Accepted Article View metadata,citationandsimilarpapersatcore.ac.uk 3 University of Helsinki, Helsinki, Finland [email protected] Allée des Alpes, La 38700 Tronche Team of environmental epidemiology applied to re Chanoine Sebastien [email protected] (Meilahdentie 2), 00029 Hospital District of Helsinki and Uusimaa, Helsinki, Finland. Finland. This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/all.13971 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has 7 Juha Pekkanen 6 Jussi Karjalainen 5 4 2 1 Toppila-Salmi Sanna multimorbidities and decreases with age Risk ofadult-onsetasthmaof allergic withthenumber increases Disease Airway Lower and Asthma Article: :Original type Article DR. VALÉRIE: SIROUX(Orcid ID 0000-0001-7329-7237) DR. SANNA TOPPILA-SALMI: 0000-0003-0890-6686) (Orcid ID Sanna Toppila-Salmi Toppila-Salmi Sanna [email protected] [email protected] Valérie Siroux Departmentof Public Health, PO Box20 (Tukholmankatu 8B), University of Helsinki, 00014 PO Hospital, University Allergy Centre, Tampere Université Grenoble Alpes, Grenoble, 38000 France Pôle Pharmacie, Grenoble CHU Alpes, 38000 Grenoble, France Institute for Advanced Biosciences, /InsermUGA U1209/ 5309 UMR CNRS joint researchcenter Skin andAllergy Hospital, Helsinki UniversityHo Haartman Institute, Medicum, PO Box (Haartmaninkatu21 3), 00014 University of Helsinki, Helsinki, 3

1,2 , Sebastien Chanoine , Sebastien 3,4,5 3,4,5 Jussi Karjalainen Jussi BOX 2000 BOX 2000 (Teiskontie 35), 33521 Tampere, Finland. Version of Record. Please Version as this cite of Record. article spitaland University of Helsinki, POBox 160 production and respiratory health, Site Santé - Santé Site health, respiratory and production 6 , Juha Pekkanen , Juha 7,8 , Jean Bousquet , Jean provided byHelsinginyliopistondigitaalinenarkisto 9 , brought toyouby CORE Accepted Article personal fees from AstraZeneca, non-financial su non-financial fees from AstraZeneca, personal reports SC Products. Roche and ERT Laboratories, Mylan for consultant paid as acted has STS interests Competing subjects. all from obtained was consent written anda (2/1996) Approval from studywas obtained theet the for participate to consent and approval Ethics Declarations: Total Running title: E-mail address: [email protected] +358-9-19125155 number: Telefax Phone number: +358-9-4711 00029 HUS,Finland Sanna Toppila-Salmi, MDPhD, Skin and Allergy Hospital, Helsinki University Hospital,P.O.Box160, to: requests reprint and correspondence Address [email protected] Allée des Alpes, La 38700 Tronche Team of environmental epidemiology applied to re Valérie Siroux [email protected] Belgium Brussels, and Euforea, France Bretonneux, le Montigny 1168, UMR-S Quentin-en-Yvelines, St- Versailles Université Villejuif, approaches, health public and Epidemiological diseases chronic Jean Bousquet [email protected] This by is protectedarticle reserved. Allrights copyright. 3 9 8 Institute for Advanced Biosciences, /InsermUGA U1209/ 5309 UMR CNRS joint researchcenter and :Ageing VIMA 1168, U INSERM France, Montpellier, MACVIA-France, & VIA-LR FMC Fondation Environmental Health, National Institute for Health Welfare, and PO Box 95,Kuopio, 70701 Finland.

Allergic multi-morbidity associated is with an increasedof asthma risk pport from Boehringer Ingelheim, non-financial non-financial Ingelheim, from Boehringer pport hics committeehics atTampere University Hospital production and respiratory health, Site Santé - Santé Site health, respiratory and production Accepted Article This by is protectedarticle reserved. Allrights copyright. allergic (AD),dermatitis was de and (AC) conjunctivitis allergic (AR), rhinitis Allergic (n=2050). controls two or one with region living (a asthma diagnosed recently with age of years 30 over adults 1205 including registers national Finnish from data population-based used We Methods: effect. age the and diseases allergic of number the considering asthma adult-onset and multimorbidity allergic between association the study to was aim The Background: Abstract Nieminen from ofUniversity Tampere. M. Markku Professor and Helsinki, of University from Lemmetyinen Riikka Klaukka†, Timo Professor Tampere, of University from the Huhtala Heini MSc Welfare, and for Health Institute National We thank the following people for their valuable contributions: Professor Arpo Aromaa from the Acknowledgements management, analyses and critical review of the manuscript. data in assisted have authors All manuscript. the wrote and analyses data the performed VS and SC STS, strategy, andthe analytical study ofthe conception and planning on the participated authors All contributions Authors' association. Medical Tampere and Letters, and Science for Society Finnish the and Research and Education Higher Education, of Ministry French the Helsinki, in Français progra mobility short Researchers from the grants travel as well as Foundation, Jahnsson Yrjö the and Kivi Foundation, Laina and Väinö the Foundation, State funding for university-level health research (TYH2018103), the Tampere Tuberculosis Foundation, Paulo Erkko Aatos Foundation, and Jane the Immunology, and Allergology of Society Finnish the Foundation, Medical Finnish from grants research by part in supported was The study Funding outside the submittedwork.other All auth are these All INNOV. from Kyomed other Uriach, Teva, Takeda, Sanofi-Aventis, Novartis, Mylan, Mundipharma, Menarini, Hikma, Cipla, Chiesi, from other and personal fees JB reports Astellas. non-financia Pharmaceuticals, from Actelion support fined from self-completed questionnaire. Conditional logistic logistic Conditional questionnaire. from self-completed fined ors declare no conflicts of interest. interest. of conflicts no declare ors m (RSM) from the Joint funding from the Institut from Institut the funding Joint the from m (RSM) ge range: 30-93), matched for gender, age, and and age, for gender, matched 30-93), range: ge l support from MSD, non-financial support from from support non-financial fromMSD, support l Accepted Article This by is protectedarticle reserved. Allrights copyright. flow expiratory =peak PEF ratio =odds OR firstsecond the volume during expiratory FEV1 =forced interval confidence CI = AR =allergic rhinitis AD allergic = dermatitis conjunctivitis AC =allergic Abbreviations count: word Total Allergicmultimorbidity is associatedwith an increased risk of asthma inadults Short title asthma, atopic dermatitis, epidemiology, ocular allergy, rhinitis. Key words this association decreases with age. Conclusions: Adult-onset asthma waspositively associatedwith the number of allergicdiseases and .002). years,<50 50-62 yearsand years, >62 respectivelyfor age* (p decreasedwith increasing age (3.52 [2.51-4.94], 2.44 [1.74-3.42] and 1.68 [1.04-2.71]) in subjects 5.90], respectively. association The betweenadult-onset asthma and associated with1, 2, and 3allergic diseases were 1.95[1.52-2.49], 2.87[2.19-3.77], and 4.26 [3.07- adult-onset asthma asthmanumberfor increased with [CI95%]the ofallergicdiseases; adjusted OR among subjects with asthma and 26.1 %, 20.0 %, 23.5 %, among controls. Compared to non-atopics, (11, 31-71) years, 37% men)]. AR,AC or reported ADwere by50.2 %, %, 39.6 %, 33.8 respectively Results: 1118 cases with asthma and matched 1772 controls were included [mean (sd, min-max) 53 associated with allergic multimorbidity. birth and siblings, of number training, professional level, education smoking, parental asthma/allergy, parental infection/pneumonia, hospitalized childhood countryside, in growing (smoking, confounders on potential adjusted regression order) was appliedestimate to asthmathe risk ≥ 1 allergic multimorbidity interaction, ≥ 1 allergic multimorbidity Accepted Article This by is protectedarticle reserved. Allrights copyright. affect between polysensitization and asthma(12). adults in and itsasthma-risk increases in adults who were born after 1930proposing a cohort and/or age and polysensitization (10,11), in adults asthma with associated was polysensitization have foundthat and2006further to2016, while prevalence the of non-allergic asthma hasremainedstable (9). We to 1996 from increased has asthma allergic of prevalence the that shown been has It and asthma. diseases allergic co-existing ofthe effect age or cohort- have addressed studies previous Only few onset asthma. insigh haveabetter to needed are and conjunctivitis (8). Further comprehensive studies simultaneously considering allergic rhinitis, allergic dermatitis asthma for incident risk the doubles rhinoconjunctivitis allergic that found study population-based A Finnish (7). subjects nonatopic and atopic both in asthma forlate-onset risk factor significant (6). Anested case-controlstudy cohort from a inTucson apopulation showed that rhinitis was a subjects in nonatopic asthma and rhinitis perennial between association strong detected population adult A ofaEuropean study rhinitis. only considered the studies of andmost population, adult among inasthma diseases ofallergic role the on exist studies less population, pediatric to Compared conjunctivitis was a frequent co-morbidity to allergic rhinitis and to asthma and eczema (5). with coexisting allergies than as a single entity (4). In a secondary pediatric outpatient clinic, allergic (3,4). Astudyof asthma children, several cohort studies showed that allergic diseases were associated with increased risk of disease, is ahealth major public issue, with over million 300 people affectedworldwide (1,2). In critically increased across theworldoverpast the decades. Asthma,common a non-communicable The prevalence of allergic diseases, including asthma, rhinitis, atopic dermatitis and food allergy, Background SII =Social Insurance Institution of Finland German childrenGerman showed asthmaoc that t on the role of allergic multimorbidity on adult- on multimorbidity allergic of role the on t curs in both sexes more frequently frequently more sexes both in curs Accepted Article This by is protectedarticle reserved. Allrights copyright. maximal to (reference recording (PEF) flow expiratory peak indiurnal or greater of20% variation history,clinical features, asthmacourse, and at leastone following of the physiologiccriteria:a (i) All asthmatics fulfilled the following criteria for doctor-diagnosed asthma in this register: typical data, variable as bySII stored not are parameters stores the certificates, in which thelung function certificates arereviewed by case case by SII´s as well findings as and conclusions asthma after treatment period test ofmonths. 6 These results test function lung results, exam´s clinical information, background include to has certificate This physician. bypatient´s made been has that certificate by granted is right reimbursement reimburseme drug asthma bythe couldbe identified population study the in cases diagnosed newly all which in Finland, of (SII) Institution Insurance Social by maintained register, Reimbursement Drug Finnish the from drawn sample a random patients older than 30 years of age with a recent asthma diagnosis year).(<1 The asthmatics formed (Figurepreviously 1)as described(13,14).This study collected informationfrom 1400 asthma in 1997 conducted study control case matched is population-based a inFinland Asthma The Adult Population Study controls. matched their and Finland of asthmatics of sample Population-based Setting 1996-97. in factors adulthood and childhood of aquestionnaire used We Finland. in asthma adult-onset of study case-control population-based across-sectional is This design Study Methods associated with allergic multimobidity increases with younger age. risk asthma the that was hypothesis secondary Our multimorbidities. allergic numberof the ADpositivelyisAC, and associated with adult-onset asthma and asthma that the with risk increases AR, disease, each allergic that hypothesized We (13). inFinland Asthma Adult the on study asthma, control case population-based alarge in asthma adult-onset and multimorbidity allergic between association the assess to was aim the adults, in asthma and multimorbidity allergic between effect causal putative ofthe limited knowledge there still As in is adults. burden reduce asthma putatively could adulthood in persists that multimorbidity allergic of prevention and detection Early

physician, who gives right.physician, thereimbursement SII yet this data are stored by the patient´s this stored bythe hospital.patient´s data yet are s test s test results are referred. Lung function test nt decision of diagnosed asthma. In detail, the detail, In asthma. diagnosed of decision nt Accepted Article

This by is protectedarticle reserved. Allrights copyright. asthma to due night the in up wake AND/OR months 12 past the during ( AND caused byasthma Severe asthma was defined as self-reported severe asthma symptoms regularAND impairment 1). (Table asthma physician-diagnosed of place the and symptoms, ofasthma severity onset, asthma at age asked were asthmatics The 1). ever(Table wheeze with cough/dyspnea years. 48.8±12.7 was asthma of doctor-diagnosed earlier (15,16). The responders asked were the ye greater in PEF or in exercise FEV1 testing. This in PEF or forcedpeak expiratoryexpiratory flow (PEF) recording (reference to maximalvalue); (ii) an increase of 15% or greater volumecourse;leastat one following of the physiologic criteria:or avariationdiurnal (i) in greater of % 20 in 1 sec (FEV1)All asthmaticsfulfilled following the criteria for asthma:typical history, clinical features, and asthma with asthma severe and asthma adult-onset of Definition Outcomes 0.9 % asthmatics of the they responded not have (Table 1). that do and medication, asthma current with asthma diagnosed doctor a have they that responded controls severity physician-diagnosed and of as asthma medication, and asthmatics were additionally asked age at onset of asthma symptoms, the place of asthma current and asthma asked doctor-diagnosed were subjects all asthma, had cases and that th that To makesure register. Reimbursement Drug controlsdid not have invalid 1997a decision drug reimbursement for of diagnosed asthma in the Selected subjects. all from was obtained consent written a and Hospital University Tampere at 86.1% and 73.2%, correspondingly. Approval for the study was obtained from ethical the committee was group control and asthma in responders the of proportion The patients. asthma for questions asthma-specific and groups), both (for questions demographic of consisted Questionnaire (13). 1) (Figure register population a Survey, through and Health Finland Mini through Registers, National residence of (area region living and years), (±2 age gender, for werematched asthmatics The (15,16). earlier beenvalidated has case ascertainment b-agonist; or(iii)decrease anof or15% greater in PEF or FEV1 in exercise testing.This method of value);increasean (ii) of 15% in greater PEF or forcedor expiratorywith volume second in 1 (FEV1) ≥ 1 oral corticosteroid course/regular oral corticosteroids due to course/regular due corticosteroids asthma 1 oraloral corticosteroid thma symptoms. only that Wefound 1.4% of the method of case ascertainment has been validated been ascertainmentcase has method of ar of doctor-diagnosed (mean±SD)asthma. The age All responders were asked whether they have had have they whether asked were responders All by postal code) with two controls drawn from drawnfrom controls two code)with by postal e controls did not have accidentally an asthma, asthma, an have accidentally not did e controls β -agonist; or (iii) an decrease of 15% or or of15% decrease an (iii) or -agonist; ≥ 1/week). Accepted Article multimorbidity could be associated with more severe more with associated be could multimorbidity the asthma severitystatus(mild-moderate vs. severe), addresshypothesis to the allergicthat This by is protectedarticle reserved. Allrights copyright. between association the addition, In (21). suggested previously as asthma, adult-onset and multimorbidity allergic between association the in effect a sex address to Sex, 2) (12); age with decreases polysensitization with associated asthma adult-onset of risk that indicating findings previous following years, >62 and years 50-62 years, regressionmodels:considerinterm inthe age, 1) between association 20). In further analyses, 2 order(13,17- andbirth no),number trade school; of siblings, courses/completed college/university; pr school), primary secondary; (baccalaureate; at infection (pneum infections childhood severe countryside, in ever), growing (nevervs. smoking region, living (continuous), age : gender, S1) (figure directed-acyclic-graph the in identified factors confounding potential following onthe adjustment models were adjusted by age, gender and living region. The models (i.-iii.) were also performed with All magnitude. ofsimilar risk anasthma confers multimorbidity each whether allergic to test disease of allergic multi-morbidities toaddress apossibledose-response relationship; (iii.) type allergic of (i.) variables: multimorbidity allergic 3 consecutive considering conducted was asthma adult-onset and multi-morbidity allergic between The association intervals. confidence 95% with (OR) logist byconditional performed were groups control or allergic data The comparisons of demographic analyses Statistical missing values were both regarded as missing values. regarded as “No” in the main analysis. In the complete case analysis, the “Idon´t know” values and were questions AC AD AR, and to controls) among and 7.7% % 5.0 between and asthmatics, amongcontrols), and “I don´t know” responses (representing between 6.0 % and % 12.5 among responses (representingbetween% and 4.4 % among 7.7 asthmatics, andand3.6 % between9.3% allergic symptoms? Skin symptoms, symptoms, Eye Airwaysymptoms, Other, what?”Bothmissing any other youget “Do asked ADwere AC and know). Don´t Yes, (No, animals?’ or pollens to related are that symptoms rhinitis hayfeverorother you had ‘Have ever question by the asked AR was multimorbidity allergic of Definition ≤ 3 years of age), parental asthma/aller parental age), of years 3 ≥ 1 allergic multimorbidity and adult-onset asthma by adding an interaction interaction an byadding asthma adult-onset and multimorbidity allergic 1 variables were successively tested as potential effect modifier in the onia before or during school age and/or hospitalization due to to due hospitalization and/or age school or during before onia ≥ 1 allergic multimorbidity and asthma was stratified by g three age categoriesin size: age <50 equal subjects g three multimorbidity prevalence between asthmaand prevalence between multimorbidity ≥ 1 allergic 1 disease (main model); (ii.) the number ofessional training (completed professional professional (completed training ofessional asthma, as suggested in children (22). ic regression and were reported as odds ratios odds as reported were ic regression and gy, parental smoking, education level level education smoking, gy, parental Accepted Article [CI95%]were4.90 [1.95-12.32] and [2.06-3.19], 2.56 respectively)2). The (Table sensitivity analysis OR (adjusted nonsignificant was term interaction the although asthma, mild-moderate with to those years, respectively (Table 2). associationThe was stronger in those with severe asthma, as compared 3.52 [2.51-4.94], 2.44 [1.74-3.42] and [1.04-2.71]1.68 in subjects <50 years, 50-62 years and >62 This by is protectedarticle reserved. Allrights copyright. associated with association (adjusted p value for interaction was 0.002). The odds ratio of adult-onset asthma this in effect modifier an was Age 2). 2,Table Figure 0.45, was interaction for pvalue (adjusted difference gender significant no statistically was there but respectively), [1.70-3.39], 2.40 and 3.66] onset asthma and asthma,withan adjusted [CI95%] OR [2.11-3.19], of (2.60 ThisTable association 2). between adult- leastThe presence allergic one was at of disease asthma adult-onset and multimorbidity allergic one least At (Table training professional and level education lower a had and smoking, parental asthma/allergy, parental and infections childhood severe often hadmore smoker, ever weremore often cases asthma controls, to As 4). compared 1, Table (Table 39.6 %, %, 33.8 respectively in comparison to control group 26.1%, 20.0 %, 23.5 %, respectively females was%. The63 proportion of asthmacases havingself-reported AR,AC ADor were50.2%, (Table 1).The mean ± min-maxSD, subjects ageof thewas 53±11, 31-71 years. proportion The of The total number of asthma cases with available data was 1118 and matched controls was 1772 characteristics Subject Results Base 24Statistical Software Package Chicago, (SPSS, IL, USA). P-valuesthan0.05 less wereconsidered statistically significant. were performed Statistics with SPSS ofage). years 15 before asthma onset reported who cases 65 and using report not did who cases 10 medication, asthma regular current using reported who controls (24 data questionnaire the given misclassification potential with subjects 99 excluding by definition, case and control to the “N as imputed priori a were values (missing question multimorbidity each allergic for data missing without only subjects by including missingness, to 1) results of the the robustness address to conducted were analyses sensitivity Finally, ≥ 1 allergic multimorbidity increased with decreasing age: adjusted OR [CI95%] ORwere [CI95%] adjusted age: decreasing with increased multimorbidity 1 allergic ≥ 1 allergic multimorbidity was slightly higher in females than in males (2.80 [2.14- 1). Among asthmacases, 10% had severeasthma. associated with an increased risk for adult onset onset adult for risk increased an with associated o” for each allergy multimorbidity question); 2) Accepted Article positively associated with the number of allergic diseases and this association decreases with age. was asthma adult-onset that was finding major Our adulthood. in diagnosis andasthma diseases allergic between associations strong detected we study case-control population-based In this Discussion S1). (Table analysis (n=1955) showed similar patterns of associ observed for co-existing[2.17-4.26]3.04AR+AC, (Table 3). The sensitivity analysis on completecase OR [CI95%] [3.02-5.81]) 4.19 3). (Table nextstrongestThe association with adult-onsetasthmawas (adjusted asthma adult-onset on effect strongest hadthe (AR+AC+AD) diseases allergic three of all was of similar magnitude(2.35 [1.48-3.71] and [1.83-3.50], 2.53 respectively,Table 3).The presence was[0.87-1.80] 1.25 (Table 3).The associationbetween adult-onset asthma and AConly or ARonly higher risk of asthma with >2.2except OR ADfor only, which theadjusted OR[CI95%] estimated In adjusted models, all single and combined allergic diseases were significantly associated with asthma adult-onset and multimorbidities allergic of Type very similar results S2).(Figure 5.15 [3.56-7.45], respectively. Sensitivity analysis on the definition of asthma and control showed females). In the complete case analysis adjusted OR [CI95%] were 2.27 [1.66-3.10], 3.67 [2.66-5.07], [1.72-4.63],2.82 and 6.51 [2.92-14.46], respectively value (p for trend test <0.001 in males and in 3.06 [2.18-4.30], and 4.08 [2.80-5.94], respectivelyand inOR [CI95%] males were [1.18-2.68],1.78 <0.0001).A similar pattern associationof was observedfemales, in with [CI95%] OR [1.51-2.86],2.08 [3.07-5.90]as compared tonoallergicdisease, respectively2, Table(Figure3,for trend test p adjusted OR[CI95%] for 1, 2, and 3allergic diseases were 1.95 [1.52-2.49], 2.87 [2.19-3.77], and 4.26 ofconsidering When number the asthma adult-onset and diseases allergic of Number [2.41-6.00], [0.95-3.14],1.72 subjects in years, <50 50-62years and years, >62 respectively. 3.73 [2.67-5.22],[1.97-4.78] 3.07 in all, females and males respectively, and 4.58[3.00-6.97],3.80 This by is protectedarticle reserved. Allrights copyright. higher adjustedOR point estima conducted oncomplete case analysis (n=1955) showed similar patterns of association and lead to

tes (e.g. risk associated for for associated risk (e.g. tes allergic diseases,dose-responsea relationship was observed: ation, and tended to increase OR point estimates estimates point OR increase to tended and ation,

≥ 1 allergic1 disease [2.56-4.28],was 3.31 Accepted Article This by is protectedarticle reserved. Allrights copyright. (25). effe an ageing from and overtime, development host-m in change e.g. from acohort-effect, amongasthmatics is increasing with decades later of observations suggest that the proportion of allergic multimorbidity and allergic polysensitization these Altogether, (12). 1930 born after were who adults in stronger was association and this (10), adults in asthma with associated was polysensitization that showing observation our previous asthmahasremained ona stable prevalence level(9). In addition, our findings arein agreement with two past the during increased has asthma allergic in the youngest group are in line with results from with age. These findings of a stronger increase in asthma risk associated with allergic multimorbidity decreased multimorbidity allergic and asthma adult-onset between association the that found We allergic conjunctivitis (AR/AC) andpolysensitization co-associate with adult asthma (11). and/or rhinitis allergic that population adult asmaller in detected previously we have In addition, associated witha significant increasein thenumber of IgE-reactivitiesto respiratory allergens (24). di the of irrespective multimorbidity, allergic considering conjunctivitis in addition to rhinitis and asthma; the study showed that increase in by were recently extending observations These (23). only phenotypes onlyboth andasthma AR the of pattern sensitization the combined and polysensitization strong with associated is multimorbidity inare accordance previous within adults data demonstrating thethat asthma-plus-rhinitis allergic diseases shouldconsider multiple organs eye, (nose,skin andairways). lower results These of approach multimorbid the that suggest results our Therefore, asthma. and multimorbidities adose-respons showed we Noteworthy, adulthood. in diagnosed asthma with associated is multimorbidity allergic that we demonstrate here findings, these with In agreement (10). adults in asthma with associated was polysensitization found that knowledge of effect the of allergic multimorbidity on asthma-riskadults. in In a previous studywe severity explained over severityof variancehalf However,the asthma (22). in therehas been limited andrhinitis physiology, pulmonary exposure, smoke tobacco environmental inflammation, allergic sensitization, allergen that shown has children school-aged in network Causal analysis (3). in children asthma and allergic multimorbidity, including rhinitis,conjunctivitis, anddermatitis, is well described between Theassociation children. in demonstrated well observations adulthood to extends study this in observed asthma and adult-onset multimorbidity allergic between association The strong sease (rhinitis, conjunctivitis and asthma) was asthma) and conjunctivitis (rhinitis, sease ct remains unknown and requires further studies studies further requires and unknown remains ct a Swedish study showing thattheprevalence of icrobiome-environmental interactions icrobiome-environmental during e relationshipe between the number of allergic birth. To which extent this observation results results observation this To extent which birth. ofnon-allergic prevalence the while decades, Accepted Article This by is protectedarticle reserved. Allrights copyright. characterized a profile to compared as exacerbations asthma and asthma uncontrolled subsequent of risk an increased showed profile multimobidity This (31). population ofthe 33% represented that multimorbidity” “allergic by characterized mainly pattern a including asthma, with associated patterns multimorbidity three identified databases administrative based drug approach using publications previous from results with line in asignificant as identified not was more stronglyassociatedwith asthma than severe formalthoughmilder of asthma, asthmaseverity be might multimorbidity allergic that suggest asthma, severe with adults of 10% including Our data, diseases. allergic and asthma between mechanisms morbidity and asthmacausala true is associationwhich and toonextent it relies it shared whic remains open, to it Yet studied. been less has which asthma, andadult-onset multimorbidity allergic between association the addressed study Our (30). multimorbidity allergic of mechanism causal dominant the as considered be longer can no asthma), its presence accounted for less than 40% ofmultimobidity, suggesting that IgE sensitization showed that although IgE sensitization isassociated with excess allergic multimorbidity (including multimorbidity rhinitis and asthma eczema, on focusing astudy addition, In expected. than lower except HLA-DRin suggesting(29), that the causal role of IgE in the developmentof asthma might be overlap betweenloci strongly associatedwith asthma and those stronglyassociated withlevels, IgE no showed IgE and asthma on GWAs European large A understood. fully not still is cause common a share andasthma diseases allergic the which to extent the children, in particularly chance, Although theco-occurrence of allergic diseases adulthood. in asthma and multimorbidity allergic between association the in differences gender of strong evidence bring not study did Our (21). and females males between diagnoses and obesity smoking, in bydifferences explained not was observation This multimorbidity, and showedthat female gender is of instead asthma non-atopic vs. atopic on focused has study population-based European allergens, initial atopic dermatitis, severe recurrent wheezing and hypereosinophilia (28). A previous for asthma persisting intoof yearsallergic 13 ofage were sensitization to multiple airborne with asthmapersistence (27). A associates polysensitization and/or multimorbidity allergic that shown have also studies Pediatric (26). males in multimorbidity allergic of predominance by a characterized is asthma Childhood

follow-up study including French children showed that risk factors factors risk that showed children French including study follow-up modifier effect given the large confidence intervals. Our results are are Our results intervals. confidence large the given effect modifier (31). Among adult women with asthma, a clustering clustering a asthma, with women adult Among (31). h extent the association between allergic multi- allergic between association the extent h and asthma is more common than expected is morecommonby expected than asthma and an independent risk for non-atopic asthma (21). (21). asthma non-atopic for risk independent an Accepted Article This by is protectedarticle reserved. Allrights copyright. however because ofassociations, direction causal onthe allow assertion not does design sectional stronger magnitude of the effects and age modifyingthe effect remained significant.cross- The thatconsidered know”“I don’tas missing values showed similarof patterns associationswith results because subjects had the possibility to reply “I don’t know” and the complete case analysis age group. Nevertheless,webelieve that,bithis if contributing have partly might it occurred, biased towardsthe null theassociation in particular in th bias to lead would which group, age oldest the in likely more and haveoccurred, might diseases allergic of report the in bias amemory addition, In misclassifications. bypotential biased are not findings our that indicating conclusions, same the to led data questionnaire using controls and cases sensitivity However, adulthood. in relapsed that asthma childhood-onset had might of asthmatics portion a small andthat register), reimbursement of the diagnosis asthma fulfilling not (although medication asthma current with asthma diagnosed doctor- reported controls few that acknowledge we study, this in andcontrols cases of definition effe modifying the addressing analysis the particular weaknesses of our study include the limited statistical power of some analysis on sub-groups, in be should study of this results the population; another to results our extrapolating about needed is caution smoking), of duration and the amount the for account into take not does variable smoking the (i.e. variables some independent of assessment the in accuracy limited due to or exposure), occupational (i.e. model regression the in confounders potential missing to due either confounding, for residual by biased partly be could adjust for a large set of potential confounders in the analysis. Nevertheless, the association reported info detailed the given addition, In rate. responder ahigh and 1900´s, early in born subjects of aspect ahistorical and range age high bias, sampling for potential mitigates that design population-based large the study include ofthe The strengths limitationsStrengths and needed. are prove this to studies More prognosis. and severity mechanisms, of terms in alone asthma from differ considerably that phenotypes amongadults asthmatic Overall,is (13). asthma likely that it withallergicmultimorbidity represent mortality excess explain AR/AC not that did indicate studies previous mortality of terms in although, for the “metabolic multimorbidity” profile (31). Thus, allergic diseases affect morbidity life-long (32), by “few multimorbidity” and, importantly, this risk was of similar magnitude than the risk observed confirmed in other population and countries. The The countries. and population other in confirmed analyses relying on ofanalyses more definitions stringent in showingassociations strongest in theyoungest as occurred, it was of limited impact on our main main on our impact limited of was it as occurred, e oldest age group; therefore, if such a memory group; ifsuch a oldest age therefore, e rmation recorded in the study, we were able to able were we study, the in recorded rmation ct of asthma severity. Despite the efforts in the efforts Despite severity. ofasthma the ct Accepted Article This by is protectedarticle reserved. Allrights copyright. surveys. ClinExp 2017Nov;47(11):1426-1435.Allergy prevalence of allergic asthma from 1996to and2006 further to 2016-results from population three Increased al. et A, Lindberg M, C,Andersson Stridsman L, Hedman P, Raisanen H, Backman (9) Finland. Respir 2011 Med Oct;105(10):1449-1456. Helsinki, in study population froma asthma--results incident for risk the doubles rhinoconjunctivitis Allergic E. Ronmark B, Lundback A, Sovijarvi A, Lindqvist M, Juusela P, Pallasaho (8) onset asthma. JAllergy Clin Mar;109(3):419-425.Immunol 2002 FD, Martinez RA. Barbee DL, Sherrill (7) Guerra S, Survey. JAllergyImmunol Clin Aug;104(2 1999 Pt 1):301-304. Health Respiratory Community European the from results subjects: nonatopic in asthma for factor R, Liard C, Neukirch J, Bousquet B, Leynaert (6) secondary outpatient clinic. Pediatr Allergy Immunol Nov;17(7):524-526. 2006 (5) Gradman J,Wolthers OD. Allergic conjunctivitischildren in with asthma, rhinitis and eczema in a Pediatr Allergy Immunol 2015Aug;26(5):431-437. multimorbidity of asthma,rhinitis and eczema over 20yearsGerman inthe birth cohort MAS. Allergic al. et D, O, Schramm Nitsche N, Eckers A, Reich L, Grabenhenrich H, Gough (4) Feb;139(2):388-399. of Allergy (MeDALL): Introducing novelconcepts in allergy phenotypes.J Allergy Clin Immunol 2017 Development the of Mechanisms al. et I, Momas T, Keil C, Auffray M, J, Akdis Bousquet JM, Anto (3) GINA strategy: a roadmap to asthma control. Eur J2015Sep;46(3):622-639.Respir LP, A, Becker Boulet (2) Reddel HK, BatemanED, the life cycle. Clin Transl Allergy Dec 2016 30;6:47-016-0137-4. eCollection 2016. across asthma and rhinitis in medicine predictive for technologies emerging implementing pathways (1) Bousquet J, Hellings AgachePW, I,Bedbrook A, Bachert C,BergmannARIA etal. 2016:CareKC, cohorts confirm theseresults. to wouldneeded be prospective on research Further cycle. life the across concept important an becomes multimorbidity Al group. age younger the in stronger and was over 30years of age. This association wasgradually increasing withnumberthe of allergic diseases individuals in diagnosed asthma with associated was diseases multimorbid allergic of presence The Conclusion allergic multimorbities occurred befo that hypotheses might we design, study the to given year) (past diagnosed recently was asthma References References re asthmaon most cases. of the Neukirch F. Perennial rhinitis: An independent risk risk independent An rhinitis: Perennial F. Neukirch Cruz AA, Drazen JM, et al. Asummary of the new Rhinitis as an independent risk factor for adult- for factor risk independent an as Rhinitis together our results support that allergic allergic that support our results together Accepted Article This by is protectedarticle reserved. Allrights copyright. Jul;73(7):1447-1458. multimorbidity isassociated with IgE polysensitization in adolescents and adults. Allergy 2018 Theasthma-rhinitis al. et I, Pin A, Boudier C, Lupinek M, Soler N, Ballardini V, Siroux (23) 2016 Oct;138(4):1042-1050. which asthma riskfactors contribute to asthma severitychildren. inner-city in ClinAllergy ImmunolJ (22) Liu AH, Babineau DC, Krouse RZ, Zoratti EM, Pongracic JA, O'Connor GT, Pathways al.et through Thorax Jul;67(7):625-631. 2012 cohort. apopulation-based asthma: non-allergic and allergic of incidence and diagnosis prevalence, in differences Gender al. et I, Cerveri D, Jarvis C, Svanes R, Garcia-Esteban J, B, Sunyer Leynaert (21) asthma is associated with socio-economic low status. Clin Respir J2010Jul;4(3):147-156. K, Larsson E, Ronmark BM, Sundblad L, Ekerljung (20) infections and risk the of asthma: alongitudinalover study years.37 Sep;142(3):647-654. Chest 2012 (19) Burgess JA,MJ,GurrinGB, LC,Matheson Abramson Byrnes MC,al. May CL, et Childhood Finland. 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Incidence and prevalence of adult adult of prevalence and Incidence B. Lundback Accepted Article This by is protectedarticle reserved. Allrights copyright. for presented are asthma of adult-onset and 95%CI OR Adjusted Forest plot summarizing the associations betweenallergic disease(s) and adult-onset asthma. Figure 2. region. living and age, from Na were drawn controls Two reimbursement. that asthmatics, diagnosed (in 2 years) recently old, years 30 over were register Reimbursement Drug Finnish the the from drawn Asthmatics population. study the of chart Flow 1. Figure May;133(5):1484-7, 1487.e1-5. asthma and allergic disease and mortality: a30-year follow-up study. J Allergy Clin Immunol 2014 (32) Savage JH, MatsuiMcCormack EC, M,Litonjua AA, Wood RA, Keet CA. The association between 2017. Print Apr. 2018 medications and poor asthma prognosis. RespirEur Apr J2018 12;51(4):10.1183/13993003.02114- Multimorbidity al. A, et Fournier N, Le Moual TemamS, I, Pin M, Sanchez S, Chanoine (31) population-based cohort study. Lancet Respir Feb;2(2):131-140. Med 2014 eczema, rhinitis, and asthma in IgE-sensitised of Comorbidity al. et KC, Carlsen D, Berdel BergA, von I, Annesi-Maesano M, M, Benet Pinart (30) 23;363(13):1211-1221. consortium-based genomewide association study of asthma. NEngl J Sep 2010 Med large-scale, A al. et S, Heath E, Bouzigon DP, Strachan F, Demenais IG, Gut MF, Moffatt (29) wheezing infants ischallenge. a still ISRNAllergy 2011 Jul 27;2011:493624. Ju A, Labbe I, Petit B, Pereira A, Vial F, Amat (28) Prediction and Prevention.Front Pediatr 2017Jul 31;5:166. Asthma in Allergen to Sensitization of Role The K. Douros S, Tsabouri I, Loukou M, Moustaki (27) Dec;27(8):831-837. with allergicmultimorbidity PARIS birthin cohort infants. Pediatr Allergy Immunol 2016 associated is polysensitization Early I. Momas N, Seta J, Bousquet R, J, Couderc S, Just Gabet (26) Clin Immunol 2016Apr;16(2):165-171. Allergy Curr Opin disease. allergic of development and microbiome The HA. Boushey Lynch SV, (25) Nov 25. rhinitis and conjunctivitis multimorbiditieswith molecular IgE sensitization inadults. Allergy 2018 asthma, between Association J. Bousquet R, Valenta C, Lupinek R, A,Nadif Boudier V, Siroux (24) and region, smoking, growing in countryside, childhood pneumonia/hospitalization due to infection, infection, to due pneumonia/hospitalization childhood countryside, in growing smoking, and region, age gender, on adjusted were Models diseases. of allergic numberfor the and group) and byage

and non-IgE-sensitised children in MeDALL: a a MeDALL: children in non-IgE-sensitised and st J. Predicting the long-term course of asthma in in ofasthma course long-term the Predicting J. st had received the right for asthma medication tional registers and were matched for gender, gender, for matched were and registers tional ≥ 1 allergic1 disease (in all,gender by

Accepted Article This by is protectedarticle reserved. Allrights copyright. and birth order. The total number of asthmatics is 930and matchedcontrols is1289. smoking,education parental asthma/allergy, parental level, professional training, number of siblings, ofsiblings, number training, professional level, Childhood spent in farm or countryside countryside or farm in spent Childhood smoking or paternal toChildhoodexposure maternal order Birth Number of siblings Parentalasthma orallergy Smoking Allergic dermatitis Allergic conjunctivitis Allergic rhinitis Control Yes Yes Yes No No 451 Yes No ≥ 2.-3. 1. ≥ (25.7) 2-3 0-1 Ever Never 268 No No (24.3) Accepted ArticleYes No 4. 4 This by is protectedarticle reserved. Allrights copyright. Table 1. Association between self-reported demogr self-reported between Association 1

1

1

2 344 (20.2) 1359 (79.8) 416 (23.5) 1356 (76.5) 354 (20.0) 1418 (80.0) 513 (29.8) 712 (41.3) 497 (28.9) 752 (43.0) 586 (33.5) 409 (23.4) 925 (53.3) 810 (46.7) n (%) (n=1772) 463 (26.1) 1309 (73.9) 871 (49.2) .901 (50.8)

aphic factors and asthma diagnosis. diagnosis. asthma and factors aphic 400 (36.7) 689 (63.3) 378 (33.8) 740 (66.2) 443 (39.6) 675 (60.4) 319 (29.4) 450 (41.5) 316 (29.1) 486 (44.6) 356 (32.7) 248 (22.8) 671 (61.3) 423 (38.7) n(%) (N=1118) Asthma 561 (50.2) 557 (49.8) 582 (52.1) .536 (47.9)

2.42 (2.01-2.92)2.42 1 1.68 (1.42-2.00)1.68 1 2.59 (2.18-3.08)2.59 1 1 (0.80-1.21)0.98 (0.81-1.19)0.98 1 (0.91-1.38)1.12 (0.82-1.26)1.02 1 (1.15-1.61)1.37 1 OR 2.84 (2.40-3.36)2.84 1 1.11 (0.95-1.30)1.11 1 a (95% CI) CI) (95%

medication asthma current with asthma Doctor-diagnosed Asthma symptoms, (%) n Age at onset of asthma symptoms, n (%) n symptoms, asthma of onset at Age Severe asthma Training Education level The place of physician-diagnosed asthma, n (%) n asthma, physician-diagnosed of place The Severe childhood infections childhood Severe

Yes 1305 (74.3) 833 (75.7) 1.13 (0.94-1.37 1.13 833 (75.7) 1305(74.3) Yes Yes No Severe Moderate None to mild Hospital care Primary Yes No No Courses /Trade school Professional college /University Primary school or less equivalent / school Secondary Baccalaureate Accepted adulthood In Over 15yof age At school age In childhood Article This by is protectedarticle reserved. Allrights copyright. 1 have either of the asked relatives (mother or father). relatives or (mother father). have eitherof asked the severe asthmasevere symptomsregular harmcaused AND ( by asthma AND before or during school age and/or hospitalization due to infection at at infection to due hospitalization and/or age school orduring before self-reported allergic disease ever, 8

4 -110 - - (10.0) 5,7 3 5,6 2

missing value= The subject responded that he/she does not does he/she that responded subject The value= missing 5,7 - 260 - 283 23.3) (25.6) 389 (23.3) 798 (47.7) 485 (29.0) 961 (55.4) 429 (24.7) 344 (19.8) - 37 (3.4) 24 (1.4)24 1669 (98.6) 214 (12.4) 1515 (87.6)

3 Severe childhood infections = Pneumonia Pneumonia = infections childhood Severe 120 (10.7) 725 (64.8) 822 (74.4) 260 (25.5) 521 (51.1) 239 (23.4) 661 (60.7) 272 (25.0) 156 (14.3) 992 (91.9) 23 (2.1) 28 (2.6) 1056 (99.1)1056 10 (0.9) 198 (18.4) 881 (81.6)

≤ 3 yrs of3 yrs age. ≥ 1 peroral corticosteroid - - 1.51 (1.17-1.93)1.51 (1.11-1.65)1.35 1 (1.37-2.25)1.76 (1.10-1.83)1.42 1

- 107.5 (63.8-181.2) 1 1.16 (1.31-2.04)1.16 1 4 Self-reported

Accepted Article This by is protectedarticle reserved. Allrights copyright. night due to asthma at the AND/OR wakeupin months 12 past during the asthma to due corticosteroids course/regular was 13. of missingresponses from asthmaticswas 38. region. and age gender, for adjusted ratio odds 8 The numberThe of missing responses from asthmatics was 52and from nonasthmatics 79.OR ≥ 1/week). 1/week). 5 The questions were asked only from the asthmatics. asthmatics. the from only wereasked questions The 7 The number of missing responses from asthmatics fromasthmatics responses missing numberof The 6 The number number The a = Controls eee 7(37 0(36 31 (1.88- 3.18 (63.6) 70 (33.7) 57 (2.29- 2.73 Severe 675(67.0) 485(30.3) Mild-moderate status severity asthma By Gender By Total By age group group age By

Accepted (1.40- 1.91 142(49.5) 154(33.8) (2.02- 2.65 250(65.3) > 62years (2.93- 3.93 256(41.0) 353(78.8) 50-62 years 350(50.6) (1.82- 2.37 227(53.5) < 50years 218(33.7) (2.48- 3.08 518(74.6) Males 542(48.2) ArticleFemales controls. seve andasthma age by group gender, stratified This by is protectedarticle reserved. Allrights copyright. Allergic disease 1772. is controls matched and 1118 is asthmatics of number The total Table 2. rhinitis,conjunctivitis, allergic allergicdermatitis. OR region; OR Association of b = adjustedfor gender, age region, as welland as for selected covariates: smoking, disease allergic with

745 760 (42.9%) n (%) n (%) 1 = presence of at least one of the following self-reported diseases ever:allergic following diseases self-reported ofthe one presence least at of = 1 ≥ ≥ 1 allergic disease with adult onset asthma, in the whole population and and population whole the in asthma, onset adult with disease allergic 1 1 disease allergic (66.6%) s with Asthmatic n (%) n (%) 1 ≥ 1 2.62) 3.48) 5.34) 3.09) 3.83) 3.28) 2.78 (2.35- 5.40) 3.26) OR a (95% CI) rity. The reference group for OR-values are the groupfor OR-values reference The rity. a = odds ratio adjusted for gender, age and and age gender, for adjusted ratio = odds

2.80 (2.14-3.66) 2.60 (2.11-3.19) OR 4.90 (1.95-12.32) 2.56 (2.06-3.19) 1.68 (1.04-2.71) 2.44 (1.74-3.42) 3.52 (2.51-4.94) 2.40 (1.70-3.39) b (95% CI)

Accepted Article This by is protectedarticle reserved. Allrights copyright. trend: p for ≥ ≥ interaction: p for order. birth asthma/allergy, parental smoking, education level, parental infection, to due pneumonia/hospitalization childhood countryside, in growing 1 allergic disease* asthma severity status p=.59, adjusted p=.72 1 allergic disease* gender p=.13, adjustedp=.45 ≥ 1 allergic disease* age p=.016, adjusted p=.002 professional training, number of siblings, and and siblings, of number training, professional diseases ofallergic Type Model 2: diseases ofallergic Number Model 1: Controls

AcceptedAR+AC+AD 115 (6.5) (2.26- 3.00 AC+AD 45 147(13.1) 39 (0.87- (2.5) 1.18 AR+AD 64 134 (7.6) (2.14- (3.5) 2.50 3.13 73 (6.9) 77 (3.6) (1.56-AR+AC 192 (10.8) (6.1) 68 (6.5) 3.39 (2.12- Only(2.32- AD 2.78 1 60(3.4) 152(13.6) 373(33.4) Only AC 1012 (57.1) 150 (8.5) (3.32- 4.36 Only AR 189(16.9) No (2.46- 3.09 115 (6.5) Article 259(23.2) (1.71- 2.09 243 (13.7) 297(26.6) 3 1 373(33.4) 402 (22.7) 2 1012 (57.1) 1 0 OR This by is protectedarticle reserved. Allrights copyright. 1 Table 3. wellas forselected covariates: smoking, growingcountryside, in childhood Allergic diseases include allergic rhinitis (AR), allerg a = odds ratio adjusted for gender, age and region; OR region; and age gender, for adjusted ratio odds = 1 1

Association of different combinations of allergic diseases with adult-onset asthma. (n=1772) n (%) n (%)

8 1.) .3 (3.30- 4.33 189 (16.9) (n=1118) Asthmatics

n (%) n (%)

5.72) 3.87) 2.57) 5.70) 4.02) 4.94) 3.98) 1.59) 4.58) 3.65) OR a (95% CI) 2 2

ic conjunctivitisic allergic and (AC), dermatitis (AD). b = adjusted for gender, age and region, as as age forgender, and region, = adjusted

4.26 (3.07-5.90) 2.87 (2.19-3.77) 1.95 (1.52-2.49) 1 OR 4.19 (3.02-5.81) 2.20 (1.28-3.78) 2.81 (1.81-4.35) 3.04 (2.17-4.26) 1.25 (0.87-1.80) 2.35 (1.48-3.71) 2.53 (1.83-3.50) 1 b (95% CI) 2 2

Accepted Article methods. This by is protectedarticle reserved. Allrights copyright. 2 numbe training, professional level, education smoking, parental asthma/allergy, parental infection, to due pneumonia/hospitalization small differences in the estimates between model r of siblings, and birth order. 1 and 2 comes from differences of estimating ofestimating fromdifferences comes and 2 1 Controls allergic diseases followingPresenceof the Accepted (1.42- 1.68 378 (33.8) Article (2.18- 2.59 416 (23.5) 443Model 3: (39.6) AD (2.40- 2.84 354 (20.0) Model 2: 561 AC (50.2) 463 (26.1) Model 1: AR This by is protectedarticle reserved. Allrights copyright. AR=allergic rhinitis, AC=allergic conjunctivitis,AD= allergicdermatitis. OR regression. logistic Table 4. order. birth asthma/allergy, parental smoking, education level, pneumo childhood countryside, in growing smoking, gender, age andregion; OR gender, age Association of each allergic disease with adult onset asthma in all subjects by conditional conditional by subjects all in asthma onset adult with disease allergic each of Association (n=1772) n (%) n (%)

b

(n=1118) (n=1118) Asthmatics n (%) n (%) = adjusted age andregion, gender, for adjusted =

2.00) 3.08) 3.36) OR a (95% CI)(95% professional training, number of siblings, and and siblings, of number training, professional nia/hospitalization due to infection, parental

1.61 (1.31-1.98) 2.37 (1.93-2.91) 2.68 (2.19-3.28) OR as wellas asfor selected covariates: b (95% CI) a = odds ratio adjusted for

Accepted Article