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Prediction and prevention of allergy and asthma in EAACI journals (2016)

Prediction and prevention of allergy and asthma in EAACI journals (2016) The European Academy of Allergy and Clinical Immunology (EAACI) owns three journals: Allergy, Pediatric Allergy and Immunology and Clinical and Translational Allergy. One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stake- holders including the EAACI junior members. Keywords: Allergy, Asthma, EAACI, Prediction, Prevention The European Academy of Allergy and Clinical Immu - Atopic dermatitis (AD) is a chronic inflammatory skin nology (EAACI) has three official journals: Allergy, Pedi - condition with a multifactorial pathogenesis. Several atric Allergy and Immunology and Clinical and Trans- perinatal factors may influence the risk of AD. In a Dan - lational Allergy. One of the major goals of EAACI is to ish nationwide register-based study [3], the risk of devel- support health promotion in which prevention of allergy oping AD in the first 5  years of life was examined. Low plays a critical role and to disseminate the knowledge of birth  weight and preterm birth were inversely associ- allergy to all stakeholders including the EAACI junior ated with a lower risk of AD, while neonatal jaundice and members [1]. birth during autumn or winter were associated with an The EAACI journals have reported on the prediction increased risk of AD. and primary and secondary prevention of allergic dis- The prevalence of childhood AD varies considerably eases and asthma in 2016. This paper summarises these between ethnic groups. The Generation R Study assessed achievements. the role of environmental exposures and filaggrin (FLG) mutations on associations between ethnic origin and risk of Risk and protective factors childhood AD in 5082 children [4]. Compared with Dutch IgE-mediated allergy is much more common in Finnish children, Cape Verdean, Dutch Antillean, Surinamese- compared with Russian Karelia, although these areas are Creole and Surinamese-Hindustani children had increased geographically and genetically close. Many studies are risks of AD in the first 4  years of life. Environmental and trying to find the reasons explaining these differences. genetic risk factors partly weakened these associations. Higher concentrations of common environmental chemi- Early gut colonization by Bifidobacterium breve and B. cals were measured in Russian compared with Finnish catenulatum differentially modulates AD risk in children Karelian children and their mothers [2]. The chemicals at high risk of developing allergic disease [5]. Faecal sam- did not explain the higher prevalence of atopy on the ples were collected at age 1 week, 1 month and 3 months Finnish side. from 117 infants at high risk of allergic disease. Temporal variations in Bifidobacterium colonization patterns early in life are associated with later development of eczema and/or atopic sensitization in infants at high risk of aller- gic disease. *Correspondence: jean.bousquet@orange.fr CHU Montpellier, 371 Avenue du Doyen Gaston Giraud, Evidence linking maternal psychosocial stress during 34295 Montpellier Cedex 5, France pregnancy to subsequent child AD is growing, but the Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 2 of 6 definition of AD is diverse and results are inconsistent. Allergic sensitization was a strong risk factor for current The first systematic review to date addressed prenatal asthma and current rhinitis but not for current eczema. maternal stress and the subsequent risk of atopy-related Obesity was a risk factor for current asthma and cur- outcomes in the child [6]. Results suggest a relationship rent rhinitis, while farm childhood decreased the risk for between maternal stress during pregnancy and atopic current asthma and rhinitis. Occupational exposure to disorders in the child. However, the existing studies are gas dust or fumes and female sex was associated with an of diverse quality and the wide definitions of often self- increased risk of current asthma and eczema [10]. reported stress exposures imply a substantial risk for Allergen exposure is associated with the develop- information bias and false-positive results. ment of allergic sensitization in childhood as reflected Routine vaccinations can have non-targeted effects by global variations in sensitization patterns. However, on susceptibility to infections and allergic disease. Such there is little evidence to support a direct association. The effects may depend on age at vaccination, and a delay in Copenhagen Prospective Study on Asthma in Childhood pertussis vaccination has been linked to reduced risk of 2000 birth cohort showed in children of 7 and 13  years allergic disease. In a population-based cohort of Mel- that perinatal indoor aeroallergen exposure does not bourne, HealthNuts, 4433 12-month-old infants had seem to affect development of allergic sensitization or skin tests and oral challenges to determine food allergy rhinitis during childhood [11]. [7]. There was no overall association between delayed Finally, a hypothesis was proposed: may e-cigarette Diphtheria, Tetanus, Pertusis (DTaP) vaccination and vaping boost the allergic epidemic by affecting human food allergy; however, children with delayed DTaP had host defences, Staphylococcus aureus virulence and IgE less AD and less use of AD medication. Timing of routine sensitization? [12]. infant immunizations may affect susceptibility to allergic disease. Allergic March Body mass index (BMI) and physical activity in early Infants hospitalized for severe bronchiolitis are at childhood are inconsistently associated with atopic sen- increased risk of childhood asthma. A nested cohort sitization, AD and asthma in later childhood. Higher BMI study within the Massachusetts General Hospital Obstet- and over or under physical activities in early childhood ric Maternal Study (MOMS) carried out a prospective were associated with atopic sensitization, AD and asthma cohort of pregnant women enrolled during 1998–2006 in later childhood [8]. Larger cohorts with repeated (n  =  5407) [13]. AD was significantly associated with measurements of both predictors and outcomes are severe bronchiolitis in infancy. The mechanism of the required to confirm the data. AD-bronchiolitis association is unclear. Greater infant weight gain is associated with lower lung function and increased risk of childhood asthma. The Mechanisms role of early childhood peak growth patterns is unclear. Finnish and Russian Karelian children have a highly con- A population-based prospective cohort study among trasting occurrence of asthma and allergy: The methyla - 5364 children assessed repeated growth measurements tion levels in the promoter region of the CD14 gene were between 0 and 3  years of age as well  as  BMI and age at higher in the Finnish compared to Russian Karelian chil- adiposity peak [9]. Respiratory resistance and fractional dren. However, the methylation variation of this candi- exhaled nitric oxide were measured at 6  years of age. date gene did not explain the asthma and allergy contrast Greater peak height and weight velocities (PHV) were between these two areas and the answer is not simple associated with lower respiratory resistance. Greater [14]. peak weight velocity (PWV) and BMI at adiposity peak The role of FLG mutations during pregnancy and post - were associated with increased risks of early and persis- partum is unknown. FLG-genotyping was performed in tent wheezing. Childhood weight status partly explained a population-based sample of 1837 women interviewed these associations. No other associations were observed. in the 12th and 30th weeks of pregnancy and 6  months Follow-up studies at older ages are needed to elucidate postpartum as part of the Danish National Birth Cohort whether these effects persist at later ages. study 1996–2002. Women with FLG mutations had The increased prevalence of atopic diseases has been an increased risk of AD flares during pregnancy and of largely studied in children and adolescents, but fewer enduring postpartum physical problems linked to per- data exist in adults. Results from the cross-sectional ineal trauma during delivery [15]. West Sweden Asthma Study in 30,000 randomly-selected First-born children are at higher risk of develop- individuals showed that there are different risk factor ing a range of immune-mediated diseases and may patterns for asthma, rhinitis and eczema in adults with have a  divergent activated T-cells  profile suggesting in some risk factors overlapping between these conditions. utero programming of the child’s immune system. In a Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 3 of 6 subgroup of 28 children enrolled in the COPSAC2010 and in the case of early polysensitization, multimorbidity birth cohort, it was found that first-born infants display is more frequent as early as infancy [23]. a reduced anti-inflammatory profile in  Tv-cells  at birth. The longitudinal pattern of allergen-specific IgE levels This possible in utero ‘birth-order’ T-cells  programming from the prenatal stage to early life has remained largely may contribute to a later development of immune-medi- unexplored. 103 mother-infant pairs, part of an ongoing ated diseases by increasing overall immune reactivity in population-based prospective birth cohort study in Tai- first-born children as compared to younger siblings [16]. wan, found that an influence of maternal allergen-specific Although total IgE levels have been proposed as a bio- IgE levels on infant immune response might occur at marker for disease severity in AD and are increased in birth and then wane in infants at 12 months of age [24]. the majority of AD patients, they do not correlate with A  longitudinal study of maternal body mass index, disease severity. During the synthesis of immunoglobu- gestational weight gain, and offspring asthma was car - lins, free light chains (Ig-FLCs) are produced in excess ried out in the Growing Up Today Study [25]. Physician- over heavy chains. In comparison with IgE molecules, diagnosed asthma during childhood or adolescence was Ig-FLCs have a very short serum half-life. Therefore, Ig- reported by 2694 children (21%). Maternal prepregnancy FLCs might be more suitable as a biomarker for disease overweightness and obesity were associated with off - severity during follow-up. However, immunoglobulin spring asthma. The relation of several prenatal factors free light chains in adult AD patients do not correlate to risk of childhood asthma supports the early origins with disease severity [17]. hypothesis for asthma. Epigenetics Prevention DNA methylation in adulthood is associated with season Breastfeeding is associated with a lower risk of asthma of birth, supporting the hypothesis that DNA methyla- symptoms in early childhood, but its effect at older tion could mechanistically underlie the effect of season ages remains unclear. The Food Allergy and Intolerance of birth on allergy, although other mechanisms are also Research (FAIR) cohort (n  =  988) [26] showed incon- likely to be involved [18]. There may be  an association sistent protective effects of nonexclusive and exclusive between season of birth and blood DNA methylation in breastfeeding against long-term allergic outcomes. The adulthood but a recent study was unable to replicate pre- Generation R Study [27] examined the associations of vious findings and the question is still open [19]. duration and exclusiveness of breastfeeding with asthma Early environmental factors are likely to contribute outcomes in children aged 6  years, and whether these to CMA. In a small sample size from the Dutch Euro- associations were explained by atopic or infectious mech- Prevall birth cohort study (N  =  20 CMA, N  =  23 con- anisms. Breastfeeding patterns may influence wheez - trols, N  =  10 tolerant boys), general hypermethylation ing and asthma in childhood, which seem to be partly was found in the CMA group compared to control chil- explained by infectious mechanisms. dren, while this effect was absent in the tolerant group Prevention guidelines for infants at high risk of aller- [20]. Methylation differences were, among others, found gic disease recommend hydrolysed formula if formula is in regions of DHX58, ZNF281, EIF42A and HTRA2 introduced before 6 months, but evidence is mixed. Add- genes. Several of these genes are associated with allergic ing specific oligosaccharides may improve outcomes. A diseases. partially hydrolysed whey formula containing oligosac- Consumption of unboiled farm milk in early life pre- charides does not prevent AD in the first year in high- vents the development of atopic diseases. Milk is a com- risk infants [28]. The immunological changes (increased plex signalling and epigenetic imprinting network that regulatory T-cell and plasmacytoid dendritic cell per- promotes stable FoxP3 expression and long-lasting Treg centages) that were found require confirmation in a sepa - differentiation, crucial postnatal events preventing atopic rate cohort. and autoimmune diseases [21]. Data on the long-term impact of hydrolyzed formulas on allergies are scarce. The GINI (German Infant Study Prediction on the influence of Nutrition Intervention) trial partici - Profiles of allergic sensitization are poorly documented pants (n  =  2252) received one of four formulas in the in infancy. Early polysensitization is associated with aller- first four months of life as breast milk substitute if nec - gic multimorbidity in the Pollution and Asthma Risk: an essary: partial or extensive whey hydrolyzate (pHF-W, Infant Study (PARIS) birth cohort of infants [22] as early eHF-W), extensive casein hydrolyzate (eHF-C) or stand- as 18 months of age. Three profiles were found, differing ard cow’s milk formula (CMF) as Ref. [29]. Between 11 in terms of allergic morbidity at 6  years. Early sensitiza- and 15  years, the prevalence of asthma and the cumu- tion can predict allergic multimorbidity in childhood, lative incidence of AR were reduced in the eHF-C. The Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 4 of 6 cumulative incidence of AD was reduced in pHF-W and The political agenda eHF-C, AD prevalence was reduced in eHF-C. No sig- Preventive strategies for allergic diseases need to be nificant effects were found in the eHF-W group on any anchored on a strong political agenda to implement the manifestation, nor was there an effect on sensitization results of the research into practice. The European Sym - with any formula. In high-risk children, early interven- posium on Precision Medicine in Allergy and Airways tion using different hydrolyzed formulas has variable pre - Diseases at the European Union Parliament (October 14, ventative effects on asthma, allergic rhinitis and AD up to 2015) stressed that the socioeconomic impact of allergies adolescence. and chronic airways diseases cannot be underestimated Nutritional adequacy of a cow′s milk exclusion diet [34]. Participants underscored the need for optimal in infancy is essential since infants with suspected patient care in Europe, supporting joint action plans for cow’s milk allergy are required to follow a strict milk disease prevention, patient empowerment, and cost- exclusion diet [30]. In a group of UK infants (subgroup effective treatment strategies. AIRWAYS-ICPs (Inte - of the Prevalence of Infant Food Allergy study), the grated care pathways for airway diseases, Action Plan B3 diets of 39 infants (13 milk-free and 26 controls) were of the European Innovation Partnership on Active and assessed. Although infants consuming a milk-free diet Healthy Ageing, DG Santé and DG Connect) focuses on have a nutritional intake that is significantly different to the prevention and integrated care of chronic diseases. It matched controls who are eating an unrestricted diet, has proposed a scale-up strategy for the management and this difference is not constant and it is not seen for all prevention of allergic diseases using the recommenda- nutrients. tions of the European Innovation Partnership on Active The impact of the elimination diet on growth and nutri - and Healthy Ageing [35]. ARIA, the Allergic Rhinitis ent intake in children with food protein induced gastro- and its Impact on Asthma (ARIA) initiative commenced intestinal allergies was examined in children with delayed during a World Health Organization workshop in 1999, type allergies [31]. A prospective, observational study was is also targeting preventive strategies to prevent asthma performed at a tertiary gastroenterology department in and rhinitis by implementing emerging technologies children ranging in age from 4  weeks to 16  years. With using the ARIA Allergy  Diary app  and the  ARIA allergy appropriate dietary advice, including optimal energy and companion  app [36]. In close collaboration with the protein intake, hypoallergenic formulas and vitamins and European Forum for Research and Education in Allergy mineral supplementation, growth parameters increased and Airways diseases (EUFOREA) [37], an action plan for from before to after dietary elimination. These factors increasing awareness on prevention, patient empower- were positively associated with growth, irrespective of ment and cost-effective treatments is being elaborated. the type of elimination diet and the numbers of foods eliminated. Abbreviations The prevalence of food hypersensitivity in the UK is AD: atopic dermatitis; AR: allergic rhinitis; BMI: body mass index; CMA: cow’s still largely open to debate [32]. In a population based milk allergy; CMF: standard cow’s milk formula; DTaP: diphtheria, tetanus, per- tusis; EAACI: European Academy of Allergy and Clinical Immunology; eHF-C: birth cohort study conducted in Hampshire, UK as part extensive casein hydrolyzate; eHF-W: extensive whey hydrolyzate; FLG: fillagrin; of the European Initiative on Food Allergy, EuroPrevall, FoxP3: forkhead box P3; Ig-FLCs: immunoglobulin, free light chains; LC-PUFAs: birth cohort study, 1140 infants were recruited with 823 long chain polyunsaturated fatty acids; pHF-W: partial whey hydrolyzate; PHV: peak height and weight velocities; PWV: peak weight velocity; SNIP: single being followed up until 2  years of age. The diagnosis of nucleotide polymorphisms; TGF-β: transforming growth factor-β; Treg: T regu- food allergy was ascertained by positive double-blind, latory cell; TSLP: thymic stromal lymphopoietin. placebo-controlled food challenge (DBPCFC). Cumula- Authors’ contributions tive incidence of food hypersensitivity by 2  years of age Each author reviewed the referenced papers and the text. The paper was writ- was 5.0%. The cumulative incidence for individual food ten by JB. All authors read and approved the final manuscript. allergens were hens’ egg 2.7% (1.6–3.8); cows’ milk 2.4% Author details (1.4–3.5); peanut 0.7% (0.1–1.3); soy 0.4% (0.0–0.8); MACVIA-France, Contre les MAladies Chroniques pour un VIeillissement wheat 0.2% (0.0–0.5) and 0.1% (0.0–0.32) for fish. Just Actif en France European Innovation Partnership on Active and Healthy under half the infants with confirmed food hypersensitiv - Ageing Reference Site, Montpellier, France. INSERM U 1168, VIMA: Ageing and Chronic Diseases Epidemiological and Public Health Approaches, Villejuif, ity had no demonstrable IgE. France. UMR-S 1168, Université Versailles St-Quentin-en-Yvelines, Montigny le In the Probiotics in Prevention of Allergy among 4 5 Bretonneux, France. Euforea, Brussels, Belgium. Dermatology Centre, Norfolk Children in Trondheim (ProPACT, n  =  259) study, AD and Norwich University Hospital, Norwich, UK. Department of Dermatology and Allergy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany. prevention in children following maternal probiotic sup- AG Molecular Allergology and Immunomodulation, Department of Pediatric plementation does not appear to be mediated by breast Pneumology and Immunology, Charité Medical University, Berlin, Germany. 8 9 milk TSLP or TGF-beta [33]. Institute of Pharmacology, University of Bern, Bern, Switzerland. Pediatric Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 5 of 6 Department, Charité, Berlin, Germany. Food Allergy Referral Centre Veneto 11. Schoos AM, Chawes BL, Jelding-Dannemand E, Elfman LB, Bisgaard Region, Department of Women and Child Health, Padua General University H. Early indoor aeroallergen exposure is not associated with develop- Hospital, Padua, Italy. Laboratory of Clinical Immunology, Department ment of sensitization or allergic rhinitis in high-risk children. Allergy. of Microbiology and Immunology, KU Leuven, Leuven, Belgium. Faculty 2016;71(5):684–91. of Medicine, Transylvania University, Brasov, Romania. CHU Montpellier, 371 12. Bousquet J, Bachert C, Alexander LC, Leone FT. Hypothesis: may e-ciga- Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. rette smoking boost the allergic epidemic? Clin Transl Allergy. 2016;6:40. 13. Balekian DS, Linnemann RW, Castro VM, Perlis R, Thadhani R, Camargo Acknowledgements CA Jr. Pre-birth cohort study of atopic dermatitis and severe bronchiolitis None. during infancy. Pediatr Allergy Immunol. 2016;27(4):413–8. 14. Khoo SK, Makela M, Chandler D, Schultz EN, Jamieson SE, Goldb- Competing interests latt J, et al. No simple answers for the Finnish and Russian Karelia The authors declare that they have no competing interests.. allergy contrast: methylation of CD14 gene. Pediatr Allergy Immunol. 2016;27(7):721–7. Availability of data and materials 15. Bager P, Wohlfahrt J, Boyd H, Thyssen JP, Melbye M. The role of filaggrin Not applicable. mutations during pregnancy and postpartum: atopic dermatitis and genital skin diseases. Allergy. 2016;71(5):724–7. Consent for publication 16. Kragh M, Larsen JM, Thysen AH, Rasmussen MA, Wolsk HM, Bisgaard H, Not applicable. et al. Divergent response profile in activated cord blood T cells from first- born child implies birth-order-associated in utero immune programming. Ethics approval and consent to participate Allergy. 2016;71(3):323–32. Not applicable. 17. Thijs JL, Knipping K, Bruijnzeel-Koomen CA, Garssen J, de Bruin-Weller MS, Hijnen DJ. Immunoglobulin free light chains in adult atopic dermati- tis patients do not correlate with disease severity. Clin Transl Allergy. Publisher’s Note 2016;6:44. Springer Nature remains neutral with regard to jurisdictional claims in pub- 18. 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Prediction and prevention of allergy and asthma in EAACI journals (2016)

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Springer Journals
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Copyright © 2017 by The Author(s)
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Medicine & Public Health; Allergology; Immunology; Pneumology/Respiratory System
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Abstract

The European Academy of Allergy and Clinical Immunology (EAACI) owns three journals: Allergy, Pediatric Allergy and Immunology and Clinical and Translational Allergy. One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stake- holders including the EAACI junior members. Keywords: Allergy, Asthma, EAACI, Prediction, Prevention The European Academy of Allergy and Clinical Immu - Atopic dermatitis (AD) is a chronic inflammatory skin nology (EAACI) has three official journals: Allergy, Pedi - condition with a multifactorial pathogenesis. Several atric Allergy and Immunology and Clinical and Trans- perinatal factors may influence the risk of AD. In a Dan - lational Allergy. One of the major goals of EAACI is to ish nationwide register-based study [3], the risk of devel- support health promotion in which prevention of allergy oping AD in the first 5  years of life was examined. Low plays a critical role and to disseminate the knowledge of birth  weight and preterm birth were inversely associ- allergy to all stakeholders including the EAACI junior ated with a lower risk of AD, while neonatal jaundice and members [1]. birth during autumn or winter were associated with an The EAACI journals have reported on the prediction increased risk of AD. and primary and secondary prevention of allergic dis- The prevalence of childhood AD varies considerably eases and asthma in 2016. This paper summarises these between ethnic groups. The Generation R Study assessed achievements. the role of environmental exposures and filaggrin (FLG) mutations on associations between ethnic origin and risk of Risk and protective factors childhood AD in 5082 children [4]. Compared with Dutch IgE-mediated allergy is much more common in Finnish children, Cape Verdean, Dutch Antillean, Surinamese- compared with Russian Karelia, although these areas are Creole and Surinamese-Hindustani children had increased geographically and genetically close. Many studies are risks of AD in the first 4  years of life. Environmental and trying to find the reasons explaining these differences. genetic risk factors partly weakened these associations. Higher concentrations of common environmental chemi- Early gut colonization by Bifidobacterium breve and B. cals were measured in Russian compared with Finnish catenulatum differentially modulates AD risk in children Karelian children and their mothers [2]. The chemicals at high risk of developing allergic disease [5]. Faecal sam- did not explain the higher prevalence of atopy on the ples were collected at age 1 week, 1 month and 3 months Finnish side. from 117 infants at high risk of allergic disease. Temporal variations in Bifidobacterium colonization patterns early in life are associated with later development of eczema and/or atopic sensitization in infants at high risk of aller- gic disease. *Correspondence: jean.bousquet@orange.fr CHU Montpellier, 371 Avenue du Doyen Gaston Giraud, Evidence linking maternal psychosocial stress during 34295 Montpellier Cedex 5, France pregnancy to subsequent child AD is growing, but the Full list of author information is available at the end of the article © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 2 of 6 definition of AD is diverse and results are inconsistent. Allergic sensitization was a strong risk factor for current The first systematic review to date addressed prenatal asthma and current rhinitis but not for current eczema. maternal stress and the subsequent risk of atopy-related Obesity was a risk factor for current asthma and cur- outcomes in the child [6]. Results suggest a relationship rent rhinitis, while farm childhood decreased the risk for between maternal stress during pregnancy and atopic current asthma and rhinitis. Occupational exposure to disorders in the child. However, the existing studies are gas dust or fumes and female sex was associated with an of diverse quality and the wide definitions of often self- increased risk of current asthma and eczema [10]. reported stress exposures imply a substantial risk for Allergen exposure is associated with the develop- information bias and false-positive results. ment of allergic sensitization in childhood as reflected Routine vaccinations can have non-targeted effects by global variations in sensitization patterns. However, on susceptibility to infections and allergic disease. Such there is little evidence to support a direct association. The effects may depend on age at vaccination, and a delay in Copenhagen Prospective Study on Asthma in Childhood pertussis vaccination has been linked to reduced risk of 2000 birth cohort showed in children of 7 and 13  years allergic disease. In a population-based cohort of Mel- that perinatal indoor aeroallergen exposure does not bourne, HealthNuts, 4433 12-month-old infants had seem to affect development of allergic sensitization or skin tests and oral challenges to determine food allergy rhinitis during childhood [11]. [7]. There was no overall association between delayed Finally, a hypothesis was proposed: may e-cigarette Diphtheria, Tetanus, Pertusis (DTaP) vaccination and vaping boost the allergic epidemic by affecting human food allergy; however, children with delayed DTaP had host defences, Staphylococcus aureus virulence and IgE less AD and less use of AD medication. Timing of routine sensitization? [12]. infant immunizations may affect susceptibility to allergic disease. Allergic March Body mass index (BMI) and physical activity in early Infants hospitalized for severe bronchiolitis are at childhood are inconsistently associated with atopic sen- increased risk of childhood asthma. A nested cohort sitization, AD and asthma in later childhood. Higher BMI study within the Massachusetts General Hospital Obstet- and over or under physical activities in early childhood ric Maternal Study (MOMS) carried out a prospective were associated with atopic sensitization, AD and asthma cohort of pregnant women enrolled during 1998–2006 in later childhood [8]. Larger cohorts with repeated (n  =  5407) [13]. AD was significantly associated with measurements of both predictors and outcomes are severe bronchiolitis in infancy. The mechanism of the required to confirm the data. AD-bronchiolitis association is unclear. Greater infant weight gain is associated with lower lung function and increased risk of childhood asthma. The Mechanisms role of early childhood peak growth patterns is unclear. Finnish and Russian Karelian children have a highly con- A population-based prospective cohort study among trasting occurrence of asthma and allergy: The methyla - 5364 children assessed repeated growth measurements tion levels in the promoter region of the CD14 gene were between 0 and 3  years of age as well  as  BMI and age at higher in the Finnish compared to Russian Karelian chil- adiposity peak [9]. Respiratory resistance and fractional dren. However, the methylation variation of this candi- exhaled nitric oxide were measured at 6  years of age. date gene did not explain the asthma and allergy contrast Greater peak height and weight velocities (PHV) were between these two areas and the answer is not simple associated with lower respiratory resistance. Greater [14]. peak weight velocity (PWV) and BMI at adiposity peak The role of FLG mutations during pregnancy and post - were associated with increased risks of early and persis- partum is unknown. FLG-genotyping was performed in tent wheezing. Childhood weight status partly explained a population-based sample of 1837 women interviewed these associations. No other associations were observed. in the 12th and 30th weeks of pregnancy and 6  months Follow-up studies at older ages are needed to elucidate postpartum as part of the Danish National Birth Cohort whether these effects persist at later ages. study 1996–2002. Women with FLG mutations had The increased prevalence of atopic diseases has been an increased risk of AD flares during pregnancy and of largely studied in children and adolescents, but fewer enduring postpartum physical problems linked to per- data exist in adults. Results from the cross-sectional ineal trauma during delivery [15]. West Sweden Asthma Study in 30,000 randomly-selected First-born children are at higher risk of develop- individuals showed that there are different risk factor ing a range of immune-mediated diseases and may patterns for asthma, rhinitis and eczema in adults with have a  divergent activated T-cells  profile suggesting in some risk factors overlapping between these conditions. utero programming of the child’s immune system. In a Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 3 of 6 subgroup of 28 children enrolled in the COPSAC2010 and in the case of early polysensitization, multimorbidity birth cohort, it was found that first-born infants display is more frequent as early as infancy [23]. a reduced anti-inflammatory profile in  Tv-cells  at birth. The longitudinal pattern of allergen-specific IgE levels This possible in utero ‘birth-order’ T-cells  programming from the prenatal stage to early life has remained largely may contribute to a later development of immune-medi- unexplored. 103 mother-infant pairs, part of an ongoing ated diseases by increasing overall immune reactivity in population-based prospective birth cohort study in Tai- first-born children as compared to younger siblings [16]. wan, found that an influence of maternal allergen-specific Although total IgE levels have been proposed as a bio- IgE levels on infant immune response might occur at marker for disease severity in AD and are increased in birth and then wane in infants at 12 months of age [24]. the majority of AD patients, they do not correlate with A  longitudinal study of maternal body mass index, disease severity. During the synthesis of immunoglobu- gestational weight gain, and offspring asthma was car - lins, free light chains (Ig-FLCs) are produced in excess ried out in the Growing Up Today Study [25]. Physician- over heavy chains. In comparison with IgE molecules, diagnosed asthma during childhood or adolescence was Ig-FLCs have a very short serum half-life. Therefore, Ig- reported by 2694 children (21%). Maternal prepregnancy FLCs might be more suitable as a biomarker for disease overweightness and obesity were associated with off - severity during follow-up. However, immunoglobulin spring asthma. The relation of several prenatal factors free light chains in adult AD patients do not correlate to risk of childhood asthma supports the early origins with disease severity [17]. hypothesis for asthma. Epigenetics Prevention DNA methylation in adulthood is associated with season Breastfeeding is associated with a lower risk of asthma of birth, supporting the hypothesis that DNA methyla- symptoms in early childhood, but its effect at older tion could mechanistically underlie the effect of season ages remains unclear. The Food Allergy and Intolerance of birth on allergy, although other mechanisms are also Research (FAIR) cohort (n  =  988) [26] showed incon- likely to be involved [18]. There may be  an association sistent protective effects of nonexclusive and exclusive between season of birth and blood DNA methylation in breastfeeding against long-term allergic outcomes. The adulthood but a recent study was unable to replicate pre- Generation R Study [27] examined the associations of vious findings and the question is still open [19]. duration and exclusiveness of breastfeeding with asthma Early environmental factors are likely to contribute outcomes in children aged 6  years, and whether these to CMA. In a small sample size from the Dutch Euro- associations were explained by atopic or infectious mech- Prevall birth cohort study (N  =  20 CMA, N  =  23 con- anisms. Breastfeeding patterns may influence wheez - trols, N  =  10 tolerant boys), general hypermethylation ing and asthma in childhood, which seem to be partly was found in the CMA group compared to control chil- explained by infectious mechanisms. dren, while this effect was absent in the tolerant group Prevention guidelines for infants at high risk of aller- [20]. Methylation differences were, among others, found gic disease recommend hydrolysed formula if formula is in regions of DHX58, ZNF281, EIF42A and HTRA2 introduced before 6 months, but evidence is mixed. Add- genes. Several of these genes are associated with allergic ing specific oligosaccharides may improve outcomes. A diseases. partially hydrolysed whey formula containing oligosac- Consumption of unboiled farm milk in early life pre- charides does not prevent AD in the first year in high- vents the development of atopic diseases. Milk is a com- risk infants [28]. The immunological changes (increased plex signalling and epigenetic imprinting network that regulatory T-cell and plasmacytoid dendritic cell per- promotes stable FoxP3 expression and long-lasting Treg centages) that were found require confirmation in a sepa - differentiation, crucial postnatal events preventing atopic rate cohort. and autoimmune diseases [21]. Data on the long-term impact of hydrolyzed formulas on allergies are scarce. The GINI (German Infant Study Prediction on the influence of Nutrition Intervention) trial partici - Profiles of allergic sensitization are poorly documented pants (n  =  2252) received one of four formulas in the in infancy. Early polysensitization is associated with aller- first four months of life as breast milk substitute if nec - gic multimorbidity in the Pollution and Asthma Risk: an essary: partial or extensive whey hydrolyzate (pHF-W, Infant Study (PARIS) birth cohort of infants [22] as early eHF-W), extensive casein hydrolyzate (eHF-C) or stand- as 18 months of age. Three profiles were found, differing ard cow’s milk formula (CMF) as Ref. [29]. Between 11 in terms of allergic morbidity at 6  years. Early sensitiza- and 15  years, the prevalence of asthma and the cumu- tion can predict allergic multimorbidity in childhood, lative incidence of AR were reduced in the eHF-C. The Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 4 of 6 cumulative incidence of AD was reduced in pHF-W and The political agenda eHF-C, AD prevalence was reduced in eHF-C. No sig- Preventive strategies for allergic diseases need to be nificant effects were found in the eHF-W group on any anchored on a strong political agenda to implement the manifestation, nor was there an effect on sensitization results of the research into practice. The European Sym - with any formula. In high-risk children, early interven- posium on Precision Medicine in Allergy and Airways tion using different hydrolyzed formulas has variable pre - Diseases at the European Union Parliament (October 14, ventative effects on asthma, allergic rhinitis and AD up to 2015) stressed that the socioeconomic impact of allergies adolescence. and chronic airways diseases cannot be underestimated Nutritional adequacy of a cow′s milk exclusion diet [34]. Participants underscored the need for optimal in infancy is essential since infants with suspected patient care in Europe, supporting joint action plans for cow’s milk allergy are required to follow a strict milk disease prevention, patient empowerment, and cost- exclusion diet [30]. In a group of UK infants (subgroup effective treatment strategies. AIRWAYS-ICPs (Inte - of the Prevalence of Infant Food Allergy study), the grated care pathways for airway diseases, Action Plan B3 diets of 39 infants (13 milk-free and 26 controls) were of the European Innovation Partnership on Active and assessed. Although infants consuming a milk-free diet Healthy Ageing, DG Santé and DG Connect) focuses on have a nutritional intake that is significantly different to the prevention and integrated care of chronic diseases. It matched controls who are eating an unrestricted diet, has proposed a scale-up strategy for the management and this difference is not constant and it is not seen for all prevention of allergic diseases using the recommenda- nutrients. tions of the European Innovation Partnership on Active The impact of the elimination diet on growth and nutri - and Healthy Ageing [35]. ARIA, the Allergic Rhinitis ent intake in children with food protein induced gastro- and its Impact on Asthma (ARIA) initiative commenced intestinal allergies was examined in children with delayed during a World Health Organization workshop in 1999, type allergies [31]. A prospective, observational study was is also targeting preventive strategies to prevent asthma performed at a tertiary gastroenterology department in and rhinitis by implementing emerging technologies children ranging in age from 4  weeks to 16  years. With using the ARIA Allergy  Diary app  and the  ARIA allergy appropriate dietary advice, including optimal energy and companion  app [36]. In close collaboration with the protein intake, hypoallergenic formulas and vitamins and European Forum for Research and Education in Allergy mineral supplementation, growth parameters increased and Airways diseases (EUFOREA) [37], an action plan for from before to after dietary elimination. These factors increasing awareness on prevention, patient empower- were positively associated with growth, irrespective of ment and cost-effective treatments is being elaborated. the type of elimination diet and the numbers of foods eliminated. Abbreviations The prevalence of food hypersensitivity in the UK is AD: atopic dermatitis; AR: allergic rhinitis; BMI: body mass index; CMA: cow’s still largely open to debate [32]. In a population based milk allergy; CMF: standard cow’s milk formula; DTaP: diphtheria, tetanus, per- tusis; EAACI: European Academy of Allergy and Clinical Immunology; eHF-C: birth cohort study conducted in Hampshire, UK as part extensive casein hydrolyzate; eHF-W: extensive whey hydrolyzate; FLG: fillagrin; of the European Initiative on Food Allergy, EuroPrevall, FoxP3: forkhead box P3; Ig-FLCs: immunoglobulin, free light chains; LC-PUFAs: birth cohort study, 1140 infants were recruited with 823 long chain polyunsaturated fatty acids; pHF-W: partial whey hydrolyzate; PHV: peak height and weight velocities; PWV: peak weight velocity; SNIP: single being followed up until 2  years of age. The diagnosis of nucleotide polymorphisms; TGF-β: transforming growth factor-β; Treg: T regu- food allergy was ascertained by positive double-blind, latory cell; TSLP: thymic stromal lymphopoietin. placebo-controlled food challenge (DBPCFC). Cumula- Authors’ contributions tive incidence of food hypersensitivity by 2  years of age Each author reviewed the referenced papers and the text. The paper was writ- was 5.0%. The cumulative incidence for individual food ten by JB. All authors read and approved the final manuscript. allergens were hens’ egg 2.7% (1.6–3.8); cows’ milk 2.4% Author details (1.4–3.5); peanut 0.7% (0.1–1.3); soy 0.4% (0.0–0.8); MACVIA-France, Contre les MAladies Chroniques pour un VIeillissement wheat 0.2% (0.0–0.5) and 0.1% (0.0–0.32) for fish. Just Actif en France European Innovation Partnership on Active and Healthy under half the infants with confirmed food hypersensitiv - Ageing Reference Site, Montpellier, France. INSERM U 1168, VIMA: Ageing and Chronic Diseases Epidemiological and Public Health Approaches, Villejuif, ity had no demonstrable IgE. France. UMR-S 1168, Université Versailles St-Quentin-en-Yvelines, Montigny le In the Probiotics in Prevention of Allergy among 4 5 Bretonneux, France. Euforea, Brussels, Belgium. Dermatology Centre, Norfolk Children in Trondheim (ProPACT, n  =  259) study, AD and Norwich University Hospital, Norwich, UK. Department of Dermatology and Allergy, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany. prevention in children following maternal probiotic sup- AG Molecular Allergology and Immunomodulation, Department of Pediatric plementation does not appear to be mediated by breast Pneumology and Immunology, Charité Medical University, Berlin, Germany. 8 9 milk TSLP or TGF-beta [33]. Institute of Pharmacology, University of Bern, Bern, Switzerland. Pediatric Bousquet et al. Clin Transl Allergy (2017) 7:46 Page 5 of 6 Department, Charité, Berlin, Germany. Food Allergy Referral Centre Veneto 11. Schoos AM, Chawes BL, Jelding-Dannemand E, Elfman LB, Bisgaard Region, Department of Women and Child Health, Padua General University H. Early indoor aeroallergen exposure is not associated with develop- Hospital, Padua, Italy. 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Clinical and Translational Allergy – Springer Journals

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