cumulative incidence of asthma and rhinitis at age 12 years increased considerably by the age of 19 years.For those who developed sensitization between age 12 and 19 years, the cumulative incidence of asthma and rhinitis at age 8 and 12 years was similar to the cumulative incidence in those never sensitized, but had increased markedly at age 19 years.The association between sensitization and symptoms was stronger for rhinitis than for asthma, which is in accordance with other studies. 10,40,41In line with findings from the few available longitudinal cohort studies, 5,7,33,34,[42][43][44] the current study with 3 observation points clearly illustrated the temporality of the associations between allergic sensitization and development of allergic diseases.
Based on cross-sectional studies, it might be assumed that subjects may be sensitized to aeroallergens without experiencing clinical symptoms throughout life. 12,16,22However, a Swedish birth cohort study found that 77% of those sensitized to food or aeroallergens at any time during the follow-up reported asthma, rhinitis, or eczema at any time up to the age of 16 years. 5In  contrast to our study, they also included eczema among the outcomes, and did not take age at sensitization into account.In our study, 84% of those with early sensitization developed symptoms or diagnosis of asthma or rhinitis before until young adulthood.Because the prevalence of allergic rhinitis peaks in early adulthood, 10,44 a further incidence among the few remaining asymptomatic sensitized individuals can be expected.
In line with the findings of others, 8,10,14,40 we found that sensitization to pollen was more strongly associated with rhinitis, whereas sensitization to animals tended to be strongly associated with asthma.However, the impact of age at onset of sensitization showed the same pattern for the 2 allergen groups.In accordance with previous data, 4,10,22,23 having a family history of asthma and rhinitis was consistently associated with development of airway disease.The contribution of heredity to the risk of developing asthma and rhinitis was, however, not as strong as the contribution of preschool sensitization.This was especially evident for current rhinitis, reflected by an RR of 4.4 for those never sensitized but with a family history compared with an RR of 31 for those sensitized early without a family history and an RR of 40 for those with both early sensitization and a family history.
Sensitization to aeroallergens was more common among boys than among girls at all 3 time points.Despite this, reported symptoms of asthma and rhinitis were more common among girls than among boys at age 19 years.6][47] It has also been shown that adult-onset asthma is more often nonallergic compared with asthma with onset at younger ages. 10,47However, in the current study, the incidence of asthma and rhinitis among those never sensitized remained low during the entire observation period, and the effect of age at sensitization on clinical symptoms followed the same pattern among boys and girls.
The strengths of this study are the size of our study population, the very high participation rates, the longitudinal study design, and the representative sample. 20The 3 observation points during the 11-year study period allowed us to investigate the impact of age at sensitization on the association with the sometimes year-long process of developing clinical symptoms, an association that could be underestimated when using a crosssectional study design.The ISAAC questionnaire has been extensively used and validated internationally, 28 and also in our cohort. 23,30The SPTs were performed by a limited number of specifically trained staff at the same time of year using test extracts from the same supplier at all surveys.Allergic sensitization was mainly assessed by SPT, and SPT results in the cohort have been validated against specific IgE with good agreement, 7,23,27 and the consistency of the SPT was high. 20In other studies assessing SPT versus IgE, good correlations between the measurements as well as associations with clinical symptoms has been reported. 48The prevalence of allergic sensitization and diseases is in level to other studies, 5,16,17,45 ensuring external validity.Because the cohort was recruited at age 8 years, we are lacking data on allergic sensitization before age 8 years, which is a limitation of the study.

CONCLUSIONS
In this longitudinal cohort followed from age 8 to 19 years, we found that sensitization to aeroallergens before age 8 years was associated with a very high incidence of asthma and rhinitis from childhood to young adulthood.In fact, early sensitization was associated with an "allergy cluster" defined by early sensitization, multisensitization, higher levels of sensitization, and a very high risk of allergic disease, and this was independent of parental allergic disease.

FIGURE 1 .
FIGURE 1. Prevalence (%) of asthma, rhinitis, and allergic sensitization (positive skin prick test result) by increasing age at examination.

FIGURE 2 .
FIGURE 2. Cumulative incidence (%) of current wheeze and current asthma, respectively, by increasing age and by age at onset of allergic sensitization.*Current wheeze: "Has your child/Have you had wheezing or whistling in the chest in the last 12 months?"†Current asthma: Physician-diagnosed asthma and either current wheeze or use of asthma medication in the last 12 months.

FIGURE 3 .
FIGURE 3. Cumulative incidence (%) of current symptoms of rhinitis and current rhinitis, respectively, by increasing age and by age at onset of allergic sensitization.*Current symptoms of rhinitis: "In the last 12 months, has your child/have you had a problem with sneezing, or a runny, or a blocked nose when your child/you did not have a cold?" †Current rhinitis: Physician-diagnosed allergic rhinitis and either current symptoms of rhinitis or use of medication for rhinitis in the last 12 months.

FIGURE 4 .
FIGURE 4. Proportion (%) of number of positive SPTresults at (A) age 19 years by age at development of sensitization, and (B) at age at first reading a positive SPT result.

Table E2
in this article's Online Repository at www.jaciinpractice.org).The prevalence of any positive SPT result increased by age, from 21.4% at age 8 years to 31.1% (at age 12 years) and 43.0%(at age 19 years), and was significantly more common among boys than among girls at all examinations (Figure

TABLE I .
Prevalence (%) of asthma and rhinitis at 19 y, by age at onset of allergic sensitization to any allergen among girls, boys, and all Condition Age at onset of sensitization Difference by age at onset, P value Never (n [ 843) 12-19 y (n [ 184) 8-12 y (n [ 160) £8 y (n [ 323)

TABLE II .
Risk for asthma and rhinitis at 19 y, by age at onset of allergic sensitization to any allergen, pollen, and animal, respectively, by Poisson regression analyses and presented as RR with 95% CI Adjusted for sex, family history of condition (asthma or allergic rhinitis, respectively), rural/urban living, any furry animal at home, and having a smoking mother at age 8 y.

TABLE III .
Cumulative incidence (%) of asthma at 19 y by age at onset of allergic sensitization to any allergen and family history Risk ratio with 95% confidence interval analyzed by Poisson regression analyses.*Adjusted for sex, rural/urban living, any furry animal at home, and having a smoking mother at age 8 y.

TABLE IV .
Cumulative incidence (%) of rhinitis at 19 y by age at onset of allergic sensitization to any allergen and family history

TABLE V .
Levels of specific IgE at age 19 y expressed in geometric means and percentiles (25% and 75%) by age at onset of sensitization as measured by SPT International Unit.The lowest level of detection of IgE antibody was 0.35 IU/mL, and levels below that were given a value of 0.18 IU/mL.*Differences by groups analyzed by Kruskal-Wallis test.†Sum of specific IgE to cat, dog, horse, birch, and timothy.

TABLE E2 .
Prevalence (%) of asthma, rhinitis, and allergic sensitization by sex and increasing age

TABLE E3 .
Prevalence (%) of asthma and rhinitis at 19 y, by age at onset of allergic sensitization to pollen and animal, respectively