Definition, assessment and treatment of wheezing disorders ...tvscn.nhs.uk/wp-content/uploads/2014/09/Academic-papers.pdf · wheezing disorders (including asthma) in general, and

ERS TASK FORCE

Definition, assessment and treatment of

wheezing disorders in preschool children:

an evidence-based approachP.L.P. Brand, E. Baraldi, H. Bisgaard, A.L. Boner, J.A. Castro-Rodriguez, A. Custovic,J. de Blic, J.C. de Jongste, E. Eber, M.L. Everard, U. Frey, M. Gappa,L. Garcia-Marcos, J. Grigg, W. Lenney, P. Le Souef, S. McKenzie, P.J.F.M. Merkus,F. Midulla, J.Y. Paton, G. Piacentini, P. Pohunek, G.A. Rossi, P. Seddon,M. Silverman, P.D. Sly, S. Stick, A. Valiulis, W.M.C. van Aalderen, J.H. Wildhaber,G. Wennergren, N. Wilson, Z. Zivkovic and A. Bush

ABSTRACT: There is poor agreement on definitions of different phenotypes of preschool

wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to

describe children who wheeze intermittently and are well between episodes, and multiple-trigger

wheeze for children who wheeze both during and outside discrete episodes. Investigations are

only needed when in doubt about the diagnosis.

Based on the limited evidence available, inhaled short-acting b2-agonists by metered-dose

inhaler/spacer combination are recommended for symptomatic relief. Educating parents

regarding causative factors and treatment is useful. Exposure to tobacco smoke should be

avoided; allergen avoidance may be considered when sensitisation has been established.

Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze;

benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze

and can be started when symptoms of a viral cold develop.

Given the large overlap in phenotypes, and the fact that patients can move from one phenotype

to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost

any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical

benefit.

Large well-designed randomised controlled trials with clear descriptions of patients are needed

to improve the present recommendations on the treatment of these common syndromes.

KEYWORDS: Asthma, episodic viral wheeze, inhaled corticosteroids, montelukast, multiple-

trigger wheeze

CONTENTS

Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097

Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097

Definitions of temporal pattern of wheeze . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098

Retrospective epidemiological description of duration of wheeze . . . . . . . . . . . . . . . . . . . . . . . 1099

Long-term outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099

Recommendations: definitions of phenotypes (based on low-level evidence) . . . . . . . . . . . . . . 1099

Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099

History and physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099

Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100

Recommendations: assessment (based on very low-level evidence) . . . . . . . . . . . . . . . . . . . . 1101

AFFILIATIONS

For affiliation details, please see the

Acknowledgements section.

CORRESPONDENCE

P.L.P. Brand

Princess Amalia Children’s Clinic

Isala klinieken

P.O. Box 10400

8000 K Zwolle

The Netherlands

Fax: 31 384247660

E-mail: [email protected]

Received:

January 06 2008

Accepted after revision:

May 26 2008

STATEMENT OF INTEREST

Statements of interest for

P.L.P. Brand, E. Baraldi, H. Bisgaard,

A.L. Boner, J.A. Castro-Rodriguez,

A. Custovic, J.C. de Jongste, E. Eber,

M.L. Everard, U. Frey, M. Gappa,

L. Garcia-Marcos, W. Lenney,

S. McKenzie, G. Piacentini,

G.A. Rossi, P. Seddon, M. Silverman,

A. Valiulis, W.M.C. van Aalderen,

J.H. Wildhaber, G. Wennergren and

A. Bush can be found at

www.erj.ersjournals.com/misc/

statements.shtml

European Respiratory Journal

Print ISSN 0903-1936

Online ISSN 1399-3003

1096 VOLUME 32 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL

Eur Respir J 2008; 32: 1096–1110

DOI: 10.1183/09031936.00002108

Copyright�ERS Journals Ltd 2008

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101

Environmental manipulation . . . . . . . . . . . . . . . . . . . 1101

Parent and patient education . . . . . . . . . . . . . . . . . . 1101

Pharmacological therapy . . . . . . . . . . . . . . . . . . . . . 1102

Delivery devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104

Methodological considerations . . . . . . . . . . . . . . . . . 1104

Recommendations for treatment (based on low-level evidence

unless otherwise specified) . . . . . . . . . . . . . . . . . . . . 1104

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106

Population studies have shown that approximately onein three children has at least one episode of wheezingprior to their third birthday, and the cumulative

prevalence of wheeze is almost 50% at the age of 6 yrs [1, 2].Most wheeze in preschool children is associated with viralupper respiratory tract infections, which recur frequently inthis age group. As a result, recurrent wheeze is a very commonclinical problem facing practitioners throughout the world. Ithas been estimated that the problem of preschool wheezeutilises 0.15% of the total healthcare budget in the UK [3].Despite its high prevalence, there is a lack of evidenceregarding the pathophysiology and treatment of preschoolwheeze.

The understanding of preschool wheezing illness has beenenhanced by a number of birth cohort studies, in particular byhighlighting the existence of different phenotypes [1, 4, 5].However, the possible implications of these different pheno-types for treatment are poorly acknowledged in currentinternational guidelines on the diagnosis and management ofasthma [6–8]. Indeed, although two paediatric societies recentlypublished guidelines on preschool wheezing disorders [9, 10],comprehensive evidence-based guidelines on the diagnosis andmanagement of wheezing disorders in preschool children havenot been published to date. The present ERS Task Force wasinstituted for exactly that purpose. The Task Force defined aphenotype as a cluster of associated features that are useful insome way, such as in managing the child or understanding themechanisms of disease. Given the multifactorial nature of allwheezing disorders (including asthma) in general, and pre-school wheezing disorders in particular, it is highly likely thatclinical phenotypes described in the literature are the extremesof a broad spectrum of wheezing disorders [11, 12]. The TaskForce therefore realises that the phenotypes defined in thepresent report are not exhaustive, and that many individualpatients may not fit into the categories described. There may beoverlap between phenotypes and they may change over time.

The purpose of the present Task Force was to produceguidelines for the treatment of wheezing in children aged,6 yrs based on all of the available evidence.

METHODSLiterature searches were performed in order to identifymaterial relating to preschool wheeze. Eleven relevant studyareas were identified, and, for each area, a literature searchwas carried out based on a predefined series of key clinicalquestions and keywords by a single clinical librarian. Searchstrategies were constructed by the clinical librarian incollaboration with a representative of each group in the TaskForce. Searching included the Cochrane library, PubMed andEMBASE, and the strategies included filters to limit the resultsby study type (reviews, randomised controlled trials and othertypes of experimental research) and age range (0–5 yrs).

The details of the search strategies are available on request.In most cases, the results were limited to English languagematerial. No date limits were applied.

Each subgroup, consisting of at least three people, reviewed theretrieved references for relevant papers, adding additionalpapers from personal files if required. The evidence from theretrieved relevant papers was graded, according to recentrecommendations [13], as high-, moderate-, low- or very low-grade evidence based on the following criteria: study designand quality (systematic reviews and randomised controlledtrials: high quality; observational studies: low quality; any othertype of article: very low quality), consistency of the data andrelevance. A draft report was prepared by each subgroup. Thiswas submitted to the whole Task Force for comments. Theindividual reports were then combined by the Task Force chairs(P.L.P. Brand and A. Bush), and the present manuscript wasorganised into three main sections: Definitions, Assessment andTreatment. Based on the evidence reviewed and graded by eachsubgroup, the Task Force chairs put together a list ofrecommendations that were graded according to the Gradingof Recommendations Assessment, Development and Evaluation(GRADE) methodology [13]. Instead of the usual system ofgrading the strength of recommendations as A, B, C or D, theGRADE working group proposal to use a different, and morereadily interpretable, system of categorising recommendationsin four groups was followed: should (or should not) be done, orpossibly should (or should not) be done. Recommendationscould only be categorised as should (or should not) be donewhen the entire Task Force unanimously endorsed thisrecommendation.

RESULTSOne of the main findings of the present Task Force was that theevidence on which to base recommendations is limited in thisage group. When no evidence was available from originalstudies, narrative reviews and published expert opinions wereconsidered for inclusion in the present report. All of theevidence presented is of low quality unless specifically statedotherwise. The present recommendations are likely to changewhen more evidence becomes available.

DEFINITIONSDefinitions used in children aged ,6 yrs are often confusing.Although many individuals later diagnosed with asthmaexhibit their first symptoms during the preschool age period,making a diagnosis of asthma in preschool children is difficult.According to the latest edition of the Global Initiative forAsthma (GINA) guidelines, asthma is a syndrome with ahighly variable clinical spectrum, characterised by airwayinflammation [6]. Inflammation, however, has been poorlystudied in preschool children, and may be absent in veryyoung children who wheeze [14]. Therefore, a symptoms-onlydescriptive approach, outlined in table 1, was adopted.

P.L.P. BRAND ET AL. WHEEZING DISORDERS IN PRESCHOOL CHILDREN

cEUROPEAN RESPIRATORY JOURNAL VOLUME 32 NUMBER 4 1097

The majority of the Task Force agreed not to use the termasthma to describe preschool wheezing illness since there isinsufficient evidence showing that the pathophysiology ofpreschool wheezing illness is similar to that of asthma in olderchildren and adults.

Wheeze is defined as a continuous high-pitched sound withmusical quality emitting from the chest during expiration. It isone of a number of forms of noisy breathing in preschoolchildren [15]. Parents differ widely in their understanding anddefinition of wheeze; some think it is a sound such aswhistling, squeaking or gasping, whereas others define it asa different rate or style of breathing, or think it is the same ascough [15–19]. If based on parental report alone, therefore,children may be labelled as having wheeze when they do not.If possible, therefore, wheeze should be confirmed by a healthprofessional, bearing in mind that not all healthcare workersare equally accurate in estimating the severity of wheeze [20].

By definition, the present Task Force has not addressed theclinical problem of isolated cough without wheeze. Guidelineson the diagnosis and management of chronic cough inchildhood are available elsewhere [21]. Since wheeze is theend result of narrowing of intrathoracic airways and expira-tory flow limitation, irrespective of the underlying mechanism,there are numerous reasons for a child to wheeze, includinganatomical abnormalities of the airways, cystic fibrosis andbronchomalacia. The Task Force unanimously agreed that thedifferential diagnosis of wheeze in preschool children shouldnot be discussed in detail in the present report for a number ofreasons. First, there is very little, if any, evidence to supportrecommendations regarding the diagnostic approach to awheezing infant. Secondly, the differential diagnosis of wheezein preschool children has been discussed in detail in textbooks[22, 23]. Thirdly, it was felt that most clinicians and researcherswould recognise the clinical problem of recurrent wheezing inpreschool children without an in-depth discussion of itsdifferential diagnosis.

Causative factors for recurrent wheeze may vary from child tochild and within a child over time, due to a large number ofinteractions between genetic factors and the environment [24]. Asin adults [25], specific combinations of genetic and environmentalfactors determine the individual patient’s phenotype. In clinicalpractice, however, most of these factors are unknown.

The phenotypes used in epidemiological studies (transientversus persistent wheeze) can only be applied retrospectively[1, 4, 5]. Although the use of these phenotypes has improvedmechanistic understanding, they are of little use to theclinician. Although the epidemiological phenotype of transientwheeze is often assumed to be equivalent to the clinicalphenotype of episodic wheeze, this has never been demon-strated. Therefore, definitions of temporal pattern of wheeze(which are useful to clinicians) were distinguished from theretrospective definitions of duration of wheeze (which areused in epidemiological studies; table 1).

Definitions of temporal pattern of wheeze

Episodic (viral) wheeze

Episodic (viral) wheeze is defined as wheeze in discreteepisodes, with the child being well between episodes.Although not unique to the preschool age group [26, 27], thisphenotype appears to be most common in preschool children[1, 4, 5]. It is usually associated with clinical evidence of a viralrespiratory tract infection, although microbiological diagnosticstudies are rarely performed in clinical practice. The mostcommon causative agents include rhinovirus, respiratorysyncytial virus (RSV), coronavirus, human metapneumovirus,parainfluenza virus and adenovirus [28]. Repeated episodestend to occur seasonally.

Factors underlying the frequency and severity of episodes areonly partially understood, but the severity of the first episode(which is, in turn, related to pre-existent impaired lungfunction and younger age), atopy, prematurity and exposureto tobacco smoke have been implicated [29–35]. Whether or not

TABLE 1 Definitions used in the present report

Term Definition

Temporal pattern of wheeze

Episodic (viral) wheeze Wheezing during discrete time periods, often in

association with clinical evidence of a viral cold,

with absence of wheeze between episodes

Multiple-trigger wheeze Wheezing that shows discrete exacerbations,

but also symptoms between episodes

Duration of wheeze

Transient wheeze Symptoms that commenced before the age of

3 yrs and are found (retrospectively) to have disappeared

by the age of 6 yrs; transient wheeze may be episodic

or multiple-trigger wheeze

Persistent wheeze Symptoms that are found (retrospectively) to have

continued until the age of o6 yrs; persistent wheeze may

be episodic or multiple-trigger wheeze

Late-onset wheeze Symptoms that start after the age of 3 yrs;

late-onset wheeze may be episodic

or multiple-trigger wheeze

WHEEZING DISORDERS IN PRESCHOOL CHILDREN P.L.P. BRAND ET AL.


the initial episode is classified as bronchiolitis is irrelevant.Similarly, it is not known whether or not the causative agent ofthe initial episode plays a major role in determining long-termoutcome. Both RSV and rhinovirus have been linked to anincreased risk of persistent wheezing over time [36–38]. In thecase of RSV, most studies show that this has disappeared bythe age of 11 yrs, and is not associated with an increased risk ofatopy [37]. For rhinovirus, such long-term data are lacking.

Episodic (viral) wheeze most commonly declines over time,disappearing by the age of 6 yrs, but can continue as episodicwheeze into school age, change into multiple-trigger wheeze ordisappear at an older age [1, 26].

Multiple-trigger wheezeAlthough a viral respiratory tract infection is the most commontrigger factor for wheeze in preschool children, some youngchildren also wheeze in response to other triggers (multiple-trigger wheeze; table 1). Others have used the term persistentwheeze for this syndrome, but this is confusing because thisterm is also used to describe the long-term temporal outcomeof wheeze (discussed further later).

Systematic studies of other such triggers are lacking. A textbook,written by two experts in the field, suggests that tobacco smokeand allergen exposure are important triggers, and that somechildren may also wheeze in response to mist, crying, laughter orexercise [23]. Although many believe that multiple-triggerwheeze in preschool children reflects chronic allergic airwayinflammation (and could, therefore, be classified as asthma),there is little evidence to support this (see Investigations section).

Retrospective epidemiological description of duration ofwheezeThe outcome and related characteristics of preschool wheezehave been determined by prospective birth cohort studies;however, in individuals, these categories can only be recog-nised retrospectively [1, 4, 5]. Therefore, these phenotypes canonly be used in epidemiological studies and are of no value inclinical practice. Three groups have been recognised (table 1)but it should be stressed that the overlap between these groupsis considerable and that the age limits applied are arbitrary.

In the Tucson birth cohort, 34% of children wheezed during thefirst 3 yrs of life but 60% of these had ceased to wheeze by theage of 6 yrs. As a group, these infants with transient wheezeshow reduced lung function prior to the first respiratoryillness, are exposed to maternal smoking, and are notcharacterised by a personal history of eczema or a familyhistory of asthma [1]. In an attempt to predict which preschoolwheezers continue to wheeze beyond the age of 6 yrs, thesehistory data have been combined with characteristics such asblood eosinophilia into an asthma predictive index [39].Although groups of children with a positive asthma predictiveindex respond to inhaled corticosteroid (ICS) therapy [40, 41],the predictive value of this index for the disappearance orpersistence of wheeze over time in individual patients is ofonly modest clinical value [39].

The 15% of children who started wheezing after the age of 3 yrsand were still wheezing at the age of 6 yrs were defined ashaving late-onset wheeze. This was associated with maternalasthma, male sex and a history of rhinitis [1]. This group tended

to be atopic and show normal lung function at birth and throughthe teenage years [42].

Children who wheezed in the first 3 yrs and continued beyondthe age of 6 yrs were termed persistent wheezers [1]. This wasassociated with normal lung function during the first year oflife, but reduced lung function from the preschool age periodand through adulthood (in most but not all cohort studies),with atopy and a family history of asthma [1, 4, 5].

Long-term outcomeLong-term studies have shown that ,25% of children withpersistent asthma had started to wheeze by the age of6 months and 75% by the age of 3 yrs [1, 4, 5, 43]. Althoughthe long-term outcome of asthma in school-age children hasbeen extensively studied, both at the general population leveland in patients with more severe disease, little evidenceregarding the outcome of preschool wheezing into adulthoodis available. Ongoing birth cohort studies should be able toprovide information on the outcome in general populationsduring the 2010s. Considering more severe early wheeze, halfof the children hospitalised with acute wheeze before the ageof 2 yrs were symptom-free by the age of 5 yrs and 70% by10 yrs, but only 57% by 17–20 yrs [44–46], illustrating thetendency for relapse during adolescence. Female sex, passivesmoking during infancy and early sensitisation to allergenswere risk factors for symptoms continuing into early adult-hood, but type of virus and premature birth were not.

Recommendations: definitions of phenotypes (based onlow-level evidence)1) For clinical purposes, wheeze should be described in termsof its temporal pattern and classified as episodic (viral) ormultiple-trigger wheeze.

2) Use of the terms transient, late-onset and persistent wheezeshould probably be limited to population-based cohort studiesand should not be used clinically.

3) The term asthma should probably not be used in preschoolchildren because data regarding underlying inflammation arelacking.

ASSESSMENTHistory and physical examinationThe purpose of history-taking and physical examination is toconfirm that the preschool child has a wheezing disorder, toidentify the pattern of symptoms, the severity of the conditionand any possible trigger factors, and to look for featuressuggestive of another diagnosis or associated condition. Thedetailed diagnostic tests for these conditions are beyond the scopeof the present report and have been discussed by others [23].

HistoryHistory-taking is the main diagnostic instrument in theassessment of preschool wheeze in those who are notwheezing during the consultation. Accurately identifyingwheeze from the history can be difficult since the term is usedby parents and healthcare workers to describe a variety ofsymptoms [15, 17–19]. Children with doctor-confirmed wheezeexhibit greater airways resistance than children with onlyreported wheeze [47], even though interobserver agreementbetween doctors is poor [48]. A video questionnaire may help



parents to distinguish wheeze from upper airway noises [49].Symptom scoring systems have been insufficiently validated tojustify general use, and validated questionnaires for thispurpose in this particular age group are needed. Noisybreathing is common among infants aged ,6 months but onlya small proportion have wheeze [15]. Reported noisy breathingthat responds to bronchodilator therapy is likely to be genuinewheeze and to be caused, at least in part, by constriction ofairway smooth muscle [50].

Physical examinationNo evidence is available regarding the usefulness of physicalexamination in wheeze assessment. A textbook states that thedegree of airway narrowing can only be estimated crudely andindirectly, by assessing work of breathing (chest retractions,nasal flaring and use of accessory respiratory muscles) and byauscultation of the chest to assess the ratio of expiration toinspiration and the degree of wheeze [23]. Upper airwayobstruction (in particular, nasal congestion) can contribute torespiratory distress. The aim of further physical examination isthe identification of unusual or atypical features that wouldsuggest another underlying condition [23].

InvestigationsThe diagnosis of a preschool wheezing disorder can be madeby history-taking alone. The type, invasiveness and number ofany investigation largely depends upon the degree ofmorbidity and the doubt about the diagnosis [23]. This is amatter of clinical judgement. Most clinicians would agree thatinvestigations are only justified when symptoms are presentfrom birth, airway obstruction is abnormally severe, recoveryis very slow or incomplete (resulting in prolonged or repeatedhospital admission in the first few years of life), episodescontinue in the absence of a viral infection or, sometimes, incases when parents are very anxious [22, 23]. There is littleresearch evidence to guide the choice of investigations. Amonginfants and preschool children with severe persistent symp-toms who were investigated according to a fixed diagnosticprotocol, a considerable number of pathological findings wereobserved suggesting that invasive investigations are justifiedin this category [51, 52].

Microbiological investigationsWith current viral culture and PCR technology, a wide range ofrespiratory viruses can be identified, including the mostcommon causative viruses [28]. There is no evidence, however,that this contributes to management, either in the short term(the acute episode) or in the long term, and it is recommendedonly for research purposes.

Tests of sensitisation to allergensThe reported prevalence of sensitisation in preschool childrenwith wheeze in population studies varies widely [1, 4, 5].Limited evidence is available regarding the prevalence ofsensitisation in preschool children presenting to healthcareworkers with wheeze. One study comparing children aged 2–5 yrs with doctor-confirmed wheeze who were respondingfavourably to a bronchodilator to healthy non-wheezingchildren found that 32% of wheezy children gave positiveskin-prick test results to one or more aeroallergens, comparedto 11% of healthy children (likelihood ratio 2.9) [53].

Sensitisation to inhalant allergens in 1–4-yr-old children fromgeneral practice increases the likelihood of the presence ofasthma at the age of 6 yrs by a factor of two to three [54].Sensitisation to hen’s egg at the age of 1 yr is a reasonablemarker for allergic sensitisation to aeroallergens at the age of3 yrs, with a specificity of .90% and sensitivity of .30% [55].

Total serum immunoglobulin E measurements in early life arenot predictive of outcome [56]. Although elevated eosinophiliccationic protein levels in preschool wheezers are associatedwith symptom persistence [57], the degree of overlap betweengroups renders such measurements useless for clinicalpurposes. Blood eosinophilia can be used as part of an asthmapredictive index, but the predictive value of this index (inparticular, that of a positive result) is low [39].

Radiological examinationsThere is no evidence that chest radiographs help in thediagnosis or treatment of preschool children with acute orrecurrent wheezing [58]. Improvements in diagnostic imagingtechniques may improve understanding of the mechanismsand long-term outcome of early childhood wheezing disordersby providing details about airway structure, airway wallthickness and airway calibre. At present, however, specialisedimaging should be restricted to unusual or severe disease [22].

Measurement of gastro-oesophageal refluxAlthough gastro-oesophageal reflux is common among infantsand preschool children with chronic or recurrent respiratorysymptoms [59], a beneficial effect of demonstrating andtreating gastro-oesophageal reflux in infants with wheeze hasnot been shown.

Lung function testsStudies have shown reduced forced expiratory flows asso-ciated with wheeze [50, 52, 60, 61]. Low lung function inschool-age children [62–64] and infants [65] appears to trackinto early adulthood. It is not known, therefore, whether lungfunction deficits in school-age children with wheezing reflectdevelopmental characteristics of the lung and airways inwheezy children, disease activity while symptomatic orremodelling secondary to airway inflammation. The presenceof airway reactivity in infancy is associated with lowerchildhood lung function and increased risk of asthma in laterchildhood [66], but the mechanisms of airway reactivity in thisage group are poorly understood and probably include factorsother than inflammation [67].

There are no studies supporting the usefulness of pulmonaryfunction tests in children with nonspecific symptoms, or indistinguishing between episodic and multiple-trigger wheeze.In the individual patient, however, determination of lungfunction (and bronchodilator response) in preschool childrencan help in the discrimination of common wheezing disordersfrom other conditions [68, 69].

Exhaled nitric oxide and other assessments of airwaysinflammationElevated exhaled nitric oxide fractions (FeNO) have been found inwheezing infants, especially when they are atopic [70, 71], andthese normalise during treatment with ICSs [72] and montelukast[73, 74]. FeNO in infants are affected by environmental exposures



and genetic predisposition to atopy [75]. Reference values forFeNO are only available for children aged o4 yrs [76]. Foruncooperative children aged ,4 yrs, measurement of FeNO hasnot been standardised and there is no evidence supporting theusefulness of measuring or monitoring FeNO in this age group.Other tests of inflammation, such as analysis of induced sputum,have not been studied at all in preschool children.

Airway wall biopsy and bronchoalveolar lavageFew studies have applied bronchoalveolar lavage or bronchialbiopsy in preschool wheezing disorders. Most such investiga-tions have been performed in children with severe or unusualclinical features, limiting the generalisability of findings. Boththe degree of inflammation and the composition of the infiltratehave been variable, with neutrophils dominating in somestudies, eosinophils in others and no evidence of either inothers [77]. The only consistent finding was thickening of thereticular basement membrane in wheezy children [77], but notin infants (median age 12 months), even when reversible airflowobstruction and atopy were demonstrated [14]. A recent studyshowed that, by a median age of 29 months, some children withconfirmed wheeze exhibit eosinophilic airway inflammationand reticular basement membrane thickening, implying an agewindow at 12–30 months during which interventions aimed atpreventing established airway inflammation might be possible[78]. Further studies of airway inflammation using bronchoal-veolar lavage and bronchial biopsy in large groups ofrepresentative patients with episodic and multiple-triggerwheeze are urgently needed in order to improve understandingof the pathophysiology of preschool wheezing disorders.Unfortunately, such studies are hindered by ethical andpractical constraints. At present, such invasive investigationsshould only be used in unusual cases in specialised centres.

Recommendations: assessment (based on very low-levelevidence)1) The pattern and triggers of wheeze, personal and familyhistory of atopy, and household smoking should be assessedby history-taking.

2) Parentally reported wheeze should be confirmed by a healthprofessional whenever possible.

3) Tests of allergic sensitisation should be performed inpatients requiring long-term treatment and follow-up.

4) Other investigations should probably not be carried outunless wheeze is unusually severe, therapy-resistant oraccompanied by unusual clinical features.

TREATMENT

Environmental manipulationReducing tobacco smoke exposureThere is consistent strong evidence that passive exposure toenvironmental tobacco smoke is harmful, in terms of bothinduction and exacerbation of preschool wheeze [79], andshould be firmly discouraged.

Allergen avoidanceAllergen avoidance to prevent the development of symptoms, ineither the population as a whole or high-risk subgroups(primary prevention), is not discussed here. The rationale for

using environmental control in the treatment of preschool agewheezing to reduce existing symptoms (secondary prevention)is the notion that allergen exposure contributes to the severity ofsymptoms [80]. There is some evidence that exposure toallergens in early life increases the risk of wheezing, but this isdependent upon the allergen, the population and otherenvironmental factors [81]. The combination of sensitisationand high exposure to sensitising allergen in early life isassociated with significantly poorer lung function at the age of3 yrs [82]. Sensitisation to perennial allergens during the first3 yrs of life is associated with reduced lung function at schoolage, with concomitant high exposure to perennial allergensearly in life aggravating this [83]. High allergen exposure duringpreschool age enhances the development of airway hyperre-sponsiveness in sensitised children with wheeze (with later-lifesensitisation and exposure having much weaker effects) [83].

Moving school-age atopic asthmatic children from their homesto the low-allergen environment of high-altitude sanatoriatemporarily improves levels of markers of airway inflamma-tion and asthma severity [84]. Some studies suggest thatallergen avoidance at home may also be of some benefitamongst children of this age range [85, 86]. It remains unclear,however, whether the required major reduction in exposurecan be achieved in normal life and whether it would be ofbeneficial effect in young children since no studies on theeffects of allergen avoidance have been performed in preschoolchildren with wheeze [87].

Parent and patient educationParental knowledge and understanding of wheezing disordersin preschool children and their treatment is often inadequate(especially with respect to medication and the preceding signsand preventive actions) [88]; however, few educational studiesin wheezy children have explicitly focused on the preschoolage group.

Many educational studies have included children aged asyoung as 2 yrs, but the age range of the study group isfrequently not described, and there is rarely an analysis ofwhether outcomes are different in younger children. Forexample, the Cochrane Review on educational interventions inchildren and adolescents aged 2–18 yrs with asthma includedno separate analysis of outcomes in younger children [89].Indeed, of the 32 studies included in the review, only onestudied preschool children exclusively [90]; two other studiesthat included children aged ,2 yrs were excluded.

Of the few studies in preschool children, those that haveutilised multiple teaching sessions have shown improvementsin morbidity, with more symptom-free days and bettercaregiver quality of life [90, 91], as well as improved knowl-edge and improved self-efficacy [92], and outcomes similar tothose in older children. These studies all used differentformats: reading of a home booklet followed by practitionerreview on next consultation [92], small group teaching bynurses [90] and home-based education [91]. One other largerandomised controlled trial in preschool children with acutewheeze found no effect of an education programme uponsubsequent healthcare utilisation, disability score, parent’squality of life and parental knowledge of asthma [93]. Thisstudy included two structured 20-min one-to-one sessions, the



first during hospital attendance and the other 1 month later.This raises the possibility that multiple educational sessions oflonger duration might be more effective in preschool children.

Virtually all studies in preschool children have targetededucation at parents or carers. However, young childrenthemselves may benefit from asthma education and practicaltraining in skills. One study found that children aged 2–5 yrswho were exposed to a developmentally appropriate educa-tional intervention that included a picture book and video tapeshowed improved asthma knowledge, as well as bettercompliance and health, compared to controls [94].

Therefore, although educating parents of preschool childrenwith wheeze (and perhaps also the children themselves)appears effective, and is advised, more work is needed beforespecific educational approaches can be recommended.

Pharmacological therapy

Short-acting b2-agonists

Inhaled rapidly acting b2-agonists are the most effectivebronchodilators available, and, therefore, the drugs of choicefor acute symptoms of wheeze. Double-blind placebo-con-trolled studies have demonstrated significant bronchodilatoryeffects [95–98] and protective effects against bronchoconstric-tor agents [99, 100] in infants and preschool children treatedwith rapidly acting inhaled b2-agonist. Thus, infants possessfunctional b2-receptors from birth, and stimulation of thesereceptors can produce the same effects as in older children,although paradoxical responses to inhaled b2-agonists havebeen reported in infants [50, 101]. Oral administration of b2-agonist is also effective but is limited by systemic side-effects[102]. Intravenous infusion of b2-agonists has only shown anadvantage over hourly inhaled treatment in very severe acutewheeze in young children [103].

After inhalation, b2-agonists are usually well tolerated. Side-effects, such as muscle tremor, headache, palpitations, agita-tion and hypokalaemia, are only seen when high doses areused [104].

Single-isomer R-albuterol is theoretically preferable (althoughmuch more expensive) to the racemic mixture of albuterolsince the S-isomer is therapeutically inactive [104]. There is,however, no evidence regarding the clinical effectiveness orsuperiority of the use of R-albuterol compared to the racemicmixture in this age group.

Long-acting inhaled b2-agonists

Formoterol and salmeterol have shown long-lasting broncho-dilatory and bronchoprotective effects in preschool children[99, 105]. There are no published double-blind randomisedplacebo-controlled trials in preschool children on the additionof long-acting inhaled b2-adrenergic agents to ICSs.

Inhaled corticosteroids

Treatment with ICSs may be considered for the treatment ofcurrent symptoms, or possibly for the prevention of progres-sion of symptoms (disease modification). Each is considered inturn, as follows.

Inhaled corticosteroids in treatment of symptoms of multiple-trigger wheeze

A systematic review of randomised double-blind controlledtrials of inhaled glucocorticosteroids in preschool children withmultiple-trigger wheeze has shown significant improvements inimportant health outcomes, including symptoms, exacerbationrates, lung function and airway hyperresponsiveness [106]. Thetreatment effect appears to be smaller than that seen in school-age children and adults. For example, studies of ICSs inpreschool children with multiple-trigger wheeze have reporteda reduction in exacerbations by ,50% [107, 108]. Compared toplacebo, children using 200 mg?day-1 fluticasone exhibit a meanof 5% fewer days with symptoms [106].

The dose–response relationship of ICSs in preschool children isnot entirely clear. Dose-related effects have been shown forexacerbation rate on treatment with daily ICS doses of up to400 mg?day-1 beclometasone equivalent (or 200 mg?day-1 flutica-sone) via pressurised metered-dose inhaler (pMDI) with spacer(pMDI-S) [107], without any further benefit from higher doses.Comparison of 0.25, 0.5 and 1.0 mg nebulised budesonide daily,however, showed similar improvement to that with placebo inone study [109], whereas another suggested a dose relation inthe range 0.25–1.0 mg nebulised budesonide b.i.d. [110]. Markedindividual variations in response are seen between patients. In apost hoc analysis of two large randomised controlled trials inyoung children (aged 12–47 months), those with frequentsymptoms, aged .2 yrs and/or with a family history of asthmashowed the best response to treatment with fluticasone(200 mg?day-1), whereas those with less frequent symptoms,without a family history of asthma and aged ,2 yrs showed nosignificant treatment effect [111]. Two recent studies usinginhaled fluticasone to treat wheezy infants and preschoolchildren failed to find any improvement in lung function [112,113]. Atopic markers, such as a history of atopic dermatitis orallergic rhinitis, did not improve the chance of responding toICSs [111]. However, preschool children with wheeze, selectedbased on the asthma predictive index for the prediction ofpersistent wheeze (including atopic dermatitis, allergic rhinitisand eosinophilia), respond to ICSs as a group [40, 41].

Local side-effects, such as hoarseness and candidiasis, are rarein preschool children [114], probably because medication isusually delivered by metered-dose inhaler with spacer (MDI-S)combination. Studies on the systemic side-effects of inhaledsteroids have yielded inconsistent results. In a 1-yr study of200 mg?day-1 fluticasone in preschool children, height growthwas similar in the fluticasone-treated children to that in thecromoglycate-treated children [114]. In another study, how-ever, height growth was reduced by 1.1 cm after 2 yrs ofinhaled 200 mg?day-1 fluticasone compared with placebo [41].The long-term consequences of inhaled steroid therapy ongrowth in preschool children have not been studied. Clinicallyrelevant effects on adrenal function have only been observed inchildren receiving high doses of ICSs (.400 mg?day-1 beclo-metasone equivalent) [106]. The risk of cataract was notincreased in a study of 358 children aged 1–3 yrs receivingdaily treatment with ICSs for o1 yr [114]. No other potentialsystemic side-effects have been studied in preschool children.

Thus ICSs are effective in preschool children with multiple-trigger wheeze, but the effect is smaller than that in older



children, and there is some concern about the effect on height.This justifies a more critical approach to long-term ICS use inpreschool children with multiple-trigger wheeze than in olderchildren and adults with asthma. Many clinicians tend first togive a trial of ICS for a period of ,3 months. If there is noimprovement, the treatment should not be stepped up butstopped, and further investigations should be carried out inorder to identify the cause of symptoms. If preschool childrenwith multiple-trigger wheeze respond well to ICS therapy, it isunclear whether this is due to treatment or the naturalresolution of symptoms. It is recommended, therefore, thattreatment be withdrawn in children who become (almost)completely free of wheeze after ICS therapy. There are alsoclinicians who only continue treatment with ICSs in multiple-trigger wheeze if symptoms recur after withdrawal, andrespond to reintroduction of the medication.

Inhaled corticosteroids in treatment of symptoms of episodic(viral) wheeze

The clinical benefits of ICSs for episodic (viral) wheeze arecontroversial [106]. Systematic reviews have concluded thatepisodic high-dose inhaled glucocorticosteroids (1,600–3,200 mg?day-1 budesonide) provide some benefit in episodic(viral) wheeze (with a 50% reduction in the requirement for oralsteroids, but no effect on hospitalisation rates or duration ofsymptoms), but that maintenance treatment with 400 mg?day-1

beclometasone equivalent does not reduce the number or theseverity of wheezing episodes in episodic (viral) wheeze [106,115]. It should be emphasised that the available evidence isbased on a few small trials that may be underpowered for thedetection of a treatment effect. For example, the study on theeffect of maintenance treatment with ICSs in episodic (viral)wheeze analysed only 41 patients [116]. The most recent study,published only in abstract form, showed that intermittenttreatment with 1.5 mg?day-1 fluticasone for f10 days forepisodic (viral) wheeze reduced the severity and duration ofsymptoms but at a cost of slightly reduced height [117]. Thus,the use of high-dose intermittent steroids in this age grouprequires careful consideration.

Nasal corticosteroids to reduce episodic (viral) wheeze

Although treatment of allergic rhinitis may help to ameliorateasthma in school-age children and adolescents, a randomisedcontrolled trial of nasal corticosteroids in preschool childrenwith recurrent wheeze failed to demonstrate any benefit [118].

Treatment of episodic (viral) wheeze in preschool children toreduce risk of persistent wheeze during later childhood

Three randomised controlled trials (two on daily ICSs and oneon intermittent use when the child was wheezy) have shownthat use of ICSs in preschool children with episodic (viral)wheeze does not reduce the risk of persistent wheeze at the ageof 6 yrs, and that symptoms return when steroid therapy isdiscontinued [41, 119, 120].

Systemic glucocorticosteroids

A systematic review of systemic corticosteroids in hospitalisedchildren with acute asthma found that corticosteroid-treatedchildren were seven times more likely to be discharged earlythan placebo-treated children, and five times less likely torelapse within 1–3 months following discharge (number

needed to treat 3) [121]. Although that review included severalstudies in preschool children, they were not analysedseparately. A systematic review of two studies found noevidence that parent-initiated oral corticosteroids are asso-ciated with a benefit in terms of hospital admissions,unscheduled medical reviews, symptoms scores, bronchodi-lator use, parent and patient impressions, physician assess-ment, or days lost from work or school [122].

Leukotriene modifiersMontelukast is the only cysteinyl leukotriene receptor antago-nist licensed for the treatment of young children, at a dosage of4 mg orally once daily. No clinically relevant side-effects havebeen reported [123].

Montelukast in multiple-trigger wheeze

In two studies, montelukast provided protection againstbronchoconstriction induced by hyperventilation with colddry air, and improved airways hyperresponsiveness by onedoubling dose after 4 weeks, compared to placebo [124, 125].The bronchoprotective effect was independent of concurrentsteroid treatment. In a multicentric study of 689 young childrenwith multiple-trigger wheeze, montelukast improved symp-toms and achieved a 30% reduction in exacerbations [123]. Onerecent study showed that nebulised budesonide was moreeffective at reducing exacerbation rates in 2–8-yr-old childrenwith multiple-trigger wheeze than oral montelukast [126]. Sincepreschool children were not analysed separately, it is not knownwhether this difference in efficacy also applies to this age range.

Montelukast in episodic (viral) wheeze

Daily use of montelukast over a 1-yr period reduced the rate ofwheezing episodes in 549 children with episodic (viral) wheezeby 32% compared to placebo (number needed to treat 12) [127].A trial of intermittent montelukast, started when patientsdeveloped signs of a common cold, compared with placebo in220 children with episodic wheeze showed a 30% reduction inunscheduled health visits (number needed to treat 11), but noeffect on hospitalisations, duration of episode, and b-agonistand prednisolone use [128].

CromonesClinical documentation regarding sodium cromoglycate use inpreschool children is sparse and there are no reports oninfants. The Cochrane Review concluded that a beneficial effectof cromolyn therapy in preschool children with multiple-trigger wheeze could not be proven [129]. Most studies were ofpoor quality, but one well-designed randomised controlledtrial found no effect on symptom scores or exacerbationfrequency in children aged 1–4 yrs with multiple-triggerwheeze [130]. No studies have been performed with nedocro-mil in preschool children.

XanthinesThe Cochrane Review on the effects of xanthines (theophyllineand aminophylline) in the chronic treatment of children withasthma, the effects on symptoms and exacerbations of wheezein preschool children were small and mostly nonsignificant[131]. The studies were all small however. There have been nogood studies comparing xanthines to other medications inpreschool wheeze.



Anticholinergic agents

In the Cochrane Review it was concluded that inhaledipratropium may be beneficial in older children [132], butthere is no good evidence in preschool children [133]. There areno important side-effects when ipratropium is inhaled byMDI-S combination.

Antihistamines

The antihistamines ketotifen and cetirizine have been studiedin preschool wheeze. In the Cochrane Review it was concludedthat children treated with ketotifen were 2.4 times as likely tobe able to reduce or stop bronchodilator treatment than thosetreated with placebo. There were also less consistent benefitswith respect to asthma symptoms and exacerbations [134]. Theinterpretation of these studies, however, is hampered by thefact that the description of patients is insufficient to classifythem as having episodic (viral) wheeze or multiple-triggerwheeze. In addition, the initial favourable reports in the 1980swere never confirmed in later studies. There are no goodstudies comparing ketotifen to other asthma medications.

Cetirizine was compared to placebo in a randomised trial ininfants with atopic dermatitis, with the aim of preventing thedevelopment of asthma. At the age of 3 yrs, there was nodifference in wheeze prevalence between the two groups. In apost-hoc analysis in a subgroup of patients radioallergosorbenttest-positive for cat, house dust mite or grass pollen, thereappeared to be a protective effect of cetirizine [135]. This needsto be confirmed in further studies. There are no studies ofcetirizine in preschool children with wheeze.

Other treatment options

No studies have been performed on the effects of immu-notherapy or influenza immunisation in preschool childrenwith wheeze.

Delivery devicesAs a general principle, inhaled drug delivery is preferable tothe oral and parenteral routes, in order to provide rapid reliefof symptoms and minimise systemic side-effects. Inhalationtherapy in preschool children is hampered by numerousfactors, including narrower airways, increased turbulence,deposition high in the respiratory tree, and lack of cooperationand coordination. Although there is anecdotal evidencesuggesting that some preschool children may be able to usedry powder inhalers effectively and reliably [136], there isconsensus among experts that these devices should not beused in preschool children because they lack the ability togenerate sufficiently high inspiratory flows [137]. Similarly,pMDIs cannot be used by preschool children without the useof a spacer device because of difficulties in the appropriatetiming of the inspiratory effort. The two inhalation systems tobe considered, therefore, are pMDI-S and nebuliser.

A systematic review has shown that the delivery of inhaled b2-agonists by pMDI-S in acutely wheezy infants and preschoolchildren is more effective than by nebuliser; recovery wasquicker and the risk of hospital admission was reduced by 60%[138]. There are no studies comparing the two delivery devicesfor long-term management. The economic, practical andhygienic advantages of pMDI-S over nebulisers support the

use of pMDI-S as the preferred means of delivery of inhaleddrugs in preschool children.

Although there is no formal evidence to support this, there isconsensus that cooperative children should use a spacer devicewith a mouthpiece wherever possible [137]. Noncooperativechildren aged ,3 yrs should use a spacer with a face mask; atight face mask seal is considered important for optimal drugdelivery. Crying children are unlikely to receive any drug tothe lower airways [139].

Filter studies have shown high day-to-day variability indelivered doses in preschool children [140]. This should beborne in mind when prescribing therapy and judging its effects.

If a spacer is used, it should be noted that electrostatic chargereduces MDI-S delivery. New unwashed and unprimed plasticspacers are electrostatically charged, and, therefore, yieldreduced drug delivery [141]. This can be overcome by washingthe plastic spacer in detergent and allowing it to drip dry,priming it with 5–10 puffs of aerosol or using a metal spacer.There are no data on the safety of the detergent washing methodhowever. Since priming with aerosol is the most expensive andwasteful method of the three, it is not recommended.

Methodological considerationsIn accordance with others [106], the Task Force found itdifficult to synthesise the evidence on the efficacy of treatmentin preschool wheeze for a number of reasons. First, inclusioncriteria were commonly unclear. Studies have includedchildren with asthma or wheeze without further specification.Even when inclusion criteria were specified, pooling suchstudies was frequently impossible because of clinical hetero-geneity or the lack of distinction of different phenotypes.Secondly, treatment (agents, dosages and delivery devices)differed considerably between studies. Thirdly, different out-come parameters have been studied, most of which wereneither standardised nor validated. Fourthly, the number ofstudies and the number of patients enrolled was generallyquite low, especially for studies on ICSs in episodic wheeze.Fifthly, given the fact that symptoms of wheeze in preschoolchildren tend to resolve spontaneously and that the mosttroublesome symptoms occur episodically, adherence totreatment by parents and caregivers is probably low, althoughfew studies have examined this. The one study specificallyaddressing this found that parents of preschool children withtroublesome wheeze would not give their child a broncho-dilator on 40% of the occasions when the child was wheezy,even though they knew their adherence was monitored andeven though they were instructed to administer inhaledbronchodilator when their child was wheezing [142]. Finally,age appears to be an important effect modifier, in that theyounger the child is, the poorer the response to any treatment.

Recommendations for treatment (based on low-levelevidence unless otherwise specified)1) Passive smoking is deleterious to preschool children withwheeze, as at all ages (high-level evidence), and should befirmly discouraged.

2) There is insufficient evidence on which to base recommend-ations for the reduction of exposure to environmental allergensin the treatment of preschool wheezing.



3) An educational programme using multiple teaching sessionson causes of wheeze, recognising warning signals andtreatment should be provided to parents of wheezy preschoolchildren.

4) A pMDI-S combination should be used as the preferreddelivery device for inhalation therapy in preschool children(high-level evidence).

5) In cooperative children, spacers with a mouthpiece shouldprobably be used.

6) In uncooperative young children, spacers with a tight-fittingface mask should probably be used.

7) Plastic spacers should be treated with detergent before usein order to reduce their electrostatic charge.

Acute wheezing episode1) Inhaled short-acting b2-agonists on an as-needed basisshould be used for the symptomatic treatment of acutewheezing in preschool children. These drugs should be usedcautiously in infants since paradoxical responses have beenreported in this age group.

2) Alternative routes of administration (oral and intravenous)should not be used.

3) Single-isomer salbutamol should not be used.

4) Addition of ipratropium bromide to short-acting b2-agonistsmay be considered in patients with severe wheeze.

5) A trial of oral corticosteroids should probably be given topreschool children with acute wheeze of such severity thatthey need to be admitted to hospital.

6) Parent-initiated treatment with a short course of oralcorticosteroids should not be given.

7) Although high-dose ICS therapy appears to have a smallbeneficial effect in the treatment of acute wheezing inpreschool children, this treatment is not recommended becauseof high cost and lack of comparison to bronchodilator therapy.

Maintenance treatment of multiple-trigger wheeze1) ICSs at a daily dose of up to 400 mg?day-1 beclometasoneequivalent should be given for the treatment of preschoolchildren with multiple-trigger wheeze.

2) When the response to this treatment is poor, patients shouldnot be treated with higher doses but should probably be referredto a specialist for further evaluation and investigations.

3) If response to inhaled steroids is favourable, treatmentshould probably be discontinued after several weeks ormonths, in order to judge whether symptoms have resolvedor whether ongoing treatment is needed.

4) Linear growth should be measured in preschool childrenusing ICSs.

5) Infants younger than 1 yr should probably not be prescribedICSs.

6) Infants aged 1–2 yrs should only be prescribed ICSs if theirsymptoms are troublesome and they show a clear-cut responseto treatment.

7) A trial of montelukast may be considered in preschoolchildren with multiple-trigger wheeze.

8) Cromones, ketotifen and xanthines are not recommendedfor use in preschool children with wheeze.

9) Immunotherapy is not recommended for preschool childrenwith wheeze outside the setting of a randomised controlledtrial.

10) Influenza immunisation is not recommended for preschoolchildren with wheeze.

Maintenance treatment of episodic (viral) wheeze1) Montelukast 4 mg once daily should probably be given forthe treatment of episodic (viral) wheeze.

2) A trial of inhaled corticosteroids may be considered inpreschool children with episodic (viral) wheeze, in particularwhen episodes occur frequently or if the family history ofasthma is positive.

ACKNOWLEDGEMENTSThe affiliation details of the present study’s authors are asfollows. P.L.P. Brand: Princess Amalia Children’s Clinic, IsalaClinics, Zwolle; J.C. de Jongste: Dept of Paediatric RespiratoryMedicine, Erasmus Medical Centre/Sophia Children’sHospital, Rotterdam; P.J.F.M. Merkus: Dept of Paediatrics,Division of Respiratory Medicine, Children’s Hospital,Radboud Medical Centre Nijmegen, Nijmegen; and W.M.C.van Aalderen: Dept of Paediatric Pulmonology, EmmaChildren’s Hospital, Academic Medical Centre, Amsterdam(all the Netherlands). E. Baraldi: Dept of Paediatrics, Unit ofRespiratory Medicine and Allergy, Unit of Neonatal IntensiveCare, University of Padua School of Medicine, Padua; A.L.Boner and G. Piacentini: Dept of Paediatrics, G.B. RossiPolyclinic, Verona; F. Midulla: Dept of Paediatric Emergency,University of Rome La Sapienza, Rome; and G.A. Rossi:Pulmonary Disease Unit, G. Gaslini Institute, Genoa (all Italy).H. Bisgaard: Danish Paediatric Asthma Centre, CopenhagenUniversity Hospital, Copenhagen, Denmark. J.A. Castro-Rodriguez: School of Medicine, Pontifical Catholic Universityof Chile, Santiago, Chile. A. Custovic: North West LungResearch Centre, Wythenshawe Hospital, Manchester; M.L.Everard: University Division of Child Health, SheffieldChildren’s Hospital, Sheffield; J. Grigg: Academic Unit ofPaediatrics, Institute of Cell and Molecular Science, Barts andThe London Medical School, London; S. McKenzie: FieldenHouse, Royal London Hospital, Barts and The London NHSTrust, London; N. Wilson: Dept of Paediatrics, RoyalBrompton Hospital, London; A. Bush: Dept of PaediatricRespirology, National Heart and Lung Institute, RoyalBrompton Hospital and Imperial College, London; W.Lenney: Academic Dept of Child Health, University Hospitalof North Staffordshire, Stoke-on-Trent; J.Y. Paton: UniversityDivision of Developmental Medicine, Yorkhill Hospitals,Glasgow; P. Seddon: Royal Alexandra Children’s Hospital,Brighton; and M. Silverman: Dept of Infection, Inflammationand Immunology, University of Leicester, Leicester (all UK).J. de Blic: Paediatric Pneumology and Allergology Service,Paris Public Assistance Hospitals, Necker Hospital for SickChildren, Paris, France. E. Eber: Respiratory and AllergicDisease Division, Dept of Paediatrics and Adolescent



Medicine, Medical University of Graz, Graz, Austria. U. Frey:Paediatric Respiratory Medicine, Inselspital, Berne UniversityHospital and University of Berne, Berne; and J.H. Wildhaber:Dept of Paediatrics, Fribourg Bertigny Hospital, Fribourg (allSwitzerland). M. Gappa: Dept of Paediatric Pulmonology andNeonatology, Medical University of Hanover, Hanover,Germany. L. Garcia-Marcos: Institute of Respiratory Health,University of Murcia, Murcia, Spain. P. Le Souef: School ofPaediatrics and Child Health; P.D. Sly: Division of ClinicalSciences, Telethon Institute for Child Health Research, Centrefor Child Health Research; and S. Stick: Centre for Asthma,Allergy and Respiratory Research (all University of WesternAustralia, Perth, Australia). P. Pohunek: Motol UniversityHospital, Prague, Czech Republic. A. Valiulis: Vilnius CityUniversity Hospital, Vilnius, Lithuania. G. Wennergren: Deptof Paediatrics, Gothenburg University, Queen Silvia Children’sHospital, Gothenburg, Sweden. Z. Zivkovic: Centre forPaediatric Pulmonology, Dr Dragisa Misovic Medical Centre,Belgrade, Serbia.

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40 Teper AM, Kofman CD, Szulman GA, Vidaurreta SM,Maffey AF. Fluticasone improves pulmonary function inchildren under 2 years old with risk factors for asthma.Am J Respir Crit Care Med 2005; 171: 587–590.

41 Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-terminhaled corticosteroids in preschool children at high riskfor asthma. N Engl J Med 2006; 354: 1985–1997.

42 Taussig LM, Wright AL, Holberg CJ, Halonen M,Morgan WJ, Martinez FD. Tucson children’s respiratorystudy: 1980 to present. J Allergy Clin Immunol 2003; 111:661–675.

43 Hess J, de Jongste JC. Epidemiological aspects ofpaediatric asthma. Clin Exp Allergy 2004; 34: 680–685.

44 Goksor E, Amark M, Alm B, Gustafsson PM,Wennergren G. Asthma symptoms in early childhood –what happens then? Acta Paediatr 2006; 95: 471–478.

45 Wennergren G, Hansson S, Engstrom I, et al. Character-istics and prognosis of hospital-treated obstructivebronchitis in children aged less than two years. ActaPaediatr 1992; 81: 40–45.

46 Piippo-Savolainen E, Remes S, Kannisto S, Korhonen K,Korppi M. Asthma and lung function 20 years afterwheezing in infancy: results from a prospective follow-up study. Arch Pediatr Adolesc Med 2004; 158: 1070–1076.

47 Lowe L, Murray CS, Martin L, et al. Reported versusconfirmed wheeze and lung function in early life. ArchDis Child 2004; 89: 540–543.

48 Elphick HE, Lancaster GA, Solis A, Majumdar A,Gupta R, Smyth RL. Validity and reliability of acoustic

analysis of respiratory sounds in infants. Arch Dis Child2004; 89: 1059–1063.

49 Saglani S, McKenzie SA, Bush A, Payne DN. A videoquestionnaire identifies upper airway abnormalities inpreschool children with reported wheeze. Arch Dis Child2005; 90: 961–964.

50 Hofhuis W, van der Wiel EC, Tiddens HAWM, et al.Bronchodilation in infants with malacia or recurrentwheeze. Arch Dis Child 2003; 88: 246–249.

51 Saglani S, Nicholson AG, Scallan M, et al. Investigation ofyoung children with severe recurrent wheeze: anyclinical benefit? Eur Respir J 2006; 27: 29–35.

52 Saito J, Harris WT, Gelfond J, et al. Physiologic,bronchoscopic, and bronchoalveolar lavage fluid findingsin young children with recurrent wheeze and cough.Pediatr Pulmonol 2006; 41: 709–719.

53 Chan EY, Dundas I, Bridge PD, Healy MJ, McKenzie SA.Skin-prick testing as a diagnostic aid for childhoodasthma. Pediatr Pulmonol 2005; 39: 558–562.

54 Eysink PE, ter Riet G, Aalberse RC, et al. Accuracy ofspecific IgE in the prediction of asthma: development of ascoring formula for general practice. Br J Gen Pract 2005;55: 125–131.

55 Nickel R, Kulig M, Forster J, et al. Sensitization to hen’segg at the age of twelve months is predictive for allergicsensitization to common indoor and outdoor allergens atthe age of three years. J Allergy Clin Immunol 1997; 99:613–617.

56 Rusconi F, Patria MF, Cislaghi GU, Sideri S, Gagliardi L.Total serum IgE and outcome in infants with recurrentwheezing. Arch Dis Child 2001; 85: 23–25.

57 Koller DY, Wojnarowski C, Herkner KR, et al. High levelsof eosinophil cationic protein in wheezing infants predictthe development of asthma. J Allergy Clin Immunol 1997;99: 752–756.

58 Hederos CA, Janson S, Andersson H, Hedlin G. Chest X-ray investigation in newly discovered asthma. PediatrAllergy Immunol 2004; 15: 163–165.

59 Sheikh S, Stephen T, Howell L, Eid N. Gastroesophagealreflux in infants with wheezing. Pediatr Pulmonol 1999; 28:181–186.

60 Neve V, Edme JL, Devos P, et al. Spirometry in 3–5-year-oldchildren with asthma. Pediatr Pulmonol 2006; 41: 735–743.

61 Young S, Arnott J, O’Keeffe PT, Le Souef PN, Landau LI.The association between early life lung function andwheezing during the first 2 yrs of life. Eur Respir J 2000;15: 151–157.

62 de Gooijer A, Brand PLP, Gerritsen J, Koeter GH,Postma DS, Knol K. Changes in respiratory symptomsand airway reactivity after 27 years in a population-basedsample of school children. Eur Respir J 1993; 6: 848–854.

63 Roorda RJ, Gerritsen J, van Aalderen WMC, et al. Follow-up of asthma from childhood to adulthood: influence ofpotential childhood risk factors on the outcome ofpulmonary function and bronchial responsiveness inadulthood. J Allergy Clin Immunol 1994; 93: 575–584.

64 Sears MR, Greene JM, Willan AR, et al. A longitudinal,population-based, cohort study of childhood asthmafollowed to adulthood. N Engl J Med 2003; 349: 1414–1422.

65 Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD.Poor airway function in early infancy and lung function



by age 22 years: a non-selective longitudinal cohortstudy. Lancet 2007; 370: 758–764.

66 Turner SW, Palmer LJ, Rye PJ, et al. The relationshipbetween infant airway function, childhood airwayresponsiveness, and asthma. Am J Respir Crit Care Med2004; 169: 921–927.

67 Kim DK, Choi SH, Yu J, Yoo Y, Koh YY. Bronchialresponsiveness to methacholine and adenosine 59-mono-phosphate in atopic and non-atopic preschool childrenwith recurrent wheezing. Clin Exp Allergy 2007; 37: 15–21.

68 Nielsen KG, Bisgaard H. Discriminative capacity ofbronchodilator response measured with three differentlung function techniques in asthmatic and healthychildren aged 2 to 5 years. Am J Respir Crit Care Med2001; 164: 554–559.

69 Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnosticaccuracy of bronchodilator responsiveness in wheezychildren. Thorax 2005; 60: 13–16.

70 Gabriele C, Nieuwhof EM, van der Wiel EC, et al. Exhalednitric oxide differentiates airway diseases in the first twoyears of life. Pediatr Res 2006; 60: 461–465.

71 Baraldi E, Dario C, Ongaro R, et al. Exhaled nitric oxideconcentrations during treatment of wheezing exacerba-tion in infants and young children. Am J Respir Crit CareMed 1999; 159: 1284–1288.

72 Moeller A, Franklin P, Hall GL, et al. Inhaled fluticasonedipropionate decreases levels of nitric oxide in recurrentwheezy infants. Pediatr Pulmonol 2004; 38: 250–255.

73 Straub DA, Moeller A, Minocchieri S, et al. The effect ofmontelukast on lung function and exhaled nitric oxide ininfants with early childhood asthma. Eur Respir J 2005; 25:289–294.

74 Straub DA, Minocchieri S, Moeller A, Hamacher J,Wildhaber JH. The effect of montelukast on exhalednitric oxide and lung function in asthmatic children 2 to5 years old. Chest 2005; 127: 509–514.

75 Frey U, Kuehni C, Roiha H, et al. Maternal atopic diseasemodifies effects of prenatal risk factors on exhaled nitricoxide in infants. Am J Respir Crit Care Med 2004; 170:260–265.

76 Buchvald F, Baraldi E, Carraro S, et al. Measurements ofexhaled nitric oxide in healthy subjects age 4 to 17 years. JAllergy Clin Immunol 2005; 115: 1130–1136.

77 Wildhaber JH, Sennhauser FH, Brand PLP. Asthma inschool-aged children and adolescents. In: Frey U,Gerritsen J, eds. Respiratory Diseases in Infants andChildrend. Eur Respir Mon 2006; 11: 191–216.

78 Saglani S, Payne DN, Zhu J, et al. Early detection ofairway wall remodelling and eosinophilic inflammationin preschool wheezers. Am J Respir Crit Care Med 2007;176: 858–864.

79 Strachan DP, Cook DG. Parental smoking and lowerrespiratory illness in infancy and early childhood. Thorax1997; 52: 905–914.

80 Murray CS, Poletti G, Kebadze T, et al. Study of modifiablerisk factors for asthma exacerbations: virus infection andallergen exposure increase the risk of asthma hospitaladmissions in children. Thorax 2006; 61: 376–382.

81 Torrent M, Sunyer J, Garcia R, et al. Early-life allergenexposure and atopy, asthma, and wheeze up to 6 years ofage. Am J Respir Crit Care Med 2007; 176: 446–453.

82 Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A,Custovic A. Lung function at age 3 years: effect of petownership and exposure to indoor allergens. Arch PediatrAdolesc Med 2004; 158: 996–1001.

83 Illi S, von Mutius E, Lau S, Niggemann B, Gruber C,Wahn U. Perennial allergen sensitisation early in life andchronic asthma in children: a birth cohort study. Lancet2006; 368: 763–770.

84 Peroni DG, Piacentini GL, Costella S, et al. Mite avoidancecan reduce air trapping and airway inflammation in allergicasthmatic children. Clin Exp Allergy 2002; 32: 850–855.

85 Custovic A, Wijk RG. The effectiveness of measures tochange the indoor environment in the treatment ofallergic rhinitis and asthma: ARIA update (in collabora-tion with GA2LEN). Allergy 2005; 60: 1112–1115.

86 Morgan WJ, Crain EF, Gruchalla RS, et al. Results of ahome-based environmental intervention among urbanchildren with asthma. N Engl J Med 2004; 351: 1068–1080.

87 Gore RB, Custovic A. Is allergen avoidance effective? ClinExp Allergy 2002; 32: 662–666.

88 Mesters I, Pieterse M, Meertens R. Pediatric asthma, aqualitative and quantitative approach to needs assess-ment. Patient Educ Couns 1991; 17: 23–34.

89 Wolf FM, Guevara JP, Grum CM, Clark NM, Cates CJ.Educational interventions for asthma in children.Cochrane Database Syst Rev 2003; Issue 4: CD000326.

90 Wilson SR, Latini D, Starr NJ, et al. Education of parentsof infants and very young children with asthma: adevelopmental evaluation of the Wee Wheezers program.J Asthma 1996; 33: 239–254.

91 Brown JV, Bakeman R, Celano MP, Demi AS,Kobrynski L, Wilson SR. Home-based asthma educationof young low-income children and their families. J PediatrPsychol 2002; 27: 677–688.

92 Mesters I, Meertens R, Kok G, Parcel GS. Effectiveness ofa multidisciplinary education protocol in children withasthma (0–4 years) in primary health care. J Asthma 1994;31: 347–359.

93 Stevens CA, Wesseldine LJ, Couriel JM, Dyer AJ,Osman LM, Silverman M. Parental education and guidedself-management of asthma and wheezing in the pre-school child: a randomised controlled trial. Thorax 2002;57: 39–44.

94 Holzheimer L, Mohay H, Masters IB. Educating youngchildren about asthma: comparing the effectiveness of adevelopmentally appropriate asthma education videotape and picture book. Child Care Health Dev 1998; 24:85–99.

95 Holmgren D, Bjure J, Engstrom I, Sixt R, Sten G,Wennergren G. Transcutaneous blood gas monitoringduring salbutamol inhalations in young children with acuteasthmatic symptoms. Pediatr Pulmonol 1992; 14: 75–79.

96 Kraemer R, Frey U, Sommer CW, Russi E. Short-termeffect of albuterol, delivered via a new auxiliary device, inwheezy infants. Am Rev Respir Dis 1991; 144: 347–351.

97 Conner WT, Dolovich MB, Frame RA, Newhouse MT.Reliable salbutamol administration in 6- to 36-month-oldchildren by means of a metered dose inhaler andAerochamber with mask. Pediatr Pulmonol 1989; 6:263–267.



98 Pool JB, Greenough A, Gleeson JG, Price JF. Inhaledbronchodilator treatment via the nebuhaler in youngasthmatic patients. Arch Dis Child 1988; 63: 288–291.

99 Nielsen KG, Bisgaard H. Bronchodilation and broncho-protection in asthmatic preschool children from formo-terol administered by mechanically actuated dry-powderinhaler and spacer. Am J Respir Crit Care Med 2001; 164:256–259.

100 Avital A, Godfrey S, Schachter J, Springer C. Protectiveeffect of albuterol delivered via a spacer device(Babyhaler) against methacholine induced bronchocon-striction in young wheezy children. Pediatr Pulmonol1995; 17: 281–284.

101 Prendiville A, Green S, Silverman M. Airway respon-siveness in wheezy infants: evidence for functional betaadrenergic receptors. Thorax 1987; 42: 100–104.

102 Fox GF, Marsh MJ, Milner AD. Treatment of recurrentacute wheezing episodes in infancy with oral salbutamoland prednisolone. Eur J Pediatr 1996; 155: 512–516.

103 Browne GJ, Penna AS, Phung X, Soo M. Randomised trialof intravenous salbutamol in early management of acutesevere asthma in children. Lancet 1997; 349: 301–305.

104 Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M,Baumgartner RA. Evaluation of the safety and efficacy oflevalbuterol in 2–5-year-old patients with asthma. PediatrPulmonol 2005; 40: 477–486.

105 Primhak RA, Smith CM, Yong SC, et al. The bronchopro-tective effect of inhaled salmeterol in preschool children:a dose-ranging study. Eur Respir J 1999; 13: 78–81.

106 Kaditis AG, Winnie G, Syrogiannopoulos GA. Anti-inflammatory pharmacotherapy for wheezing in pre-school children. Pediatr Pulmonol 2007; 42: 407–420.

107 Bisgaard H, Gillies J, Groenewald M, Maden C, anInternational Study Group, The effect of inhaled flutica-sone propionate in the treatment of young asthmaticchildren. A dose comparison study. Am J Respir Crit CareMed 1999; 160: 126–131.

108 de Blic J, Delacourt C, Le Bourgeois M, et al. Efficacy ofnebulized budesonide in treatment of severe infantileasthma: a double-blind study. J Allergy Clin Immunol1996; 98: 14–20.

109 Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M,Walton-Bowen K. A multiple-dosing, placebo-controlledstudy of budesonide inhalation suspension given once ortwice daily for treatment of persistent asthma in youngchildren and infants. Pediatrics 1999; 103: 414–421.

110 Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M,Walton-Bowen K, Smith JA. Efficacy and safety ofbudesonide inhalation suspension (Pulmicort Respules)in young children with inhaled steroid-dependent, persis-tent asthma. J Allergy Clin Immunol 1998; 102: 789–796.

111 Roorda RJ, Mezei G, Bisgaard H, Maden C. Response ofpreschool children with asthma symptoms to fluticasonepropionate. J Allergy Clin Immunol 2001; 108: 540–546.

112 Hofhuis W, van der Wiel EC, Nieuwhof EM, et al.Efficacy of fluticasone propionate on lung function andsymptoms in wheezy infants. Am J Respir Crit Care Med2005; 171: 328–333.

113 Schokker S, Kooi EM, de Vries TW, et al. Inhaledcorticosteroids for recurrent respiratory symptoms in

preschool children: randomized controlled trial. PulmPharmacol Ther 2008; 21: 88–97.

114 Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L,Davies P. Twelve-month safety and efficacy of inhaledfluticasone propionate in children aged 1 to 3 years withrecurrent wheezing. Pediatrics 2004; 113: e87–e94.

115 McKean M, Ducharme F. Inhaled steroids for episodicviral wheeze of childhood. Cochrane Database Syst Rev2000; Issue 1: CD001107.

116 Wilson N, Sloper K, Silverman M. Effect of continuoustreatment with topical corticosteroid on episodic viralwheeze in preschool children. Arch Dis Child 1995; 72:317–320.

117 Ducharme FM, Lemire C, Nova FJ, et al. Randomizedcontrolled trial of intermittent high dose fluticasone versusplacebo in young children with viral-induced asthma. AmJ Respir Crit Care Med 2007; 175: Suppl. 1, A958.

118 Silverman M, Wang M, Hunter G, Taub N. Episodic viralwheeze in preschool children: effect of topical nasalcorticosteroid prophylaxis. Thorax 2003; 58: 431–434.

119 Bisgaard H, Hermansen MN, Loland L, Halkjaer LB,Buchvald F. Intermittent inhaled corticosteroids ininfants with episodic wheezing. N Engl J Med 2006; 354:1998–2005.

120 Murray CS, Woodcock A, Langley SJ, Morris J,Custovic A. Secondary prevention of asthma by the useof inhaled fluticasone propionate in wheezy infants(IFWIN): double-blind, randomised, controlled study.Lancet 2006; 368: 754–762.

121 Smith M, Iqbal S, Elliott TM, Everard M, Rowe BH.Corticosteroids for hospitalised children with acuteasthma. Cochrane Database Syst Rev 2003; Issue 1:CD002886.

122 Vuillermin P, South M, Robertson C. Parent-initiated oralcorticosteroid therapy for intermittent wheezing illnessesin children. Cochrane Database Syst Rev 2006; Issue 3:CD005311.

123 Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, aleukotriene receptor antagonist, for the treatment ofpersistent asthma in children aged 2 to 5 years.Pediatrics 2001; 108: e48.

124 Bisgaard H, Nielsen KG. Bronchoprotection with aleukotriene receptor antagonist in asthmatic preschoolchildren. Am J Respir Crit Care Med 2000; 162: 187–190.

125 Hakim F, Vilozni D, Adler A, Livnat G, Tal A, Bentur L.The effect of montelukast on bronchial hyperreactivity inpreschool children. Chest 2007; 131: 180–186.

126 Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE.Comparative study of budesonide inhalation suspensionand montelukast in young children with mild persistentasthma. J Allergy Clin Immunol 2007; 120: 1043–1050.

127 Bisgaard H, Zielen S, Garcia-Garcia ML, et al.Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J RespirCrit Care Med 2005; 171: 315–322.

128 Robertson CF, Price D, Henry R, et al. Short-coursemontelukast for intermittent asthma in children: arandomized controlled trial. Am J Respir Crit Care Med2007; 175: 323–329.

129 van der Wouden JC, Tasche MJ, Bernsen RM, Uijen JH, deJongste JC, Ducharme FM. Inhaled sodium cromoglycate



for asthma in children. Cochrane Database Syst Rev 2003;Issue 3: CD002173.

130 Tasche MJA, van der Wouden JC, Uijen JHJM,Bernsen RM, van Suijlekom-Smit LWA, de Jongste JC.Randomised placebo-controlled trial of inhaled sodiumcromoglycate in 1–4 year-old children with moderateasthma. Lancet 1997; 350: 1060–1064.

131 Seddon P, Bara A, Ducharme FM, Lasserson TJ. Oralxanthines as maintenance treatment for asthma inchildren. Cochrane Database Syst Rev 2006; Issue 1:CD002885.

132 McDonald NJ, Bara AI. Anticholinergic therapy forchronic asthma in children over two years of age.Cochrane Database Syst Rev 2003; Issue 1: CD003535.

133 Everard ML, Bara A, Kurian M, Elliott TM, Ducharme F,Mayowe V. Anticholinergic drugs for wheeze in childrenunder the age of two years. Cochrane Database Syst Rev2005; Issue 3: CD001279.

134 Schwarzer G, Bassler D, Mitra A, Ducharme FM, Forster J.Ketotifen alone or as additional medication for long-termcontrol of asthma and wheeze in children. CochraneDatabase Syst Rev 2004; Issue 1: CD001384.

135 Warner JO. A double-blind, randomized, placebo-con-trolled trial of cetirizine in preventing the onset of asthmain children with atopic dermatitis: 18 months’ treatment

and 18 months’ posttreatment follow-up. J Allergy ClinImmunol 2001; 108: 929–937.

136 Agertoft L, Pedersen S. Importance of training for correctTurbuhaler use in preschool children. Acta Paediatr 1998;87: 842–847.

137 O’Callaghan C, Barry PW. How to choose deliverydevices for asthma. Arch Dis Child 2000; 82: 185–187.

138 Castro-Rodriguez JA, Rodrigo GJ. b-agonists throughmetered-dose inhaler with valved holding chamberversus nebulizer for acute exacerbation of wheezing orasthma in children under 5 years of age: a systematicreview with meta-analysis. J Pediatr 2004; 145: 172–177.

139 Iles R, Lister P, Edmunds AT. Crying significantlyreduces absorption of aerosolized drug in infants. ArchDis Child 1999; 81: 163–165.

140 Janssens HM, Devadason SG, Hop WCJ, Le Souef PN, deJongste JC, Tiddens HAWM. Variability of aerosoldelivery via spacer devices in young asthmatic childrenin daily life. Eur Respir J 1999; 13: 787–791.

141 Janssens HM, Heijnen EMEW, de Jong VM, et al. Aerosoldelivery from spacers in wheezy infants: a daily lifestudy. Eur Respir J 2000; 16: 850–856.

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Primary Care Respiratory Journal (2010); 19(1): 75-83

DISCUSSION PAPER

Setting the standard for routine asthma consultations: a discussion of the aims, process and outcomes of reviewingpeople with asthma in primary care

*Hilary Pinnocka, Monica Fletcherb, Steve Holmesc, Duncan Keeleyd, Jane Leyshone,

David Pricef, Richard Russellg, Jenny Versnelh, Bronwen Wagstaffi

a Senior Clinical Research Fellow, Allergy and Respiratory Research Group, Centre of Population Health Sciences: GP Section, University of Edinburgh, Scotland, UK

b Chief Executive, Education for Health, The Athenaeum, Warwick, UKc General Practitioner, The Park Medical Practice, Shepton Mallet, UKd General Practitioner, The Rycote Practice, East Street, Thame, UKe Team Leader: Respiratory & Asthma, Education for Health, The Athenaeum, Warwick, UKf Professor of Primary Care Respiratory Medicine, Centre of Academic Primary Care, University of Aberdeen; Foresterhill Health Centre,

Westburn Road, Aberdeen, Scotland, UKg Honorary Clinical Senior Lecturer at the National Heart and Lung Institute, Imperial College, London, UKh Executive Director of Research and Policy, Asthma UK, London, UKi Policy Advisor, Primary Care Respiratory Society UK, Lockerbie, UK

Originally submitted 31st December 2008; resubmitted 15th July 2009; revised version received 8th November 2009; accepted 18th November 2009; online 29th January 2010

Abstract

Globally, asthma morbidity remains unacceptably high. If outcomes are to be improved, it is crucial that routine review consultations inprimary care are performed to a high standard. Key components of a review include:

• Assessment of control using specific morbidity questions to elucidate the presence of symptoms, in conjunction with the frequency of use of short-acting bronchodilators and any recent history of acute attacks

• After consideration of the diagnosis, and an assessment of compliance, inhaler technique, smoking status, triggers, and rhinitis, identification of poor control should result in a step-up of treatment in accordance with evidence-based guideline recommendations

• Discussion should address understanding of the condition, patient-centred management goals and attitudes to regular treatment, andshould include personalised self-management education

Regular review of people with asthma coupled with provision of self-management education improves outcomes. Underpinned by atheoretical framework integrating professional reviews and patient self-care we discuss the practical barriers to implementing guided self-management in routine clinical practice.

© 2010 Primary Care Respiratory Society UK. All rights reserved.H Pinnock et al. Prim Care Resp J 2010; 19(1): 75-83. doi:10.4104/pcrj.2010.00006

Keywords asthma, primary care, guided self-management, monitoring long-term conditions, asthma action plan

* Corresponding author: Dr Hilary Pinnock, Allergy and Respiratory Research Group, Centre of Population Health Sciences: GP Section, University ofEdinburgh, Doorway 3, Medical School, Teviot Place, Edinburgh, EH8 9AG. Tel: +44 (0)131 650 8102 Fax: +44 (0)131 650 9119 E-mail: [email protected]

75

Introduction: the burden of asthmaWorldwide, asthma is an important cause of morbidity,economic cost, and mortality. It is estimated that about 300million people have asthma, with the highest prevalence in theUK, Australasia and North America.1 In England, data from

general practice suggest that 5.8% of the population have‘active asthma’ (defined as a diagnosis of asthma and aprescription for asthma treatment in the previous 12 months).2

Despite the focus in international guidelines on assessingand achieving good disease control in international

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guidelines,3 surveys have consistently shown unacceptablemorbidity associated with low expectations on the part ofpatients.4-8 It has been estimated that up to three-quarters ofthe 80,000 admissions for asthma in the UK in 2004 mighthave been prevented with improved long-term care.9 A keystrategy for reducing the burden of asthma is a shift inemphasis from acute management to long-term care andsupported self-management, in order to reduce chronicmorbidity and impairment of quality of life, as well asreducing exacerbations, admissions and mortality.3,10 Proactivecare, with structured reviews provided by clinicians withtraining in asthma care, improves outcomes.11-15

After describing the policy and theoretical frameworklinking regular reviews and guided self-management, thisdiscussion paper sets out the evidence base supporting therecommended content of good asthma reviews in primarycare. It then discusses the role of ‘pay-for-performance’ –exemplified by the UK Quality and Outcomes Framework16 –as a driver for improving treatment outcomes. An Opinionsheet providing practical guidance for clinicians is availablefrom www.pcrs-uk.org.

Policy and theoretical framework The framework for monitoring chronic disease described byGlasziou et al. emphasises the inter-relationship betweenprofessional review and patient self-management,17 usingasthma as an exemplar condition (see Figure 1). Cochranereviews provide support for this concept, concluding thatimproved outcomes are the result of training in asthma self-management coupled with regular review.18-20 This dualapproach is summarised in the GINA asthma guideline as‘guided self-management’,9 is explicitly recommended (GradeA) in the 2008 update of the BTS/SIGN asthma guideline,10

and is a core strategy of national programmes to improveasthma care in Finland and Australia.21,22

Self care is a ‘key pillar’ of the policy approach to meetingthe challenge of providing care for people with long-term

conditions.23-27 The widely cited Long-Term Conditionspyramid of care (LTC pyramid) emphases the importance ofself-management to “ensure patients and carers have theskills and knowledge they need to understand how to besthandle their condition, including how to deal with flare-ups,to adjust medicines, improve their life-styles and access healthcare services”26. Routine reviews operate in the boundarybetween patient self-care and professional management,28,29

not only offering opportunities specifically to reinforce andrefine self-management skills, but also more generally tobuild the trusted relationship valued by patients (see Figure2).29

Asthma reviewsAsthma reviews in primary care should incorporate three keysteps:1. Assessing control in order to target care appropriately 2. Responding to that assessment by identifying reasons for

poor control and adjusting management strategyaccordingly

3. Exploring patients’ ideas, concerns and expectations, andguiding self-management to facilitate on-going control

1. Assessing controlAsthma control reflects the degree to which symptoms arereduced, exacerbations are prevented and normal lungfunction is maintained by treatment,30 with current guidelinesdefining ‘control’ as no symptoms, no exacerbations andnormal lung function9 (see Table 1). Occasional daytimesymptoms (defined as less than twice a week) may beconsistent with good control, but disturbed sleep due toasthma signals loss of control. Challenge tests for assessment

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Pretreatment

Initial treatment,gaining control Maintenance

Exacerbationregainingcontrol Maintenance

Steppingdown

Bestpeakflow

80%

60%

Arrows are professional reviewsLine is patient self-management

Figure 1. The inter-relationship between professionaland self-monitoring (adapted from Glaziou et al.17 toillustrate the management and self-management ofasthma).

Level 1At risk of a long-

term conditionSelf-care

Level 2With a long-term condition

Level 3Complex co-morbidities

Self-managementfor health

Caremanagement

Casemanagement

Communicatio

n

Boundary

Professional managem

ent

Figure 2. The long-term condition pyramid with theboundary between professional and self care (adaptedfrom Degeling et al.28).



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of bronchial hyper-responsiveness are unlikely to be practicalmeasures of control in primary care settings, thoughestimation of exhaled nitric oxide as a measure ofinflammation may have a place in clinical care in the future.30

In primary care, asthma control is normally assessed onthe basis of symptoms, supplemented by examination of theclinical records. Frequent use of reliever inhalers implies poorcontrol, and intermittent requests for preventer treatmentsignals the need to address patients’ perception of, and fearsabout, regular treatment.10 The occurrence of an acuteexacerbation is evidence of poor control over a longer time-frame than the duration of current symptoms.31 A primarycare clinician with access to patient records can easily checkthe number of courses of oral steroid required over theprevious year. A ‘one-off’ peak expiratory flow (PEF) orspirometry reading taken in clinic is of limited value inassessing the control of a variable condition, though if thepatient is well-controlled it can provide an up-to-date ‘best’reading for use in action plans. Although few patients willmaintain an accurate paper-based PEF diary on a dailybasis,32,33 use of mobile technology may engage some patientswith on-going PEF and symptom monitoring.34,35

Surveys have consistently shown unacceptably high levels ofasthma morbidity.4-8 Trials demonstrate that by adopting a policyof ‘zero tolerance’ to symptoms, patients with asthma canachieve good control;36 however, it remains unclear to whatextent good control as defined by guidelines can be achieved inreal-life practice.37 Patients will wish to balance the benefits ofstepping up therapy until control is achieved against perceptionsof, and preferences for, long-term treatment, and thepracticalities of short consultations may restrict the time availableto address all the diverse factors which result in poor control.37

• Measures of morbidityPatients’ perception of control may differ markedly from thatbased on objective assessment of symptoms,5,8 and cliniciansover-estimate improvements in asthma control.6 This hasgiven impetus to the development of morbidity scores,

suitable for use in clinical practice, which can facilitatedetection of poor control. A review of some asthma controltools is available on the web-site of the International PrimaryCare Respiratory Group.38,39 Common to all these tools isspecific enquiry about the presence of symptoms,interference with activities and disturbance at night.

There are two short, well-validated questionnaires widelyused in research which may be suitable for use in clinicalpractice.10,30 The Asthma Control Questionnaire40,41 uses fivemorbidity questions plus an optional measure of the forcedexpiratory volume in one second (FEV1), has been tested foruse in clinical practice, and a score of more than 1.5 indicatespoor control.42 The Asthma Control Test uses similar morbidityquestions but also includes a rating of overall control, with ascore of 20 or more indicating good control.43,44 Both areavailable in a number of languages and have been validatedfor self-administration.

However, validity of questionnaires is determined undercarefully controlled conditions, since the mode, circumstancesand place of administration may affect the responses.45 Bycontrast, conditions of administration in routine clinicalpractice are likely to be very variable, with some practicesarranging completion prior to the asthma review at home orin the waiting room, whilst others administer them formally inthe consultation. Some clinicians may explain or paraphrasethe questions to assist with completion. There is, therefore, aneed to establish the value of such scores for assessing


Characteristic Controlled (All of Partly Controlled (Any measure Uncontrolledthe following) present in any week)

Daytime symptoms None (twice or less/week) More than twice/week

Limitations of activities None Any

Nocturnal symptoms/awakening None Any

Need for reliever/rescue treatment None (twice or less/week) More than twice/week

Lung function (PEF or FEV1)iii Normal < 80% predicted or personal best(if known)

Exacerbations None One or more/yeari One in any weekii

i.Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate

ii.By definition, an exacerbation in any week makes that an uncontrolled asthma week.

iii.In adults and older children.

Table 1. Levels of Asthma Control (reproduced from GINA guidelines9).

Three or more features

of partly controlled

asthma present in

any week

In the last month

1. Have you had difficulty sleeping because of asthma symptoms

(including cough)?

2. Have you had your usual asthma symptoms during the day

(cough, wheeze, chest tightness or breathlessness)?

3. Has your asthma interfered with your usual activities

(eg housework, work, school, etc)?

Table 2. The Royal College of Physicians three questions46.



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control in a range of normal clinical scenarios. The ‘Royal College of Physicians (RCP) three questions’

represent a consensus UK view on a short symptomquestionnaire,46 which correlates with the Asthma ControlQuestionnaire and is responsive to change.47 A refinement ofthe RCP three questions which scores the number of days inthe previous week affected by symptoms has been suggestedto improve discriminatory power. The questions (or verysimilar precursors of the ‘RCP three questions’) have beenused successfully to target care,48 including use by postalquestionnaire49 and during telephone reviews.50 Whilstoccasional symptoms (e.g. on two or less days a week) maybe acceptable, any nocturnal waking or activity limitationshould be considered as less than well-controlled disease, andmanagement should be adjusted accordingly.3,10

2. Response to assessment and adjustment ofmanagementIf control is good, a reminder of action to be taken if asthmadeteriorates may be all that is necessary. However, ifassessment of symptoms, taken in conjunction with thereported and recorded use of short-acting bronchodilatorsand any recent history of any acute attacks, suggests thatcontrol is not ideal, the reasons for this should be consideredand addressed appropriately before increasing asthmatherapy.10 A recent primary care review has considered thecauses for poor control in detail.51 Here, we present asummary of the key implications for routine practice:• Reviewing the diagnosisAn increase in symptoms, or failure to respond to treatment,should lead to reconsideration of the diagnosis.10,52 Anunrecognised diagnosis (for example chronic obstructivepulmonary disease (COPD) in a smoker, gastro-oesophagealreflux as a trigger for cough, obesity as a cause ofbreathlessness), or the development of a co-morbidcondition, may be responsible for apparent poor control.52 Awide range of rare conditions in childhood may be initiallymisdiagnosed as asthma.53

• Checking and correcting inhaler techniquePoor inhaler technique is a well documented problem whichresults in ineffective and wasteful use of therapy, and is animportant cause of poor control.51-56 As few as a quarter ofpatients make no mistakes when using a pressurisedmetered-dose inhaler (pMDI), while just over a half can usedry powder inhalers, breath-actuated pMDI or pMDI with aspacer without errors.57 Provision of a spacer for use in anacute situation may improve effectiveness at a time whenbreathlessness makes usual pMDI technique more difficult.

Meta-analysis of the effect of teaching inhaler techniqueshows significant improvement after an educationalintervention with a ‘number needed to teach’ (to achieve an‘ideal’ technique) of 2.6 patients.57 However, repeated

training is required to maintain good technique.55,56 Thoseunable to master or maintain good technique with one deviceshould be offered an alternative.51 This has been specificallyhighlighted in children, where inadequate technique –resulting either from poor training or from choosing a devicepoorly suited to the child – significantly reduces drug deliveryto the lungs and results in poor asthma control.58

Practical training when a device is first prescribed,supported by review of inhaler technique at every asthmaconsultation (whether with a nurse, doctor, pharmacist orother healthcare professional) is good practice.3,10,55,56,58

• Assessing adherence Adherence with regular preventative medication is known tobe poor, and under-use should be considered when there is afailure to control asthma symptoms.59,60 Patients self-reportingand health care professional assessment both overestimateregular use of prophylactic medication.59,61,62 In primary care,repeat prescribing records provide an indication of adherencewith prescribed asthma regimens.10

Simple, verbal and written instructions and information onasthma and its treatment for patients and carers may help toovercome unintentional non-adherence.10 Patents balancetheir perceived need for treatment against their concernsabout taking a medication.51 Enquiry, based on a non-judgemental assumption of non-adherence, can facilitate anopen discussion of the rationale and potential benefits ofregular therapy versus the disadvantages of taking a drugwith (perceived or real) side effects, thus enabling the patientto reach an informed decision about concordance withclinical advice on the use of inhaled steroids. • Asking about, and treating rhinitis Rhinitis and asthma are common diseases which co-exist in75-80% of patients52 and are associated with substantial costto patients, employers and health care systems. Therelationship between rhinitis and asthma is stronglysupported by epidemiological, pathophysiological and clinicalevidence.63-71 Patients with co-existent asthma and rhinitisincur greater prescription drug costs and experience moregeneral practitioner (GP) visits and hospitalisations for asthmathan those with asthma alone.72,73

Treatment of concomitant allergic rhinitis, particularly withintranasal steroids and/or leukotriene receptor antagonists, isassociated with significant reductions in risk of emergencyroom treatment and hospitalisation for asthma.74-76 Rhinitis(including seasonal rhinitis) should therefore be sought as aco-morbidity in all patients with uncontrolled asthma andtreated appropriately.52

• Assessing smoking status and offering cessation adviceSmoking adversely affects asthma control. This may signal adiagnosis of COPD, either as a co-morbidity or because the COPDhas been incorrectly diagnosed as asthma. Smoking also reduces




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the effectiveness of inhaled steroids.63,77,78 It is therefore importantto enquire about smoking status and to offer cessation advice topatients with poorly controlled asthma. Persistent smokers mayneed relatively high doses of inhaled steroids.10

• Adjusting therapy according to evidence-basedguidelinesAfter consideration of diagnosis, compliance, inhalertechnique, smoking status, triggers and rhinitis, theidentification of poor control should result in a step-up oftreatment in accordance with the evidence-based advice ofinternational or national guidelines.3,10 Discussion of theadvantages and disadvantages of treatment options, andacknowledgement of patient preferences – i.e. whether toaccept symptoms, or whether to accept a change or anincrease in treatment such as a higher dose of inhaledsteroids, an additional therapy, a combination inhaler insteadof separate inhalers, an inhaled long-acting bronchodilator oran oral leukotriene receptor antagonist – is good consultingpractice and would seem likely to optimise futureconcordance.79

Control should be maintained on the lowest possible doseand stepping down treatment is an important and frequently-overlooked step for patients who are consistently wellcontrolled, especially in children who often ‘grow out’ of theirasthma.3,10

3. Exploring perceptions and supporting self-management• Guideline recommendations International guidelines emphasise that “Patient education isthe key to success of every aspect of asthma management andprevention”,3 as many of the obstacles to achieving bestcontrol relate to misunderstanding of the condition, under-estimation of the potential benefits of regular treatment, andexaggerated fears about side effects of asthma treatment. TheUK national guideline includes the Grade A recommendationthat “Patients with asthma should be offered self-management education that should focus on individual needs,and be reinforced by a written action plan”.10

The provision of self-management education,incorporating a written asthma action plan, can reducehospitalisation,80 unscheduled consultations, time lost fromwork and nocturnal asthma, as well as improving self-efficacyand asthma-related quality of life.16,81 Similar benefits havebeen shown in school age children,20 though an innovativeapproach may be required for pre-school children.81

Clear advice from a systematic review on the componentsof effective asthma action plans – i.e. written instructions, 2-3 action points triggered by symptoms or based on best peakflow, advice on increasing inhaled steroids and commencingoral steroids – is now available.82 Health professionals shouldtailor the self-management intervention to allow for patient

preference (e.g. preferred degree of autonomy versusfrequency of professional review; peak flow versus symptommonitoring) as well as the severity of asthma, risk of verysevere attacks and the maintenance treatment plan.19

• Implementation in primary care The challenge for primary care is that of implementing theseevidence-based recommendations. Studies have shownconsistently that provision of self-management education ispoorly implemented in practice.8,83,84 Some of the recognisedbarriers, such as time and resources, are practical issues whichneed to be addressed when planning routine care for peoplewith asthma.85,86 Confusion about details of action plans (suchas the relevance of increasing inhaled steroids) are a furtherbarrier.87 Despite the growing body of evidence from primarycare,88-92 there is scepticism about whether the evidenceapplies to the relatively low risk mild patients in whom benefitis harder to demonstrate.84 More fundamentally, provision ofasthma action plans is often perceived as an optional taskdelegated to a nurse educator.80 Recognition that self-careand professional care are inextricably linked ascomplementary aspects of the management of all peoplewith long-term conditions – as illustrated in the frameworkfor monitoring and self-monitoring (see Figure 2)17 – may bethe conceptual key that will help unlock implementation.

A systematic review of the implementation of asthmaaction plans highlighted the importance of this inter-relationship between the facilitation of regular, structuredreview and the provision of self-management education.93 Allthree primary care studies in this review demonstratedincreased ownership of asthma action plans,92,94,95 and showeda consistent trend to improved clinical outcomes, though theonly significant benefits were a reduction in episodes of‘speech limiting wheeze’,92 and night time waking.94 Similarly,within managed care programmes, nurse-led telephone-based reviews incorporating self-management educationsupported by written information can increase the use ofinhaled steroids.96,97 This inter-relationship is encompassed ininternational guidelines as the concept of ‘guided self-management’.3

Ensuring access to professional advicePatients value flexible access to professional advice in order tosupport self-care,29,98 but not all patients are willing to attenda pre-arranged appointment for a regular review.83,99 Repeatprescribing arrangements should aim to be sufficiently flexibleto enable patients to order more inhalers promptly whenneeded, but should include checks to ensure that thosepatients requesting reliever inhalers frequently are remindedto arrange a review.

There is now evidence to inform the appropriate role oftelephone asthma reviews.10,50,101,102 Telephone asthma reviews




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increase the proportion of patients reviewed without loss ofclinical effectiveness,100 though patients whose asthma iscausing concern prefer a face-to-face review.101 Askingstandard morbidity questions by telephone can identify thosewho should be invited for a face-to-face review whilstoffering a convenient telephone option to those currentlyunder good control.50 The provision of a telephone asthmareview option within routine practice showed thatopportunistic telephone calls could provide consultations tonon-responders who would otherwise not have had areview.102 A suggested model of care incorporating thisevidence is given in Table 3.

Ensuring qualityAppropriate trainingAsthma reviews should be undertaken by healthcareprofessionals with appropriate training to enable them not onlyto assess control but also to adjust treatment as necessary.20 Inthe UK, this is frequently an experienced practice nurse,though a survey published in 2007 highlighted that 20% ofnurses did not have any specialist asthma training.103 Whilstguidelines (and clinical governance) might recommend that atleast one member of the primary care team has specialistrespiratory training, this raises concerns about the potentialdeskilling of other members of the team.84 Poorly defined inter-professional roles and inadequate communication betweencolleagues can act as barriers to the implementation ofguideline recommendations,86 an issue of particular importancein the context of guided self-management. Although aspecialist clinician may initiate education, it is incumbent on allmembers of the team to provide the on-going, consistentsupport for guided self-management.104 Multi-disciplinaryeducation and support for professionals was a core componentof the successful Finnish programme.21

Audit and standardsA systematic review of 118 randomised controlled trials

spanning a range of countries, professionals and diseaseareas concluded that audit and feedback can be moderatelyeffective at improving professional practice.105 The process ofasthma reviews, particularly when the consultations arerecorded on computer templates, offers ready opportunitiesfor repeated audit cycles. However, detailing and auditing allthe possible functions of an asthma review, whilst potentiallyimproving process, risks automating the consultation andmaking it less responsive to individual patient needs. The UKQuality and Outcomes Framework (QOF) – a ‘pay forperformance’ scheme which was introduced as part of the UKGeneral Medical Services Contract in 2004 and whichrewards practices for achieving pre-determined standards ofcare for a range of long-term conditions16 – recognised thispotential risk, and the approach adopted was to reward the‘provision of an asthma review’ recorded as a single codedentry in the computerised clinical records.106 Concerns remainabout the quality of the review represented by this ‘tick box’,though serial detailed audits in 60 representative practicesshowed significant progress in assessing control by therecording of specific symptoms, and checking inhalertechnique as part of the review.107 Disappointingly, despiteuniformly high achievement in the process measures forQOF,108 the proportion of well-controlled patients variesconsiderably between practices.109

ConclusionToo many of the 300 million people around the world livingwith asthma are coping on a daily basis with a variablecondition that significantly affects their quality of life, despitethe existence of treatment which could substantially improvetheir symptoms. At the core of a routine review is theopportunity to identify patients with sub-optimal control and(for both patients and professionals) the need to adopt anapproach of ‘zero tolerance’ to symptoms. Recognition of theinter-relationship of professional reviews and patient self-


• Ensure adequate and updated specialist training of clinicians.

• Consider strategies for maximising access – e.g flexible timing of ‘clinics’, offering a choice of mode of review, expecting that most

patients will make a choice appropriate to the severity of their asthma.

• Set up a register and devise a recall system using a range of reminders (verbal, postal, telephone, e-mail, SMS). Consider opportunistic

phone calls to non-attenders.

• Ask standard morbidity questions to enable objective assessment of control and tailor the review (both in content and mode of

delivery) appropriate to the needs of the patient.

• Adopt a policy of ‘zero tolerance’ of symptoms, addressing the potential reasons for poor control and recommending stepping up

treatment as appropriate.

• Prioritise guided self-management and the provision of personal asthma action plans, using every opportunity to review, revise, and

refine the plan with the patient.

• Audit the asthma review service, ideally focusing not only on process, but also on patient outcomes.

Table 3. A suggested service model for provision of asthma reviews.



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management underpins the partnership as futuremanagement strategies are negotiated.

FundingNo direct funding. HP is supported by a Primary Care Research Career Award fromthe Chief Scientist’s Office, Scottish Government.

Conflict of interest declarationsNone known.

AcknowledgementsThis paper builds on work on asthma reviews, commissioned by the Primary CareRespiratory Society UK (PCRS-UK) formerly known as the General Practice AirwaysGroup (GPIAG), together with the British Thoracic Society, Education for Health andAsthma UK, in preparation for a joint submission to the UK QOF review panel. Wethank Professor Chris Griffiths for his helpful comments on an earlier draft.

ContributorshipHP, BW, JL, JV, MF, and RR prepared the original QOF submission and all the authorscontributed to the preparation of this discussion paper.

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Managing wheeze in preschool childrenAndrew Bush professor of paediatrics and head of section (paediatrics) 1 professor of paediatricrespirology2 consultant paediatric chest physician3, Jonathan Grigg professor of paediatric respiratoryand environmental medicine 4, Sejal Saglani reader in paediatric respiratory medicine 3 5

1Imperial College, London UK; 2National Heart and Lung Institute, Imperial College, London, UK; 3Respiratory Paediatrics, Royal Brompton HarefieldNHS Foundation Trust, London, UK; 4Blizzard Institute, Barts and the London Hospital, London, UK; 5Leukocyte Biology, NHLI, Imperial CollegeLondon, UK

Lower respiratory tract illnesses with wheeze are common,occurring in around a third of all preschool children (heredefined as aged between 1 and 5 years). They are a major sourceof morbidity and healthcare costs, including time off work forcarers, and are often difficult to treat. This review focuses onthe two areas in which there have been recent developments.The first is the classification of these children by symptompattern into “episodic viral” and “multiple trigger” wheezers.1These phenotypes can change within an individual over time,2but they are a useful guide to current treatment, and there arealso physiological and pathological rationales for their use.3 4

The second area is the recent series of large randomisedcontrolled trials of treatment, specifically related to the roles ofintermittent montelukast and inhaled and oral corticosteroids.These trials have shown clearly that inhaled corticosteroids andprednisolone in particular have been misused and overused inthe past, mandating a reappraisal of treatment algorithms.

What is wheeze?Wheeze is a term that is often used imprecisely, as has beenshown in studies with a video questionnaire and directquantification of wheeze.5-8 Indeed, some European languagesdo not even have a word for wheeze. Our definition is highpitched whistling sounds usually in expiration and associatedwith increased work of breathing, but which can also sometimesbe heard in inspiration. In research studies, wheeze can bequantified directly by using surface microphones, which is theideal. With this technique, it was shown that physiciansauscultating the chest accurately identify wheeze8; parents andnurses were much less reliable.

How common is wheeze in preschoolchildren?Preschool wheeze is common. In the Avon Longitudinal Studyof Parents and Children (ALSPAC) study, a prospectivelongitudinal observational study, 26% of 6265 infants reported

on had had at least one episode of wheeze by the age of 18months.9

What is the best clinical approach to thepreschool wheezer?Once it is established that the child has actual wheeze, historyand a careful physical examination should be used to place thechild in one of four categories (table⇓). History and physicalexamination are used to categorise the child and to decidewhether further investigation is needed. In general, there arethree reasons for a referral: if diagnosis is in doubt, if treatmentis not working, and if any party (general practitioner, parent) isunhappy with progress. A report of two cross sectional,community based observational studies found that isolated drycough in a community setting, without wheeze or breathlessness,is most unlikely to be caused by any form of asthma.9 Mostpreschool wheezers do not require any additional tests.Confusion arises from the different uses of the term“bronchiolitis.” In the United Kingdom, this is an illnesscharacterised by respiratory distress and showers of fine cracklesin a child aged under 1 year; though wheeze can be present aswell, it is the crackles that define the illness. It should beemphasised that any rigid definitions based on age are likely,to some extent, to be artificial. In the United States andelsewhere, “bronchiolitis” is used synonymously with wheezingillness. We have not discussed the approach to bronchiolitis asdefined in the UK; interested readers are referred elsewhere.10-12

Should preschoolwheezers be subdivided(phenotyped)?Several approaches have been used to categorise preschoolwheezers. The first two are mentioned because they are ofscientific importance and are widely quoted in the literature,but they are not useful in guiding treatment.

Correspondence to: A Bush, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK [email protected]

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BMJ 2014;348:g15 doi: 10.1136/bmj.g15 (Published 4 February 2014) Page 1 of 7

Clinical Review

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Summary points

Preschool wheeze should be divided into “episodic viral” and “multiple trigger” according to the history, and these categories, which canchange over time, should be used to guide treatmentNo treatment has been shown to prevent progression of preschool wheeze to school age asthma, so treatment is driven solely by currentsymptomsIn all but the most severe cases, episodic symptoms should be treated with episodic treatmentIf trials of prophylactic treatment are contemplated, they should be discontinued at the end of a strictly defined time period becausemany respiratory symptoms remit spontaneously in preschool childrenPrednisolone is not indicated in preschool children with attacks of wheeze who are well enough to remain at home and in many suchchildren, especially those with episodic viral wheeze, who are admitted to hospital

Sources and selection criteria

We performed a PubMed search using the terms ((“asthma” or “wheeze”) and preschool), with the filters “clinical trial”, “published in the last5 years”, “humans”, “English” activated, with the subject age range “infant” (0-23 months) and “preschool” (2-5 years). Additionally, weseparately searched the Cochrane database and Clinical Evidence, as well as our personal archives of references, extending beyond theprevious five years, and also checked the reference lists in all manuscripts.We selected only those manuscripts that either related to practical phenotyping of preschool wheezers or contributed to the evidence basefor treatment. We eliminated all manuscripts that also included children of school age and above unless we could differentiate data frompre-schoolers aged 5 and under from data from older children because the pathophysiology of wheeze and the treatment algorithms aredifferent in these two age spans. We also eliminated small trials and case series if the findings had been subsumed into a meta-analysis orCochrane review.

• Epidemiological: patterns such as transient early (wheezeonly in the first three years of life) and persistent (wheezethroughout the first six years of life).9 13 These studies haveled to many insights into the evolution of symptoms andlung function, but the categories can be determined onlyretrospectively and give no guide to treatment, so are notuseful for the clinician

• Atopic versus non-atopic: early aeroallergen sensitisationis certainly predictive of ongoing symptoms and loss oflung function at school age,14 but does not predict theresponse to treatment with inhaled corticosteroids15

• Symptom pattern: the European Respiratory Society TaskForce1 suggested that preschool wheezers should be placedinto one of two pragmatic categories. This is our favouredcategorisation for planning treatment:–Episodic viral wheeze (EVW): the child wheezes onlywith usually clinically diagnosed viral upper respiratoryinfections and is otherwise totally symptom free

–Multiple trigger wheeze (MTW): the child wheezes withclinically diagnosed upper respiratory infections but alsowith other triggers, such as exercise and smoke andallergen exposure.

This last classification is used to guide treatment (see below).It has been criticised because children might change betweencategories over time,2 but in that event pharmacologicaltreatment should also change. This is analogous to the situationin school age children with asthma; treatment is not left fixedover time but is increased or decreased depending on symptompattern and severity. Unfortunately, few studies adopt thisclassification; most randomised controlled trials and geneticand epidemiological studies combine children with bothsymptom patterns.

Is it asthma?This question is commonly asked by parents who want to knowwhether their child will continue to have symptoms and requiredrug treatment into school age and beyond. The answer,however, depends on what definition of asthma is being usedby the questioner. If a purely symptomatic definition is used(symptoms of wheeze and breathlessness fluctuating over timeand with treatment), then the answer is affirmative. If, however,

the definition includes evidence of airway eosinophilicinflammation, the answer is more difficult as few if any havethe ability to measure this in preschool children. What mostparents actually want to know is whether their child will go onwith symptoms and the need for treatment into school age andbeyond. The evidence from cross sectional physiological workand studies of endobronchial biopsies in children with severepreschool wheeze is that multiple trigger wheeze is associatedwith more airflow obstruction than episodic viral wheeze, andthe airway pathology (eosinophilic inflammation andremodelling) is similar to childhood and adult asthma.16 Bycontrast, episodic viral wheeze is not associated with evidenceof eosinophilic inflammation, so the use of inhaledcorticosteroids in this group is questionable.

Does preschool wheeze lead to asthma?Several clinical predictive indices for future risk of asthma havebeen developed based on combinations of the presence of atopicmanifestations, indirect evidence of airway inflammation, suchas peripheral blood eosinophil count, and severity of preschoolwheeze.17-19 They all have a high negative predictive value anda poor positive predictive value (typically positive predictivevalues 44-54, negative 81-8817-19). Children who have episodicviral wheeze only have no increased risk of atopy or respiratorysymptoms in the long term once they reach the age of 14.20

Can we prevent preschool wheezeprogressing to school age asthma?The clear cut evidence from good randomised controlled trialsis that early use of inhaled corticosteroids, whether continuouslyor intermittently with viral colds, does not affect progressionof disease.21-23 A trial of oral cetirizine in high risk childrenseemed to show benefit in preventing symptoms in subgroupssensitised to particular aeroallergens,24 but a subsequent trialwith L-cetirizine did not replicate these findings (J Warner,personal communication, 2013). This means that we have nodisease modifying drug treatments, and treatment should solelybe focused on current symptoms.



CLINICAL REVIEW



What are the broad treatment strategiesfor children with preschool wheeze?Before any drugs are prescribed for either episodic viral wheezeor multiple trigger wheeze, it is essential to ensure that the homeenvironment is optimal, particularly that the child is not exposedto tobacco smoke; parental smoking “not in front of the children”does not protect them from harm.25 A birth cohort study foundthat air pollution can increase vulnerability to preschoolwheeze,26 but to date we have no specific advice based onindividual exposure profiles. Drugsmight reasonably be targetedat prevention of future complications such as airway remodellingand persistent airflow obstruction, and, additionally, to treatpresent symptoms. In practice, we have no drug strategies toreduce future risk of asthma; neither early use of continuous21 22

nor intermittent23 inhaled corticosteroids reduces the risk ofprogression to school age asthma. If inhaled drugs areprescribed, repeated education of the parents in the correct useof spacers is essential. If inhaled drugs in particular do not seemto be working, check that they are being properly administeredrather than escalate treatment. The use of a skilled respiratorynurse to help carers give inhaled drugs to children is invaluable.

How to treat episodic viral wheeze?Intermittent symptoms should be treated with intermittenttherapy (and in practice this is likely to be what parents doanyway). Failure to instigate regular inhaled treatment will notprejudice future respiratory health. It is important to considerwhether the child needs treatment at all. The use of inhaledtherapy to treat mild respiratory noises with minimal respiratorydistress might be more problematic than the disease. If treatmentis required, then initial treatment should be with an intermittentbronchodilator (either short acting β2 agonist or anticholinergic).If treatment needs to be escalated beyond intermittent β2 agonistor anticholinergic because of failure to control symptoms, thenext options are intermittent leucotriene receptor antagonist(montelukast), intermittent inhaled corticosteroids, or both.There have been important recent randomised controlled trialsof intermittent therapy.The PREEMPT study examined intermittent montelukastcompared with placebo in 220 children aged 2-14.27 Treatmentwas initiated at the onset of symptoms of a respiratory tractinfection and continued for a minimum of a week or untilsymptoms had disappeared for 48 hours. Themontelukast grouphad fewer unscheduled consultations for asthma (odds ratio0.65, 95% confidence interval 0.47 to 0.89) and fewer daysaway from school or childcare and less time off work for parents(37% and 33%, respectively; P<0.001 for both). In a predefinedsubgroup analysis, the benefits were greater in children aged2-5 (about 80% of the study group). These findings were notconfirmed in amuch larger three way comparison of intermittentmontelukast, continuous montelukast, and placebo (nearly 600children in each group).28 A three way comparison betweenstandard treatment, intermittent montelukast, and intermittentnebulised budesonide (the only aerosolised steroid permittedby the FDA in preschool children) in 238 children aged 12-59months showedminor and equivalent benefits for the two activetreatments compared with standard treatment.29 Benefits weregreater in the subgroup with a modified asthma predictive index.Taken together, these studies suggest that a trial of montelukastin preschool children with troublesome viral induced wheezeis worth attempting. We recommend starting treatment at thefirst sign of a viral cold and discontinuing it when the child isclearly better, rather than for a fixed period of days.

The Cochrane review identified use of intermittent inhaledcorticosteroids as a partially effective strategy for episodicwheeze in preschool children.30A proof of concept study in 129children aged 1-6 years showed that the pre-emptive use of 750µg twice a day (compared with the maximum licensed dose of200 µg twice daily in children aged 4 and above; not licensedin any dose below age 4) of fluticasone dipropionate for up to10 days, starting at the first sign of a viral upper respiratory tractinfection, led to a reduction in dose of rescue prednisolone (8%of upper respiratory tract infections in the fluticasone group v18% in the placebo group; odds ratio 0.49, 95% confidenceinterval 0.30 to 0.83).31 This huge dose, however, wasunsurprisingly associated with side effects and cannot berecommended. Another study looked at regular twice dailynebulised budesonide 0.5 mg compared with intermittentnebulised budesonide 1 mg twice a day at the time of viralrespiratory illnesses. This was a randomised double blindcontrolled trial in 278 children aged between 12 and 53 monthswho had a positive modified asthma predictive index.32 Therewas no difference in any respiratory outcome, but in the absenceof a placebo group it is not possible to state that either strategywas beneficial. What this study definitely shows is that regularnebulised budesonide does not prevent viral exacerbations ofwheeze. Smaller older trials of inhaled beclometasone also failedto show a preventive effect.33 There is currently no evidence tosupport the use of inhaled corticosteroids at licensed doses inchildren with episodic viral wheeze. As some studies suggestthat intermittent inhaled corticosteroids might be a usefulapproach in children with viral induced wheeze at higher thanlicensed doses, further studies are required to clarify the doseand duration that might be beneficial in this setting. In practice,however, it would be unwise to go above a fluticasone dose of150 µg twice a day, given the number and duration of viral coldsin normal preschool children and the risk of side effectsincluding growth suppression and adrenal failure with higherdoses. There are currently no studies that have combinedintermittent inhaled corticosteroids with intermittent montelukastto treat episodic viral wheeze.

Is there any role for prophylacticcontinuous inhaled corticosteroids inepisodic viral wheeze?There is no evidence to support the use of regular inhaledcorticosteroids in preschool childrenwho do not wheeze betweenviral colds. In those children with really severe episodic wheezewho require repeated admission to hospital or have prolongeddisruptive symptoms managed at home, however, a trial ofprophylactic inhaled corticosteroids can be given. In some casesit might become apparent that in fact there were intervalsymptoms that were underappreciated. In any event, the clinicaltrials of inhaled corticosteroids in episodic viral wheeze werecarried out in relatively mildly affected children, so the evidencein severely affected children is less robust. Treatment shouldbe reviewed and discontinued if there is no benefit; there is noevidence to suggest the optimal duration of the therapeutic trial,but six to eight weeks would seem a reasonable time period. Ifthe viral wheezing improves on treatment, regular attemptsshould still be made to reduce the dose. It should be noted that,in a small study, even really severe episodic viral wheeze wasnot associated with eosinophilic airway inflammation4 and thatinhaled corticosteroids (fluticasone 100 µg twice a day) led togrowth suppression in the PEAK trial,21 so trials of inhaledcorticosteroids in this context should be deployed onlyexceptionally. If there is a suspicion that the child might in fact



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have symptoms between colds, which are underappreciated bythe carers, a trial of inhaled steroids can reveal that the childwas previously much more symptomatic than was thought.Whatever the context of therapeutic trials in preschool children,they should be for a fixed time period (such as six to eightweeks, see above) and discontinued at the end of the agreedperiod to see if symptoms recur or in fact have resolved andtreatment has become unnecessary (see the three stage trialproposal below).

Is there a role for oral prednisolone inprimary care for preschool wheeze?Recent evidence has questioned the role of prednisolone in acuteepisodes of episodic viral preschool wheeze. In a home basedstudy, 217 preschool children who had at least one admissionto hospital were randomised to a parent initiated course ofprednisolone or placebo at the next wheezing episode. No benefitwas observed in the treatment group.34 A hospital study thatrandomised 687 preschool children admitted with wheeze toprednisolone or placebo in addition to bronchodilator therapyfound there was no benefit in the prednisolone group.35

The implication of these two studies, involving more than 900children, is that any preschool child with viral induced wheezewho is well enough to stay in the community should not beprescribed oral prednisolone, and many children admitted tohospital also should not be prescribed oral prednisolone.36 Thesestudies, however, were undertaken in children with relativelymild symptoms and most were discharged from hospital in lessthan 24 hours, so what these studies do not tell us is whetherprednisolone is indicated in really severe preschool viral wheeze.In the absence of evidence, it is likely that prednisolone willcontinue to be prescribed in this small subgroup of children inhospital.

How should I treat multiple triggerwheeze?Preschool children who have wheeze or cough responsive tobronchodilator treatment and breathlessness on most days evenwhen they do not have a viral cold should be considered for atrial of preventive drug treatment, either inhaled corticosteroidsor a leucotriene receptor antagonist (montelukast). As airwayinflammation cannot routinely be measured in this age group,and many children will become asymptomatic before schoolage, it would be incorrect to assume the pathophysiology of thedisease is the same as school age asthma. Furthermore, theyounger the child, the less likely there is to be any eosinophilicinflammation37 and therefore more reluctance to use inhaledcorticosteroids.There is a dearth of evidence, but the box shows a pragmaticthree stage trial of treatment, which is recommended in ourpractice.The aim of this three step approach is to prevent children beingfalsely labelled and inappropriately treated because someonehas started a drug when the child was about to get betterspontaneously. Long acting β2 agonists are not licensed for usein preschool children.

Are there any other new treatmentsaround?In a small double blind trial, a total of 41 children aged 1-6years were randomised to nebulised hypertonic (7%) or normal

(0.9%) saline, in each case combined with salbutamol twice 20minutes apart in the emergency department and then, if the childwas admitted to hospital, four times a day thereafter.38Admissionrates and lengths of stay were significantly reduced in thehypertonic saline group, but there was no significant change inseverity score, possibly because of the small size of the study.Further work in larger numbers of children is needed to definethe role of hypertonic saline in acute preschool wheeze. Giventhe possibility of bronchoconstriction being induced byhypertonic saline, this treatment should be given only in ahospital setting.Palivizumab has been used to prevent infection with respiratorysyncytial virus in high risk infants—for example, survivors ofextreme prematurity. The cost and inconvenience of monthlyinjections means this has never been, and is still not, a treatmentstrategy for all babies. A recent double blind study, however,randomised 429 infants born at 33-35 weeks’ gestation topalivizumab or placebo.39 Palivizumab reduced the number ofdays with wheeze in the first year of life by 61% and theproportion of infants with recurrent wheeze from 21% to 10%.The more interesting question, which this trial could answer, isthe vexed one as to whether early respiratory syncytial virusinfection causes asthma or is merely a sign that the child waspreviously predisposed to asthma, provided the infants arefollowed up to school age. The current position is that this iswork in progress, rather than an indication for a change in publicpolicy.

What about treatment plans?Treatment plans outlining self management actions to be takendepending on the severity of symptoms and peak flowmeasurements are widely recommended in school age children.In a randomised controlled trial in which 200 children age 18months to 5 years who had an unscheduled hospital visit oradmission with wheezing were allocated either to standard careor to receive a package consisting of a booklet, a written guidedself management plan, and two structured educational sessions,there were no differences in any outcomes.40Despite this, manywill use educational sessions and plans, but there is no evidenceof efficacy.

What is the role of nebulised therapy?There is no role for nebulised therapy to deliver bronchodilatorapart from in children too sick to use inhalers. For all otherpurposes, the evidence is clear that metered dose inhalers andspacers are at least as good as nebuliser.

Contributors: AB wrote the initial draft of the manuscript and is guarantor.The manuscript was reviewed and edited by SS and JG; all authorsagreed the final version.Competing interests: We have read and understood the BMJ Grouppolicy on declaration of interests and declare the following interests: ABwas supported by the NIHR Respiratory Disease Biomedical ResearchUnit at the Royal Brompton and Harefield NHS Foundation Trust andImperial College London.Provenance and peer review: Not commissioned; externally peerreviewed.

1 Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al.Definition, assessment and treatment of wheezing disorders in preschool children: anevidence-based approach. Eur Respir J 2008;32:1096-110.

2 Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souef PN, Brand PL. The transientvalue of classifying preschool wheeze into episodic viral wheeze and multiple triggerwheeze. Acta Paediatr 2010;99:56-60.



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Pragmatic regimen for trial of treatment

Step 1: Trial of inhaled corticosteroids or montelukast in standard dose for a defined period, usually four to eight weeksStep 2: Stop treatment; either there has been no improvement, in which case further escalation is not valuable, or symptoms havedisappeared; in the latter case, it is not possible to know if this was spontaneous or as a result of treatment. If there is no benefit andthe symptoms are troublesome, referral for consideration of further investigation is recommendedStep 3: Restart treatment only if symptoms recur; then reduce treatment to the lowest level that controls symptoms

Questions for future research and ongoing studies

Is nebulised hypertonic saline an effective strategy to contemplate in children with acute preschool wheeze needing admission tohospital?What is the minimum effective dose of inhaled corticosteroids for intermittent use in preschool children with episodic viral wheeze?Would fine particle inhaled corticosteroids, which might be expected to deposit in the peripheral airways, offer additional benefit?Is intermittent high dose inhaled corticosteroid safe and beneficial in children with acute preschool wheeze who need admitting tohospital?How can we predict which children with preschool wheeze will go on to develop asthma, and how can we prevent this?Does prevention of respiratory syncytial virus infection with palivizumab lead to a reduction in prevalence of school age asthma?Parent-determined oral montelukast therapy for preschool wheeze with stratification for arachidonate-5-lipoxygenase (ALOX5) promotergenotype (http://clinicaltrials.gov/show/NCT01142505). This is a randomised controlled trial of intermittent therapy with montelukaststarted at the first sign of a viral cold or wheeze by parents. Both phenotypes of wheeze were recruited and analysis is due January2014

Tips for non-specialists

• Wheeze is a term used by lay people as a description of a multiplicity of upper and lower airway noises; be sure what exactly thefamily means by wheeze

• Isolated dry cough in a community setting is rarely if ever due to asthma• Nebulisers should not be used in preschool wheeze; inhaled drugs delivered by metered dose inhaler and spacer are at least asefficacious

• If inhaled drugs in particular do not seem to be working, check that they are being properly administered (or better yet, get a respiratorynurse to do this) rather than escalating treatment

• Although several predictive indices for future asthma risk have been proposed, negative predictive value is excellent but positivepredictive value is poor

Additional educational resources

Resources for healthcare professionalsThe European Respiratory Society e-learning resources has the following link for “paediatric asthma” (needs registration): www.ers-education.org/publications/european-respiratory-monograph/archive/paediatric-asthma.aspxWorld Allergy Organisation—summary of different management recommendations, including GINA, available free at www.worldallergy.org/professional/allergic_diseases_center/treatment_of_asthma_in_children/

Resources for patientsAsthma UK webpage (free): www.asthma.org.uk/advice-children-and-asthmaNHS Choices—Asthma in Children (free): www.nhs.uk/conditions/Asthma-in-children/Pages/Introduction.aspx

3 Sonnappa S, Bastardo CM, Wade A, Saglani S, McKenzie SA, Bush A, et al.Symptom-pattern and pulmonary function in preschool wheezers. J Allergy Clin Immunol2010;126:519-26.

4 Sonnappa S, Bastardo CM, Saglani S, Bush A, Aurora P. Relationship between pastairway pathology and current lung function in preschool wheezers. Eur Respir J2011;38:1431-6.

5 CaneRS, Ranganathan SC,McKenzie SA.What do parents of wheezy children understandby “wheeze”? Arch Dis Child 2000;82:327-32.

6 Elphick HE, Ritson S, Rodgers H, Everard ML. When a “wheeze” is not a wheeze: acousticanalysis of breath sounds in infants. Eur Respir J 2000;16:593-7.

7 Saglani S, McKenzie SA, Bush A, Payne DN. A video questionnaire identifies upper airwayabnormalities in pre-school children with reported wheeze. Arch Dis Child 2005;90:961-4.

8 Levy ML, Godfrey S, Irving CS, Sheikh A, Hanekom W, Bush A, et al. Wheeze detection:recordings vs assessment of physician and parent. J Asthma 2004;41:845-53.

9 Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, et al. Associationsof wheezing phenotypes in the first 6 years of life with atopy, lung function and airwayresponsiveness in mid-childhood. Thorax 2008;63:974-80.

10 Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance ofcough and wheeze in the diagnosis of asthma. Arch Dis Child 1996;75:489-93.

11 British Guideline on the Management of Asthma (2012 update). www.brit-thoracic.org.uk/guidelines/asthma-guidelines.aspx.

12 Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007;335:1037-41.13 Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and

wheezing in the first six years of life: the Group Health Medical Associates. N Engl J Med1995;332:133-8.

14 Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U; Multicentre Allergy Study(MAS) group. Perennial allergen sensitisation early in life and chronic asthma in children:a birth cohort study. Lancet 2006;368:763-70.

15 Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants andpreschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis.Pediatrics 2009;123:e519-25.

16 Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, et al. Early detection ofairway wall remodelling and eosinophilic inflammation in preschool wheezers. Am J RespirCrit Care Med 2007;176:858-64.

17 Savenije OE, Kerkhof M, Koppelman GH, Postma DS. Predicting who will have asthmaat school age among preschool children. J Allergy Clin Immunol 2012;130:325-31.

18 Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, et al. Atopiccharacteristics of children with recurrent wheezing at high risk for the development ofchildhood asthma. J Allergy Clin Immunol 2004;114:1282-7.

19 Devulapalli CS, Carlsen KC, Håland G, Munthe-Kaas MC, Pettersen M, Mowinckel P, etal. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years ofage. Thorax 2008;63:8-13.

20 Harris JM, Bush A, Wilson N, Mills P, White C, Moffat S, et al. Preschool wheezingphenotypes in a representative school cohort. Thorax 2010;65(suppl 4):A37.

21 Guilbert TW, MorganWJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-terminhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med2006;354:1985-97.

22 Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team. Secondaryprevention of asthma by the use of inhaled fluticasone dipropionate in wheezy infants(IWWIN): double-blind, randomised controlled study. Lancet 2006;368:754-62.

23 Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaledcorticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998-2005.



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http://clinicaltrials.gov/show/NCT01142505

http://www.ers-education.org/publications/european-respiratory-monograph/archive/paediatric-asthma.aspx

http://www.ers-education.org/publications/european-respiratory-monograph/archive/paediatric-asthma.aspx

http://www.worldallergy.org/professional/allergic_diseases_center/treatment_of_asthma_in_children/

http://www.worldallergy.org/professional/allergic_diseases_center/treatment_of_asthma_in_children/

http://www.asthma.org.uk/advice-children-and-asthma

http://www.nhs.uk/conditions/Asthma-in-children/Pages/Introduction.aspx

http://www.brit-thoracic.org.uk/guidelines/asthma-guidelines.aspx

http://www.brit-thoracic.org.uk/guidelines/asthma-guidelines.aspx



24 Pool J, Petrova N, Russell RR. Exposing children to secondhand smoke. Thorax2012;67:926.

25 Warner JO; ETAC Study Group. Early treatment of the atopic child. A double-blinded,randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma inchildren with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatmentfollow-up. J Allergy Clin Immunol 2001;108:929-37.

26 Andersen ZJ, Loft S, Ketzel M, Stage M, Scheike T, Hermansen MN, et al. Ambient airpollution triggers wheezing symptoms in infants. Thorax 2008;63:710-6.

27 Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, et al. Short-coursemontelukast for intermittent asthma in children: a randomized controlled trial. Am J RespirCrit Care Med 2007;175:323-9.

28 Valovirta E, Boza ML, Robertson CF, Verbruggen N, Smugar SS, Nelsen LM, et al.Intermittent or daily montelukast versus placebo for episodic asthma in children. AnnAllergy Asthma Immunol 2011;106:518-26.

29 Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr; CARENetwork. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist inpreschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol2008;122:1127-35.

30 McKeanM, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood.CochraneDatabase Syst Rev 2000;2:CD001107.

31 Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive useof high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med2009;360:339-53.

32 Zeiger RS, Mauger D, Bacharier LB, Giobert TW, Martinez FD, Lemanske RF Jr et al;CARE Network of the National Heart, Lung, and Blood Institute. Daily or intermittentbudesonide in preschool children with recurrent wheezing. N Engl J Med2011;365:1990-2001.

33 Wilson N, Sloper K, Silverman M. Effect of continuous treatment with topical corticosteroidon episodic viral wheeze in preschool children. Arch Dis Child 1995;72:317-20.

34 Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oralprednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial.Lancet 2003;362:1433-8.

35 Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oralprednisolone for preschool children with acute virus-induced wheezing. N Engl J Med2009;360:329-38.

36 Bush A. Practice imperfect—treatment for wheezing in preschoolers. N Engl J Med2009;360:409-10.

37 Saglani S, Malmstrom K, Pelkonen AS, Malmberg LP, Lindahl H, Kajosaari M, et al. Airwayremodeling and inflammation in symptomatic infants with reversible airflow obstruction.Am J Respir Crit Care Med 2005;171:722-7.

38 Ater D, Shai H, Bar B-E, Fireman N, Tasher D, Dalal I, et al. Hypertonic saline and acutewheezing in preschool children. Pediatrics 2012;129:e1397.

39 Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, et al;Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthypreterm infants. N Engl J Med 2013;368:1791-9.

40 Stevens CA, Wesseldine LJ, Couriel JM, Dyer AJ, Osman LM, Silverman M. Parentaleducation and guided self-management of asthma and wheezing in the pre-school child:a randomised controlled trial. Thorax 2002;57:39-44.

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Table

Table 1| Four groups of childhood wheezing disorders, based on personal practice

Suggested actionsSuggestive featuresWheeze category

ReassuranceChild well and thriving, with no other features on history orexamination to raise concerns

Normal child—commonest and also the hardestdiagnosis to make (includes those with postviralcough, pertussis, and parents who are overanxiousabout minor symptoms or do not appreciate thenumber of viral infections a normal preschooler willacquire)

Refer for investigation (by telephone ifsudden onset of signs suggestingendobronchial foreign body)

Suspect if history of symptoms from first day of life, chronic wetcough, sudden onset of symptoms, continuous unremitting symptoms,systemic illness; physical examination shows digital clubbing,unusually severe chest deformity, stridor, fixed wheeze, orasymmetric signs on auscultation, anything to suggest systemicdisease

Serious condition (such as immunodeficiency)—rarebut essential to diagnose or refer

Initial empirical trials of treatment; referif no response and symptomstroublesome.Child with prominent snoring should beconsidered for referral for sleep study

Otherwise well and thriving child with history of easy vomiting, archingaway from breast, poor feeder (gastro-oesophageal reflux), orprominent upper airway disease, inflamed nose, adenotonsillarhypertrophy

Minor conditions that might may exacerbate or mimicwheezing syndrome—for example,gastro-oesophageal reflux, chronic rhinitis

Treatment options discussed in text.Refer if child is not responding

An otherwise well and thriving child with wheeze only at time of viralcold, often but not invariably with no personal or family history ofatopic disorders (EVW); wheeze with viral colds and also betweencolds with typical asthma triggers such as exertion and excitement,cold air, allergens (MTW). There is often but not invariably a personalor family history of atopic disorders

True wheezing syndrome: episodic viral wheeze(EVW); multiple trigger wheeze (MTW)



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Definition, assessment and treatment of wheezing disorders ...tvscn.nhs.uk/wp-content/uploads/2014/09/Academic-papers.pdf · wheezing disorders (including asthma) in general, and