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1 University of Groningen Qulity of life in children with undignosed nd dignosed sthm vn Gent, R.; vn Essen, L.E.; Rovers, M.M.; Kimpen, J.L.; vn der Ent, C.K.; de Meer, G. Published in: Europen Journl of Peditrics DOI: /s y IMPORTANT NOTE: You re dvised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Plese check the document version below. Document Version Publisher's PDF, lso known s Version of record Publiction dte: 2007 Link to publiction in University of Groningen/UMCG reserch dtbse Cittion for published version (APA): vn Gent, R., vn Essen, L. E., Rovers, M. M., Kimpen, J. L., vn der Ent, C. K., & de Meer, G. (2007). Qulity of life in children with undignosed nd dignosed sthm. Europen Journl of Peditrics, 166(8), DOI: /s y Copyright Other thn for strictly personl use, it is not permitted to downlod or to forwrd/distribute the text or prt of it without the consent of the uthor(s) nd/or copyright holder(s), unless the work is under n open content license (like Cretive Commons). Tke-down policy If you believe tht this document breches copyright plese contct us providing detils, nd we will remove ccess to the work immeditely nd investigte your clim. Downloded from the University of Groningen/UMCG reserch dtbse (Pure): For technicl resons the number of uthors shown on this cover pge is limited to 10 mximum. Downlod dte:

2 Eur J Peditr (2007) 166: DOI /s y ORIGINAL PAPER Qulity of life in children with undignosed nd dignosed sthm René vn Gent & Liesbeth E. M. vn Essen & Mroesk M. Rovers & Jn L. L. Kimpen & Cornelis K. vn der Ent & Ge de Meer Received: 18 September 2006 / Accepted: 25 October 2006 / Published online: 25 November 2006 # Springer-Verlg 2006 Abstrct This study describes the impct of undignosed nd dignosed sthm on qulity of life in schoolchildren ged 7 10 yers nd their cregivers in cross-sectionl community-bsed study. Dignosed sthm ws defined s the prents confirmtion of physicin s dignosis of sthm. Undignosed sthm ws defined by sthm symptoms combined with irwy reversibility or bronchil hyperresponsiveness. Qulity of life ws evluted in ll R. vn Gent (*) Deprtment of Peditrics, Máxim Medicl Centre, P.O. Box 7777, 5500 MB Veldhoven, The Netherlnds e-mil: R.vnGent@mmc.nl L. E. M. vn Essen Deprtment of Peditrics, Asthm Centre Heideheuvel, Hilversum, The Netherlnds M. M. Rovers Julius Center for Helth Sciences nd Primry Cre nd Deprtment of Peditrics, University Medicl Center Utrecht, Utrecht, The Netherlnds J. L. L. Kimpen Peditric Infectious disese, University Medicl Center Utrecht, Utrecht, The Netherlnds C. K. vn der Ent Peditric Pulmonology, University Medicl Center Utrecht, Utrecht, The Netherlnds G. de Meer Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlnds G. de Meer Deprtment of Helth Sciences, University Medicl Center Groningen, University of Groningen, Groningen, The Netherlnds children with sthm nd smple of helthy controls by the Peditric Asthm Qulity of Life Questionnire, nd by the Peditric Asthm Cregiver s Qulity of Life Questionnire. We studied the impct of brething problems on school bsence. Compred with helthy controls, qulity of life scores mong children nd their cregivers were lower if the child hd sthm (P), with lowest scores in dignosed sthm (P compred with undignosed sthm). Children with sthm reported more school bsence (P), with highest bsence rte in those with dignosed sthm. In conclusion, both undignosed nd dignosed sthm hve significnt impct on the qulity of life of both children nd their cregivers. Keywords Asthm. Children. Qulity of life Abbrevitions UDA undignosed sthm DA dignosed sthm HC helthy controls BHR bronchil hyperresponsiveness BD bronchodiltor PAQLQ Peditric Asthm Qulity of Life Questionnire PACQLQ Peditric Asthm Cregiver s Qulity of Life Questionnire FEV 1 forced expirtory volume in 1 s Introduction In Western Europen nd ffluent countries, sthm is the most common chronic disese, with prevlence rtes of up to 32% [1]. Since 1980 numerous studies hve shown tht sthm in children is underdignosed nd subsequently

3 844 Eur J Peditr (2007) 166: undertreted [3, 6, 9, 17, 21, 23]. Recent dt show tht underdignosis is still problem [8]. Chew et l. [5] reported tht 49% of ll children with sthm-like symptoms hd not been dignosed with sthm nd Joseph et l. [10] reported prevlence of undignosed sthm of 11.7%. Informtion bout the qulity of life in children with mild to moderte sthm is scrce. The AIRE (Asthm Insight nd Relity) study showed only prtil effectiveness of sthm cre in dily life [20]. Only 5.8 % of children met ll criteri for sthm control nd over one third of children hd dytime symptoms t lest once week despite dequte tretment. For undignosed sthm, Yetts et l. [24] concluded tht undignosed frequent wheezers report more sleep disturbnces, school bsence nd ctivity limittions thn dignosed sthmtics; however, their study lcked objective mesures to dignose sthm. The present study describes the impct of hving sthm on dily life in community-bsed popultion of schoolchildren with or without physicin s dignosis of sthm. For this we evluted the qulity of life both in children nd their cregivers, s well s the occurrence of sthm symptoms nd their effect on school bsence. Mterils nd methods Popultion nd study protocol The study ws conducted in 41 out of 44 primry schools in four cities in the south of the Netherlnds. We sked ll children ged 7 10 yers nd their prents to prticipte in our study. All prticipting prents completed questionnire on respirtory symptoms, demogrphic nd household chrcteristics. All prticipting children were invited for lung function testing with ssessment of reversibility to slbutmol. Children with sthm symptoms in the pst 12 months or reversible irwy obstruction were invited for bronchil chllenge with hypertonic sline. Bsed upon results from questionnires, irwy reversibility nd bronchil hyperresponsiveness (BHR) children were identified s dignosed sthm (DA), undignosed sthm (UDA), helthy controls (HC), symptomtic irwy reversibility, or sthm symptoms only. Qulity of life ws ssessed in ll children with sthm (dignosed nd undignosed) nd smple of helthy controls tht were rndomly selected from the sme clss s children with sthm. Prents received letter with the results of the symptom questionnire nd lung function 2 weeks fter finishing the study protocol. Approvl for the study ws obtined from the centrl Committee on Reserch involving Humn Subjects (CCMO) in the Hgue, the Netherlnds. Informed written consent ws obtined from the prents of ll children. Questionnire Prents completed questionnire tht included the ISAAC core questions on symptoms of sthm, rhinitis nd eczem [2]. Additionl dt were collected on household chrcteristics. Asthm symptoms were defined s wheeze or dry cough t night in the pst 12 months. Spirometry nd reversibility Mximl flow-volume curves were mesured using hnd-held spirometer (Vitlogrph, Buckinghm, UK) ccording to the ERS guidelines [18]. A minimum of two techniclly cceptble bseline flow-volume curves were performed nd the highest of two reproducible (within 5%) mesurements of forced expirtory volume in 1 s (FEV 1 ) ws recorded s bseline FEV 1. Subsequently, 800 µg of slbutmol ws dministered vi metered dose inhler using volumtic spcer (GSK, Uxbridge, UK). Airwy reversibility ws defined s n increse of FEV 1 of 10% of the predicted vlue 10 min fter dministrtion of slbutmol. Hypertonic sline testing Bronchil hyperresponsiveness ws ssessed by inhltion chllenge with nebulized hypertonic (4.5%) sline using n ultrsound nebulizer (Klv 2000/4000, Klv Eltromed, Bielefeld, Germny) ccording to the ISAAC protocol. BHR ws ssessed on different dy thn the spirometry [22]. All children were sked to withhold ll sthm medictions for t lest 12 h beforehnd. Children with bseline FEV 1 75% were excluded. The children inhled the sline for periods of incresing durtion: 0.5, 1, 2, 4, nd 8 min. FEV 1 ws mesured 1 min fter ech inhltion period nd the next inhltion period strted fter 3 min. Bronchil chllenge ws stopped if FEV 1 hd fllen t lest 15% from bseline or if the totl inhltion period of 15.5 min hd been completed. A child ws defined s hving BHR if FEV 1 hd dropped by 15% from bseline during the inhltion chllenge. Dily impct of sthm Qulity of life ws mesured with the Peditric Asthm Qulity of Life Questionnire (PAQLQ) for children, nd with the Peditric Asthm Cregiver s Qulity of Life Questionnire (PACQLQ) for their cregivers [11, 12]. For both questionnires scores rnge from 1 to 7, with 7 indictive of mximl qulity of life. The PAQLQ consists of three domins, i.e. emotions, ctivity nd symptoms. The PACQLQ consists of two domins, i.e. the emotions domin nd ctivity domin.

4 Eur J Peditr (2007) 166: School bsence becuse of respirtory disese ws evluted by the question: How often ws your child bsent from school due to brething problems in the lst 12 months? Additionlly, children completed 5-dy diry ddressing the following question: Did you feel different or left out tody becuse of shortness of breth, coughing or wheezing? Definitions A child ws considered hving dignosed sthm if the prents confirmed tht their child hd physicin-dignosed sthm in the lst 12 months. A child ws considered hving undignosed sthm if the child hd (1) no physicindignosed sthm in the lst 12 months, (2) sthm symptoms (wheeze or dry cough) in the lst 12 months, nd (3) either hd reversible irwy obstruction or BHR. Helthy controls (HC) hd no sthm dignosis or symptoms in the lst 12 months, nd no reversible irwy obstruction. The reminder children comprised those with symptomtic irwy reversibility (irwy reversibility without sthm dignosis or symptoms), nd children with sthm symptoms only. Dt nlysis All dt of the questionnires were double-entered into the dtbse using Microsoft Access softwre. Chi-squre tests nd ANOVA with Bonferroni post-hoc test were used to nlyse differences between the groups. Dt were nlysed using the sttisticl pckge SPSS version Results Prticipnts Of 44 eligible schools, 41 prticipted in the study. Resons for non-prticiption were recent involvement in nother study (n=2) nd school policy never to prticipte in medicl studies (n=1). We invited 2,745 children nd their prents to prticipte in the study in the period September 2002 to April 2005, of which 1758 (64%) gve informed consent to prticipte. We excluded 144 children from further nlysis; resons for excluding were missing questionnire dt (n=60), refusl to prticipte in bronchil chllenge testing (n=31), not completing the bronchil chllenge test due to nuse or coughing (n=3) or inbility to meet technicl conditions (n=50). Dignosis nd demogrphics The finl study popultion comprised 1,614 children, of whom 81 (5.0%) hd dignosed sthm nd 130 (8%) undignosed sthm ccording to our criteri. Asymptomtic irwy reversibility occurred in 14% nd 19% hd sthm symptoms only. Of the remining helthy controls, we rndomly selected 202 children for ssessment of qulity of life. Tble 1 presents the chrcteristics of the study popultion. Children with dignosed sthm more frequently hd fther with sthm compred with the children with undignosed sthm (P) nd helthy controls, wheres hving mother with sthm occurred more frequently in children with both dignosed nd undignosed sthm (P<0.001). Tble 2 presents clinicl chrcteristics of the ptient groups. Wheeze in the lst 12 months occurred most frequently in dignosed sthm (86%) compred with undignosed sthm (56%) nd helthy controls (0%) (P<0.001 for ll comprisons). In contrst, children with undignosed sthm hd the lowest bseline FEV 1, which showed the gretest increse fter inhltion of slbutmol (9%, 5%, 2%, respectively; UDA vs HC; P<0.001, UDA vs DA; P=0.07). Furthermore irwy reversibility nd BHR occurred more frequently in children with undignosed sthm thn in children with dignosed sthm nd helthy controls (reversibility 52%, 24% nd 0% for, respectively, UDA, DA nd HC, P<0.001; respectively, 73%, 47%, nd 11% for BHR, P<0.001). Tble 1 Chrcteristics of the ptient groups Undignosed sthm (n=130) Dignosed sthm (n=81) Helthy controls (n=202) Gender, n (%) Mle 73 (56) 47 (58) 100 (50) Femle 57 (44) 34 (42) 102 (50) Men ge±sd (yers) 9.4± ±0,8 9.4±0.7 Mother sthm 19 (17) 16 (23) 4 (2) ever, n (%) Fther sthm 7 (5) 11 (16) 12 (7) ever, n (%) Mother current 26 (20) 10 (14) 41 (22) smoker, n (%) Fther current 30 (26) 17 (24) 42 (22) smoker, n (%) Mother s eduction Low, n (%) 17 (15) 14 (20) 33 (17) Moderte, n (%) 56 (49) 34 (48) 95 (50) High, n (%) 41 (36) 23 (32) 62 (33) Fther s eduction Low, n (%) 20 (20) 16 (24) 37 (20) Moderte, n (%) 41 (40) 22 (32) 65 (35) High, n (%) 40 (40) 30 (44) 82 (45) Pet ownership Currently, n (%) 78 (70) 39 (54) 117 (61) Ever, n (%) 89 (80) 55 (76) 142 (74)

5 846 Eur J Peditr (2007) 166: Tble 2 Clinicl chrcteristics of the ptient groups Undignosed sthm Dignosed sthm Helthy controls P vlue Symptoms in lst 12 months Wheeze, n (%) 72 (56) 70 (86) 0 (0) <0.001 Dry cough t night, n (%) 90 (71) 54 (70) 0 (0) <0.001 b, c Lung function prmeters Men bseline FEV 1 % predicted <0.001 b Men bseline FVC % predicted , b Chnge in FEV 1 fter BD (%) <0.001 b Reversibility 10%, n (%) 67 (52) 19 (24) 0 (0) <0.001 BHR, n (%) 93 (73) 38 (47) 21 (11) <0.001 Inhled corticosteroids 12 (9%) 60 (74%) 0 (0) Significnt difference between undignosed sthm nd dignosed sthm b Significnt difference between undignosed sthm nd helthy controls c Significnt difference between dignosed sthm nd helthy controls Impct on dily life Tble 3 presents dt on the qulity of life of children nd their cregivers. For ll domins, children with dignosed or undignosed sthm hd lower qulity of life scores thn helthy controls (P). Qulity of life in children with dignosed sthm ws lower thn in children with undignosed sthm for ll domins (P). Qulity of life scores in cregivers showed similr pttern. Irrespective whether dignosed or not, sthmtic children showed lower score on the ctivity domin thn their cregivers did (P). We estimted the effect on dily function by 5-dys symptom diry nd evlution of school bsence in the lst 12 months. Children with dignosed sthm reported twice s mny symptoms in the diry thn children with undignosed sthm (11% nd 5%, respectively, P). Children with dignosed nd undignosed sthm were more thn 1 week bsent from school in the lst 12 months due to respirtory symptoms thn helthy controls, i.e. 31%, 17%, nd 0%, respectively (P<0.001) (Tble 4). Becuse corticosteroid tretment my ffect lung function nd qulity of life score, we repeted the nlysis fter excluding children with undignosed sthm tht used inhled corticosteroids. Results remined essentilly the sme. Discussion In the present study, we found lower qulity of life on ll domins in children with dignosed nd undignosed sthm compred with helthy children. We found the sme results for their cregivers. Lowest scores were observed in children with dignosed sthm. Similrly, symptoms during five consecutive dys nd school bsence in the lst 12 months occurred more frequently in sthmtic children, with the highest impct in children with dignosed sthm. Tble 3 Qulity of life men score of children nd cregivers with undignosed sthm, dignosed sthm nd helthy controls Qulity of life score of children Undignosed sthm Dignosed sthm Helthy controls P vlue n Men (95% C.I.) n Men (95% C.I.) n Men (95% C.I.) Emotions domin ( ) ( ) (6.9 7) Activity domin ( ) ( ) (6.8 7) Symptom domin ( ) ( ) (6.9 7) <0.001 Combined domin ( ) ( ) (6.9 7) Qulity of life score of cregivers Emotions domin ( ) ( ) (6.9 7) <0.001 Activity domin ( ) ( ) (6.9 7) Combined domin ( ) ( ) (6.9 7) <0.001 Significnt difference between undignosed sthm nd dignosed sthm b Significnt difference between undignosed sthm nd helthy controls c Significnt difference between dignosed sthm nd helthy controls

6 Eur J Peditr (2007) 166: Tble 4 Annul bsence from school due to respirtory symptoms Undignosed sthm, n (%) Dignosed sthm, n (%) Helthy controls, n (%) Never 56 (50) 28 (40) 179 (93) <1 week 37 (33) 20 (29) 13 (7) 1 2 weeks 12 (11) 21 (30) weeks 5 (4) 1 (1) 0 >4 weeks 2 (2) 0 0 P vlue <0.001 The mjor strength of our study is tht, to our knowledge, this is the first popultion-bsed study which evluted qulity of life with stndrdized disese-specific questionnires in children with undignosed sthm nd dignosed sthm nd their cregivers nd compred these children with helthy controls. We found higher frequency of BHR nd lower prevlence of wheeze in children with undignosed sthm thn children with dignosed sthm. There re severl explntions for this finding. First, bronchil hyperresponsiveness ws used in the definition of undignosed sthm, wheres bronchil hyperresponsiveness ws not required in the definition of dignosed sthm. Another explntion might be the dependence on recll of sthm symptoms. Recll by prents cn be fulty. Furthermore, prents my not witness every sthm symptom child experiences, which might explin tht night-time symptoms re equl in children with undignosed sthm nd dignosed sthm. Nonetheless, ptient report of sthm symptoms hs long been key fctor in physicin s decision mking, nd the survey mimics the questions they pose s prt of ssessment. Responses to the questionnire re eqully relible s similr questions in the physicin s office. Our results on qulity of life with the lowest score in dignosed sthm suggest tht children with undignosed sthm hve milder degree of sthm thn children with dignosed sthm. This is in greement with qulity of life scores reported by others. For exmple, our children with dignosed sthm hd qulity of life scores similr to those in children with moderte sthm, nd our scores for undignosed sthm were comprble with those in children with mild sthm s reported by Rt et l. [19] The relevnce of mild sthm should not be underestimted. Fwcett et l. [7] showed tht life-thretening excerbtions regulrly occur in mild sthm. Moreover, mild sthm ccounts for the mjority of peditric dmissions. The clinicl interprettion of differences in qulity of life is difficult becuse experience in their use is still limited. Juniper et l. [13] proposed difference of 0.5 or higher s being cliniclly relevnt for the PAQLQ. Knorr et l. [15] studied the effect of tretment in 6- to 14-yer-old sthmtic children nd observed significnt improvement of both FEV 1 nd qulity of life scores (with 0.4 for the emotionl domin nd 0.5 for the ctivity domin). In the light of these studies, our results suggest cliniclly relevnt impirment of qulity of life in sthmtic children, irrespective of whether dignosed or not. Until now, no reports re vilble on the clinicl relevnce of the prentl scores of qulity of life. Our observtions of lowest qulity of life nd highest symptom impct in dignosed sthm compred with undignosed sthm seem in contrdiction with observtions on mrkers of irwy obstruction (FEV 1, reversibility, BHR), which ws highest in undignosed sthm. Juniper et l. [14] reported similr discrepncy. It is probble tht clinicl mesures of irwy sttus (such s irwy clibre nd mrkers of inflmmtion) evlute different component of sthm helth sttus thn qulity of life. For instnce, lung function is sttic indictor in vrible disese, wheres qulity of life scores reflect the ptient s perceptions of the condition over longer period of time. In ddition, the stigm of being lbelled s hving sthm cn be n explntion for the lower qulity of life scores in children with dignosed sthm. Further studies re needed to evlute the effect of being dignosed nd medicl tretment on qulity of life in community smple of undignosed sthm. The following points my hve ffected our study results. First, we did not collect informtion on the resons for non-response or the extent to which this my hve bised our results. Second, bis my hve been introduced if prents interpreted symptom questions different thn the questionnire definition [4, 16, 25]. Additionlly, recll bis cnnot be excluded since questions referred to period of the pst 12 months. For symptoms, we ttempted to minimize bis by using the vlidted ISAAC questionnire. One might rgue tht sthm-specific qulity of life questionnires re inpproprite to be used in helthy controls or in subjects without dignosis of sthm. However, the PAQLQ nd PACQLQ lso include questions on the impct of respirtory symptoms without mking reference to sthm. Therefore, we hve considered them pproprite to use in children with undignosed sthm nd helthy controls. Our observtions of the highest scores in helthy controls tht pproximted the mximum vlue my be considered confirmtion. Furthermore, the disese-specific qulity of life ws significntly impired in subjects who could be expected to experience impirments: the children with undignosed sthm. In ddition, the results of more school bsence in children with undignosed sthm compred with helthy controls supports the results of lower qulity of life scores in children with undignosed sthm. A lst comment ddresses the selection of our ptient groups. In this study, children with symptomtic irwy reversibility or sthm symptoms

7 848 Eur J Peditr (2007) 166: only were excluded, becuse we imed t highest discrimintion between sthm nd helthy controls. Therefore, we included objective prmeters (irwy reversibility nd BHR) for the definition of undignosed sthm. Nevertheless misclssifiction my hve occurred since irwy reversibility is vrible present in sthm. References 1. Worldwide vritions in the prevlence of sthm symptoms: the Interntionl Study of Asthm nd Allergies in Childhood (ISAAC) (1998) Eur Respir J 12: Asher MI, Keil U, Anderson HR, Besley R, Crne J, Mrtinez F, Mitchell EA, Perce N, Sibbld B, Stewrt AW (1995) Interntionl Study of Asthm nd Allergies in Childhood (ISAAC): rtionle nd methods. Eur Respir J 8: Bumn A, Young L, Pet JK, Hunt J, Lrkin P (1992) Asthm under-recognition nd under-tretment in n Austrlin community. Aust N Z J Med 22: Cne RS, Rngnthn SC, McKenzie SA (2000) Wht do prents of wheezy children understnd by wheeze? Arch Dis Child 82: Chew FT, Goh DY, Lee BW (1999) Under-recognition of childhood sthm in Singpore: evidence from questionnire survey. Ann Trop Peditr 19: Cuijpers CE, Wesseling GJ, Swen GM, Sturmns F, Wouters EF (1994) Asthm-relted symptoms nd lung function in primry school children. J Asthm 31: Fwcett WA, Gddis SE (2004) Mild sthm ccounts for the mjority of peditric sthm dmissions. Ann Allergy Asthm Immunol 92: Gerld LB, Grd R, Turner-Henson A, Hins C, Tng S, Feinstein R, Wille K, Erwin S, Biley WC (2004) Vlidtion of multistge sthm cse-detection procedure for elementry school children. Peditrics 114:e459 e Hill RA, Stnden PJ, Tttersfield AE (1989) Asthm, wheezing, nd school bsence in primry schools. Arch Dis Child 64: Joseph CL, Hvstd S, Anderson EW, Brown R, Johnson CC, Clrk NM (2005) Effect of sthm intervention on children with undignosed sthm. J Peditr 146: Juniper EF, Guytt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M (1996) Mesuring qulity of life in children with sthm. Qul Life Res 5: Juniper EF, Guytt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M (1996) Mesuring qulity of life in the prents of children with sthm. Qul Life Res 5: Juniper EF, Guytt GH, Willn A, Griffith LE (1994) Determining miniml importnt chnge in disese-specific Qulity of Life Questionnire. J Clin Epidemiol 47: Juniper EF, Wisniewski ME, Cox FM, Emmett AH, Nielsen KE, O Byrne PM (2004) Reltionship between qulity of life nd clinicl sttus in sthm: fctor nlysis. Eur Respir J 23: Knorr B, Mtz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, Becker A (1998) Montelukst for chronic sthm in 6- to 14- yer-old children: rndomized, double-blind tril. Peditric Montelukst Study Group. JAMA 279: Pet JK, Slome CM, Toelle BG, Bumn A, Woolcock AJ (1992) Relibility of respirtory history questionnire nd effect of mode of dministrtion on clssifiction of sthm in children. Chest 102: Powell CV, Primhk RA (1995) Asthm tretment, perceived respirtory disbility, nd morbidity. Arch Dis Child 72: Qunjer PH, Tmmeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernult JC (1993) Lung volumes nd forced ventiltory flows. Report Working Prty Stndrdiztion of Lung Function Tests, Europen Community for Steel nd Col. Officil Sttement of the Europen Respirtory Society. Eur Respir J Suppl 16: Rt H, Bueving HJ, de Jongste JC, Grol MH, Juniper EF, vn der Wouden JC (2005) Responsiveness, longitudinl- nd crosssectionl construct vlidity of the Peditric Asthm Qulity of Life Questionnire (PAQLQ) in Dutch children with sthm. Qul Life Res 14: Rbe KF, Vermeire PA, Sorino JB, Mier WC (2000) Clinicl mngement of sthm in 1999: the Asthm Insights nd Relity in Europe (AIRE) study. Eur Respir J 16: Speight AN, Lee DA, Hey EN (1983) Underdignosis nd undertretment of sthm in childhood. Br Med J (Clin Res Ed) 286: Weilnd SK, Bjorksten B, Brunekreef B, Cookson WO, von Mutius E, Strchn DP (2004) Phse II of the Interntionl Study of Asthm nd Allergies in Childhood (ISAAC II): rtionle nd methods. Eur Respir J 24: Yetts K, Dvis KJ, Sotir M, Herget C, Shy C (2003) Who gets dignosed with sthm? Frequent wheeze mong dolescents with nd without dignosis of sthm. Peditrics 111: Yetts K, Johnston DK, Peden D, Shy C (2003) Helth consequences ssocited with frequent wheezing in dolescents without sthm dignosis. Eur Respir J 22: Young B, Fitch GE, Dixon-Woods M, Lmbert PC, Brooke AM (2002) Prents ccounts of wheeze nd sthm relted symptoms: qulittive study. Arch Dis Child 87: