- Email: [email protected]
Allergy and atopy from infancy to adulthood
Accepted Manuscript
Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS, Susanne Lau MD, PhD , Paolo Maria Matricardi MD,PhD , Ulrich Wahn MD, PhD , Young Ae Lee MD, PhD , Thomas Keil MD, PhD PII: DOI: Reference:
S1081-1206(18)30378-8 10.1016/j.anai.2018.05.012 ANAI 2555
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
15 February 2018 1 May 2018 14 May 2018
Please cite this article as: Susanne Lau MD, PhD , Paolo Maria Matricardi MD,PhD , Ulrich Wahn MD, PhD , Young Ae Lee MD, PhD , Thomas Keil MD, PhD , Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS, , Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.05.012
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KEY MESSAGES The Multicentre Allergy Study (MAS), an observational birth cohort with follow up until the age of 20 years, indicates, that - Atopic multimorbidity of the skin and the airways is related to atopic family history and a more severe phenotype.. For asthma prevalence, the early male preponderance shifted towards females during
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adolescence leading to a sex-balanced distribution by age 20. -
Eczema prevalence switched towards a clear and persisting female predominance, whereas allergic rhinitis continued to affect more males up to age 20.
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Indoor allergen exposure is a risk factor for specific sensitization, asthma
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development and impaired lung function in childhood.
IgE – antibody responses to environmental allergens show „molecular spreading“ in early childhood and preceed clinical disease development.
Genetic variants for the prediction of longterm outcomes could be identified.
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Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS
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Susanne Lau, MD, PhD 1, Paolo Maria Matricardi MD, PhD 1, Ulrich Wahn MD, PhD 1, Young Ae Lee MD, PhD 2/3, Thomas Keil, MD, PhD 4
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1 Department of Pediatrics, Division of Pneumology, Immunology Charité Universitätsmedizin Berlin, Berlin, Germany; 2 Max-Delbrück-Center [MDC] for Molecular Medicine, 13125 Berlin, Germany 3 Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany 4 Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany;
Keywords: allergic diseases; allergic rhinitis; asthma; atopic march; birth cohort study; eczema; multicenter allergy study; prevalence; wheezing;
Main manuscript: 4,858 words
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Abstract: 255 words NCT: not applicable
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Address of correspondence: Prof. Ulrich Wahn, MD, PhD Im Hagen 26 D 14532 Kleinmachnow Germany E-mail: [email protected]
All authors declare that they do not have any conflict of interest.
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Funding The MAS study was funded by grants from the German Federal Ministry of Education and Research (BMBF; reference numbers 07015633, 07 ALE 27, 01EE9405/5, 01EE9406) and the German Research Foundation (DFG; reference numbers KE 1462/2-1, and MA-4740/1). The funders had no role in the design, management, data collection, analysis or interpretation of the data or in the writing of the manuscript or the decision to submit for publication.
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Introduction
Allergic diseases in early and late childhood have become a common health problem
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across the globe as documented by the first cross-sectional phase of the International Study on Asthma and Allergies in Childhood [ISAAC] in the mid-1990s [1,2]. In many industrialized and developing countries the prevalence of asthma, allergic rhinitis and eczema has increased since then or remained at a high plateau
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as shown by another global ISAAC assessment a decade later [3].
The reasons for the high and in many countries increasing allergy prevalence remain largely unclear. For the search of underlying causes and mechanisms prospective long-term birth and child cohort studies are essential. Especially in Europe several
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population-based birth cohort studies have been initiated in recent decades to better
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understand the natural history and identify determinants and factors influencing
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persisting or transitory asthma and allergies in the life-course [4,5,6].
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One of the first population-based birth cohort focusing on asthma and allergy worldwide was the Multi-center Allergy Study (MAS), which started in 5 German cities
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in 1990. The recruited participants have been prospectively followed since then over the first two decades of life.
The overall aims of MAS were:
to describe the incidence and natural course of allergic symptoms and their relationship with the development of
allergic sensitization [i.e. specific
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immunoglobulin E antibody responses] against common aero- and food-allergens; and
to examine early life determinants as well as genetic, environmental and lifestylerelated risk and protective factors for transient and persistent asthma and
primary and secondary prevention strategies [7].
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allergies in order to identify modifiable risk and protective factors for better
This overview aims to summarize the methods, as well as to present and interpret
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important results from the first 20 years of the MAS birth cohort.
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Methods
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Study design, setting and population
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The German Multicenter Atopy Study [MAS], a prospective observational birth cohort, recruited 1314 out of 7609 infants born in 1990 in 5 German cities. A detailed
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description of the stratified sampling scheme and study subjects is given elsewhere [7]. Briefly, 499 newborns with risk factors for atopy (increased cord blood IgE > 0.9 kU/L, and /or at least 2 atopic family members) as well as 815 newborns with none of these risk factors were included in the cohort [7]. These children were assessed at birth and followed up at the age of 1, 3, 6, 12, 18 and 24 months and from then on yearly within 4 weeks of the child’s birthday up to age 13, then at 15 and again at 20
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years. In total there have been assessments at 19 time points including 9 visits to the study centres for physical examinations, clinical tests and biosampling. The study was approved by the local ethics committees in all study centers and funded by the German Ministry of Research and Education, whereas in adulthood by grants from the German Research Foundation. A parent/guardian gave written
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informed consent, and the children gave oral approval at the visits in the study center. At age 20 years, the participants gave written informed consent.
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Parental questionnaires and interviews
At each follow-up visit, parents were interviewed by study physicians using standardized questionnaires. Foremost interest was on atopic symptoms and
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diseases (skin, airways etc). Furthermore, symptoms and diagnoses of other illnesses were assessed at every follow-up, as were a variety of nutritional, lifestyle
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and environmental factors including breast-feeding, nutritional practices, parental
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smoking habits, and pet keeping.
Definitions of allergic outcomes were based on the previously validated questions
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from the International Study of Asthma and Allergies in Childhood (ISAAC) [1]. For asthma, a single parent-reported answer on typical symptoms such as wheezing,
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medication or a doctor-confirmed diagnosis had been used in earlier analyses. Since this may over- or underestimate the true prevalence of asthma, European birth cohort researchers suggested combining relevant variables. Thus, a more stringent epidemiological outcome definition of current asthma was subsequently based on at least 2 out of 3 criteria: [i] asthma medication in the last 12 months; [ii] any indicative symptom (i.e. wheezing, and/or shortness of breath, and/or dry cough at night) in the last 12 months; or [iii] physician’s diagnosis of asthma ever [8,9].
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Bio sampling
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Serum for total/specific IgE and IgG
A total of up to 9 (1%) serum samples were obtained from the children at birth (cord blood) up to 20 years of age, allowing sequential analysis of IgE development. Total IgE, and specific IgE antibodies to food allergens [cow’s milk, hen`s egg, soy bean
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and wheat] and aero-allergens (Dermatophagoides pteronyssinus, cat and dog dander, mixed grass, and birch pollen), which were determined by ImmunoCAP FEIA (ThermoFisher Scientific, Freiburg, Germany). The determination of IgE and IgG antibodies against allergenic molecules were all performed with microarray tests,
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including ISAC-103, ISAC-112, (ThermoFisher Scientific, Uppsala, Sweden) and a
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Genetic analyses
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customized microarray developed by Lupinek et al [10].
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Genomic DNA was extracted from whole blood samples using standard DNA extraction methods. Genotyping was performed using a variety of methods including single
nucleotide
polymorphism
arrays,
allele-specific
PCR
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genome-wide
amplification protocols, and Sanger sequencing.
Indoor allergen sampling At the age of 6 months, 18 months and 5 years, Der p 1 and Der f 1 allergens from house dust mite species Dermatophagoides pteronyssinus and farinae as well as Fel d 1 from cat were extracted from dust samples collected by parents from the carpet
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and analyzed with a sandwich ELISA (ALK, Copenhagen, Denmark). High levels of exposure at a specific age were defined as a measured value above the third quartile of the respective distribution in the total population. Low levels were defined as a
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measured value below the second quartile as previously described [11,12]
Lung function and airway responsiveness tests Resting baseline lung function tests
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At age of 7, 10, 13 and 20 years, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 75%, 50%, 25% (FEF75, 50, 25) of the exhaled FVC, were measured in 800, 638, 680 and 560 individuals,
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respectively. The same type of spirometer and body plethysmograph was used [Master-Lab, Cardinal Health, Würzburg, Germany] in all centers by trained study
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nurses, and supervised by study physicians. Lung function indices were converted to
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height adjusted z scores. Also FEV1 to FVC ratio was calculated.
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Bronchial challenge tests At age of 7 years, a multi-step bronchial histamine challenge was performed in
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647/800 children. In summary, a nebulizer (Pari Provocation Test 2, Pari, Starnberg, Germany) combined with a storage bag allowed standardized pulmonary aerosol deposition at saturated ambient temperature and pressure conditions. At age of 20 years, a multi-step bronchial methacholine challenge was conducted following American Thoracic Society ATS guidelines (PARI Provocation Test 2 nebulizer, Starnberg, Germany).
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At 7, 13 and 20 years of age, bronchodilator responsiveness was determined in all consenting study members after provocation test, at 10 years of age after resting baseline lung function using two puffs of salbutamol from a metered dose inhaler
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(n=647 children at age 10 years).
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Results
Occurrence of allergic diseases
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Allergy prevalence for the general population cannot be derived directly from the overall MAS birth cohort due to its allergy risk-enriched sampling strategy. However,
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if stratified by parental allergic history MAS can deliver reasonably valid prevalence
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parents
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and incidence estimates for the 2 strata of subjects with allergic and non-allergic
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(Fig. 1).
Current atopic dermatitis (AD) / eczema prevalence [13]: the prevalence of current AD as a single entity remained at over 10% throughout school-age, regardless of parental allergy status. In both strata, it declined by about a third at age 20 (Fig.1). At that age, AD affected twice as many women than men (data not shown).
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Current asthma prevalence [13]: the prevalence of current asthma increased continuously throughout school-age, particularly among subjects with allergic parents who were affected 2-3 times more often than those with non-allergic parents (Fig. 1).
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Current allergic rhinitis prevalence [13]: the prevalence of current rhinitis increased continuously and exceeded that of asthma throughout the second decade of life. Subjects with allergic parents were affected about 3 times more often than those with
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non-allergic parents (Fig. 1).
Cumulative incidence of asthma: between 4-20 years, 218 of 1,314 recruited MAS participants developed symptoms classified as “asthma” at one or more follow-up
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assessments. About three quarters (n=156) of the asthma ever cases were sensitized (sIgE ≥0.35 kU/l serum) to at least one of 5 common aeroallergens: dust
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mite, dog, cat, birch, and/or timothy grass [14]. By age 20, the cumulative incidence among offspring from parents with an allergy
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(i.e. asthma, rhinitis, and/or eczema) was about 40% (with two allergic parents) and
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over 25% (only 1 allergic parent). Among children from non-allergic parents the cumulative incidence reached a plateau in early adolescence at just over 10%, thus
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very few new asthma cases were observed after puberty [14].
Cumulative incidence of allergic rhinitis: between 4-20 years, 290 MAS participants developed typical allergic rhinitis symptoms in combination with sIgE ≥0.35 kU/l serum to at least one of 5 common aeroallergens: dust mite, dog, cat, birch, and/or timothy grass pollen [15].
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Current allergic multimorbidity: analyses of asthma and allergy outcomes in birth cohorts have mainly focused on single allergic entities [16]. However, the coexistence of the most common allergic diseases asthma, rhinitis and eczema is considerably more prevalent than expected by chance alone as a pooled analysis of data from 4 and 8 year old European children showed [17].
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The extensive data collected longitudinally from the MAS participants allowed investigations of the prevalence of allergic multimorbidity, i.e. the coexistence of 2 or more allergic disorders in the same individual, from birth to young adulthood. From early school age onwards, this multimorbidity was seen particularly among those with
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a positive family history. At age 20 the participants with an allergic family history had three times more often coexisting allergies than those without such predisposition. Particularly asthma occurred more frequently with coexisting allergic rhinitis and/or
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eczema than as a single entity. Eczema was the condition with the least proportion of coexisting other allergic conditions. It remained more common as a single entity
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throughout the first 20 years of life (Fig. 1) [13].
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Allergic sensitization
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The MAS birth cohort allowed us to describe the complex evolution of the antibody responses to allergen molecules during the first 2 decades of life. Already at 2 years of age, normal children express a broad repertoire of IgG antibodies to a wide array of allergen molecules[18]. The intensity and frequency of these “default” or “normal” IgG responses to animal food allergens, vegetable food allergens and airborne allergens were classified as maximal, intermediate or minimal, respectively.
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Interestingly, atopic children show stronger and more frequent IgG responses than the non-atopic peers [19]. Studies focusing on the IgE response to Bet v 1 and other PR.10 molecules disclosed a second type or “pre-atopic” IgG response. This response, although directed against airborne allergens, is strong and persistent and precedes or
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accompanies the production of IgE against the same molecule. This observation led us to speculate that the IgE response to Bet v 1 in birch allergic children is the final stage of an “abnormal” evolution of a pre-existing “pre-atopic” IgG response [18]. A broader study confirmed and expanded this concept, showing that a “pre-atopic”,
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strong and persistent IgG response can be observed in atopic subjects developing IgE responses to mites, pollens, or molds [20]. Subclass-specific tests showed that IgG4 antibodies contribute only a tiny fraction (<5%) to this naturally induced
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(“default” or “pre-atopic”) IgG response, suggesting that most of it is made up of IgG1
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antibodies [18].
The IgE response against grass pollen starts simple, as it is directed against one or
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few single molecules. For examples, the IgE response to Phleum pratense evolves in
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many allergic children from a simple, often molecular monosensitization stage to an oligomolecular sensitization stage to terminate its evolution in a polymolecular
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sensitization stage. This phenomenon has been defined as “Molecular Spreading” [21]. Interestingly, in almost all children, the initial IgE response is directed against Phl p 1, a sort of “initiator” of this IgE response, which often appears in a pre-clinical stage of the disease process. Then the IgE response involves as a second molecule, in general Phl p 4 and/or Phl p 5; thereafter also Phl p 2 and Phl p 6, and finally Phl p 11, Phl p 12, and Phl p 7. Only a few children develop a full blown response with involvement of all eight allergenic molecules of Phleum pratense. However, in most
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children the IgE response evolves over time and becomes more and more complex [21].
A similar process has subsequently been described in children developing IgE sensitization to Dermatophagoides pteronyssinus [22]. The IgE response started
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almost invariably with three “initiator” molecules (Der p 1, Der p 2, Der p 23) defined as group “A” molecules and expanded sequentially first to the “group B” molecules (Der p 4, Der p 5, Der p 7, Der p 21) and finally to group “C” molecules. Early IgE sensitization onset, parental hay fever, and higher exposure to mites were associated
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with a broader polymolecular IgE sensitization pattern. Interestingly, participants reaching the broadest IgE sensitization stage (ie, ABC) had significantly higher risk of mite related allergic rhinitis and asthma than the unsensitized participants. Finally,
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IgE sensitization in healthy children to Der p 1 or Der p 23 at age 5 years or less
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predicted asthma at school age [22].
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FIGURE 2
This novel understanding of the progressive molecular spreading of the immune
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response to airborne allergens (grass, mites) led us to speculate that immunological intervention (allergen-immunotherapy) should be initiated earlier during the sensitization process [23]. An earlier intervention may have better chances of success, may prevent molecular spreading, and ultimately the development of allergic symptoms. Interestingly, in children with early, subclinical, monomolecular IgE sensitization having parents with hay fever was the strongest risk factor for the development of a polymolecular and clinically relevant IgE response later in
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childhood [24]. The “initiator” molecules like Phl p 1 for grass pollen, Bet v 1 for birch pollen, Der p 1, Der p 2, Der p 23 for mites, Fel d 1 for cat may be suitable markers to identify children in the “pre-clinical” sensitization stage who may benefit from an “allergen immunoprophylaxis” aimed at preventing the onset of allergic rhinitis and
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asthma [20, 23].
Influencing factors
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Heredity/Genetics
A positive allergic family history is one of the strongest predictors to develop childhood asthma [12]. MAS showed that this effect seemed to last up to adulthood.
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The effect of parental allergies, particularly asthma, on the incidence of IgEassociated asthma up to age 20 seemed to be larger than on the incidence of non-
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IgE associated asthma [13].
Allergic diseases are chronic inflammatory conditions that arise from environmental
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triggers acting on genetically susceptible individuals. The contribution of genetic risk factors is substantial and has been estimated at 60-80% based on large-scale twin
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studies [25]. Owing to technology developments, large strides have been made in the discovery of the genetic determinants underlying allergic disorders. Most identified and robustly replicated loci have been found in genome-wide association studies (GWAS), which identified common risk alleles that were found significantly more frequently in patients compared to controls [26-29]. The largest most recent GWAS on allergic disease discovered 136 genetic variants, doubling the number of known
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risk variants and highlighting the genetic overlap between risk loci for eczema, asthma, and hay fever [30].
Beyond GWAS, the MAS cohort has proven to be a real asset in investigating the role of genetic variation in clinical subphenotypes and in the long-term temporal
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trajectory of allergic diseases. Investigating filaggrin null mutations in the MAS cohort, we showed that the strong association of these mutations with asthma and allergic rhinitis was only detectable in children who had previously expressed eczema. It was striking that neither allergic airways disease nor specific sensitization showed an
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association with the FLG mutations in the absence of eczema. These results suggested that FLG mutations predispose to the sequential acquisition of these allergic disorders instead of acting as an independent risk factor for each disease.
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Due to the known function of filaggrin in maintaining the epidermal barrier, our results supported the concept that the inflammatory reaction and further breakdown of the
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epidermal barrier in eczema facilitated transepidermal penetration of allergens and allergic sensitization. This study highlighted the role of the skin as the interface
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between host and environment in shaping immune responses that induce chronic
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inflammation even in distant organs. Moreover, we showed in the MAS cohort that filaggrin null mutations predicted subsequent asthma development in infants with
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eczema and sensitization to food allergens. The identified subgroup of asthmatics was characterized by a significant decline of pulmonary function until puberty and represented a sizeable proportion of 19.1% of patients with eczema-associated asthma. Thus this study was the first to use genetic markers to identify a subset of high risk patients with poor outcome that should be targeted in the development of preventive measures [31].
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Similarly, the prospective evaluation of the MAS children allowed us to evaluate a functional mutation in the interleukin-6 receptor (IL6R Asp358Ala) in the long-term course of eczema. This variant determines the balance between the classical membrane-bound versus the soluble IL6R signaling pathways. We showed a significant association of the risk allele IL6R 358Ala with eczema, and demonstrated
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in two independent population-based birth cohorts that this variant specifically predisposed to the persistent form of eczema and that eczema patients had higher soluble IL6R levels than controls [32].
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While the MAS cohort has been instrumental in characterizing the role of multiple genetic variants for the long-term prognosis of allergic diseases and the atopic march [33,34] it also allowed first genetic investigations in the context of environmental
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exposures and maternal factors [35]. Environmental exposures are recognized to play a considerable role in the development of allergic diseases but can be volatile
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and difficult to assess accurately over time. First attempts to evaluate them in the context of genetic susceptibility using birth cohorts, including MAS, proposed new
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genetic variants modifying asthma risk in interaction with prenatal and childhood
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tobacco smoke exposure [36].
Sex-specific patterns of allergic disease
In early and late school-age, boys of the MAS cohort were more often affected by asthma or rhinitis than girls, whereas for eczema the prevalence in childhood was rather balanced between the sexes. In adolescence, the prevalence of asthma
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shifted towards females and, by age 20, was rather sex-balanced, whereas allergic rhinitis continued to affect more males than females, but to a lesser extent than in childhood. The prevalence of eczema had switched towards a clear female predominance at age 20, affecting now twice as many women than men [13].
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To better understand sex-related changes in allergy prevalence from childhood to adulthood, we conducted sex-specific analyses of asthma and rhinitis as single entities and as comorbid conditions considering specifically the individual puberty
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status, assessed by the validated Puberty Development Scale [37].
To increase the statistical power, individual participant data from 6 large European birth cohorts including MAS were thus combined for longitudinal age-, sex- and
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puberty-specific analyses. These meta-analyses showed a prevalence "sex-shift" from a male predominance before puberty towards females after puberty-onset,
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which was much stronger in participants who had asthma and rhinitis concurrently compared to those who had only asthma or only rhinitis. For IgE-associated rhinitis
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and IgE-associated asthma as single entities, the male predominance in childhood
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remained after puberty-onset, whereas for IgE-associated respiratory multimorbidity [i.e. asthma and concurrent rhinitis] we found a stronger shift towards females, which
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resulted in a sex-balanced prevalence after puberty-onset 37]. Sex- and pubertyspecific analyses of eczema with and without comorbid respiratory allergies are pending.
Indoor environment
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Newborns and young infants living in the moderate climatic zones spend most of the time indoors. Even in countries with a warmer climate young children spend at least 10 hours per day indoors. Therefore, the domestic environment can be assumed to play a crucial role as “exposome” and may influence the development of sensitization
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and allergic inflammation to indoor allergens. Exposure and uptake of allergens may occur via the skin, via inhalation and via the gastrointestinal tract. In MAS, we focused on early life indoor allergens measured in house dust samples, on pet
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keeping and smoking exposure during pregnancy and the first 3 years of life.
MAS demonstrated the risk of early life exposure to house dust mite and cat allergens for the development of specific sensitization to these allergens during the
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first three years of life and at early school-age (Figure 3) [11,12]. However, ownership of furry or feathered pets in early childhood had no influence on asthma at school-
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age as a large meta-analysis including MAS and 10 other European birth cohorts showed [38]. Early exposure to endotoxin in house dust samples was not a risk
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factor for later asthma [39].
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FIGURE 3
Examining the effect of early sensitization we found sIgE to perennial allergens such as house dust mite, cat and/or dog during the first 3 years of life increased the risk of persistent asthma at school age and up to the age of 20 years [13,15,40,41].
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Furthermore, children with early sensitization to indoor allergens during the first 3 years of life and with high indoor allergen exposure at home were found to have the poorest lung function outcome at school-age, while this relationship was less
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pronounced at 5 years of age [41].
Day care attendance
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FIGURE 4
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Day care attendance has been shown to play a protective role for the development of
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allergy but the age at which daycare starts has rarely been examined. MAS suggested that there seems to be a window of opportunity between 18 and 36
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months of age. Earlier and later entrance considerably increased the risk for asthma up to 20 years of age [13].
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This association can point towards the airways of very young infants as being potentially more susceptible to viral infections causing lower respiratory tract infections and prolonged hyperresponsiveness, while above the age of three years, the protective stimulation of the immune system by repeated episodes of upper respiratory tract infections would come too late [40].
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Tobacco smoke exposure MAS was the first birth cohort to formally evaluate the interaction between maternal smoking and the genetic predisposition for allergies in children up to school-age. Results showed that regular maternal smoking increased the likelihood of developing allergic sensitization in children only in those with allergic parents but not in those
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with non-allergic parents [42].
The negative effects of tobacco smoke exposure during pregnancy seem particularly long-lasting. Using the harmonized individual participant data from a collaborative
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European birth cohort initiative including MAS, Neuman et al showed that children who were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth had an increased risk for asthma at age 4-6: adjusted odds ratios 1.65; 95%-CI 1.18–2.31). The likelihood to develop wheeze and asthma increased
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significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy [43].
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Longitudinal analyses from MAS showed that regular maternal smoking during
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pregnancy (i.e. at least 5 cigarettes per day until delivery) was one of the strongest modifiable risk factors of developing asthma up to the age of 20. A comparable effect
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was seen for cotinine in cord blood, an objective measure of the exposure indicating
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recent prenatal tobacco use [14].
Lessons learned from MAS
MAS is one of the oldest population-based birth cohorts on asthma and allergies worldwide. It is unique considering the frequency, temporal range and depth of
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assessments based on 19 time points between birth and age 20. Among these were 9 evaluations of allergic sensitization by collecting serum samples for IgE analyses. It has been a role model for new birth cohorts, stimulating researchers across Europe and beyond to start new population-based birth cohorts on allergy, many using similar assessment methods [4,5]. MAS has also shared its data with the wider
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scientific community facilitating pooled and meta-analyses of birth cohorts.
Longitudinal results from MAS emphasized the role of family history and early sensitization as important predictors for the development of childhood allergy and
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asthma up to early adulthood. This effect was even stronger for IgE-associated than non-IgE associated disease up to age 20. Further evaluations showed the significance of early indoor allergen sensitization and sensitization for the
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development of lung function in school children.
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Allergy research has predominantly focused on single entities, although the coexistence of allergic diseases asthma, rhinitis and eczema is considerably more
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prevalent than expected by chance alone [17]. MAS has specifically evaluated
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allergic multimorbidity. At age 20 subjects with an allergic family history had three times more often coexisting allergies than those with non-allergic parents. Asthma
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occurred more frequently with coexisting allergic rhinitis and/or eczema than as a single entity. Eczema was the condition with the least proportion of coexisting other allergic conditions throughout the first 20 years of life [13].
The prevalence of asthma shifted towards females after puberty-onset and was rather sex-balanced by age 20, whereas allergic rhinitis continued to affect more males than females. The prevalence of eczema had switched after puberty-onset
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towards a clear female predominance, affecting twice as many women than men at age 20 [37].
The complex evolution of the antibody responses to allergen molecules during the first 2 decades of life have been specifically examined in the MAS cohort. The IgE-
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response to grass (Phleum pratense) evolved in many allergic children from a simple molecular mono- and oligomolecular to a polymolecular sensitization stage (“Molecular Spreading”).
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High indoor allergen exposure to indoor allergens was found to be a risk for specific sensitization, which was linked to the development of asthma and impaired lung function at early schoolage. Pre- and postnatal tobacco smoke exposure increased
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the development of specific allergic sensitization and asthma.
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MAS birth cohort data was used to compare classical with latent class analysisderived phenotypes [44]. Furthermore, MAS has been a real asset examining the role
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of genetic variation in clinical sub phenotypes and in the long-term temporal trajectory
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of allergic diseases. Investigating filaggrin null mutations, we showed strong associations with asthma and allergic rhinitis, but only children with eczema. This
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severe phenotype corresponds with the clinical observation of the “allergic march” phenomenon.
Clearly, not every patient with atopic dermatitis develops asthma and not all patients with asthma have preceding atopic dermatitis. Nevertheless, children with infantile eczema, early allergic sensitization, and a parental history for atopy are at dramatically increased risk of subsequent allergic airways disease.
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Interestingly, genetic studies of eczema, particularly the identification of filaggrin mutations as major risk factor for eczema [45] and subsequent asthma development [46], have highlighted the role of the skin as the interface between host and environment in shaping immune responses that induce chronic inflammation even in distant organs.
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Among all potential risk factors those that are modifiable deserve the greatest attention. The robust evidence for tobacco smoke exposure as a strong risk factor, even before birth, has been emerging from all birth cohort studies.
Given the fact that children spend most of the time in the domestic environment, the
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strong influence of indoor allergen exposure for the incidence of sensitization, the development of asthma and the persistence of airway diseases in childhood up to adolescence remains a challenge for all health authorities, who feel responsible for
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child health. Results from MAS did not support the presumed protective effect of
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breast feeding for asthma or allergy [14,47].
The longitudinal comprehensive data collection in MAS allowed further evaluations
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beyond the originally intended research questions including estimating reference
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values for the frequency of respiratory infections as well as overweight/obesity, which
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are common in childhood [48 - 51].
Conclusion
It is a long way from the identification of modifiable risk factors for allergic diseases to implement effective primary prevention strategies in childhood.
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The MAS study, which was designed in the late 1980s, has been focusing on the role of risks from allergen exposure and a number of environmental factors as potential candidates. Many of them still deserve our attention today, since recent studies strongly suggest that certain viral infections together with allergic sensitization to
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indoor allergens are highly relevant for the development of asthma.
Additionally, there has been growing interest in detecting potentially protective environmental factors, particularly microbial factors: maternal exposure to an environment rich in microbial compounds has been demonstrated to protect against
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the development of atopic sensitization and lead to an upregulation of receptors of innate immunity like TLR 2 and 4 and CD14 [52]. Moreover, intestinal microbial diversity in infancy seems to be an important factor in the development of
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inflammation and obesity [53]. An imbalance in the intestinal microbiome may influence the development of allergic disease [54]. Therefore, in recent years the
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“exposome” during pregnancy and the microbial diversity of the intestine have become a target for early intervention, although up to now no conclusive data on
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interventional approaches are available.
The impaired barrier function in infants at risk for eczema has become a target for
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studies [55,56] using early emollients in very young unaffected infants. Whether this intervention can also influence the development of a subsequent allergic march remains open. Epigenetic mechanisms through which environmental exposures can permanently alter the expression of fetal genes may also contribute to the development of immune regulation and allergic diseases.
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Acknowledgments We wish to thank all participants, collaborators and staff at the study centers who collected data and contributed to this birth cohort in different ways throughout its 20-year history: Karl E. Bergmann, Renate L. Bergmann, Claus-Peter Bauer, Johannes Forster, Wolfgang Kamin, Antje Schuster, Volker Wahn, Fred Zepp, Bodo Niggemann, Renate Krüger, Christoph Grüber †, Petra Wagner, Monika Götze, Ute Hoffmann, Heike Henckel, Anja Hess, Alexander Rohrbach, Kerstin
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Schüler, Gabriele Schulz, Ingo Marenholz, Christine Sommerfeld, Michael Kulig, Sabina Illi, Cynthia Hohmann, Linus Grabenhenrich, Andreas Reich, Hanna Gough; and the many more who have contributed over the years in the 5 study centres of MAS but are not listed here.
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We also wish to thank the ISAAC study group for the permission to use questions on allergic diseases
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and respiratory symptoms validated in the ISAAC project.
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29. Melen E, Granell R, Kogevinas M et al. Genome-wide association study of body mass index in 23 000 individuals with and without asthma. Clin Exp Allergy 43, 463-474 (2013). 30. Ferreira MA, Fonk JM, Baurecht H et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet 49, 1752-1757 (2017). 31. Marenholz I, Kerscher T, Bauernfeind A et al. An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma. J Allergy Clin
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33. Marenholz I, Bauernfeind A, Esparza-Gordillo J et al. The eczema risk variant on
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38. Lødrup Carlsen KC, Roll S, Carlsen KH, Mowinckel P, Wijga AH, Brunekreef B, Torrent M, Roberts G, Arshad SH, Kull I, Krämer U, von Berg A, Eller E, Høst A, Kuehni C, Spycher B, Sunyer J, Chen CM, Reich A, Asarnoj A, Puig C, Herbarth O, Mahachie John JM, Van Steen K, Willich SN, Wahn U, Lau S, Keil T; GALEN WP 1.5 ‘Birth Cohorts’ working group. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS One. 2012;7(8):e43214. 39. Lau S, Illi S, Platts-Mills TAE, et al. Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitisation, cat specific IgG and development of
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asthma in childhood - report of the German Multicentre Allergy Study (MAS 90). Allergy 2005; 60: 766-773. 40. Illi S, von Mutius E, Lau S, et al. MAS Group. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001 Feb 17;322(7283):390-5. 41. Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U. Perennial sensitisation early in life and chronic asthma in children. Lancet 2006; 368: 763-70.
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43. Neuman Å, Hohmann C, Orsini N, et al. ENRIECO Consortium. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am
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44. Hose AJ, Depner M, Illi S, et al. MAS; PASTURE study groups. Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts. J Allergy Clin Immunol. 2017 Jun;139(6):1935-1945.e12.
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47. Bergmann RL, Diepgen TL, Kuss O, et al. MAS-study group. Breastfeeding duration is a
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49. Karaolis-Danckert N, Buyken AE, Kulig M, et al. How pre- and postnatal risk factors modify the effect of rapid weight gain in infancy and early childhood on subsequent fat mass development: results from the Multicenter Allergy Study 90. Am J Clin Nutr. 2008 May;87(5):1356-64. 50. Kuehnen P, Mischke M, Wiegand S, et al. An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. PLoS Genet. 2012;8(3):e1002543.
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51. Rzehak P, Wijga AH, Keil T, et al. GA²LEN-WP 1.5 Birth Cohorts. Body mass index trajectory classes and incident asthma in childhood: results from 8 European Birth Cohorts - a Global Allergy and Asthma European Network initiative. J Allergy Clin Immunol. 2013 Jun;131(6):1528-36. 52. Ege MJ, Bieli C, Frei R, et al. Parsifal Study team. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in schoolage children. J Allergy Clin Immunol. 2006 Apr;117(4):817-23.
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53. Ege MJ, Mayer M, Normand AC, et al. GABRIELA Transregio 22 Study Group.
Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011 Feb 24;364(8):701-9.
54. Bisgaard H, Li N, Bonnelykke K, et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy
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Clin Immunol. 2011 Sep;128(3):646-52.e1-5.
55. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol. 2014 Oct;134(4):818-23.
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56. Horimukai K, Morita K, Narita M, et al. Application of moisturizer to neonates prevents development of atopic dermatit is. J Allergy Clin Immunol. 2014 Oct;134(4):824-824-
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Figure 1: Venn diagrams presenting the prevalence of current eczema (red), current asthma (blue), and current allergic rhinitis (yellow) including their overlap at different ages separate for 2 subgroups: (a) all participants with 1 or 2 allergic parent(s), and (b) all participants with 2 non-allergic parents. Prevalence estimates are presented as percentages in relation to the whole subgroup (a) or (b) respectively (each as 100%), and rounded to the next integer. Reprint from Gough H. et al in Pediatric Allergy and Immunology 2015 [13]
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Figure 2: Evolution of IgE responses to 12 D pteronyssinus molecules from birth to age 20 years (n = 191). Prevalence of IgE sensitization to the 12 D pteronyssinus allergen molecules among the ever mite-sensitized subjects by age at follow-up is shown. A, B, and C indicate groups of molecules according to the prevalence of IgE response at age 20 years. The number of participants examined at each time point is indicated under the x-axis. Reprint from Posa et al JACI 2017 [22]
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Figure 3 Prevalence of sensitisation to house dust and wheeze stratified by highest and lowest quartiles of housedust-mite exposure at age 6 months * p<0·01; †p<0·0001.‡p<0·0001. Dotted lines represent the quartile of highest exposure, the solid lines represent the lowest exposure group. Reprint from [12].
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Fig. 4: Effect of allergen sensitisation and exposure at ≤3 years (A) and ≤5 years (B) on lung function at age 7 years
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NS=Not sensitised to dust mites or cat dander (≤age 3 years [n=647]; ≤age 5 years [n=642]). S/LE=Sensitised to dust mites or cat dander and low exposure to these allergens (≤age 3 years [n=22]; ≤age 5 years [n=42]). S/HE=Sensitised to dust mites or cat dander and high exposure to these allergen (≤age 3 years [n=27]; ≤age 5 years [n=46]). Quartiles of allergen exposure were calculated across the whole population. Since exposure to house dust mites and cats significantly increased the 9 risk of sensitisation towards these allergens, more children sensitised to perennial allergens were found in the highest quartile of allergen exposure. Reprint from Illi S. et al Lancet 2006 [41].
Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS, Susanne Lau MD, PhD , Paolo Maria Matricardi MD,PhD , Ulrich Wahn MD, PhD , Young Ae Lee MD, PhD , Thomas Keil MD, PhD PII: DOI: Reference:
S1081-1206(18)30378-8 10.1016/j.anai.2018.05.012 ANAI 2555
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
15 February 2018 1 May 2018 14 May 2018
Please cite this article as: Susanne Lau MD, PhD , Paolo Maria Matricardi MD,PhD , Ulrich Wahn MD, PhD , Young Ae Lee MD, PhD , Thomas Keil MD, PhD , Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS, , Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.05.012
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KEY MESSAGES The Multicentre Allergy Study (MAS), an observational birth cohort with follow up until the age of 20 years, indicates, that - Atopic multimorbidity of the skin and the airways is related to atopic family history and a more severe phenotype.. For asthma prevalence, the early male preponderance shifted towards females during
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adolescence leading to a sex-balanced distribution by age 20. -
Eczema prevalence switched towards a clear and persisting female predominance, whereas allergic rhinitis continued to affect more males up to age 20.
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Indoor allergen exposure is a risk factor for specific sensitization, asthma
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development and impaired lung function in childhood.
IgE – antibody responses to environmental allergens show „molecular spreading“ in early childhood and preceed clinical disease development.
Genetic variants for the prediction of longterm outcomes could be identified.
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Allergy and atopy from infancy to adulthood: Messages from the German birth cohort MAS
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Susanne Lau, MD, PhD 1, Paolo Maria Matricardi MD, PhD 1, Ulrich Wahn MD, PhD 1, Young Ae Lee MD, PhD 2/3, Thomas Keil, MD, PhD 4
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1 Department of Pediatrics, Division of Pneumology, Immunology Charité Universitätsmedizin Berlin, Berlin, Germany; 2 Max-Delbrück-Center [MDC] for Molecular Medicine, 13125 Berlin, Germany 3 Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany 4 Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany;
Keywords: allergic diseases; allergic rhinitis; asthma; atopic march; birth cohort study; eczema; multicenter allergy study; prevalence; wheezing;
Main manuscript: 4,858 words
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Abstract: 255 words NCT: not applicable
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Address of correspondence: Prof. Ulrich Wahn, MD, PhD Im Hagen 26 D 14532 Kleinmachnow Germany E-mail: [email protected]
All authors declare that they do not have any conflict of interest.
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Funding The MAS study was funded by grants from the German Federal Ministry of Education and Research (BMBF; reference numbers 07015633, 07 ALE 27, 01EE9405/5, 01EE9406) and the German Research Foundation (DFG; reference numbers KE 1462/2-1, and MA-4740/1). The funders had no role in the design, management, data collection, analysis or interpretation of the data or in the writing of the manuscript or the decision to submit for publication.
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Introduction
Allergic diseases in early and late childhood have become a common health problem
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across the globe as documented by the first cross-sectional phase of the International Study on Asthma and Allergies in Childhood [ISAAC] in the mid-1990s [1,2]. In many industrialized and developing countries the prevalence of asthma, allergic rhinitis and eczema has increased since then or remained at a high plateau
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as shown by another global ISAAC assessment a decade later [3].
The reasons for the high and in many countries increasing allergy prevalence remain largely unclear. For the search of underlying causes and mechanisms prospective long-term birth and child cohort studies are essential. Especially in Europe several
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population-based birth cohort studies have been initiated in recent decades to better
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understand the natural history and identify determinants and factors influencing
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persisting or transitory asthma and allergies in the life-course [4,5,6].
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One of the first population-based birth cohort focusing on asthma and allergy worldwide was the Multi-center Allergy Study (MAS), which started in 5 German cities
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in 1990. The recruited participants have been prospectively followed since then over the first two decades of life.
The overall aims of MAS were:
to describe the incidence and natural course of allergic symptoms and their relationship with the development of
allergic sensitization [i.e. specific
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immunoglobulin E antibody responses] against common aero- and food-allergens; and
to examine early life determinants as well as genetic, environmental and lifestylerelated risk and protective factors for transient and persistent asthma and
primary and secondary prevention strategies [7].
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allergies in order to identify modifiable risk and protective factors for better
This overview aims to summarize the methods, as well as to present and interpret
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important results from the first 20 years of the MAS birth cohort.
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Methods
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Study design, setting and population
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The German Multicenter Atopy Study [MAS], a prospective observational birth cohort, recruited 1314 out of 7609 infants born in 1990 in 5 German cities. A detailed
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description of the stratified sampling scheme and study subjects is given elsewhere [7]. Briefly, 499 newborns with risk factors for atopy (increased cord blood IgE > 0.9 kU/L, and /or at least 2 atopic family members) as well as 815 newborns with none of these risk factors were included in the cohort [7]. These children were assessed at birth and followed up at the age of 1, 3, 6, 12, 18 and 24 months and from then on yearly within 4 weeks of the child’s birthday up to age 13, then at 15 and again at 20
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years. In total there have been assessments at 19 time points including 9 visits to the study centres for physical examinations, clinical tests and biosampling. The study was approved by the local ethics committees in all study centers and funded by the German Ministry of Research and Education, whereas in adulthood by grants from the German Research Foundation. A parent/guardian gave written
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informed consent, and the children gave oral approval at the visits in the study center. At age 20 years, the participants gave written informed consent.
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Parental questionnaires and interviews
At each follow-up visit, parents were interviewed by study physicians using standardized questionnaires. Foremost interest was on atopic symptoms and
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diseases (skin, airways etc). Furthermore, symptoms and diagnoses of other illnesses were assessed at every follow-up, as were a variety of nutritional, lifestyle
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and environmental factors including breast-feeding, nutritional practices, parental
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smoking habits, and pet keeping.
Definitions of allergic outcomes were based on the previously validated questions
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from the International Study of Asthma and Allergies in Childhood (ISAAC) [1]. For asthma, a single parent-reported answer on typical symptoms such as wheezing,
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medication or a doctor-confirmed diagnosis had been used in earlier analyses. Since this may over- or underestimate the true prevalence of asthma, European birth cohort researchers suggested combining relevant variables. Thus, a more stringent epidemiological outcome definition of current asthma was subsequently based on at least 2 out of 3 criteria: [i] asthma medication in the last 12 months; [ii] any indicative symptom (i.e. wheezing, and/or shortness of breath, and/or dry cough at night) in the last 12 months; or [iii] physician’s diagnosis of asthma ever [8,9].
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Bio sampling
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Serum for total/specific IgE and IgG
A total of up to 9 (1%) serum samples were obtained from the children at birth (cord blood) up to 20 years of age, allowing sequential analysis of IgE development. Total IgE, and specific IgE antibodies to food allergens [cow’s milk, hen`s egg, soy bean
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and wheat] and aero-allergens (Dermatophagoides pteronyssinus, cat and dog dander, mixed grass, and birch pollen), which were determined by ImmunoCAP FEIA (ThermoFisher Scientific, Freiburg, Germany). The determination of IgE and IgG antibodies against allergenic molecules were all performed with microarray tests,
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including ISAC-103, ISAC-112, (ThermoFisher Scientific, Uppsala, Sweden) and a
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Genetic analyses
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customized microarray developed by Lupinek et al [10].
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Genomic DNA was extracted from whole blood samples using standard DNA extraction methods. Genotyping was performed using a variety of methods including single
nucleotide
polymorphism
arrays,
allele-specific
PCR
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genome-wide
amplification protocols, and Sanger sequencing.
Indoor allergen sampling At the age of 6 months, 18 months and 5 years, Der p 1 and Der f 1 allergens from house dust mite species Dermatophagoides pteronyssinus and farinae as well as Fel d 1 from cat were extracted from dust samples collected by parents from the carpet
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and analyzed with a sandwich ELISA (ALK, Copenhagen, Denmark). High levels of exposure at a specific age were defined as a measured value above the third quartile of the respective distribution in the total population. Low levels were defined as a
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measured value below the second quartile as previously described [11,12]
Lung function and airway responsiveness tests Resting baseline lung function tests
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At age of 7, 10, 13 and 20 years, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 75%, 50%, 25% (FEF75, 50, 25) of the exhaled FVC, were measured in 800, 638, 680 and 560 individuals,
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respectively. The same type of spirometer and body plethysmograph was used [Master-Lab, Cardinal Health, Würzburg, Germany] in all centers by trained study
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nurses, and supervised by study physicians. Lung function indices were converted to
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height adjusted z scores. Also FEV1 to FVC ratio was calculated.
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Bronchial challenge tests At age of 7 years, a multi-step bronchial histamine challenge was performed in
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647/800 children. In summary, a nebulizer (Pari Provocation Test 2, Pari, Starnberg, Germany) combined with a storage bag allowed standardized pulmonary aerosol deposition at saturated ambient temperature and pressure conditions. At age of 20 years, a multi-step bronchial methacholine challenge was conducted following American Thoracic Society ATS guidelines (PARI Provocation Test 2 nebulizer, Starnberg, Germany).
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At 7, 13 and 20 years of age, bronchodilator responsiveness was determined in all consenting study members after provocation test, at 10 years of age after resting baseline lung function using two puffs of salbutamol from a metered dose inhaler
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(n=647 children at age 10 years).
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Results
Occurrence of allergic diseases
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Allergy prevalence for the general population cannot be derived directly from the overall MAS birth cohort due to its allergy risk-enriched sampling strategy. However,
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if stratified by parental allergic history MAS can deliver reasonably valid prevalence
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parents
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and incidence estimates for the 2 strata of subjects with allergic and non-allergic
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(Fig. 1).
Current atopic dermatitis (AD) / eczema prevalence [13]: the prevalence of current AD as a single entity remained at over 10% throughout school-age, regardless of parental allergy status. In both strata, it declined by about a third at age 20 (Fig.1). At that age, AD affected twice as many women than men (data not shown).
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Current asthma prevalence [13]: the prevalence of current asthma increased continuously throughout school-age, particularly among subjects with allergic parents who were affected 2-3 times more often than those with non-allergic parents (Fig. 1).
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Current allergic rhinitis prevalence [13]: the prevalence of current rhinitis increased continuously and exceeded that of asthma throughout the second decade of life. Subjects with allergic parents were affected about 3 times more often than those with
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non-allergic parents (Fig. 1).
Cumulative incidence of asthma: between 4-20 years, 218 of 1,314 recruited MAS participants developed symptoms classified as “asthma” at one or more follow-up
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assessments. About three quarters (n=156) of the asthma ever cases were sensitized (sIgE ≥0.35 kU/l serum) to at least one of 5 common aeroallergens: dust
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mite, dog, cat, birch, and/or timothy grass [14]. By age 20, the cumulative incidence among offspring from parents with an allergy
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(i.e. asthma, rhinitis, and/or eczema) was about 40% (with two allergic parents) and
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over 25% (only 1 allergic parent). Among children from non-allergic parents the cumulative incidence reached a plateau in early adolescence at just over 10%, thus
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very few new asthma cases were observed after puberty [14].
Cumulative incidence of allergic rhinitis: between 4-20 years, 290 MAS participants developed typical allergic rhinitis symptoms in combination with sIgE ≥0.35 kU/l serum to at least one of 5 common aeroallergens: dust mite, dog, cat, birch, and/or timothy grass pollen [15].
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Current allergic multimorbidity: analyses of asthma and allergy outcomes in birth cohorts have mainly focused on single allergic entities [16]. However, the coexistence of the most common allergic diseases asthma, rhinitis and eczema is considerably more prevalent than expected by chance alone as a pooled analysis of data from 4 and 8 year old European children showed [17].
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The extensive data collected longitudinally from the MAS participants allowed investigations of the prevalence of allergic multimorbidity, i.e. the coexistence of 2 or more allergic disorders in the same individual, from birth to young adulthood. From early school age onwards, this multimorbidity was seen particularly among those with
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a positive family history. At age 20 the participants with an allergic family history had three times more often coexisting allergies than those without such predisposition. Particularly asthma occurred more frequently with coexisting allergic rhinitis and/or
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eczema than as a single entity. Eczema was the condition with the least proportion of coexisting other allergic conditions. It remained more common as a single entity
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throughout the first 20 years of life (Fig. 1) [13].
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Allergic sensitization
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The MAS birth cohort allowed us to describe the complex evolution of the antibody responses to allergen molecules during the first 2 decades of life. Already at 2 years of age, normal children express a broad repertoire of IgG antibodies to a wide array of allergen molecules[18]. The intensity and frequency of these “default” or “normal” IgG responses to animal food allergens, vegetable food allergens and airborne allergens were classified as maximal, intermediate or minimal, respectively.
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Interestingly, atopic children show stronger and more frequent IgG responses than the non-atopic peers [19]. Studies focusing on the IgE response to Bet v 1 and other PR.10 molecules disclosed a second type or “pre-atopic” IgG response. This response, although directed against airborne allergens, is strong and persistent and precedes or
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accompanies the production of IgE against the same molecule. This observation led us to speculate that the IgE response to Bet v 1 in birch allergic children is the final stage of an “abnormal” evolution of a pre-existing “pre-atopic” IgG response [18]. A broader study confirmed and expanded this concept, showing that a “pre-atopic”,
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strong and persistent IgG response can be observed in atopic subjects developing IgE responses to mites, pollens, or molds [20]. Subclass-specific tests showed that IgG4 antibodies contribute only a tiny fraction (<5%) to this naturally induced
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(“default” or “pre-atopic”) IgG response, suggesting that most of it is made up of IgG1
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antibodies [18].
The IgE response against grass pollen starts simple, as it is directed against one or
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few single molecules. For examples, the IgE response to Phleum pratense evolves in
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many allergic children from a simple, often molecular monosensitization stage to an oligomolecular sensitization stage to terminate its evolution in a polymolecular
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sensitization stage. This phenomenon has been defined as “Molecular Spreading” [21]. Interestingly, in almost all children, the initial IgE response is directed against Phl p 1, a sort of “initiator” of this IgE response, which often appears in a pre-clinical stage of the disease process. Then the IgE response involves as a second molecule, in general Phl p 4 and/or Phl p 5; thereafter also Phl p 2 and Phl p 6, and finally Phl p 11, Phl p 12, and Phl p 7. Only a few children develop a full blown response with involvement of all eight allergenic molecules of Phleum pratense. However, in most
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children the IgE response evolves over time and becomes more and more complex [21].
A similar process has subsequently been described in children developing IgE sensitization to Dermatophagoides pteronyssinus [22]. The IgE response started
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almost invariably with three “initiator” molecules (Der p 1, Der p 2, Der p 23) defined as group “A” molecules and expanded sequentially first to the “group B” molecules (Der p 4, Der p 5, Der p 7, Der p 21) and finally to group “C” molecules. Early IgE sensitization onset, parental hay fever, and higher exposure to mites were associated
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with a broader polymolecular IgE sensitization pattern. Interestingly, participants reaching the broadest IgE sensitization stage (ie, ABC) had significantly higher risk of mite related allergic rhinitis and asthma than the unsensitized participants. Finally,
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IgE sensitization in healthy children to Der p 1 or Der p 23 at age 5 years or less
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predicted asthma at school age [22].
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FIGURE 2
This novel understanding of the progressive molecular spreading of the immune
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response to airborne allergens (grass, mites) led us to speculate that immunological intervention (allergen-immunotherapy) should be initiated earlier during the sensitization process [23]. An earlier intervention may have better chances of success, may prevent molecular spreading, and ultimately the development of allergic symptoms. Interestingly, in children with early, subclinical, monomolecular IgE sensitization having parents with hay fever was the strongest risk factor for the development of a polymolecular and clinically relevant IgE response later in
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childhood [24]. The “initiator” molecules like Phl p 1 for grass pollen, Bet v 1 for birch pollen, Der p 1, Der p 2, Der p 23 for mites, Fel d 1 for cat may be suitable markers to identify children in the “pre-clinical” sensitization stage who may benefit from an “allergen immunoprophylaxis” aimed at preventing the onset of allergic rhinitis and
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asthma [20, 23].
Influencing factors
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Heredity/Genetics
A positive allergic family history is one of the strongest predictors to develop childhood asthma [12]. MAS showed that this effect seemed to last up to adulthood.
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The effect of parental allergies, particularly asthma, on the incidence of IgEassociated asthma up to age 20 seemed to be larger than on the incidence of non-
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IgE associated asthma [13].
Allergic diseases are chronic inflammatory conditions that arise from environmental
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triggers acting on genetically susceptible individuals. The contribution of genetic risk factors is substantial and has been estimated at 60-80% based on large-scale twin
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studies [25]. Owing to technology developments, large strides have been made in the discovery of the genetic determinants underlying allergic disorders. Most identified and robustly replicated loci have been found in genome-wide association studies (GWAS), which identified common risk alleles that were found significantly more frequently in patients compared to controls [26-29]. The largest most recent GWAS on allergic disease discovered 136 genetic variants, doubling the number of known
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risk variants and highlighting the genetic overlap between risk loci for eczema, asthma, and hay fever [30].
Beyond GWAS, the MAS cohort has proven to be a real asset in investigating the role of genetic variation in clinical subphenotypes and in the long-term temporal
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trajectory of allergic diseases. Investigating filaggrin null mutations in the MAS cohort, we showed that the strong association of these mutations with asthma and allergic rhinitis was only detectable in children who had previously expressed eczema. It was striking that neither allergic airways disease nor specific sensitization showed an
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association with the FLG mutations in the absence of eczema. These results suggested that FLG mutations predispose to the sequential acquisition of these allergic disorders instead of acting as an independent risk factor for each disease.
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Due to the known function of filaggrin in maintaining the epidermal barrier, our results supported the concept that the inflammatory reaction and further breakdown of the
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epidermal barrier in eczema facilitated transepidermal penetration of allergens and allergic sensitization. This study highlighted the role of the skin as the interface
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between host and environment in shaping immune responses that induce chronic
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inflammation even in distant organs. Moreover, we showed in the MAS cohort that filaggrin null mutations predicted subsequent asthma development in infants with
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eczema and sensitization to food allergens. The identified subgroup of asthmatics was characterized by a significant decline of pulmonary function until puberty and represented a sizeable proportion of 19.1% of patients with eczema-associated asthma. Thus this study was the first to use genetic markers to identify a subset of high risk patients with poor outcome that should be targeted in the development of preventive measures [31].
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Similarly, the prospective evaluation of the MAS children allowed us to evaluate a functional mutation in the interleukin-6 receptor (IL6R Asp358Ala) in the long-term course of eczema. This variant determines the balance between the classical membrane-bound versus the soluble IL6R signaling pathways. We showed a significant association of the risk allele IL6R 358Ala with eczema, and demonstrated
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in two independent population-based birth cohorts that this variant specifically predisposed to the persistent form of eczema and that eczema patients had higher soluble IL6R levels than controls [32].
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While the MAS cohort has been instrumental in characterizing the role of multiple genetic variants for the long-term prognosis of allergic diseases and the atopic march [33,34] it also allowed first genetic investigations in the context of environmental
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exposures and maternal factors [35]. Environmental exposures are recognized to play a considerable role in the development of allergic diseases but can be volatile
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and difficult to assess accurately over time. First attempts to evaluate them in the context of genetic susceptibility using birth cohorts, including MAS, proposed new
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genetic variants modifying asthma risk in interaction with prenatal and childhood
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tobacco smoke exposure [36].
Sex-specific patterns of allergic disease
In early and late school-age, boys of the MAS cohort were more often affected by asthma or rhinitis than girls, whereas for eczema the prevalence in childhood was rather balanced between the sexes. In adolescence, the prevalence of asthma
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shifted towards females and, by age 20, was rather sex-balanced, whereas allergic rhinitis continued to affect more males than females, but to a lesser extent than in childhood. The prevalence of eczema had switched towards a clear female predominance at age 20, affecting now twice as many women than men [13].
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To better understand sex-related changes in allergy prevalence from childhood to adulthood, we conducted sex-specific analyses of asthma and rhinitis as single entities and as comorbid conditions considering specifically the individual puberty
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status, assessed by the validated Puberty Development Scale [37].
To increase the statistical power, individual participant data from 6 large European birth cohorts including MAS were thus combined for longitudinal age-, sex- and
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puberty-specific analyses. These meta-analyses showed a prevalence "sex-shift" from a male predominance before puberty towards females after puberty-onset,
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which was much stronger in participants who had asthma and rhinitis concurrently compared to those who had only asthma or only rhinitis. For IgE-associated rhinitis
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and IgE-associated asthma as single entities, the male predominance in childhood
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remained after puberty-onset, whereas for IgE-associated respiratory multimorbidity [i.e. asthma and concurrent rhinitis] we found a stronger shift towards females, which
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resulted in a sex-balanced prevalence after puberty-onset 37]. Sex- and pubertyspecific analyses of eczema with and without comorbid respiratory allergies are pending.
Indoor environment
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Newborns and young infants living in the moderate climatic zones spend most of the time indoors. Even in countries with a warmer climate young children spend at least 10 hours per day indoors. Therefore, the domestic environment can be assumed to play a crucial role as “exposome” and may influence the development of sensitization
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and allergic inflammation to indoor allergens. Exposure and uptake of allergens may occur via the skin, via inhalation and via the gastrointestinal tract. In MAS, we focused on early life indoor allergens measured in house dust samples, on pet
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keeping and smoking exposure during pregnancy and the first 3 years of life.
MAS demonstrated the risk of early life exposure to house dust mite and cat allergens for the development of specific sensitization to these allergens during the
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first three years of life and at early school-age (Figure 3) [11,12]. However, ownership of furry or feathered pets in early childhood had no influence on asthma at school-
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age as a large meta-analysis including MAS and 10 other European birth cohorts showed [38]. Early exposure to endotoxin in house dust samples was not a risk
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factor for later asthma [39].
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FIGURE 3
Examining the effect of early sensitization we found sIgE to perennial allergens such as house dust mite, cat and/or dog during the first 3 years of life increased the risk of persistent asthma at school age and up to the age of 20 years [13,15,40,41].
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Furthermore, children with early sensitization to indoor allergens during the first 3 years of life and with high indoor allergen exposure at home were found to have the poorest lung function outcome at school-age, while this relationship was less
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pronounced at 5 years of age [41].
Day care attendance
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FIGURE 4
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Day care attendance has been shown to play a protective role for the development of
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allergy but the age at which daycare starts has rarely been examined. MAS suggested that there seems to be a window of opportunity between 18 and 36
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months of age. Earlier and later entrance considerably increased the risk for asthma up to 20 years of age [13].
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This association can point towards the airways of very young infants as being potentially more susceptible to viral infections causing lower respiratory tract infections and prolonged hyperresponsiveness, while above the age of three years, the protective stimulation of the immune system by repeated episodes of upper respiratory tract infections would come too late [40].
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Tobacco smoke exposure MAS was the first birth cohort to formally evaluate the interaction between maternal smoking and the genetic predisposition for allergies in children up to school-age. Results showed that regular maternal smoking increased the likelihood of developing allergic sensitization in children only in those with allergic parents but not in those
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with non-allergic parents [42].
The negative effects of tobacco smoke exposure during pregnancy seem particularly long-lasting. Using the harmonized individual participant data from a collaborative
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European birth cohort initiative including MAS, Neuman et al showed that children who were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth had an increased risk for asthma at age 4-6: adjusted odds ratios 1.65; 95%-CI 1.18–2.31). The likelihood to develop wheeze and asthma increased
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significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy [43].
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Longitudinal analyses from MAS showed that regular maternal smoking during
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pregnancy (i.e. at least 5 cigarettes per day until delivery) was one of the strongest modifiable risk factors of developing asthma up to the age of 20. A comparable effect
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was seen for cotinine in cord blood, an objective measure of the exposure indicating
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recent prenatal tobacco use [14].
Lessons learned from MAS
MAS is one of the oldest population-based birth cohorts on asthma and allergies worldwide. It is unique considering the frequency, temporal range and depth of
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assessments based on 19 time points between birth and age 20. Among these were 9 evaluations of allergic sensitization by collecting serum samples for IgE analyses. It has been a role model for new birth cohorts, stimulating researchers across Europe and beyond to start new population-based birth cohorts on allergy, many using similar assessment methods [4,5]. MAS has also shared its data with the wider
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scientific community facilitating pooled and meta-analyses of birth cohorts.
Longitudinal results from MAS emphasized the role of family history and early sensitization as important predictors for the development of childhood allergy and
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asthma up to early adulthood. This effect was even stronger for IgE-associated than non-IgE associated disease up to age 20. Further evaluations showed the significance of early indoor allergen sensitization and sensitization for the
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development of lung function in school children.
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Allergy research has predominantly focused on single entities, although the coexistence of allergic diseases asthma, rhinitis and eczema is considerably more
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prevalent than expected by chance alone [17]. MAS has specifically evaluated
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allergic multimorbidity. At age 20 subjects with an allergic family history had three times more often coexisting allergies than those with non-allergic parents. Asthma
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occurred more frequently with coexisting allergic rhinitis and/or eczema than as a single entity. Eczema was the condition with the least proportion of coexisting other allergic conditions throughout the first 20 years of life [13].
The prevalence of asthma shifted towards females after puberty-onset and was rather sex-balanced by age 20, whereas allergic rhinitis continued to affect more males than females. The prevalence of eczema had switched after puberty-onset
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towards a clear female predominance, affecting twice as many women than men at age 20 [37].
The complex evolution of the antibody responses to allergen molecules during the first 2 decades of life have been specifically examined in the MAS cohort. The IgE-
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response to grass (Phleum pratense) evolved in many allergic children from a simple molecular mono- and oligomolecular to a polymolecular sensitization stage (“Molecular Spreading”).
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High indoor allergen exposure to indoor allergens was found to be a risk for specific sensitization, which was linked to the development of asthma and impaired lung function at early schoolage. Pre- and postnatal tobacco smoke exposure increased
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the development of specific allergic sensitization and asthma.
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MAS birth cohort data was used to compare classical with latent class analysisderived phenotypes [44]. Furthermore, MAS has been a real asset examining the role
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of genetic variation in clinical sub phenotypes and in the long-term temporal trajectory
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of allergic diseases. Investigating filaggrin null mutations, we showed strong associations with asthma and allergic rhinitis, but only children with eczema. This
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severe phenotype corresponds with the clinical observation of the “allergic march” phenomenon.
Clearly, not every patient with atopic dermatitis develops asthma and not all patients with asthma have preceding atopic dermatitis. Nevertheless, children with infantile eczema, early allergic sensitization, and a parental history for atopy are at dramatically increased risk of subsequent allergic airways disease.
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Interestingly, genetic studies of eczema, particularly the identification of filaggrin mutations as major risk factor for eczema [45] and subsequent asthma development [46], have highlighted the role of the skin as the interface between host and environment in shaping immune responses that induce chronic inflammation even in distant organs.
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Among all potential risk factors those that are modifiable deserve the greatest attention. The robust evidence for tobacco smoke exposure as a strong risk factor, even before birth, has been emerging from all birth cohort studies.
Given the fact that children spend most of the time in the domestic environment, the
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strong influence of indoor allergen exposure for the incidence of sensitization, the development of asthma and the persistence of airway diseases in childhood up to adolescence remains a challenge for all health authorities, who feel responsible for
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child health. Results from MAS did not support the presumed protective effect of
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breast feeding for asthma or allergy [14,47].
The longitudinal comprehensive data collection in MAS allowed further evaluations
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beyond the originally intended research questions including estimating reference
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values for the frequency of respiratory infections as well as overweight/obesity, which
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are common in childhood [48 - 51].
Conclusion
It is a long way from the identification of modifiable risk factors for allergic diseases to implement effective primary prevention strategies in childhood.
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The MAS study, which was designed in the late 1980s, has been focusing on the role of risks from allergen exposure and a number of environmental factors as potential candidates. Many of them still deserve our attention today, since recent studies strongly suggest that certain viral infections together with allergic sensitization to
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indoor allergens are highly relevant for the development of asthma.
Additionally, there has been growing interest in detecting potentially protective environmental factors, particularly microbial factors: maternal exposure to an environment rich in microbial compounds has been demonstrated to protect against
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the development of atopic sensitization and lead to an upregulation of receptors of innate immunity like TLR 2 and 4 and CD14 [52]. Moreover, intestinal microbial diversity in infancy seems to be an important factor in the development of
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inflammation and obesity [53]. An imbalance in the intestinal microbiome may influence the development of allergic disease [54]. Therefore, in recent years the
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“exposome” during pregnancy and the microbial diversity of the intestine have become a target for early intervention, although up to now no conclusive data on
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interventional approaches are available.
The impaired barrier function in infants at risk for eczema has become a target for
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studies [55,56] using early emollients in very young unaffected infants. Whether this intervention can also influence the development of a subsequent allergic march remains open. Epigenetic mechanisms through which environmental exposures can permanently alter the expression of fetal genes may also contribute to the development of immune regulation and allergic diseases.
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Acknowledgments We wish to thank all participants, collaborators and staff at the study centers who collected data and contributed to this birth cohort in different ways throughout its 20-year history: Karl E. Bergmann, Renate L. Bergmann, Claus-Peter Bauer, Johannes Forster, Wolfgang Kamin, Antje Schuster, Volker Wahn, Fred Zepp, Bodo Niggemann, Renate Krüger, Christoph Grüber †, Petra Wagner, Monika Götze, Ute Hoffmann, Heike Henckel, Anja Hess, Alexander Rohrbach, Kerstin
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Schüler, Gabriele Schulz, Ingo Marenholz, Christine Sommerfeld, Michael Kulig, Sabina Illi, Cynthia Hohmann, Linus Grabenhenrich, Andreas Reich, Hanna Gough; and the many more who have contributed over the years in the 5 study centres of MAS but are not listed here.
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We also wish to thank the ISAAC study group for the permission to use questions on allergic diseases
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and respiratory symptoms validated in the ISAAC project.
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Figure 1: Venn diagrams presenting the prevalence of current eczema (red), current asthma (blue), and current allergic rhinitis (yellow) including their overlap at different ages separate for 2 subgroups: (a) all participants with 1 or 2 allergic parent(s), and (b) all participants with 2 non-allergic parents. Prevalence estimates are presented as percentages in relation to the whole subgroup (a) or (b) respectively (each as 100%), and rounded to the next integer. Reprint from Gough H. et al in Pediatric Allergy and Immunology 2015 [13]
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Figure 2: Evolution of IgE responses to 12 D pteronyssinus molecules from birth to age 20 years (n = 191). Prevalence of IgE sensitization to the 12 D pteronyssinus allergen molecules among the ever mite-sensitized subjects by age at follow-up is shown. A, B, and C indicate groups of molecules according to the prevalence of IgE response at age 20 years. The number of participants examined at each time point is indicated under the x-axis. Reprint from Posa et al JACI 2017 [22]
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Figure 3 Prevalence of sensitisation to house dust and wheeze stratified by highest and lowest quartiles of housedust-mite exposure at age 6 months * p<0·01; †p<0·0001.‡p<0·0001. Dotted lines represent the quartile of highest exposure, the solid lines represent the lowest exposure group. Reprint from [12].
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Fig. 4: Effect of allergen sensitisation and exposure at ≤3 years (A) and ≤5 years (B) on lung function at age 7 years
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NS=Not sensitised to dust mites or cat dander (≤age 3 years [n=647]; ≤age 5 years [n=642]). S/LE=Sensitised to dust mites or cat dander and low exposure to these allergens (≤age 3 years [n=22]; ≤age 5 years [n=42]). S/HE=Sensitised to dust mites or cat dander and high exposure to these allergen (≤age 3 years [n=27]; ≤age 5 years [n=46]). Quartiles of allergen exposure were calculated across the whole population. Since exposure to house dust mites and cats significantly increased the 9 risk of sensitisation towards these allergens, more children sensitised to perennial allergens were found in the highest quartile of allergen exposure. Reprint from Illi S. et al Lancet 2006 [41].