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The transient value of classifying preschool wheeze into episodic viralwheeze and multiple trigger wheezeA Schultz (,2,3, SG Devadason1,4, OEM Savenije5, PD Sly6, PN Le Souëf1,3, PLP Brand7,8 1.School of Paediatric and Child Health, University of Western Australia, Perth, WA, Australia2.Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital for Children, Perth, WA, Australia3.Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA, Australia4.Division of Clinical Research, Princess Margaret Hospital for Children, Perth, WA, Australia5.Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands6.Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, WA, Australia7.Princess Amalia Children’s Clinic, Isala Klinieken, Zwolle, the Netherlands8.UMCG Postgraduate School of Medicine, University Medical Centre, Groningen, the Netherlands Classification, Episodic wheeze, Multiple trigger Background: A recently proposed method for classifying preschool wheeze is to describe it as either episodic (viral) wheeze or multiple trigger wheeze. In research studies, phenotype is generally determined by retrospective questionnaire.
A Schultz, Princess Margaret Hospital for Children, Aim: To determine whether recently proposed phenotypes of preschool wheeze are stable over GPO Box D184, Perth, WA 6840, Australia.
Tel: +61-8-9340-8222 | Methods: In all, 132 two to six-year-old children with doctor diagnosed asthma on maintenance inhaled corticosteroids were classified as having episodic (viral) wheeze or multiple trigger wheeze at a screening visit and then followed up at three-monthly intervals for a year. At each follow-up visit, stan- dardized questionnaires were used to determine whether the subjects wheezed only with, or also in the absence of colds. Stability of the phenotypes was assessed at the end of the study.
Results: Phenotype as determined by retrospective parental report at the start of the study wasnot predictive of phenotype during the study year. Phenotypic classification remained the same in45.9% of children and altered in 54.1% of children.
Conclusion: When children with preschool wheeze are classified into episodic (viral) wheeze or multiple trigger wheeze based on retrospective questionnaire, the classification is likely to change significantly within a 1-year ‘wheezing’ or ‘asthma’. Classification of preschool wheeze Preschool recurrent wheeze is very common, with a cumu- into EVW or MTW, to study either group, is usually based lative prevalence of up to 40% during the first 6 years of life on parental responses at a single visit to questions regard- (1). Different phenotypes of recurrent wheezing have been ing wheeze in the previous year (1,10). Little is known recognized in this age group and various labels have come about the stability of wheezing phenotypes in preschool into widespread use (2–6). The European Respiratory Soci- ety Task Force on Preschool Wheeze has recently pub-lished a report (7) recommending that preschool childrenwith wheezing disorders should be classified as episodic (viral) wheeze (EVW) and multiple trigger wheeze (MTW).
To determine whether preschool wheeze phenotypes classi- These phenotypic categorizations are believed by some to fied as Episodic Viral Wheeze or Multiple Trigger Wheeze be important determinants of response to treatment (6,8,9): are stable over time in preschool children.
patients with EVW are thought not to respond to mainte-nance inhaled corticosteroids (6,8,10,11), while those withMTW do respond to maintenance inhaled corticosteroids (2,4,6,8,12–19). Conversely, EVW seems to respond Wheezing phenotypes EVW and MTW are not stable over a favourably to montelukast (20–22) or episodic high dose one-year period in 2–6 year old children with doctor diag- inhaled steroids (15,23,24). Methodological issues related nosed asthma who are receiving inhaled steroid treatment.
to diagnostic labels have led to problems in interpretingstudies and pooling of data (8). In particular, many studiesof children with preschool wheezing do not report the wheezing phenotype using any published category at all, This study was performed using data derived from a ran- but simply refer to their patients as suffering from domized clinical trial of two small-volume spacers ª2009 The Author(s)/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2010 99, pp. 56–60 The transient value of retrospective preschool wheeze classification conducted in preschool asthmatics. This analysis focused asthma was not controlled, the study medication was on the stability of characteristics of wheeze over time in these children, while they were on maintenance treatmentwith inhaled corticosteroids.
Re-classificationAt each follow-up visit, information was collected on whether the subjects had wheezed in the month preceding Preschool children (2–6 year old) in whom asthma had each visit. This information was collected by the study doc- been diagnosed by a doctor in the community, and who tor using a standardized questionnaire. If the subjects did had been on inhaled steroids for treatment of their asthma, wheeze in the month preceding the visit, the subjects’ par- were eligible for inclusion in the study. In Australia, pre- ents were asked whether the wheeze was present during school children with wheeze are usually labelled with ‘asthma’, and treated with inhaled corticosteroids when The variation in wheezing phenotype classification in symptoms are recurrent and appear to respond to bron- individual patients throughout the study period was deter- chodilators. Exclusion criteria were: known or suspected mined. Children were labelled stable no wheeze if they had immunodeficiency, other chronic lung diseases (such as never wheezed throughout the entire follow-up of 1 year.
bronchopulmonary dysplasia or cystic fibrosis), known They were labelled stable viral wheeze if they wheezed only allergy to study medication and having taken systemic ste- in the presence of colds in the months prior to one or more roids in the 3 months prior to enrolment. Ethics approval follow-up visits and no wheeze at the other visits, stable was obtained from Princess Margaret Hospital for Chil- MTW if they wheezed during, but also apart from colds in dren’s Ethics Committee. Parents or guardians provided the month prior to one or more visits and no wheeze at the To investigate the effect of season on wheeze symptoms, we then re-organized the first four study visits by season.
Subjects were seen at a screening visit, at a baseline visit Parental answers to the question ‘Did your child wheeze and then followed up for a year. At the screening visit, with or without colds in the month before this visit?’ were candidates were checked for eligibility, and background information was obtained by standardized questionnaire At the final visit, skin prick allergy testing was performed about symptoms of wheeze and cough, personal and for rye grass pollen, house dust mite, cat dander and egg family history of atopy and asthma, smoking in the house white. A positive skin prick test was seen as a wheal size and during pregnancy. All children were treated with Statistical analysis was performed with SPSS version 15.0. Comparison of phenotypes was based in Chi square statistics. Binary logistic regression was used to investigate At the screening visit, parents were asked whether their the effect of co-variates, e.g. atopy on the retrospectively child had wheezed in the absence of colds in the past year determined phenotype (EVW and MTW). Multinomial and if they had only wheezed during colds. Based on the logistic regression was used to investigate the effect of response to these questions, subjects were classified as hav- co-variates on the prospectively determined phenotype ing either episodic viral wheeze (EVW, wheezing only dur- ing colds and not in the absence of colds), multiple triggerwheeze (MTW, wheeze in the absence of colds, irrespectiveof the presence or absence of wheeze with colds).
The screening visit was followed by a month long run-in One hundred and thirty two preschool children with phy- period where the subject had to prove a certain degree of sician diagnosed asthma entered the study. Over the asthma stability before the actual study commenced. For 1-year follow-up period, 21 subjects (16%) dropped out of practical purposes, ‘stable asthma’ was defined as not the study: six subjects were lost to follow-up, four moved requiring oral steroids for the past 3 months. If the subject’s away from the study centre, five cited time constraints, asthma was unstable, the run-in period was extended and four lost interest, one cited parental illness and one cited the medication dose adjusted appropriately.
not liking the spacer allocated for the study. Of the 111 After the run-in period, the subjects were seen for a patients who completed the study, one was excluded from baseline visit and followed up at three-monthly intervals analysis after being found to have been randomized on its for a year. At each visit, inhalation technique was checked seventh birthday and one was excluded from analysis and corrected if necessary. At each visit, the inhaled after being unable to answer necessary study questions.
asthma preventer medication was reduced if a subject did Therefore, 109 (83%) subjects were included in the analy- not have regular asthma symptoms or recent asthma ses of phenotype classification and stability reported here.
exacerbations and the parents agreed to it. Regular asthma Clinical characteristics of these patients are given in symptoms was defined as having daytime asthma symp- toms more than twice a week or night time awakenings At the screening visit, 38 patients (34.9%) were classified more than twice a month. At each visit, if the subject’s as EVW, 71 (65.1%) as MTW. The retrospectively ª2009 The Author(s)/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2010 99, pp. 56–60 The transient value of retrospective preschool wheeze classification Phenotype determinedretrospectively at screening visit Parent report of smoker living in home n (%) Mother reports smoking during pregnancy n(%) Daily dose of ICS at baseline in microgram ‡Dose of ICS at final visit median (range) On concurrent salmeterol at baseline n (%) On concurrent salmeterol by end of study n (%) †Atopy defined as a history of asthma, eczema or hay fever.
‡38 children had inhaled steroids discontinued during the study period.
inhaled corticosteroids for at least a month before the Retrospective phenotype determined at start of study compared with screening visit’. The median dose of fluticasone was200 mcg per day at the beginning of the study, while the Retrospective phenotype determined at start ofstudy median dose of fluticasone for subjects classified as ‘nowheeze’, ‘episodic viral wheeze’ and ‘multiple trigger wheeze’ by the end of the study was respectively 100 mcg, EVW = Episodic viral wheeze; MTW = Multiple trigger wheeze.
This study demonstrates that in a group of preschool Numbers in brackets indicate percentage of phenotype at the start of the children with recurrent wheezing being treated with inhaled steroids, wheezing phenotype (EVW, MTW) asdetermined by a single assessment at the beginning of a determined phenotype at screening was independent of 12 month observation period was not predictive of wheez- gender, presence of eczema, hay fever, smokers living in the ing patterns in the following year. Based on data obtained home or family history of atopy (p > 0.05).
The change in phenotype classification during the patients classified as EVW at screening were equally likely study, i.e. by comparing the classification based on to be re-classified as No wheeze, EVW or MTW by the parental report at the screening, and that determined prospectively during the study, is presented in Table 2.
As our results are based on subjects recruited on the basis Phenotypic classification remained the same in 50 of ‘doctor diagnosed asthma’, we cannot comment on out- (45.9%) children and altered in 59 (54.1%) children. A comes for children who had not been given this diagnosis.
similar number of children who changed from EVW to The children in this study, therefore, are representative of MTW, changed from EVW to no wheeze. (Table 2). Ele- the overall population of children with more severe recur- ven (15.5%) of subjects who where classified as MTW rent wheezing and presence of risk factors for persistence of at screening were classified as ‘no wheeze’ by the end wheezing that may be prescribed maintenance treatment with inhaled corticosteroids in primary care or in a hospi- Overall, prospectively determined, there were 24 (22.0%) tal-based environment. Change in classification was inde- non-wheezers, 34 (31.2%) viral wheezers, 51 (46.8%) MTW patients. The prospectively determined phenotype was Based on the retrospective data gathered by parental independent of gender, atopy, smokers in the home and report at the screening visit, a third of the subjects were ini- maternal smoking during pregnancy (all p values >0.05).
tially classified as EVW and two thirds as MTW. Only one The age range of subjects classified into different groups third of subjects who where classified as having EVW at the were very similar throughout the study (median age for all screening visit were still found to have EVW by the end of classification groups ranged between 47 months and the study. One third was classified prospectively as MTW 55 months). ‘All subjects in the study had been prescribed and another third fell into the ‘no wheeze’ category when ª2009 The Author(s)/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2010 99, pp. 56–60 The transient value of retrospective preschool wheeze classification classified prospectively. Therefore, subjects who initially In conclusion, this study demonstrates that when chil- had EVW were equally likely to remain having EVW, to dren with preschool wheeze are classified into EVW or MTW based on retrospective questionnaire, the classifi- Multiple reasons for a change in phenotype have been cation is likely to change significantly within a one-year described. First, episodic (viral) wheezers, especially if period. Preschool children whose parents report that atopic, frequently evolve with the passage of time into a they only wheezed during colds in the past year stand a multi-trigger pattern, or, if non-atopic, lose their symptoms significant chance of wheezing in the following year.
altogether. In our study, change in phenotype appeared to Conversely, preschool children whose parents report that they wheezed in the absence of colds in the past year It could be argued that the decrease of interval symptoms stand a significant chance of only wheezing during colds was the result of inhaled corticosteroid treatment (8,25,26).
in the following year. Therefore, a system of classifying Steroids certainly would have had a role in influencing preschool wheeze into EVW or MTW based on parental wheezing symptoms (27), but the effect of inhaled steroids questionnaires may not be accurate for researching these on preschool wheeze appears to be the modest (7), and unlikely to cause a change in phenotype as marked as thechange seen in this study. A recent meta-analysis (27)concluded that seven children with preschool wheeze need to be treated with inhaled corticosteroids to prevent a single The fluticasone used in this study was sponsored by Glaxo- wheeze exacerbation. When considering MTW, as noted in the ERS Task Force report (7), ‘Compared to placebo, Half of the small-volume spacer devices used to adminis- children using 200 mcg ⁄ day fluticasone exhibit a mean of ter fluticasone to the study subjects were sponsored by Visi- 5% fewer days with symptoms’ (19). Therefore, MTW would unlikely have been be completely changed to EVW by the In 2003, Glaxo paid for Andre´ Schultz’s flight ticket and registration fees to attend a national scientific conference.
During the prospective part of the study, parents were Paul Brand has received funding for research and for con- only asked about their children’s wheeze in the month sulting activities from Glaxo Smith Kline in 2006, 2007 and prior to each study visit. Symptoms during the two-month periods after each study could therefore have beenmissed, resulting in the misclassification of a number ofsubjects. However, the 34.2% of subjects who were classi- fied at the start of the study as EVW, and reclassified as Andre´ Schultz received a salary as a research fellow from MTW during the study, all had symptoms in the absence the Telethon Institute for Child Health Research, Perth, of colds reported during the study, and therefore were Australia for one year of the study.
unlikely to have been misclassified due to the monitoringprocess.
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atopy, family history of atopy and gender were not helpful Wheeze and asthma prevalence and related health-service use in predicting whether the phenotype would be stable or var- in white and south Asian pre-schoolchildren in the United iable, this study was not designed to study predictors of Kingdom. Clin Exp Allergy 2007; 37: 1738–46.
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phenotype bears little relation to phenotype in the year to 5. Silverman M, Wang M, Hunter G, Taub N. Episodic viral come, and this may seriously undermine the applicability of wheeze in preschool children: effect of topical nasal corticoste- study data to clinical practice. Our data, therefore, suggest roid prophylaxis. Thorax 2003; 58: 431–4.
6. McKean M, Ducharme F. Inhaled steroids for episodic viral that taking a once-off history from parents of preschool wheeze of childhood. Cochrane Database Syst Rev 2000; 2: children with recurrent wheeze may be insufficient to pro- vide a reliable classification of wheezing phenotype as EVW 7. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez or MTW. Clinical decisions on treatment options that rely JA, Custovic A, et al. Definition, assessment and treatment of on studies where the EVW ⁄ MTW classification system was wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008; 32: 1096–110.
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Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354: 17. Kemp JP, Skoner DP, Szefler SJ, Walton-Bowen K, Cruz- Rivera M, Smith JA. Once-daily budesonide inhalation sus- 27. Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticos- pension for the treatment of persistent asthma in infants teroids in infants and preschoolers with recurrent wheezing and young children. Ann Allergy Asthma Immunol 1999; and asthma: a systematic review with meta-analysis. Pediatrics ª2009 The Author(s)/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2010 99, pp. 56–60


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