Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. uhdtst hc antb eetdb rdtoa prahs hsapoc a enscesul used successfully been has approach This approaches. within traditional structures latent by identify detected and be hypotheses, cannot prior diseases(7). which without allergic datasets datasets of large such phenotypes of identify resort- analysis to approaches allow emerged methods epidemiologic recently These have novel strategies classifications, disease”(6). between phenotyping consensus-driven one data-driven link airway, mainly to based ing “one classical, and the these of mainly emphasized patterns to concept was additionally addition sensitization the In have classification introduced to guidelines and the according ARIA asthma, patients guidelines, and peren- persistence(6). rhinitis classify ARIA and allergic and to seasonal of severity as made introduction symptoms symptom also of the on pattern were Following temporal attempts the productivity other can co-morbidities(3-5). on and based symptoms Several was activities, its AR daily controlled(2).nial. and of sleep, poorly classification childhood(1) well-being, years are of emotional many they For diseases (QOL), when life chronic especially adolescents, of common and quality most children on the of effect of major one a is have (AR) rhinitis Allergic in phenotypes comorbidities. 4 and identified symptoms have clinical INTRODUCTION We of Conclusion: patterns different with asthma. children with more among coexisting associated was severe were and AR more which and rhinitis are 1. AR, symptoms Mild with Class with respiratory in those p=0.006). children upper those in that 1.36-6.13, school-age to indicating than 95%CI common compared classes, rhinitis, 2.88, 3 more 3 seasonal (OR other Class significantly isolated to 3 in was compared children Class AR 1, in and Class Perennial common p<0.001) in more severe 3.42-9.94, 7.6%). significantly 95%CI (n=39, were 5.83, removed 6.9%) symptoms (OR (n=35, AR adenoids conjunctivitis intermittent 2 and and Class tonsils polysensitization house in grass with with children and AR children (2) among pet common 70.8%); among with statistical (n=361, 8 AR AR conjunctivitis on (3) to and (4) based 14.7%); mono-sensitization sensitization and (n=75, model grass asthma with skin optimal and AR the rhinitis, (1) sensitization as mite (allergic as: allergic had dust selected variables classes of latent was (40%) 17 AR solution history using labeled 205 We four-class set family whom A data fit. asthma, the of Results: within of adenoidectomy). AR, structure history tonsillectomy, latent physician-diagnosed subgroups allergens, family identify with distinct to asthma, performed children identify eczema, concomitant was and to 510 conjunctivitis, (LCA) sensitization analysis aimed recruited allergic class We We symptoms, Latent of patterns asthma. Methods: heterogeneous. with association highly their asthma. ascertain clinically to physician-diagnosed is and AR, (AR) with children rhinitis amongst allergic Childhood Background: Abstract 2021 8, March 4 3 2 1 Yavuz Tolga S. latent by identified analysis rhinitis class allergic childhood of subtypes Four aetp nvriyFclyo Medicine of Faculty University Hacettepe London College Imperial Technology of Institute Bonn Izmir of University Hospital, Children’s 1 ed ke Karakus Oksel Ceyda , 2 da Custovic Adnan , 1 3 and , mrKalaycı Omer ¨ 4 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. ens nteee)adpstv SPT. positive and eyes) the in redness work conjunctivitis: or Allergic school of “ impairment as items. “ and aforementioned sport, present, as the and/or “ was classified of leisure symptoms) or was troublesome activities, weeks) AR of daily consecutive weeks). presence of 4 consecutive and impairment than 4 disturbance, less than (sleep more for items for or “ and week as week a guidelines(6) a days ARIA days 4 to as as according than classified and classified less were season, was present symptoms a (2) symptoms or The the exposure); period of allergens. allergen certain Duration inhalant a after common to sneezing limited to were and SPT they itching positive nasal one least rhinorrhea, At blockage, (nasal symptoms respiratory rhinitis Allergic was height(18)) and outcomes weight, gender, of age, recorded, Definitions to were according efforts analysis. predicted best the percent Three Germany) in as Oberthulba, Society(17). (presented used value Health, Respiratory highest (Nspire European the spirometer the and 100 by USA) Zan recommendations using CA, to performed Fullerton, according were Coulter, tests (Beckman function Pulmonary Counter were Coulter saline from 0.9% determined measurements. and were leucocyte phosphate) ImmunoCAP counts using histamine measured eosinophil was of Blood level mg/ml IgE serum (10 Sweden). Aspergillus) Total Uppsala, Histamine respectively. and AB, controls, avellane, Penicillium, negative (Phadia dog). Corylus and Cladosporium, positive and glutinosa, (Alternaria, as (Alnus weed (cat molds used mix eliator) dander alba) Avena pollen animal Betula and tree and minor, pratensis, Plantago) Ulmus Festuca Taraxacum, alba, perenne, Urtica, Populus Lolium (Artemisia, glomerata, mix house Dactylis including pollen region(16), pratensis, our Poa for aeroallergens pratense, was common ( to symptoms mites (SPT) from troublesome testing dust prick collected of skin were underwent adenoidectomy presence children and All and tonsillectomy work regarding Data or ac- AR. records. school daily of medical severity the of of the assessed impairment impairment define were disturbance, to sport, exposures collected sleep environmental and/or on and leisure Information diseases tivities, allergic questionnaires. of be interviewer-administered diagnoses can using doctor’s protocol of medication, study School Symptoms, the Military of Gulhane Details of Pediatric between sources board parents. the AR Data review from to of institutional obtained presented diagnosis the was a who by consent received elsewhere(15). 17 approved informed and found was to Medicine written study 2011 5 of and The in School aged Medicine Military established children 2017. Gulhane study consecutive and of cross-sectional 2011 510 Unit a Asthma recruited is and We (GAARS) Allergy Study Turkey. Rhinitis Ankara, Allergic in and Asthma Gulhane The participants and setting design, with Study association their asthma. ascertain physician-diagnosed to concomitant and and METHODS AR, sensitization with allergic children symptoms, amongst of subgroups patterns distinct clinical identify to aimed We 14). dermatitis(12), adults(13, atopic in 11), sensitization(10, rhinitis allergic allergic asthma(9), and wheezing(8), childhood of subtypes identify to emtpaodspteronyssinus Dermatophagoides a igoe yapdarcalryseils sn h olwn rtra 1 urn upper Current (1) criteria: following the using specialist allergy pediatric a by diagnosed was enda h rsneo urn clrsmtm taig unn,icigand itching burning, (tearing, symptoms ocular current of presence the as Defined and emtpaodsfarinae Dermatophagoides 2 “perennial“ moderate/severe hnte curdtruhu h year. the throughout occurred they when Persistent mild Intermittent nptet ihoeo more or one with patients in ” ,gasple i (Phleum mix pollen grass ), hnnn fteseverity the of none when ” peetmr hn4 than more (present ” tesymptoms (the ” “seasonal” when Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. n ojntvts(=5 .% n 4 Raogcide ihtnisadaeod eoe (n=39, removed adenoids and tonsils classes with latent polysensitization children of grass AR characteristics among and (2) Clinical pet AR 70.8%); with (4) (n=361, AR and (3) conjunctivitis 14.7%); 6.9%) and 7.6%). (n=75, mono-sensitization (n=35, asthma grass and conjunctivitis latent with sensitization the and interpretation, mite AR clinical dust and (1) optimal five-class=6568). this house the on four-class=6496, as: with as Based solution three-class=6512, labeled classes. four-class across were two-class=6552, variables a classes of (BIC: selected distribution We the fit shows class. with 2 statistical membership models Figure analysis likely on class most latent based on of sequence model based a classes over phenotypes five- AR to into two- children of assignment 1). shows (Table 1 Figure asthma AR with with children children among of asthma. lower classes significantly with Latent were those p=0.001) 5%, function in lung vs. p=0.001) vs. (13% of without %, (71 sensitizations children measures 4.9 mold conjunctivitis in All and vs. frequent coexisting p=0.01) % more and %, p<0.001), (13.2 17.4 were demographic 67%, common p=0.005) vs. the 90%, more % (26.8 were vs. summarizes vs. mite Persistent (48 dust (81 1 house asthma. sensitization AR Table whereas coexisting pollen asthma, moderate-severe grass without asthma. and and 35 and had p=0.012) p<0.001) with population; 80%, those years) 73%, study among 2.9 of and vs. +- participants, (40% (52 this 9.8 all children moderate-severe in of patients; 205 recruited (12.4%) characteristics were 63 male AR. clinical years) persistent, 180 persistent [+-3.1] mild 10.5 and moderate-severe (18.0%) SD] 92 (46.7%) female [+- intermittent, age 238 mild mean had and [69%]; (22.9%) intermittent, male 117 (352 these, AR Of with study. children 510 of total A statistics Descriptive (http://www.r-project.org/). (OR) R and ratio (IBM, 8, v21.0 odds MPlus Statistics TX), The SPSS Station, RESULTS using rhinitis. College adjusted performed (StataCorp, allergic were 16 models Stata of Analyses regression USA), reported. history IL, were using Chicago, maternal (CI) examined interval and interpretability. confidence was gender and 95% outcomes BIC, and including lowest clinical confounders, the with potential on and classes for based iterations The LCA-driven selected 000 (BIC). was of 100 classes criterion Association with of information parameters, number Bayesian relevant we optimal estimate the classes, The to using 2 replications. used including classes 500 was model of algorithm latent numbers maximization a sensitization increasing expectation with skin with rhinitis, Starting (allergic allergic models adenoidectomy). variables of tonsillectomy, compared 17 history allergens, using family common clusters asthma, 8 clinical of of to history patterns family identify asthma, to eczema, performed conjunctivitis, was (LCA) chi-square analysis the class and variables. Latent continuous, categorical the total for student for test using and appropriate as Fisher out as counts carried or expressed test (eosinophil comparisons Wallis test were Kruskal Group data or (IQR). measures) ANOVA continuous ranges U-test, interquartile function distributed Mann–Whitney and not-normally lung median as and diagnosis, values) deviation, IgE at standard age and (age, mean data continuous Normally-distributed Methods Statistical asthma Parental corticosteroids(19). oral sensitization: or Allergic inhaled with therapy of dermatitis: trial Atopic a to response positive a and/or FEV of (improvement responsiveness asthma: Physician-diagnosed and urn rrtsadarlpigezmtu ahtpclyfudoe eo surfaces. flexor over found typically rash eczematous relapsing a and pruritus Current aetlalri rhinitis allergic parental P enweldaee tlat3m rae oprdt h eaiecontrol. negative the to compared greater mm 3 least at diameter wheal mean SPT enda urn ypos(heeadcuh n oiiebronchodilator positive and cough) and (wheeze symptoms current as Defined 1 y1%o oefloigamnsrto f20mgsalbutamol), mcg 200 of administration following more or 12% by eedtrie yqetoniea enrollment. at questionnaire by determined were 3 ´ t-test, s Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. ihmdrt-eeepritn Rwssbtnilyhge norchr oprdt rvoschildhood patients previous of to proportion compared of the cohort that our 51.7% the note in However, in We higher children. present substantially higher. Spanish were was 1275 significantly male AR conjunctivitis in was persistent However, 53.6% and childhood cohort moderate-severe of our AR, previous prevalence with 31%). AR. in a with with with vs conjunctivitis reported children agreement patients have of (69% Italian al.(21) prevalence our In girls et 1200 amongst Ibanez the severity. co-morbidity included whereas outnumbered (76.5%) have AR them, frequent boys al.(3) or most study, et presence males the our Zicari more was asthma In affect conjunctivitis with to allergic continues years(20). associated adolescence, studies, AR 20 In not females, of toward boys. was shifts prepubertal age gender that in the prevalence frequent to eczema more and are up similar diseases asthma allergic to with contrast and population atopy in to that study us well-established enabled is large It LCA a SPT. from as data such AR. with of measures Interpretation children availability objective in the and clusters clinical diagnosis is novel inaccurate clinical identify study (e.g. well-defined our parents a study of characteristics, the advantage of interviewer). may responses and key this the respondent our The that in between in and interaction bias allow used and/or introducing questionnaires, by would information We exposures interviewer-administered results misreported environmental that using the recall, time. and of evaluation reporting over accuracy use parental monitored longitudinal the medication on be reduce of symptoms, based to absence of are functions the definitions pulmonary models and that is acknowledge progression study disease also cross-sectional in trends this phenotype-specific of limitation One gender male 39 with were strengths associated children was there and pattern 35 Limitations This cluster, included pollens. third cluster grass the fourth with symptoms. along The seasonal In group, dogs and and/or this Adenoidectomy. cats AR perennial. In & to the Tonsillectomy sensitized and asthma. in (6.9%) underwent intermittent co-existing allocated who milder, were and (%7.6) (14.7%) sensitization significantly children children mite were 75 dust symptoms classes. house coexisting AR of other predominantly prevalence all by the Although seasonal), to characterized (albeit symptoms. compared class class lower ocular latent population) clinical this significantly concomitant study in was had sensitization, severe the asthma most and of allergic the pollens (70.8% were of children symptoms grass airway 361 to patterns upper of monosensitized children different consisted predominantly of class by were largest subgroups who characterized The distinct optimal classes comorbidities. The identify AR. and latent physician-diagnosed to presentations with four analysis patients well-defined identified class clinically of latent solution number large performed a in we rhinitis study, allergic cross-sectional this In findings Key rhinitis seasonal classes, isolated 3 1, asthma. with other Class children coexisting to DISCUSSION in and among compared children 1, rhinitis severe Class with among more those in those are common severe to in symptoms more more compared than was respiratory significantly 3 AR was upper Mild Class clusters. rhinitis that other in p=0.006). allergic indicating to children 1.36-6.13, of assigned in 95%CI children history to Class common 2.88, Maternal compared and OR more p<0.001) 1. significantly conjunctivitis; 3.42-9.94, Class were and 95%CI in in symptoms 5.83, polysensitization children OR AR grass among asthma; 2.51, intermittent and common OR and and pet more conjunctivitis; sensitization with and significantly mite polysensitization dust (AR and grass house 3 markedly and with was pet (AR AR with 2 (AR Perennial Class family classes. 3 in latent Class the p=0.03). differences four logistic in significant the as 1.08-5.80, between found be multinomial well 95%CI conjunctivitis We to the allergic as likely 3. and severity, of more Table AR, were of and in results Boys patterns shown duration The temporal are and its classes severity class. AR, different duration, latent the between of each diseases pattern allergic in temporal of patients history the of comparing features analysis clinical regression the shows 2 Table 4 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. a copn rs olnsniiainepcal nby.Arfra ooohnlrnooiti order in otorhinolaryngologist to referral sensitization A Pet children. boys. such in sensitizations. in especially mold immunotherapy sensitization and allergen pollen mite the grass dust of therefore, and accompany house initiation monosensitization, queried pollen with can early grass be children with consider children should in in can symptoms expected especially physicians be Asthma should performed symptoms findings. persistent be and our Severe can our were from surgery. tests cluster in the extracted this function demonstrated to be in lung due not children can relieved association the was implications that be an relationship clinical be could Several may this found severity association However, symptom have this the al.(33) of children. and lack et in operated the for already with AR Dogru explanation compared of plausible when severity higher The conjunctivitis. significantly adenoidectomy study. the hypertrophy with was and and adenoid patients molds tonsillectomy AH for to underwent grass-sensitized between factor sensitization who the risk finding, children in this rhinitis(21, a of with allergic as patients consisted agreement with sensitization cluster In children mold our 33). in reported in AR(32, co-morbidities have with frequent studies children most previous in the of associated of Results was one 31). sensitization is in pet (AH) greater findings, hypertrophy were our Adenoid symptoms. hyperreactivity with AR bronchial accordance perennial of in AR and severity However, milder the with with and sensitization. children prevalence characteristics, grass pet in clinical asthma with vs. and agent findings, children co-morbidities monosensitization our sensitizing the pollen to prevalent compared (grass contrast they most groups in cohort When without second sensitization birth patients, polysensitization)(4). the Asthma major of pets two were Childhood 2.5% pollen/furry documented and cat) in al.(30), investigators Environment only and et the the sensitization (dog Konradsen and in with pet However, children allergens of of in prevalence symptoms. study pet allergy the AR study, pet the to reported and of In relevance al.(3) dog features clinical cat, the et investigated including any asthma(29). Zicari which animals for limited. studies furry towards the factor is antibodies of AR risk IgE number of the major period. levels Nevertheless, related a time higher more horse. had limited as be asthma a severe regarded can during with association is allergens only children significant to occurs pets a which findings, exposure to was exposure their perennial Allergy pollen there with that to and accordance speculated compared have group, In when al.(4) this asthma, allergy(28). et to in outdoor Bertelsen reduced with prone significantly asthma. more those were are with allergic sensitization than sensitizations parameters pollen our HDM co-morbidity with function grass whilst a patients and investigator-led-assignments lung that as concluded HDM on asthma have between based have al. severity are to et and Boulet studies pattern contrast data-driven. these are HDM temporal in of patterns AR, of - results with and terms Zicari The by adults results), in study children(3). our 591 found the with was included In (consistent which difference in rhinitis. symptoms al.(24) no lower persistent sen- milder - was et mold and data sensitization Bousquet found our and perennial by have pollen to with HDM study grass associated of al. cross-sectional whereas was prevalence et the asthma allergy the Chiu In with study, study, children group. our recent in significantly this In a higher were significantly In which development(27). was metabolites asthma 26). sitizations urinary one childhood various children(25, as and with in Aspergillus, sensitization asthma associated and HDM for HDM between factors to association particularly risk significant sensitization, independent symptoms aeroallergen the rhinitis indicated of the studies studies, asthma(24). several asthma-oriented without of children the Results has in with adolescents and persistent contrast children and in in study, severe symptoms rhinitis AR more our the uncontrolled of were In pattern and emphasized However, persistence investigated. severe predominantly and that 23). been severity adolescents(22, have shown the rarely and on been children studies present asthma has in of epidemiological was asthma it impact uncontrolled and asthma the Previous and severe asthma, data, with of associated previous 21). symptoms were with on symptoms 19, AR Consistent patients(3, of hyperre- effect stimuli(6). our bronchial worsening occur of of increased frequently variety that 40% including a diseases features in to common immunopathological reactivity are symptoms. common and asthma ocular and share sponsiveness with AR patients those 5 tal. et hc nldd21 pns hlrnwt AR, with children Spanish 2319 included which Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 5 au T ibr ,Ai ,Asa ,CvlkE ac .Prntlrs atr o shai children in asthma for 2018;39:1-7. factors Proc risk Asthma Perinatal Allergy S. Bagci sensitization. E, pollen Civelek grass cluster 2015;166:231-40. M, and Immunol of Arslan rhinitis relevance O, Allergy allergic Akin Arch Clinical S, with Int J. Siebert study. Bousquet ST, P, real-life Yavuz a Demoly 15. in K, in rhinitis Mesbah Status allergic Asthma A, phenotyping 2015;10:e0136191. Tadmouri the P, in One to Devillier analysis PLoS According PJ, Study. Rhinitis EGEA Bousquet of the Characterization 14. in from al. Approach dermatitis et Unsupervised atopic 2018;48:48-59. R, an Varraso Allergy and Using J, Exp sensitization Adults Bousquet Clin allergic E, of diseases. Burte Patterns allergic 13. on asthma: al. Effects with et years: associations MM, Tran 3 their to to DL, and relation 1 Lefebvre phenotypes in C, atopy 2013;68:764-70. sensitization Dharma Multiple Allergy of 12. al. cohorts. patterns et birth multiple A, 2010;181:1200-6. two Custovic Med from atopy: G, Care findings Beyond Crit similar Roberts Respir N, al. J Lazic under- Am et 11. for study. J, insights cohort Winn meaningful birth provide VY, a which Tan in asthma asthma A, of Simpson Features 2018;48:39-47. Allergy wheeze. al. 10. Exp childhood et Clin of M, heterogeneity. phenotypes Sperrin disease latent From TS, the in Yavuz standing variability Asthma: M, of Deliu Pediatric Causes of 9. al. et Classification 2019;143:1783-90.e11. O, Immunol A. Mahmoud Clin Custovic R, Allergy Granell J C, C, Frainay Oksel 2018;6:258. S, Pediatr 8. Front Fontanella Practice. S, Clinical Suppl Haider to 2008;63 Discovery C, Allergy Phenotype Oksel update AllerGen). 2008 (ARIA) and Asthma 7. on GA(2)LEN Impact Organization, its and Health Rhinitis World Allergic the 86:8-160. al. with et impact AA, collaboration their Cruz and N, (in Khaltaev rhinitis J, of Bousquet endotypes 2015;70:474-94. Pediatr and 6. Allergy Phenotypes report. phenotypes. al. PRACTALL et and a P, co-morbidities Demoly management: JA, on Curr children: Bernstein NG, in children. Papadopoulos in Rhinitis 5. rhinitis KH. allergic Carlsen of KC, features 2010;21:612-22. Carlsen Immunol on Allergy survey RJ, A Bertelsen al. 4. et G, Castro 2013;29:415-20. De Opin and L, Res rhinitis Indinnimeo Med allergic AM, 2018;121:43- of Immunol Zicari burden Asthma The 3. Allergy S. Ann Buchs review. in T, literature expenditures Kennedy-Martin e3. A care 52 S, adolescents: health Robinson on on E, rhinoconjunctivitis diseases Hammerby allergic chronic MS, multiple Blaiss of 2015;6:2-9. Effect 2. Health al. Community et Care and ND, Prim Shah computer J DM, includes childhood. Finnie which W, Zhong team, 1. study the of dedication cross- References and work this nurses. hard in and the LCA technicians, acknowledge laboratory using comorbidities. to AR and like with symptoms also clinical children of of patterns subgroups different Acknowledgements: with different associated treatment- four were and identified which severe study, have sectional with we children conclusion, in In particularly considered snoring. and be obstruction should nasal hypertrophy resistant adenoid exclude to eaeeteeygaeu oaltefmle h okpr nti td.W would We study. this in part took who families the all to grateful extremely are We 6 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. 3 or ,EcmkM,ClmO.De dni yetoh ffc ies eeiyi hlrnwith children in 1. severity Table disease affect hypertrophy adenoid Does Tables 2017;274:209-13. Otorhinolaryngol OF. Arch Allergy Calim Eur Ann MF, rhinitis? rhinitis. Evcimik allergic allergic M, with Dogru children in 33. hypertrophy disease adenoid allergic of with risk 2001;87:350-5. The children Immunol C. in Asthma Giannoni hypertrophy SW, Adenoid 2015;79:694-7. Huang Otorhinolaryngol MI. 32. Pediatr Nepesov asthma J AA, childhood Int Cirik Severe factors. M, influential G. Allergy Dogru and Pediatr Hedlin MF, diagnostics. Evcimik H, allergy Gronlund 31. molecular-based MP, using Borres assessment refined A, 2014;25:187-92. 2002;166:696-702. animals: Onell Immunol Med furry B, Care to Crit Nordlund allergy Respir JR, and J sensitiza- Konradsen on Am ownership children. dog and preteenage 30. cat among 1997;27:52-9. of asthma Allergy Effect of Exp B. development Lundback indoor Clin TA, and common Platts-Mills asthma. to tion E, sensitization and/or Ronmark of MS, rhinitis Perzanowski type allergic and 29. with degree for Comparative subjects metabolites in al. reveals et allergens profiling C, outdoor Laprise metabolomic and H, urinary 2018;29:496-503. Turcotte LP, Immunol Longitudinal Boulet Allergy al. 28. Pediatr et development childhood. and ML, early 2000;356:1392-7. allergens Cheng in Lancet cat G, development and Group. Lin asthma mite Study CY, house-dust Allergy to Chiu Multicentre exposure study. 27. Early cohort al. a et C, asthma: Sommerfeld childhood 6 S, age of Illi by S, diagnosis Lau 2003;90:41-4. asthma 26. allergen Immunol and mite Asthma hyperresponsiveness house-dust bronchial Allergy of to Ann allergic Relationship infancy CC. 7. persistent in Johnson to and EM, bedrooms Zoratti intermittent children’s DR, of in Ownby EL, exposure Characteristics Peterson 2005;35:728-32. PM, to al. Carter Allergy contribute et Exp 25. factors Clin F, risk group. Carat asthma study I, which DREAMS Annesi-Maesano through rhinitis: 2016;138:1042-50. J, Pathways Immunol Bousquet Clin al. Allergy difficult-to-control et 24. J of RZ, children. characteristics Krouse inner-city Distinguishing DC, in severity 2016;138:1030-41. Babineau Immunol asthma AH, al. Clin Liu Allergy et J DC, 23. adolescents. Babineau and RZ, children inner-city allergic Krouse 2013;24:678-84. in for Immunol JA, asthma approach Allergy therapeutic Pongracic Pediatr and comorbidities Spain. of 22. in Annals Analysis population adulthood. al. pediatric to et a infancy J, in Montoro from AL, rhinitis atopy Valero and MD, Allergy Ibanez T. 21. Keil 2019;122:25-32. YA, Immunology Lee & U, Asthma Wahn Allergy, PM, of Available Matricardi S, 2020. Prevention, Lau and 20. Management 2020). Asthma 27, for Med December Strategy Care (Accessed Global www.ginasthma.org Crit Asthma. from Respir for J Initiative Am Global Society. 19. Thoracic respiratory American European The Update. 1994 spirometry. Spirometry, 1995;152:1107-36. of of Standardisation Standardization to Allergy al. 18. testing Arch et prick Int V, Skin Brusasco Turkey? J, BE. 2005;26:319-38. in Hankinson journal adolescents Sekerel MR, and A, Miller children Tuncer 17. in AB, panel Buyuktiryaki optimal ST, the Yavuz 2012;157:391-8. is Immunol E, what Civelek extracts: UM, aeroallergen Sahiner 16. eorpi aao h td ouainadcmaio codn oasthma to according comparison and population study the of data Demographic 7 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. oiohl (%) eosinophils .29 Blood (kU/L) IgE Total sitization - Molds Dog - Cat - mites dust House - pollens 4.3 Weed - pollens Tree - pollens Grass Sensitization Adenoidectomy & Tonsillectomy - Adenoidectomy - Tonsillectomy - 6.4 dermatitis Atopic - conjunctivitis Allergic conditions Co-morbid rhinitis allergic Paternal - 5.1 rhinitis allergic Maternal - asthma Paternal - asthma Maternal - disease allergic of history Family exposure ETS - exposure Pet characteristics Environmental Moderate/severe Severity Persistent - Intermittent Duration Perennial - Seasonal - pattern Temporal (y) start symptoms AR at Age (male) Sex (y) Age Monosen- id- Mild - - - - - . 2770 . 2374 . 2869 .12 .70 (2.8-6.9) 4.5 (34-170) 96 (2.3-7.4) 4.0 (37-202) 88 (2.7-7-0) 4.3 .62 (34-183) 92 .49 .13 18.4 62.4 2.9 8.4 15.3 26.2 21.1 6.1 8.4 86.7 8.2 16.7 23.5 .27 .41 7.8 14.1 0.001 8.6 < 12.3 11.8 76.5 17.7 <0.001 37.9 12.7 25.1 66.9 33.1 .20 .25 9.8 72.9 27.1 42.9 10.3 48.0 52.0 21.0 79.0 66.9 52.5 47.5 39.9 11.7 59.1 40.9 25.4 74.6 64.7 35.3 72.2 22.8 77.2 7.0 69.0 10.5 (n=510) Population Study ± ± . 6.2 3.1 . 9.8 3.1 61881, 58.5 13,2 8.8 16.1 26.8 3.9 8.3 81.5 7.8 14.1 8.8 14.1 70.7 (n=205) asthma with Children ± ± . 11.0 2.9 . 7.4 2.9 8 48824964.9 4.9 8.2 14.8 17.4 7.5 8.5 90.2 7.9 14.1 8.5 10.2 80.3 (n=305) asthma without Children ± ± . 0.001 < 3.2 . 0.001 < 3.1 6 8 01.15 .001 .82 .68 .01 .09 .93 .005 .98 .98 .92 .17 .012 p* Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. nemtet3. 006. 25.6 28.2 71.8 60.0 52.0 48.0 40.0 34.3 65.7 30.8 15.0 85.0 Intermittent - Duration -Perennial -Seasonal pattern Temporal (y) start symptoms AR at Age (male) Sex (y) Age N 2. Table FEF predicted % PEF FEV predicted % FVC predicted FEV (/mm eosinophils Blood ihu asthma without and with children between difference the denoted p value The *: (%). frequency as given are variables binary and range) (interquartile median or deviation standard and mean as given are variables Continuous smoke. tobacco Environmental = ETS predicted 25-75 1 1 FC% /FVC 3 % ) lnclfaue fptet codn oclasses to according patients of features Clinical % 688. 207. .22 71.8 39 72.0 75 82.9 35 7.0 66.8 10.5 361 %) (70.8 conjunctivitis and sensitization mono- grass with AR 90 94 97 9 1047 9 1358 9 1045 .86 (190-485) 290 90 (173-518) 295 (180-497) 290 ihu asthma without and with children between difference the denoted p value The *: (%). frequency as given are variables binary and range) (interquartile median or deviation standard and mean as given are variables Continuous smoke. tobacco Environmental = ETS 94 ± ± . 6.8 3.1 ± ± ± ± ± . 11.2 3.1 782 89 87 17 13 15 87 7 177 21 69%) (6.9 conjunctivitis and ysensitization pol- grass and pet with AR ± ± . 6.8 2.7 ihu asthma without and with children between difference the denoted p value The *: (%). frequency as given are variables binary and range) (interquartile median or deviation standard and mean as given are variables Continuous smoke. tobacco Environmental = ETS . 10.2 2.9 ± ± ± ± ± 695 91 98 104 16 8 14 13 9108 19 9 1. %) (14.7 asthma and sensitization mite dust house with AR ± ± . 7.2 3.2 . 11.1 2.9 ihu asthma without and with children between difference the denoted p value The *: (%). frequency as given are variables binary and range) (interquartile median or deviation standard and mean as given are variables Continuous smoke. tobacco Environmental = ETS ± ± ± ± ± 6<0.001 < 0.001 < 0.001 < 16 6 11 1<0.001 < 11 0<0.001 < 20 (7.6%) removed adenoids and tonsils with children among AR ± ± . .89 3.4 . .31 3.2 ihu asthma without and with children between difference the denoted p value The *: (%). frequency as given are variables binary and range) (interquartile median or deviation standard and mean as given are variables Continuous smoke. tobacco Environmental = ETS p* <.001 <.001 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. o . 0. . . <.001 <.001 <.001 17.9 2.6 .07 .26 5.1 <.001 17.3 1.3 7.7 7.7 16.0 82.1 20.0 100.0 100.0 0.0 2.7 25.3 .002 4.2 1.7 8.0 11.4 8.6 (kU/L) IgE Total Monosensitization 85.7 43.6 Molds - Dog - Cat - 6.6 mites 9.7 dust House - pollens 100.0 Weed - 60.0 pollens Tree - pollens Grass - Sensitization Adenoidectomy & Tonsillectomy 37.1 0.21 - Adenoidectomy - Tonsillectomy - 36.0 dermatitis Atopic - 8.1 conjunctivitis Allergic - Asthma - 43.6 conditions Co-morbid rhinitis 18.9 allergic Paternal - 74.4 rhinitis allergic Maternal - 53.3 asthma Paternal - 14.3 asthma Maternal - 40.0 disease 42.9 allergic of history Family 10.4 exposure ETS 60.0 - exposure Pet - 37.6 tics characteris- Environmental Moderate/severe 69.2 - Mild - Severity Persistent - 73006. 67<.001 <.001 66.7 .39 <.001 20.5 65.3 (27-160) 58 <.001 <.001 (31-184) 85 82.7 100 0.0 (59-203) .59 118 100 <.001 100 (35-196) 22.9 91 0 67.3 10.3 .88 5.3 69.2 1.3 .005 8.3 .83 5.2 14.7 .23 20.5 11.4 41.3 11.4 10.3 2.6 0 5.7 15.4 16.0 0.12 7.2 85.7 17.3 0 6.7 11.9 8.0 14.3 48.6 83.7 14.3 2.9 18.1 2.9 35.1 56.4 29.4 5.3 10.3 55.9 46.7 38.5 57.1 62.4 10 0.04 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. lse lse lse lse lse lse Classes Classes Classes Classes Classes Classes Classes conjunctivitis) and sensitization 3. Table variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous FEF predicted % PEF % FEV predicted % FVC predicted FEV (/mm eosinophils Blood (%) eosinophils Blood Sex predicted 25-75 1 1 /FVC 3 % ) % nvraemlioillgsi ersinrsls(eeec aeoy Rwt rs mono- grass with AR category: (reference results regression logistic multinomial Univariate ai (95%CI) Ratio Risk Relative asthma and sensitization mite dust house with AR variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous .71 .77 90 (163-390) 255 90 (2.3-5.7) 4.3 (185-465) 300 94 (2.7-6.2) 4.1 97 (190-380) 300 (2.5-6.2) (180-540) 4.2 290 (2.7-7.6) 4.3 95 ± ± ± ± ± 790 89 95 17 99 7 13 15 595 25 eaieRisk Relative p asthma and sensitization mite dust house with AR variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous ± ± ± ± ± 588 89 93 15 93 6 11 14 489 24 11 ai (95%CI) Ratio tis conjunctivi- and zation polysensiti- grass and pet with AR variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous ± ± ± ± ± 791 89 98 17 100 7 12 14 396 23 eaieRisk Relative p tis conjunctivi- and zation polysensiti- grass and pet with AR variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous ± ± ± ± ± 3.72 .48 .24 23 8 13 7.38 27 5.08 15 ai (95%CI) Ratio removed adenoids & tonsils with children among AR variables. continuous for Kruskal-Wallis or variance of analysis one-way and variables categorical for test chi-square using computed are *p-values (%). frequency as given are variables binary and deviation standard and mean as given are variables Continuous p removed adenoids & tonsils with children among AR Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. ls rprin hw ntefiueaecmue ae nms ieycasmembership. class likely most on based computed are figure moving the children in of shown classes. proportions % of Class the number represent increasing arrow an with the 2: models along Figure in values another the to whilst class membership one membership class from class likely show most nodes on Ellipse based classes five and four three, 1: Figure Legends Figure 1.30 gender Male Seasonal) class: (reference pattern Temporal AR Intermittent) class: (reference 5.83 Duration AR Perennial ls:mild) class: (reference Severity 0.29 AR Persistent rhinitis allergic Maternal disease allergic of history Family 0.55 Moderate/severe Rsbye dnie yltn ls nlssi 1 children 510 in analysis class latent by identified subtypes AR sineto 1 hlrnit itntcassoe euneo aetcasmdlwt two, with model class latent of sequence a over classes distinct into children 510 of Assignment (0.75-2.25) Seasonal) class: (reference pattern Temporal AR Intermittent) class: (reference Duration AR (3.42-9.94) ls:mild) class: (reference Severity AR (0.17-0.48) (0.52-0.98) 0.71 disease allergic of history Family (0.33-0.90) .52.51 0.35 Seasonal) class: (reference pattern Temporal AR Intermittent) class: (reference 2.88 Duration AR 0.001 < ls:mild) class: (reference 0.66 Severity AR 0.001 < .40.51 0.04 disease 0.81 allergic of history Family 0.02 12 (1.08-5.80) Seasonal) class: (reference pattern Temporal AR Intermittent) class: (reference Duration AR (1.36-6.13) ls:mild) class: (reference Severity AR (0.32-1.35) (0.33-0.85) disease allergic of history Family (0.40-1-64) .31.26 0.03 Seasonal) class: (reference pattern Temporal AR Intermittent) class: 1.91 (reference Duration AR 0.006 ls:mild) class: 1.28 (reference Severity AR 0.26 .30.28 0.03 disease 0.79 allergic of history Family 0.56 (0.61-2.62) (0.88-4.13) (0.60-2.72) (0.09-0.79) disease allergic of history Family (0.40-1.54) 0.53 0.10 0.52 0.02 disease allergic of history Family 0.49 Posted on Authorea 8 Mar 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161518359.93052043/v1 | This a preprint and has not been peer reviewed. Data may be preliminary.

Allergic Conjunctivitis Frequencies 0,00 0,10 0,20 0,30 0,40 0,50 0,60 0,70 0,80 0,90 1,00 Grass mono-sensitized children with conjunctivitis,Tonsils 68.5% and adenoids removed chidren, 7.7% AR AR AR AR Eczema among with grass Asthma children

Ma ternal asthma mono with - sensitization Paternal asthma tonsils and Ma ternal AR and adenoids conjunctivitis

Paternal AR removed Grass Sensitized , 70.8% , 7.6%

Tree Sensitized 13

We ed Sensitized

HDM-sensitized asthmatics, 17.2% 6.7% conjunctivitis, with children Pet-sensitized Cat Sensitized AR AR AR AR with with

Dog Sensitized mite pet and sensitization

Mo ld Sensitized grass poly HDM Sensitized and - sensitization Cockroach Sensitized asthma , 14.7% and Tonsillectomy conjunctivitis

Adenoidectomy , 6.9%